5 6291902715253490806

OBSTETRIC EVIDENCE
BASED GUIDELINES
Series in Maternal-Fetal Medicine
About the Series

Published in association with the Journal of Maternal-Fetal and Neonatal Medicine, the series in Maternal-Fetal Medicine keeps read-
ers up to date with the latest clinical therapies to improve the health of pregnant patients and ensure a successful birth. Each volume
in the series is prepared separately and typically focuses on a topical theme. Volumes are published on an occasional basis, depending
on the emergence of new developments.
Maternal-Fetal Evidence Based Guidelines, Fourth Edition

Vincenzo Berghella
Obstetric Evidence Based Guidelines, Fourth Edition

Vincenzo Berghella
Maternal-Fetal and Obstetric Evidence Based Guidelines, Two Volume Set, Fourth Edition
Vincenzo Berghella
The Long-Term Impact of Medical Complications in Pregnancy: A Window into Maternal and Fetal Future Health
Eyal Sheiner
Operative Obstetrics, Fourth Edition

Joseph J. Apuzzio, Anthony M. Vintzileos, Vincenzo Berghella, Jesus R. Alvarez-Perez
Placenta Accreta Syndrome

Robert M. Silver
Neurology and Pregnancy: Clinical Management

Michael S. Marsh, Lina Nashef, Peter Brex
Fetal Cardiology: Embryology, Genetics, Physiology, Echocardiographic Evaluation, Diagnosis, and Perinatal Management of
Cardiac Diseases, Third Edition
Simcha Yagel, Norman H. Silverman, Ulrich Gembruch
New Technologies and Perinatal Medicine: Prediction and Prevention of Pregnancy Complications
Moshe Hod, Vincenzo Berghella, Mary D’Alton, Gian Carlo Di Renzo, Eduard Gratacos, Vassilios Fanos
Problem-Based Obstetric Ultrasound, Second Edition

Amar Bhide, Asma Khalil, Aris T Papageorghiou, Susana Pereira, Shanthi Sairam, Basky Thilaganathan
Recurrent Pregnancy Loss: Causes, Controversies and Treatment, Third Edition

Howard Carp
For more information about this series please visit: https://www.routledge.com/Series-in-Maternal-Fetal-Medicine/book-series/

CRCSERMATFET
OBSTETRIC EVIDENCE
BASED GUIDELINES
FOURTH EDITION
Edited by
Vincenzo Berghella, MD, FACOG

Director, Division of Maternal-Fetal Medicine
Director, Maternal-Fetal Medicine Fellowship Program
Professor, Department of Obstetrics and Gynecology
Sidney Kimmel Medical College of Thomas Jefferson University
Philadelphia, PA, USA
Fourth edition published 2022
by CRC Press
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and by CRC Press

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© 2022 Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, LLC

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responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any
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not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is
intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the
medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufac-
turer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any
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urged to consult the relevant national drug formulary and the drug companies’ and device or material manufactur-
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DOI: 10.1201/9781003102342
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by KnowledgeWorks Global Ltd.
I dedicate this fourth edition to my father Andrea Berghella, who passed away at 87 in January 2019.
He was and remains my professional inspiration and guiding light. The bright light of his lighthouse,
to use a metaphor, keeps on shining inside my mind and heart and leading me onwards and upwards.
To Federica, Andrea, Pietro, Mamma, Anna, and Michele, for giving me
the serenity, love, and strength at home now, then, and in the future to
fulfill my dreams and spend my talents as best as possible
To all those who loved the prior editions
To the health of mothers and babies
And, as I often toast – To the next generation!
Taylor & Francis
Taylor & Francis Group
http://taylorandfrancis.com
CONTENTS
Introduction...........................................................................................................................................................................................................................ix
How to “Read” This Book....................................................................................................................................................................................................xi
Contributors........................................................................................................................................................................................................................ xii
List of Abbreviations...........................................................................................................................................................................................................xv
1. Preconception Care............................................................................................................................................................................... 1
Johanna Quist-Nelson
2. Prenatal Care....................................................................................................................................................................................... 15
Gabriele Saccone and Kerri Sendek
3. Physiologic Changes............................................................................................................................................................................34
Jason Baxter and Julia Burd
4. Ultrasound............................................................................................................................................................................................48
L. M. Porche, S. P. Chauhan, and A. Abuhamad
5. Prenatal Diagnosis and Screening for Aneuploidy.........................................................................................................................60

Sarah Harris, Angie Jelin, and Neeta Vora
6. Carrier Screening for Inherited Genetic Conditions...................................................................................................................... 78

Whitney Bender and Lorraine Dugoff
7. Preparation before Labor................................................................................................................................................................... 91

Daniele Di Mascio and Leen Al-Hafez
8. First Stage of Labor.............................................................................................................................................................................98

Leen Al-Hafez
9. Second Stage of Labor.......................................................................................................................................................................105

Alexis C. Gimovsky
10. Third Stage of Labor..........................................................................................................................................................................113

Alyssa R. Hersh and Jorge E. Tolosa
11. Intrapartum Fetal Monitoring........................................................................................................................................................122

Nandini Raghuraman and Alison G. Cahill
12. Analgesia and Anesthesia.................................................................................................................................................................137

Michele Mele, Valentina Bellussi, and Laura Felder
13. Operative Vaginal Delivery..............................................................................................................................................................152

Adeeb Khalifeh and Megan Piacquadio
14. Cesarean Delivery..............................................................................................................................................................................157

A. Dhanya Mackeen and Meike Schuster
15. Trial of Labor after Cesarean...........................................................................................................................................................180

Amen Ness
16. Early Pregnancy Loss........................................................................................................................................................................195

Lisa K. Perriera, Beatrice A. Chen, and Aileen M. Gariepy
17. Recurrent Pregnancy Loss................................................................................................................................................................203

Reshama S. Navathe and Shabani Ahluwalia
18. Preterm Birth Prevention in Asymptomatic Women................................................................................................................... 210

Anju Suhag
vii
viii Contents
19. Preterm Labor....................................................................................................................................................................................232

Rebecca Horgan
20. Preterm Prelabor Rupture of Membranes......................................................................................................................................245

Anna Locatelli, Sara Consonni, and Annalisa Inversetti
21. Prelabor Rupture of Membranes at or Near Term........................................................................................................................262

Teodora Kolarova and Kimberly Ma
22. Management of the Uncomplicated Term Pregnancy..................................................................................................................268

Rebecca Jackson
23. Induction of Labor.............................................................................................................................................................................272

Corina N. Schoen
24. Intraamniotic Infection and Inflammation (Triple I)..................................................................................................................287

Victoria Adewale, Cecily May Barber, and Elizabeth Liveright
25. Meconium...........................................................................................................................................................................................293
Meike Schuster and Justin S. Brandt
26. Malpresentation and Malposition...................................................................................................................................................299

Alexis C. Gimovsky, Andrea Dall’Asta, Giovanni Morganelli, and Tullio Ghi
27. Shoulder Dystocia............................................................................................................................................................................. 314

Julia Burd
28. Postpartum Hemorrhage, Retained Placenta, and Uterine Inversion........................................................................................324

Amy C. Hermesch and Jorge E. Tolosa
29. Placental Disorders...........................................................................................................................................................................330

Daniele Di Mascio and Francesco D’Antonio
30. Placental Abruption..........................................................................................................................................................................345

John F. Visintine
31. Postpartum Care...............................................................................................................................................................................354

Elena R. Magro-Malosso, Sarah K. Dotters-Katz, and Daniele Di Mascio
32. The Neonate........................................................................................................................................................................................ 376

Laura De Angelis and Luca Ramenghi
33. The Adnexal Mass..............................................................................................................................................................................384

Connie D. Cao and Norman G. Rosenblum
34. Cervical Cancer Screening and Management in Pregnancy.......................................................................................................390

Vaidehi Mujumdar and Scott D. Richard
Index.....................................................................................................................................................................................................................................398
INTRODUCTION
Welcome to the fourth edition of our evidence-based books on or meta-analyses is too detailed to be readily translated to advice
obstetrics and maternal-fetal medicine! I am indebted for your for the busy clinician who needs to make dozens of clinical deci-
support! I can’t believe how much praise we have received for these sions a day. Even the Cochrane Library, the undisputed leader for
companion volumes. Your words of encouragement have kept me evidence-based medicine efforts, has been criticized for its lack of
and all the wonderful collaborators going on strong for 15 years! flexibility and relevance in failing to be more easily understand-
It has been extremely worthwhile and fulfilling. You are making able and clinically readily usable [3]. It is the gap between research
me happy! In return, I hope we are helping you and your patients and clinicians that needed to be filled, making sure that proven
toward ever better evidence-based care of pregnant women and interventions are clearly highlighted, and are included in today’s
their babies, and therefore better outcomes. Indeed, most mater- care. Just as all pilots fly planes under similar rules to maximize
nal and perinatal morbidities and mortalities throughout the safety, all obstetricians should manage all aspects of pregnancy
world are improving. with similar, evidenced-based rules. Indeed, only interventions
To me, pregnancy has always been the most fascinating and that have been proven to provide benefit should be used routinely.
exciting area of interest, as care involves not one, but at least two On the other hand, primum non nocere: interventions that have
persons—the mother and the fetus—and leads to the miracle of clearly been shown to be not helpful or indeed harmful to mother
a new life. I was a third-year medical student when, during a lec- and/or baby should be avoided. Another aim of the book is to make
ture, a resident said: “I went into obstetrics because this is the sure the pregnant woman and her unborn child are not marginal-
easiest medical field. Pregnancy is a physiologic process, and ized by the medical community. In most circumstances, medical
there isn’t much to know. It is simple.” I knew from my “classical” disorders of pregnant women can be treated as in nonpregnant
background that “obstetrics” means to “stand by, stay near,” and adults. Moreover, there are several effective interventions for pre-
that indeed pregnancy used to receive no medical support at all. venting or treating specific pregnancy disorders.
After more than 31 years of practicing obstetrics, I now know that Evidence-based medicine is the concept of treating patients
although physiologic and at times simple, obstetrics and mater- according to the best available evidence. While George Bernard
nal-fetal medicine can be the most complex of the medical fields: Shaw said: “I have my own opinion, do not confuse me with the
pregnancy is based on a different physiology than for nonpregnant facts,” this can be a deadly approach, especially in medicine, and
women, can include any medical disease, require surgery, etc. It compromise two or more lives at the same time in obstetrics
is not so simple. In fact, ignorance can kill, in this case with the and maternal-fetal medicine. What should be the basis for our
health of the woman and her baby both at risk. Too often, I have interventions in medicine? Meta-analyses provide a comprehen-
gone to a lecture, journal club, rounds, or other didactic event to sive summary of the best research data available. As such, they
hear presented only one or a few articles regarding the subject, provide the best guidance for “effective” clinical care [4]. It is
without the presenter reviewing the pertinent best review of the unscientific and unethical to practice medicine, teach, or con-
total literature and data. It is increasingly difficult to read and duct research without first knowing all that has already been
acquire knowledge of all that is published, even just in obstetrics, proven [4]. In the absence of trials or meta-analyses, lower level
with over 3,000 scientific manuscripts published monthly on this evidence is reviewed. This book aims at providing a current sys-
subject. Some residents or even authorities would state at times tematic review of all the best evidence, so that current practice
that “there is no evidence” on a topic. We indeed used to be the and education, as well as future research, can be based on the full
field with the worst use of randomized trials [1]. As the best way story from the best-conducted research, not just the latest data or
to find something is to look for it, my coauthors and I searched someone’s opinion (Table I.2).
for the best evidence. On careful investigation, indeed there are These evidence-based guidelines cannot be used as a “cook-
data on almost everything we do in obstetrics, especially on our book,” or a document dictating the best care. The knowledge
interventions. Indeed, our field is now the pioneer for numbers of from the best evidence presented in the guidelines needs to be
meta-analysis and extension of work for evidence-based reviews integrated with other knowledge gained from clinical judgment,
[2]. Obstetricians are now blessed with lots of data and should individual patient circumstances, and patient preferences to lead
make the best use of it. to the best medical practice. These are guidelines, not rules. Even
The goals of this book are to summarize the best evidence the best scientific studies are not always perfectly related to any
available in the obstetrics and maternal-fetal medicine litera- given individual, and clinical judgment must still be applied to
ture and make the results of randomized controlled trials (RCTs) allow the best “particularization” of the best knowledge for the
and meta-analyses of RCTs easily accessible to guide clinical individual, unique patient. Evidence-based medicine informs
care. The intent is to bridge the gap between knowledge (the evi- clinical judgment, but does not substitute it. It is important to
dence) and its easy application. To reach these goals, we reviewed understand though that greater clinical experience by the physi-
all trials on effectiveness of interventions in obstetrics. Millions cian actually correlates with inferior quality of care if not inte-
of pregnant women have participated in thousands of properly grated with knowledge of the best evidence [5]. The appropriate
conducted RCTs. The efforts and sacrifice of mothers and their treatment is given in only 50% of visits to general physicians [5].
fetuses for science should be recognized at least by the physicians’
awareness and understanding of these studies. Some of the tri- TABLE I.1: Obstetric Evidence
als have been summarized in over 600 Cochrane reviews, with
• Over 600 current Cochrane reviews
hundreds of other meta-analyses also published in obstetrical
• Hundreds of other current meta-analyses
topics (Table I.1). All the Cochrane reviews, as well as other meta-
• Thousands of RCTs
analyses and trials in obstetrics and maternal-fetal medicine, were
• Millions of pregnant women randomized
reviewed and referenced. The material presented in single trials
ix
x Introduction
TABLE I.2: Goals of This Book TABLE I.3: This Book Is For
• Improve the health of women and their children • Obstetricians
• “Make it easy to do it right” • Midwives
• Implement the best clinical care based on science (evidence), not • Family medicine and others (practicing obstetrics)
opinion • Residents
• Education • Nurses
• Develop lectures • Medical students
• Decrease disease, use of detrimental interventions, and therefore costs • Maternal-fetal medicine attendings
• Reduce medicolegal risks • Maternal-fetal medicine fellows
• Other consultants on pregnancy
At times, limitations in resources may also limit the applicability • Lay persons who want to know “the evidence”
of the guidelines, but should not limit the physician’s knowledge. • Politicians responsible for health care
Guidelines and clinical pathways based on evidence not only
point to the right management but also can decrease medicolegal
risk [6]. We aimed for brevity and clarity. Suggested management guidelines has been a wonderful, stimulating journey. Keeping up
of the healthy or sick mother and child is stated as straightfor- with evidence-based medicine is exciting. The most rewarding
wardly as possible for everyone to easily understand and imple- part, as a teacher, is the dissemination of knowledge. I hope, truly,
ment (Table I.3). If you find the Cochrane reviews, scientific that this effort will be helpful to you, too.
manuscripts, and other publications difficult to “translate” into
care of your patients, this book is for you. We wanted to prevent
information overload.
References
On the other hand, “everything should be made as simple as 1. Cochrane AL. 1931–1971: A critical review, with particular reference to the medi-
cal profession. In: Medicines for the Year 2000. London: Office of Health Economics.
possible, but not simpler” (Albert Einstein). Key management 1979;1–11. [Review]
points are highlighted at the beginning of each guideline and in 2. Dickersin K, Manheimer E. The Cochrane collaboration: Evaluation of health care and
bold in the text. The chapters are divided in two volumes, one on services using systematic reviews of the results of randomized controlled trials. Clinic
Obstet Gynecol. 1998;41:315–331. [Review]
obstetrics and one on maternal-fetal medicine; cross-references 3. Summerskill W. Cochrane Collaboration and the evolution of evidence. Lancet.
to chapters in Maternal-Fetal Evidence Based Guidelines have 2005;366:1760. [Review]
4. Chalmers I. Academia’s failure to support systematic reviews. Lancet. 2005;365:469.
been noted in the text where applicable. Please contact me (vin- [III]
cenzo.berghella@jefferson.edu) for any comments, criticisms, 5. Arky RA. The family business—To educate. New Engl J Med. 2006;354:1922–1926.
corrections, missing evidence, etc. [Review]
6. Ransom SB, Studdert DM, Dombrowski MP, et al. Reduced medico-legal risk by
I have the most fun discovering the best ways to alleviate dis- compliance with obstetric clinical pathways: A case-control study. Obstet Gynecol.
comfort and disease. The search for the best evidence for these 2003;101:751–755. [II-2]
HOW TO “READ” THIS BOOK
The knowledge from randomized controlled trials (RCTs) and I Evidence obtained from at least one properly designed ran-
meta-analyses of RCTs is summarized and easily available for domized controlled trial.
clinical implementation. Key management points are highlighted II-1 Evidence obtained from well-designed controlled trials
at the beginning of each guideline, and in bold in the text. Relative without randomization.
risks and 95% confidence intervals from studies are quoted spar- II-2 Evidence obtained from well-designed cohort or case-
ingly. Instead, the straight recommendation for care is made control analytic studies, preferably from more than one
if one intervention is superior to the other, with the percent center or research group.
improvement often quoted to assess the degree of benefit. If there II-3 Evidence obtained from multiple time series with or
is insufficient evidence to compare to interventions or manage- without the intervention. Dramatic results in uncon-
ments, this is clearly stated. trolled experiments could also be regarded as this type
References: Cochrane reviews with 0 RCT are not referenced, of evidence.
and instead of referencing a meta-analysis with only one RCT, the III (Review) Opinions of respected authorities, based on clini-
actual RCT is usually referenced. RCTs that are already included cal experience, descriptive studies, or reports of expert
in meta-analyses are not referenced, both for brevity and because committees.
they can be easily accessed by reviewing the meta-analysis. If
new RCTs are not included in a meta-analysis, they are obvi- These levels are quoted after each reference. For RCTs and
ously referenced. Each reference was reviewed and evaluated for meta-analyses, the number of subjects studied is stated and,
quality according to a modified method as outlined by the U.S. sometimes, more details are provided to aid the reader to under-
Preventive Services Task Force (http://www.ahrq.gov): stand the study better.
xi
CONTRIBUTORS
Alfred Abuhamad Alison G. Cahill Lorraine Dugoff

Department of Obstetrics and Department of Obstetrics and Department of Obstetrics and Gynecology
Gynecology Gynecology Division of Reproductive Genetics
Eastern Virginia Medical School Dell Medical School Hospital of the University of Pennsylvania
Norfolk, VA The University of Texas at Austin Philadelphia, PA
Austin, TX
Victoria Adewale Laura Felder
Department of Obstetrics and Gynecology Connie D. Cao Department of Obstetrics and Gynecology
Thomas Jefferson University Hospital Department of Obstetrics and Gynecology Thomas Jefferson University Hospital
Philadelphia, PA Thomas Jefferson University Hospital Philadelphia, PA
Philadelphia, PA
Shabani Ahluwalia Aileen M. Gariepy
Department of Obstetrics and Suneet P. Chauhan Departments of Obstetrics Gynecology
Gynecology Department of Obstetrics and Gynecology and Reproductive Sciences and
Crozer Chester Medical Center McGovern Medical School at UTHealth of Nursing
Chester, PA Houston, TX Yale School of Medicine
New Haven, CT
Leen Al-Hafez Beatrice A. Chen
Department of Obstetrics and Gynecology Department of Obstetrics, Gynecology Tullio Ghi
UT Southwestern Medical Center and Reproductive Sciences Department of Medicine and Surgery
Dallas, TX UPMC Magee-Women’s Hospital University of Parma
and Pittsburgh, PA Parma, Italy
Department of Obstetrics and Gynecology
Thomas Jefferson University Hospital Sara Consonni Alexis C. Gimovsky
Philadelphia, PA Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine
University of Milano-Bicocca Department of Obstetrics and Gynecology
Cecily May Barber Monza, Italy Women and Infants Hospital
Department of Obstetrics and Gynecology Providence, RI
Thomas Jefferson University Hospital Andrea Dall’Asta
Philadelphia, PA Department of Medicine and Surgery Sarah Harris
University of Parma Department of Obstetrics and
Jason Baxter Parma, Italy Gynecology
Department of Obstetrics and University of North Carolina School of
Gynecology Francesco D’Antonio Medicine
Thomas Jefferson University Hospital Center for High Risk Pregnancy and Fetal Chapel Hill, NC
Philadelphia, PA Care
Department of Obstetrics and Amy C. Hermesch
Valentina Bellussi Gynecology Division of Maternal-Fetal Medicine
Department of Anesthesia University of Chieti Department of Obstetrics and
School of Medicine and Surgery Chieti, Italy Gynecology
University of Verona Oregon Health and Science University
Verona, Italy Laura De Angelis Portland, OR
Department of Mother and Child
Whitney Bender Neonatal Intensive Care Unit Alyssa R. Hersh
Division of Maternal-Fetal Medicine Gaslini Institute Department of Obstetrics and Gynecology
Hospital of the University of Pennsylvania Genoa, Italy Oregon Health and Science University
Philadelphia, PA Portland, OR
Daniele Di Mascio
Justin S. Brandt Department of Maternal and Child Rebecca Horgan
RMG Health and Urological Sciences Department of Obstetrics and
Division of Maternal-Fetal Medicine Sapienza University Gynecology
New Brunswick, NJ Rome, Italy Monmouth Medical Center
Long Branch, NJ
Julia Burd Sarah K. Dotters-Katz
Department of Obstetrics, Gynecology Division of Maternal-Fetal Medicine Annalisa Inversetti
and Reproductive Sciences Department of Obstetrics and Department of Obstetrics and Gynecology
Sidney Kimmel Medical College at Gynecology Carate Brianza Hospital
Thomas Jefferson University Duke University University of Milano-Bicocca
Philadelphia, PA Durham, NC Monza, Italy
xii
Contributors xiii
Rebecca Jackson Giovanni Morganelli Norman G. Rosenblum

Department of Obstetrics, Gynecology Department of Medicine and Surgery Department of Obstetrics and Gynecology
and Reproductive Sciences University of Parma Division of Gynecologic Oncology
ZSFG Division Parma, Italy Thomas Jefferson University Hospital
University of California Philadelphia, PA
San Francisco, CA Vaidehi Mujumdar
Department of Obstetrics and Gabriele Saccone
Angie Jelin Gynecology Department of Neuroscience,
Division of Maternal-Fetal Medicine Thomas Jefferson University Hospital Reproductive Sciences and Dentistry
Department of Gynecology and Philadelphia, PA School of Medicine
Obstetrics University of Naples “Federico II”
Johns Hopkins School of Medicine Reshama S. Navathe Naples, Italy
Baltimore, MD Department of Obstetrics and Gynecology
Crozer Chester Medical Center Corina N. Schoen
Adeeb Khalifeh Chester, PA Obstetrics and Gynecology
Division of Maternal-Fetal Medicine UMMS-Baystate
Department of Obstetrics and Amen Ness Springfield, MA
Gynecology Department of Maternal-Fetal Medicine
Thomas Jefferson University Hospital Steward Health Care Meike Schuster
Philadelphia, PA Stanford, CA Department of Obstetrics and Gynecology
Thomas Jefferson University
Teodora Kolarova Lisa K. Perriera Abington, PA
Department of Obstetrics and Gynecology Gyn-Surgical Specialties
University of Washington Medical Center Division of Family Planning Kerri Sendek
Seattle, WA Thomas Jefferson University Division of Maternal-Fetal Medicine
Philadelphia, PA Department of Obstetrics and Gynecology
Elizabeth Liveright Sidney Kimmel Medical College
Department of Obstetrics and Megan Piacquadio Thomas Jefferson University Hospital
Gynecology Department of Obstetrics and Philadelphia, PA
Thomas Jefferson University Hospital Gynecology
Philadelphia, PA Thomas Jefferson University Anju Suhag
Philadelphia, PA Division of Maternal-Fetal Medicine
Anna Locatelli Department of Obstetrics and Gynecology
Department of Obstetrics and Lea M. Porche Thomas Jefferson University Hospital
Gynecology Division of Maternal-Fetal Medicine Philadelphia, PA
ASST Vimercate Department of Obstetrics and
Carate Brianza Hospital Gynecology Jorge E. Tolosa
University of Milano-Bicocca Eastern Virginia Medical School Division of Maternal-Fetal Medicine
Monza, Italy Norfolk, VA Department of Obstetrics and
Gynecology
Kimberly Ma Johanna Quist-Nelson St. Luke’s University Health Network
Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology Bethlehem, PA
University of Washington Medical Center University of North Carolina and
Seattle, WA Chapel Hill, NC Department of Obstetrics and
Gynecology
A. Dhanya Mackeen Nandini Raghuraman Oregon Health and Science University
Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Portland, OR
Department of Obstetrics and Washington University School of Medicine
Gynecology St. Louis, MO John F. Visintine
Geisinger Division of Maternal-Fetal Medicine
Danville, PA Luca Ramenghi (Bay Area Clinic)
Department of Mother and Child Department of Obstetrics and Gynecology
Elena R. Magro-Malosso Neonatal Intensive Care Unit Corpus Christi, TX
Department of Obstetrics and Gynecology Gaslini Institute
University of Florence Genoa, Italy Neeta Vora
Florence, Italy Division of Maternal-Fetal Medicine
Scott D. Richard Department of Obstetrics and
Michele Mele Department of Obstetrics and Gynecology
Clinical Anesthesiology Gynecology University of North Carolina School of
Cooper Medical School of Rowan Division of Gynecologic Oncology Medicine
University Thomas Jefferson University Chapel Hill, NC
Camden, NJ Philadelphia, PA
xiv Contributors
The publishers would also like to thank the following contributors to the previous edition for any material used in this edition:
B. Anthony Armson Colleen Horan Jennifer Salati
Sean C. Blackwell Kyle Jespersen Sally Segel
Sara Campbell Christine H. Kim Moeun Son
Eileen M. Gariepy Dawnette Lewis Alison M. Stuebe
Alessandro Ghidini Talia M. Maas Michela Villani
William Grobman Swati Murthy Serena Xodo
Lauren Cooper Hand George Patounakis Amanda Yeaton-Massey

LIST OF ABBREVIATIONS
Ab antibody EKG (synonym of EDC) electrocardiogram

AC abdominal circumference FBS fetal blood sampling
ACA anticardiolipin antibody FDA Food and Drug Administration
ACOG American College of Obstetricians and FFN fetal fibronectin
Gynecologists FGR fetal growth restriction
ACS acute chest syndrome FHR fetal heart rate
ADR autosomic dysreflexia FISH fluorescent in situ hybridization
AF amniotic fluid FLM fetal lung maturity
AFI amniotic fluid index FOB father of baby
AFP alpha-fetoprotein FPR false-positive rate
AFV amniotic fluid volume FTS first-trimester screening
Ag antigen FVL factor V Leiden
AIDS acquired immune deficiency syndrome g grams
ALT alanine aminotransferase GA gestational age
ANA antinuclear antibodies GBS group B streptococcus
aPT activated prothrombin time GDM gestational diabetes mellitus
APS antiphospholipid syndrome GI gastrointestinal
aPTT activated partial thromboplastin time HAART highly active antiretroviral therapy
AROM artificial rupture of membranes HAV hepatitis A virus
ART assisted reproductive technologies HBV hepatitis B virus
ARV antiretroviral therapy HBsAg hepatitis B surface antigen
ASA aspirin HCG human chorionic gonadotropin
ASD atrial septal defect Hct hematocrit
AST aspartate aminotransferase HCV hepatitis C virus
AT III antithrombin III HG hyperemesis gravidarum
AZT zidovudine Hgb hemoglobin
bid “bis in die,” i.e., twice per day HIE hypoxic-ischemic encephalopathy
BPD biparietal diameter HIV human immunodeficiency virus
BPD bronchopulmonary dysplasia HR heart rate
BPP biophysical profile HSV herpes simplex virus
BPS biophysical profile score HTN hypertension
BMI body mass index ICU intensive care unit
BP blood pressure IUGR intrauterine growth restriction
CAP community-acquired pneumonia (synonym of FGR)
CBC complete blood count IV intravenous
CCB calcium channel blocker IVH intraventricular hemorrhage
CDC Centers for Disease Control and Prevention L&D labor and delivery floor
CF cystic fibrosis LA lupus anticoagulant
CHD congenital heart defect Lab laboratory
CL cervical length LFT liver function tests
CMV cytomegalovirus LMP last menstrual period
CNS central nervous system LBW low birth weight (infants)
COX cyclooxygenase LMW low molecular weight
CRL crown–rump length LMWH low-molecular-weight heparin
CSE combined spinal epidural LR likelihood ratio
CSF cerebrospinal fluid MAS meconium aspiration syndrome
CT computerized tomography MCA middle cerebral artery
CVS chorionic villus sampling MCV mean corpuscular volume
DES diethylstilbestrol MOM multiple of the median
DIC disseminated intravascular coagulation MRI magnetic resonance imaging
DM diabetes mellitus MTHFR methylenetetrahydrofolate reductase
DNA deoxyribonucleic acid MVP maximum vertical pocket
DRVVT dilute Russell’s viper venom time NA not available
DV ductus venosus NAIT neonatal alloimmune thrombocytopenia
DVP deepest vertical pocket NEC necrotizing enterocolitis
DVT deep vein thrombosis NIH National Institutes of Health
ECV external cephalic version NIH nonimmune hydrops
EDC estimated date of confinement NRFS nonreassuring fetal status
EDD estimated date of delivery NRFHR nonreassuring fetal heart rate
xv
xvi List of Abbreviations
NRFHT nonreassuring fetal heart testing RCT randomized controlled study

NSAID nonsteroidal antiinflammatory drug RDS respiratory distress syndrome
NT nuchal translucency RNA ribonucleic acid
NTD neural tube defect ROM rupture of membranes
NST nonstress test RPR rapid plasma regain
n/v nausea and/or vomiting RR respiratory rate
OR operating room Rx treatment
ORA oxytocin receptor agonist SAB spontaneous abortion
PC protein C SC subcutaneous
PCR polymerase chain reaction SCI spinal cord injury
PE pulmonary embolus SDP single deepest pocket
PFT pulmonary function tests SIDS sudden infant death syndrome
PGM prothrombin gene mutation SLE systemic lupus erythematosus
PID pelvic inflammatory disease SPTB spontaneous preterm birth
PL pregnancy loss STD sexually transmitted diseases
PNC prenatal care (synonym of STI)
po “per os,” i.e., by mouth STI sexually transmitted infections
PPH postpartum hemorrhage STS second-trimester screening
PRCD planned repeat cesarean delivery TB tuberculosis
PS protein S TG Toxoplasma gondii
PT prothrombin time tid three times per day
PTB preterm birth TOL trial of labor
PTT partial thromboplastin time TRAP twin reversal arterial perfusion
PPROM preterm prelabor rupture of membranes TRH thyrotropin-releasing hormone
pRBC packed red blood cells TSH thyroid-stimulating hormone
PROM prelabor rupture of membranes TSI thyroid-stimulating immune globulins
PSV peak systolic velocity TTTS twin–twin transfusion syndrome
PTL preterm labor TVU transvaginal ultrasound
PTU propylthiouracil UA umbilical artery
PUBS percutaneous umbilical blood sampling UFH unfractionated heparin
PVH periventricular hemorrhage U/S (or u/s) ultrasound
qd once a day VBAC vaginal birth after caesarean
qid four times per day VDRL venereal disease research laboratory
qhs before bedtime VSD ventricular septal defect
QS quadruple screen VTE venous thromboembolism
RBC red blood cell WHO World Health Organization
1
PRECONCEPTION CARE
Johanna Quist-Nelson
Key points to incorporate change in modifiable health behaviors in

response to preconception counseling [7]. General practitio-
• Preconception care is a set of interventions that aim ner–initiated preconception counseling not only can decrease
to identify and modify biomedical, behavioral, and adverse pregnancy outcomes but also reduces anxiety in repro-
social risks to a patient’s health or pregnancy outcome ductive-age patients [8].
through prevention and management. The foundation
of preconception care is prevention. Timing and target population
• Preconception care should occur any time any health
care provider sees a reproductive-age patient (e.g., 15- to The time that people should start caring for a pregnancy is before
44 years old). conception. Preconception care should occur any time any
• Personal and family history, physical exam, laboratory health care provider sees a reproductive-age patient. A repro-
screening, reproductive plan, nutrition, supplements, ductive-age patient is usually defined as one between 15 and
weight, exercise, vaccinations, and injury prevention 44 years of age, but occasionally even younger or older patients
should be reviewed in all reproductive-age patients. contemplate, or at least are at risk of, pregnancy. One should
• Folic acid 400 µg/day, as well as proper diet and exercise, engage any individual who plans or considers pregnancy in coun-
should be encouraged starting at least one month before seling, including lesbian, gay, bisexual, transgender, questioning,
conception, so anytime a pregnancy is possible. intersex, asexual, and ally (LGBTQIAA) individuals [9].
• Regarding vaccinations, patients should receive the influ- The first prenatal visit is “months too late!” [10]. It often hap-
enza vaccine if planning pregnancy during flu season; the pens after first-trimester exposure to a potential teratogen has
rubella and varicella vaccines if there is no evidence of already occurred. There are about 1 billion reproductive-age
immunity to these viruses; and tetanus/diphtheria/pertus- patients worldwide. In the United States, as an example, approxi-
sis as well as COVID vaccines if lacking adult vaccination. mately half of pregnancies are planned [11]. As patients get preg-
• Specific interventions to reduce morbidity and mortality nant later in life, disease prevalence and medication exposure
for both the woman and her baby should be offered to those increase. Approximately 80% of reproductive-age U.S. patients
identified with chronic diseases or exposed to teratogens have dental disease, 66% are obese or overweight, 55% drink alco-
or illicit substances. hol, 11% continue to smoke during pregnancy, 9% have diabetes,
6% have asthma, 3% have hypertension, and 3% have cardiac dis-
History ease [2]. The incidences of many of these conditions among preg-
nant patients are on the rise.
Preconception care has ancient origins. Plutarch (46–120 CE) While some beneficial interventions could be started as soon
wrote that the ancient Spartans “[…] ordered the maidens to exer- as a pregnancy is diagnosed, this is unrealistic. Many of the pre-
cise […], to the end that the fruit they conceived might […] take ventive measures take time—often months—such as quitting
firmer root and find better growth” [1]. smoking, losing weight, folic acid supplementation, and stabiliza-
tion of medical conditions with effective and safe medications.
Definition
Opportunities for preconception care
Preconception care is a set of interventions that aim to iden-
tify and modify biomedical, behavioral, and social risks to a By the age of 25, about 50% of U.S. patients have had at least
patient’s health or pregnancy outcome through prevention one birth. The highest fertility rate occurs in 25- to 30 years old
and management [2, 3]. This care has also been called pre-preg- patients. By the age of 44, >85% have given birth at least once.
nancy, interpregnancy care, or periconceptional medicine [4]. About 84% of reproductive-age patients, when asked, answer that
they had a health care visit within the prior year [6]. Therefore,
Aim and effectiveness universal preconception care can be achieved if health care
providers make it a priority and plan for it at every opportu-
The foundation of preconception care is prevention. Prevention nity (Table 1.1). The approach should be “every reproductive-age
of disease is the most effective form of medicine, and health care patient, every time” [6]. Every reproductive-age patient should
should shift from the delivery of procedure-based acute care be asked at every health care encounter: “Are you consider-
to the provision of counseling-based preventive care [5, 6]. For ing pregnancy?” and “Could you possibly become pregnant?”
example, the two leading causes of death in the first year of life— Increased awareness of preconception care can be accomplished
birth defects and disorders caused by preterm birth (PTB)—can through improving health resources, public outreach, and adver-
be significantly reduced by preconception care. Randomized tising. Despite its great effectiveness, not all health care plans
controlled trials have corroborated that patients are likely cover preconception care. A preconception visit (or often more
DOI: 10.1201/9781003102342-1 1
2 Obstetric Evidence Based Guidelines
TABLE 1.1: Visits That Are Opportunities for Preconception TABLE 1.3: Preconception Screening Assessment for All
Care Reproductive-Age Patients (15–44 Years Old)
• Adolescent (first gynecological exam) History
• Any visit to a doctor during reproductive years (15- to 44 years old) Reason for visit
• College—Graduate school health Health status: obstetrical, gynecological, medical, surgical, and family
• Family planning, contraception prescribing, and counseling history
• Annual ob-gyn Use of prescription, over-the-counter, complementary, and
• Postpartum alternative medicines
• Pregnancy test (especially if negative) Allergies (to medications or other)
• Health maintenance Tobacco, alcohol, other drug use
• Medical work Work-related exposures
• Emergency visit Dietary/nutrition assessment
• Fertility Physical activity
Urinary and fecal incontinence
than one) should be standard primary care, as stated by the Physical Examination
Centers for Disease Control and Prevention [2]. It should be as Height, weight, body mass index (BMI)
routine as prenatal care, as should the screening and interven- Blood pressure
tions associated with it. A clear political will to drive the funding Head
and insurance coverage for preconception care is required. Neck: adenopathy and thyroid
Therefore, providers of all specialties should be aware of the Breasts
evidence-based recommendations (Tables 1.1–1.8). Organizations Heart, lungs
representing family and internal medicine, obstetrics and gyne- Abdomen
cology, nurse midwifery, nursing, public health, diabetes, neu-
Pelvic examination
rology, cardiology, and many other associations have supported
Skin
recommendations for preconception care. Unfortunately, prac-
Laboratory Testing
titioners seldom implement them [12], even though it is an
opportunity to optimize the health of the patient independent of Rubella titera
whether she is planning pregnancy [6]. Only one out of six obste- Varicella titera
trician-gynecologists (ob-gyns) or family physicians provides Human immunodeficiency virus (HIV) testingb
preconception care to the majority of patients for whom they pro- Cervical cytologyc
vide prenatal care [13]. Hepatitis C antibodyd
Preconception care may often need to be multidisciplinary Chlamydia testing (if aged 25 years or younger and sexually active)
care. Prior to pregnancy, a patient can have numerous different Evaluation and Counseling
medical problems affecting different specialties, and her care Sexuality and Reproductive Planning
should occur in close collaboration between the different fields High-risk behaviors
involved. Maternal physiology is different from nonpregnant Discussion of a reproductive health plan
adult physiology. An entire field, maternal-fetal medicine, is
Contraceptive options for prevention of unwanted pregnancy,
dedicated to the care of pregnancies with maternal or fetal prob-
including emergency contraception
lems, and these specialists are particularly adept at directing
Genetic counseling
best practices for preconception counseling. Preconception care
Sexually Transmitted Diseases
occurs best if all practitioners, including primary and specialty
care, either directly implement or appropriately refer for imple- Partner selection
mentation of effective preconception screening and intervention. Barrier protection
The worse scenario is the belief that a positive pregnancy test is Sexual function
a good reason to “stop all medicines,” thereby stopping disease Fitness and Nutrition
Dietary/nutrition assessment
TABLE 1.2: Topics to Be Reviewed in Preconception Care Exercise program
Screening for Risk Assessment Folic acid supplementation (0.4 mg/day)
• Personal and family history, physical exam, and laboratory screening Calcium intake
Preventive Health Psychosocial Evaluation
• Reproductive plan History of abuse/neglect/violence (physical, sexual, and emotional)
• Nutrition, supplements, weight, and exercise Sexual practices
• Vaccinations/infections Lifestyle/stress
• Injury prevention Sleep disorders
Specific Individual Issues/“Exposures” Home and work (including satisfaction and environmental hazards)
• Chronic diseases Interpersonal/family relationships; social support
• Medications (teratogens) Depression (suicide)
• Substance use disorder/environmental hazards and toxins Criminality
Education
Source: Modified from Refs. [2, 14].
Preconception Care 3
TABLE 1.3 (Continued): Preconception Screening Assessment treatment. Prevent panic: get patients ready for a healthy preg-
for All Reproductive-Age Patients (15–44 Years Old) nancy before contraception is stopped.
Language and culture
Health insurance status, coverage, access, public programs Content of preconception care
Cardiovascular Risk Factors
Family history Topics pertinent to optimizing preconception health and there-
Hypertension fore future maternal and perinatal outcome should be dis-
Dyslipidemia cussed. Topics to be discussed in preconception care are listed
Obesity
in Table 1.2 [2, 14]. Further research is needed to determine the
best content of preconception care and the most effective way to
Diabetes mellitus
implement it [15, 16].
Health/Risk Behaviors
Hygiene (including dental)
Injury prevention Universal screening and
• Safety belts and helmets related interventions
• Occupational hazards
• Recreational hazards History, exam, and laboratory screen
• Firearms Suggested preconception screening assessment is shown in
• Hearing Table 1.3 [14, 17]. A questionnaire should be completed ahead
• Exercise and sports involvement of time, either on paper or online, to review this extensive list. A
Breast self-examination
standardized form improves the completeness of preconception
screening, which necessitates time and commitment [18]. This
Vaccinations
standardized preconception form should be integrated into the
See Table 1.5
permanent record of all reproductive-age patients. In a random-
Source: Modified from Refs. [1, 14, 16]. ized trial, patients assigned to be screened with a preconception
a Unless documented immunity.
risk survey were found to have an average of nine risk factors,
b HIV screening should be offered as routine to all patients of reproductive age,
supporting the facts that even low-risk patients may benefit from
under an “opt-out” policy. Physicians should be aware of and follow their states’/
preconception screening [15].
countries’ HIV screening requirements.
c Annually beginning no later than age 21 years; every 2–3 years after three consecu-
History should be detailed, especially when pertinent positives
tive negative test results if age 30 years or older with no history of cervical intraepi-
are detected. Prior inpatient and outpatient medical records
thelial neoplasia 2 or 3, immunosuppression, HIV infection, or diethylstilbestrol should be reviewed. Patients should be empowered with easy
exposure in utero. access to their records (best if electronic) to facilitate multispe-
d Most adults need to be screened only once. Persons with continued risk for hepa- cialty care coordination. Personal prenatal medical record access
titis C virus (HCV) infection should be screened periodically [45]. has been associated with increased maternal control, satisfaction
TABLE 1.4: Preconception Laboratory Screening Depending on Risk Factors

Personal History
Age
• >35: fasting glucose
Prior Obstetrical History
• Prior birth of a newborn weighting more than 9 lb or >4,500 g (macrosomia): fasting glucose
• History of gestational diabetes mellitus: fasting glucose
• Prior unexplained fetal death: check autopsy and karyotype of fetal death; antiphospholipid antibody testing; fasting glucose
• Prior infant with congenital anomaly (if not screened in that pregnancy): fasting glucose
• Prior recurrent unexplained early pregnancy loss: antiphospholipid antibody testing; study of uterine anatomy; parental karyotype
Prior Medical History
• Metabolic syndrome/obesity; family history of lipid or coronary disorders: cholesterol/lipid profile
• Diabetes: lipid profile; hemoglobin A1c; cardiac and renal baseline function assessment; ophthalmologic exam
• Hypertension: fasting glucose; baseline cardiac, renal, and liver functions
• Multiple coronary heart disease risk factors (e.g., tobacco use, hypertension): lipid profile
• High-density lipoprotein cholesterol level ≤35 mL/dL: fasting glucose
• Triglyceride level ≥250 mg/dL: fasting glucose
• History of impaired glucose tolerance or impaired fasting glucose: fasting glucose
• Chronic use of steroids: fasting glucose
• Polycystic ovary syndrome: fasting glucose
• History of vascular disease: fasting glucose
• Marfan syndrome: echocardiogram for assessment of aortic root; eye exam for lens
• History of STD, drug use, etc.: HIV, Hep C
• Recipients of blood from donors who later tested positive for HCV infection: Hep C
(Continued)
TABLE 1.4 (Continued): Preconception Laboratory Screening Depending on Risk Factors

• Recipients of blood or blood-component transfusion or organ transplant before July 1992: Hep C
• Recipients of clotting factor concentrates before 1987: Hep C
• Chronic (long-term) hemodialysis: Hep C
• History of transfusion from 1978 to 1985: HIV
• Invasive cervical cancer: HIV
• HIV infection: STD screening; PPD
• Medical risk factors known to increase risk of TB if infected: PPD
• Not sure if had varicella infection in past: varicella titer
Social History
• HIV or TB contact, illicit drug use: TB testing
• History of injecting illegal drugs: Hep C; HIV; STD screening (chlamydia, gonorrhea, syphilis, etc.); PPD
• Occupational percutaneous or mucosal exposure to HCV-positive blood: Hep C
• More than one sexual partner since most recent HIV test or a sex partner with more than one sexual partner since most recent HIV test: HIV
• Seeking treatment for STDs: HIV
• History of prostitution: STD screening; HIV
• Past or present sexual partner who is HIV positive or bisexual or injects drugs: HIV
• Long-term residence or birth in an area with high prevalence of HIV infection: HIV
• Adolescents who are or ever have been sexually active: HIV
• Adolescents entering detention facilities: HIV; STD screening
• Offer to patients seeking preconception evaluation: HIV (all patients should be screened)
• History of multiple sexual partners or a sexual partner with multiple contacts: STD screening
• Sexual contact with individuals with culture-proven STD: STD screening
• History of repeated episodes of STDs: STD screening
• Attendance at clinics for STDs: STD screening
• All sexually active patients aged 25 years or younger: chlamydia
• All sexually active adolescents: gonorrhea
• Close contact with individuals known or suspected to have TB: PPD
• Born in country with high TB prevalence: PPD
• Medically underserved: PPD
• Low income: PPD
• Alcoholism: PPD
• Resident of long-term care facility (e.g., correctional institutions, mental institutions, and nursing homes and facilities): PPD
• Health professional working in high-risk health care facilities: PPD
Family History
• Family history of diabetes mellitus: fasting glucose
• Family history of diabetes; history of gestational diabetes, overweight/obese, hypertension, high-risk ethnic group (African American, Hispanic,
Native American): fasting glucose every 3 years
• Family history suggestive of familial hyperlipidemia: lipid profile
• Family history of premature (age <50 years for men, age <60 years for patients) cardiovascular disease: lipid profile
• Colorectal cancer or adenomatous polyps in first-degree relative younger than 60 years or in two or more first-degree relatives of any ages; family
history of familial adenomatous polyposis or hereditary nonpolyposis colon cancer: colonoscopy
• First-degree relative (i.e., mother, sister, or daughter) or multiple other relatives who have a history of premenopausal breast or breast or ovarian
cancer: mammography
• Family history of Marfan syndrome: echocardiogram for assessment of aortic root; eye exam for lens
• Family history of breast cancer: mammography
• Family history of thyroid disease: TSH
• Ashkenazi Jewish testing—familial dysautonomia; Tay-Sachs; Canavan; Fanconi anemia type C; Niemann-Pick disease type A; Bloom syndrome;
Gaucher disease; glycogen storage 1a; maple syrup urine disease; mucolipidosis type IV
• Ethnicity testing; consider genetic counseling
Physical Examination
• Overweight (BMI ≥ 25): fasting glucose or hemoglobin A1c
• Hypertension: fasting glucose or hemoglobin A1c
Laboratory Screening
• Persistently abnormal alanine aminotransferase levels: Hep C
• Glycosuria: fasting glucose
Source: Modified from Ref. [14].
Abbreviations: STDs, sexually transmitted diseases; HIV, human immunodeficiency virus; Hep C, hepatitis C; HCV, hepatitis C virus; PPD, purified protein derivative; TB,
tuberculosis; IV, intravenous; TSH, thyroid-stimulating hormone; BMI, body mass index.
TABLE 1.5: Recommended Preconception Vaccinations

All Reproductive-Age Patients
No recent prior COVID vaccination: COVID
During flu season: influenza
No evidence of immunity to rubella: MMR
No evidence of immunity to varicella: varicella
No adult Td vaccination in last 2 years: tetanus/diphtheria/pertussis (Tdap)
High-Risk Populations
Hepatitis B nonimmune: hepatitis B vaccine
Age
All girls and patients 9–26 years old: HPV
All persons 18 years old and younger without immunity to hepatitis B infection: hepatitis B
Occupational
Health care workers: hepatitis B, influenza, MMR, varicella
Public safety workers who have exposure to blood in the workplace: hepatitis B
Students in schools of medicine, dentistry, nursing, laboratory technology, and other allied health professions: hepatitis B
Staff of institutions for the developmentally disabled: hepatitis B
Individuals who work with HAV-infected nonhuman primates or with HAV in a research laboratory setting: hepatitis A
Military recruits: meningococcus
Microbiologists routinely exposed to Neisseria meningitidis isolates: meningococcus
Social History/Living Situation
Individuals with more than one sexual partner in the previous 6 months: hepatitis B
Household contacts and sexual partners of individuals with chronic hepatitis B infection: hepatitis B
Inmates of correctional facilities: hepatitis B
Clients of institutions for the developmentally disabled: hepatitis B
Illegal injected drug users: hepatitis B
Illegal drug users (injected and noninjected): hepatitis A
Exposure to environment where pneumococcal outbreaks have occurred: pneumococcus
Unhealthy alcohol use : pneumococcus
Tobacco smoking: pneumococcus
Residents of long-term care facilities: influenza, pneumococcus
First-year college students living in dormitories: meningococcus
Travel/Immigration
Individuals traveling to or working in countries that have high or intermediate endemicity of hepatitis A: hepatitis A
International travelers who will be in countries with high or intermediate prevalence of chronic hepatitis B infection for more than 6 months: hepatitis B
Travel to areas hyperendemic or epidemic for Neisseria meningitides: meningococcus
Pulmonary Conditions
Chronic pulmonary disorders, including asthma: pneumococcus
Cardiac Conditions
Chronic cardiovascular disorders (e.g., CHF, cardiomyopathies): influenza, pneumococcus
Renal Conditions
Chronic metabolic diseases, including renal dysfunction: influenza, pneumococcus
Nephrotic syndrome: pneumococcus
End-stage renal disease, including those on dialysis: hepatitis B
Endocrine Conditions
Diabetes mellitus: influenza, pneumococcus
Hematologic/Immunologic Conditions
Prior transfusions: hepatitis A, hepatitis B
Patients with clotting factor disorders (those who receive clotting factor concentrates): hepatitis A
Chronic illness, such as functional asplenia (e.g., sickle cell disease) or splenectomy: pneumococcus
Immunocompromised patients (e.g., HIV infection, hematologic or solid malignancies, chemotherapy, steroid therapy): pneumococcus
Adults with anatomic or functional asplenia: pneumococcus, meningococcus
Terminal complement component deficiencies: meningococcus
Infectious Conditions
Individuals with a recently acquired or recent evaluation for STI: hepatitis B
All clients in STD clinics: hepatitis B
HIV: hepatitis B, influenza, pneumococcus, consider meningococcus
GI/Hepatic Conditions
Chronic liver disease: hepatitis A, hepatitis B, pneumococcus
Neurologic Conditions
Cerebrospinal fluid leaks: pneumococcus
Source: Modified from Ref. [14] (see also Chap. 38 in Maternal-Fetal Evidence Based Guidelines, Fourth Edition).
Abbreviations: MMR, measles, mumps, and rubella; HPV, human papillomavirus; HAV, hepatitis A virus; CHV, congestive heart failure; HIV, human immunodeficiency virus;
STI, sexually transmitted infection; STD, sexually transmitted disease.
TABLE 1.6: Preconception Interventions for All Patients

Intervention Prevention of
Folic acid 400 μg/daya NTDs and also probably cardiac defects, facial clefts
Vaccinations Maternal/perinatal infectionb (Table 1.5)
Proper diet and exercise Obesity, diabetes, hypertensive diseases, and their consequences
Injury prevention (e.g., seat belts, helmets) Physical trauma
Screen for specific risk factors See Table 1.7
Abbreviations: NTDs, neural tube defects; STD, sexually transmitted disease; MTHFR, methylenetetrahydrofolate reductase.
a Consider higher dose, especially for patients taking antiseizure medications, other drugs that might interfere with folic acid metab-
olism, those with homozygous MTHFR enzyme mutations, or those who are obese.
b By decreasing perinatal transmission, also decrease congenital defects caused by infection.
TABLE 1.7: Preconception Care for Specific Maternal Medical Disorders

Chapter in MF Evidence
Disorder Based Guidelines Brief Preconception Recommendations Prevention of
Hypertensive disorders 1 • Discontinue ACE inhibitors and ARB; Congenital anomalies, HTN complications, CD,
transition to another antihypertensive FGR, placental abruption, PTB, perinatal death
• Investigation into other etiologies
• Baseline creatinine
• Consider retinal exam, urine protein
assessment and electrocardiography in
women with longstanding disease
Cardiac disease 2 • Any necessary or possible cardiac Worsening maternal cardiac condition, PTB,
interventions undergone prior to HTN
pregnancy
• Patients with group III lesions or dilated
cardiomyopathy are advised not to
conceive
Obesity 3 • Counseling, diet and exercise to return to Infertility, fetal NTDs, PTB, CD, HTN
normal BMI disorders, diabetes, VTE
• Evaluation of fasting lipids, fasting blood
sugar
• Screening for thyroid disease, OSA, HTN
• If coexisting HTN or DM, obtain ECG
and ECHO
• Education about poor perinatal outcomes
in obese patients
• Motivational interviewing
• Those who have recently had bariatric
surgery should be counseled that
pregnancy is optimal after the period of
rapid weight loss
Pregestational diabetes 4 • Optimize glycemic control with goal Congenital anomalies, length of NICU
Hgb A1c <6.5% admission, perinatal mortality and long-term
• Screen for asymptomatic bacteriuria health consequences in infant; miscarriage;
• Consideration for retinal exams, urine maternal hospitalizations, maternal renal
proteinuria screening disease
• Thyroid screening
Hypothyroidism 6 • Monitor TSH and FT4 to assure Infertility, maternal HTN, miscarriage,
euthyroid state preeclampsia, abruption, anemia, PTB, LBW,
fetal death, possibly neurological problems in
infant
Hyperthyroidism 7 • If radioiodine is required, should be Spontaneous pregnancy loss, PTB,
completed 6–12 months before preeclampsia, fetal death, FGR, maternal
attempting conception congestive heart failure, and thyroid storm;
• Emphasize minimum of 150 µg iodine neonatal Graves’ disease
daily (recommendation for all
preconception patients)
TABLE 1.7 (Continued): Preconception Care for Specific Maternal Medical Disorders
Chapter in MFM Evidence
Prolactinoma 8 • Treat with dopamine agonist until Risk of increasing size of maternal
decreasing size of adenoma to at least prolactinoma, possibly causing optic nerve
<1 cm, and normal prolactin impairment
History of hyperemesis 9 • Start prenatal vitamins at 3 month prior Decreases risk of recurrence of hyperemesis
gravidarum to conception
Inflammatory bowel 11 • Plan conception when disease is in Birth defects
disease remission >6 months
• Discontinue MTX 3–6 months prior to
conception
• Screen for B12, vitamin D, and iron deficiency
Liver transplantation 13 • Plan pregnancy when stable on PTB, HTN, preeclampsia, FGR, GDM, graft
immunosuppressive regimen >1 year rejection
• Assess baseline kidney/liver function,
24-hour urine
• If patient is on mycophenolic acid
products, assess fetal risks and consider
switching to alternative
immunosuppressant
Anemia 14 • Evaluation of etiology, assessment for SGA, PTB, maternal CV compromise, need for
iron, B12, and folate deficiency transfusion
• In patients of African ancestry,
hemoglobin electrophoresis
• Genetic consult for patients with
hereditable disorder
Sickle cell disease 15 • Start on 4 mg folic acid daily to optimize Birth defects, crises
hemoglobin status
• Vaccinate with pneumococcal and influenza
• Discontinue teratogenic medications
(ACE inhibitors, iron chelators)
von Willebrand disease 16 • Consult hematology, genetics; administer Postpartum hemorrhage
hepatitis B vaccine
• Baseline labs (von Willebrand factor
antigen, ristocetin cofactor activity, factor
VIII, low-dose ristocetin-induced platelet
aggregation, multimer assay)
Renal disease/transplant 17 • Assess baseline creatinine, 24-hour Preeclampsia
proteinuria, intravenous pyelogram
• Plan pregnancy when stable on
immunosuppressive regimen, with drug
therapies at maintenance levels if possible
• Post-transplant, await >1 year before
conception
Seizures 19 • Recommend deferring conception until Congenital anomalies
seizure-free on minimal medication,
preferably monotherapy
• Consult neurology to consider weaning
medication if >2 years seizure-free
• Start on folic acid 2–4 mg daily
Spinal cord injury 20 • If cause is congenital, start on folic acid Congenital anomalies
4 mg daily and genetic counseling
Mood disorders 21 • Counsel on the risks of discontinuing Cardiac malformations
antidepressants in pregnancy
• Stabilize mood on lowest effective dose
prior to pregnancy
• Avoid paroxetine, given risks of cardiac
malformations
(Continued)
Chapter in MFM Evidence
Smoking 22 • Counsel regarding preventable pregnancy PTB, LBW
outcomes in patient who smoke
• Encourage cessation with behavioral and
educational interventions
Drug use disorder 23 • Encourage patients to postpone PTB, FGR, neonatal withdrawal, etc. (effect
conception until after completing depends on drug)
detoxification or instituting
replacement therapy in the case of
opioid use disorder
Asthma 26 • Control of asthma with appropriate PTB, LBW, preeclampsia, perinatal mortality
regimen through multidisciplinary care,
set expectations to continue management
throughout pregnancy
Tuberculosis 26 • Screen high-risk patients (hx of Active TB
incarceration, TB exposure, international
travel or immigration) with PPD or
interferon gamma-release assay and treat
accordingly
Lupus 27 • Recommend conception when disease is HTN, preeclampsia, PTB, fetal death, FGR,
in remission for >6 months neonatal lupus
• Screen for HTN, renal, heart, lung, or
brain disease as well as antiphospholipid
and SSA/SSB antibodies
• Decrease meds to lowest possible
effective dose
• Replace mycophenolate mofetil and with
other medications
Venous 30 • Screen all patients with history of VTE Recurrence of venous thromboembolism
thromboembolism and for thrombophilia
mechanical heart • Perform any necessary valve replacements
valves before pregnancy
• If mechanical heart valve, consider
continuing warfarin after full counseling
of risks of warfarin embryopathy and
under direction of cardiologist
Hepatitis A 31 • Vaccinate patients who travel abroad, are
at risk for contracting the disease, or are
infected with chronic hepatitis B or C
prior to pregnancy; vaccine also safe in
pregnancy
Hepatitis B 32 • Administer HBV vaccine to any patient Perinatal HBV transmission
who is susceptible before pregnancy
• If chronically infected, screen for
hepatitis A and vaccinate prior to
pregnancy
Hepatitis C 33 • Screen high risk populations prior to Cirrhosis, HCC, HCV infant transmission
pregnancy
• Vaccinate against hepatitis A and B if
nonimmune
• Consider treatment preconception
HIV 34 • Initiate or modify antiretroviral therapy Perinatal HIV infection
avoiding teratogenic agents
• CD4 count and indicated prophylaxis
based on level
• Screen for STIs
• Advise how to optimize conception, yet
minimizing risk of transmission
STI testing 35, 36, 37, 38 • Screen and treat for gonorrhea, Ectopic pregnancy
chlamydia, syphilis and trichomonas in
high risk patients (e.g. <25, prior STI,
multiple sexual partners, inconsistent
condom use, sex work, or drug use)
PKU • Low-phenylalanine diet PKU-related mental retardation
Intimate partner 24 • Counseling; Referral to appropriate Physical and emotional trauma and their
violence agency consequences, fetal loss
Alcohol use disorder • Medical and behavioral therapy Congenital anomalies, mental retardation
• Avoid all alcohol intake
Supplements and • Review and counsel: avoid excess of Congenital anomalies
over-the-counter recommended daily allowance (RDA)
medications (see also Chap. 2)
Abbreviations: MF, Maternal-Fetal; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; HTN, hypertension; CD, cesarean delivery; PTB, preterm birth;
LBW, low birth weight; NICU, neonatal intensive care unit; BMI, body mass index; DM, diabetes mellitus, EKG, electrocardiogram; ECHO, echocardiogram; OSA, obstructive
sleep apnea; NTD, neural tube defects; VTE, venous thromboembolism; FGR, fetal growth restriction; TSH, thyroid-stimulating hormone; FT4, free thyroxine; CV, cardiovas-
cular; MTX, methotrexate; TB, tuberculosis; PPD, purified protein derivative; SSA/SSB, Sjogren syndrome related antigen A and B; HIV, human immunodeficiency virus; STI,
sexually transmitted infections; PKU, phenylketonuria.
TABLE 1.8: Teratogens during pregnancy, and increased availability of antenatal records
during hospital attendance [19].
Prescribed Drugs
Prior obstetrical and gynecological history, including prior
• Androgens and testosterone derivatives (e.g., danazol) pregnancy complications, should be reviewed. Other reproduc-
• Angiotensin-converting enzyme (ACE) inhibitors (e.g., enalapril, tive issues should also be assessed: fertility, including the pos-
captopril) and angiotensin II receptor blockers sibility of assisted reproductive technology needs; sexuality (in
• Coumadin derivatives (e.g., warfarin) particular high-risk behaviors); contraception; partner selection;
• Carbamazepine and sexual function. Several social issues need to be reviewed as
• Diethylstilbestrol well (Table 1.3).
• Folic acid antagonists (methotrexate and aminopterin) All couples should have a basic screen for family history of
• HMG-CoA reductase inhibitors (statins) heritable genetic disorders, with a pedigree to at least the
• Lithium
second prior generation. Patients belonging to an ethnic group
at increased risk for a recessive condition (Table 1.4) should be
• Phenytoin
offered appropriate screening. All couples should be made aware
• Primidone
of the option for cystic fibrosis (CF) screening and hemoglobin
• Streptomycin and kanamycin
electrophoresis screening [20]. Patients with a specific indication
• Tetracycline for genetic testing should be referred for formal genetic counsel-
• Thalidomide and leflunomide ing (see Chaps. 5 and 6).
• Trimethadione and paramethadione Physical exam details are shown in Table 1.3. Pelvic exam may
• Valproic acid include cytologic and sexually transmitted infection screening
• Vitamin A above RDA and its derivatives (e.g., isotretinoin, for patients with certain risk factors. Laboratory tests are done
etretinate, and retinoids) routinely (Table 1.3) and depending on risk factors (Table 1.4) [14].
Chemicals
• Lead Reproductive health plan
• Mercury Asking a reproductive-age woman, and therefore inducing her
Drugs to think about, her reproductive health plan, should be a prior-
• Alcohol ity of any medical visit [21]. Such a plan should address the desire
• Cocaine (or not) for children; the optimal number, spacing, and timing of
Infections
pregnancies; contraception to achieve this plan; opportunities to
improve her health and therefore a successful reproductive life;
• Cytomegalovirus
and age-related changes in fertility [21]. Having a reproductive
• Rubella
health plan reduces unintended pregnancies, age-related infertil-
• Syphilis ity, and fetal exposure to teratogens [2]. Very few patients know
• Toxoplasmosis that a short interpregnancy interval (i.e., <6 months from the
• Varicella end of the last pregnancy to the next conception) is associated
Radiation with increased incidence of both small-for-gestational-age and
Source: Modified from Refs. [58, 59]. low-birth-weight neonates [22]. Folic acid depletion may be the
Abbreviations: HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA reductase; RDA, rec- etiology for these increased risks [23]. Education and contracep-
ommended daily allowance. tion advice are necessary to aim for the wished reproductive plan,
avoid unplanned pregnancies, and optimize the 18- to 24-month Supplementation should start at least 1 month before con-
interpregnancy interval goal. In a nonrandomized study, preconception and continue until at least 28 days after conception
ception care decreased the number of unintended pregnancies [24]. (time of neural tube closure). Given the unpredictability of
All patients should be counseled that 2–3% of babies are born planned conception, all reproductive-age patients should be on
with minor (usually) or major anomalies. Screening and diag- folic acid supplementation from menarche to menopause. Patients
nostic options to detect aneuploidy and birth defects should be taking antiseizure medications, such as phenytoin, carbamaze-
reviewed so that patients may consider their options in relation to pine, or barbiturates, may benefit from higher doses of folic acid.
their personal values. Patients with homozygous methylenetetrahydrofolate reductase
(MTHFR) enzyme mutations or those who are obese may also
Nutrition, weight, and exercise need higher doses of folic acid supplementation. As increases in
Lifelong habits of healthy diet and regular exercise should be baseline serum folate level are directly proportional to a decrease
established preconceptionally [25]. Proper diet and exercise can in the incidence of NTDs, some experts have advocated 5 mg of
prevent several complications of pregnancy, including gestational folic acid per day as optimal universal supplementation [35]. Folic
diabetes and hypertensive complications [26]. Some studies sug- acid supplementation has also been associated with a decrease in
gest a correlation between a diet high in fruits, vegetables, nuts, the risk of congenital anomalies other than NTDs (e.g., cardiac,
and legumes; less than two servings of meat weekly; and at least facial clefts) [36–38].
two servings of fish weekly (the “Mediterranean Diet”) with The overall benefits or risks of fortifying basic foods such as
decreased rates of infertility and PTB [27–30]. grains with added folate have been associated with a 140–200 µg/
In addition to following a healthy diet, issues of food safety are day increase in supplementation and a 20–50% decrease in inci-
important to review. All meat, seafood, and shellfish should be dence of NTDs [35]. Education with provision of printed mate-
thoroughly cooked. Eating at least 12 oz of fish weekly is asso- rial [35, 39], computerized counseling [40], and learner-centered
ciated with several benefits, including a lower rate of PTB (see nutrition education [41] all increase the awareness of the folate/
Chap. 18) [29], but patients must avoid >2 servings/week of shark, NTDs association and the use of the folate supplements. These
swordfish, king mackerel, some tuna, or tilefish, all of which may interventions may be effective in increasing the prophylactic use
contain high concentrations of methyl mercury. Albacore (white) of additional preconception care activities.
tuna has more mercury than canned light tuna [30]. Other rec- There is insufficient evidence to justify the routine use of other
ommendations include eating only pasteurized eggs and dairy supplements in reproductive-age patients, especially in the devel-
products and washing raw fruits and vegetables before eating. oped world, unless a nutritional deficiency has been identified.
Patients should try to obtain a minimum daily iodine intake of It is important to obtain a daily intake of minimum 150 mg of
150 mg/day. Education about proper hand, food, and cooking iodine and 10,000 IU of vitamin A (as beta-carotene) if deficien-
utensil hygiene is important, especially in developing countries. cies of these nutrients are identified. The use of certain supple-
Body mass index (BMI) should be calculated at least annually ments may be detrimental, especially if excessive amounts of
for reproductive-age patients [31]. For patients with a BMI that lipid-soluble vitamins such as vitamin A (>10,000 IU/day) are
falls outside the normal range [31–36], preconception counseling taken, since they can be teratogenic. All supplements, including
regarding the patient’s increased risk of complications in pregnancy alternative and complementary medicines, should be reviewed
is extremely important. Formal nutritional counseling should be (see also Chap. 2) [42, 43].
offered and goals set to avoid pregnancy until optimal weight
is achieved. Patients with a low BMI should be screened for eat- Maternal infection prevention and vaccines
ing disorders. In overweight and obese patients, calorie and por- Preconception vaccination for the prevention of fetal and mater-
tion-size control may be the most effective methods of sustained nal disease is an important preconception intervention (Table 1.5)
preconception weight loss. Unfortunately, there are no current evi- (see also Chap. 40 in Maternal-Fetal Evidence Based Guidelines).
dence-based guidelines as to the most effective method of weight Maternal immunity to infections such as rubella and vari-
loss in the preconception period for obese and overweight patients cella should be assessed for potential vaccination of nonimmune
[36]. Postpartum individual counseling on diet and physical activ- patients, thus eliminating their risk for congenital syndromes
ity increased the proportion of patients returning to pre-pregnancy associated with these viruses. Vaccination with live attenuated
weight from 30% to 50% in one randomized trial [32]. viruses should occur at least 4 weeks prior to conception due to
An exercise routine that can be started preconceptionally and the theoretical risk of live virus affecting the fetus.
safely continued in pregnancy may include yoga; brisk walking Annual influenza vaccination for patients and their partners
(including hiking and backpacking); jogging; swimming; biking; contemplating pregnancy will reduce the chance of maternal pre-
cross-country skiing; and using fitness equipment such as an natal infection, a time during which higher morbidity has been
elliptical trainer, treadmill, or stationary bike. Patients should be documented. Influenza vaccination for new mothers and other
given standard advice for engaging in regular physical activity for close contacts of the newborn will reduce the risk of infection
30–60 min/day for 5 or more days per week. for the child who is unable to receive vaccination until 6 months
of age. Through this process of “cocooning,” the newborn is pro-
Supplements tected from the high morbidity and mortality rates associated
The preconception intervention with the most evidence-based with influenza in the first year of life [44].
data to support its efficacy is folic acid supplementation. Folic Hepatitis B vaccination should be offered to all susceptible
acid supplementation is recommended, with a minimum of patients of reproductive age. This is especially true in regions
400 µg/day for all patients (93% decrease in neural tube defects with intermediate and high rates of endemicity (where ≥2% of
[NTDs]), and 4 mg/day for patients with prior children with the population is hepatitis B surface antigen [HBsAg] positive).
NTDs or those on certain epileptic medications (69% decrease Perinatal transmission of hepatitis B results in a 90% chance of
in recurrent NTDs) [34]. chronic infection in the newborn, which places the child at risk
for future cirrhosis and hepatocellular carcinoma. In regions in this population, it is reasonable to screen patients of extreme
of low prevalence, vaccination should be targeted to high-risk AMA who also have chronic hypertension, diabetes, hyperlipid-
groups (Table 1.5). emia, or heart disease with a cardiac echocardiogram.
Recent guidelines have recommended hepatitis C screening in
all adults ≥18 years old. This can be done during preconception, Chronic diseases
as treatment for hepatitis C is currently only performed in non- The incidences of several medical disorders such as obesity,
pregnant individuals [45]. diabetes mellitus, and hypertension are high and on the rise in
Tetanus vaccination should remain up-to-date in reproduc- reproductive-age patients. There is literature for evidence-based
tive-age women, particularly in regions of the world where mater- recommendations on each disease or condition that can involve
nal and neonatal tetanus is prevalent [46]. This has been shown the reproductive-age patient and affect their reproductive health
to markedly reduce the incidence of tetanus related to parturi- [3, 4, 17]. Full review of each is beyond the scope of this chap-
tion. Due to increasing prevalence and the high morbidity and ter (see individual chapters in Maternal-Fetal Evidence Based
mortality rates of neonatal pertussis, vaccination (in combina- Guidelines). Some common conditions are discussed for brief
tion with tetanus and diphtheria) is recommended for all patients preconception management review (Table 1.7).
and their partners of reproductive age who have not been immu-
nized in their adult lives (since the age of 11 years) [47]. It is well Diabetes
documented that 75% of cases of neonatal pertussis have a family Diabetes (see Chaps. 4 and 5 in Maternal-Fetal Evidence Based
member as the index case [48]. Guidelines) is associated with an increased risk of congenital
Other vaccination recommendations based on medical, occu- anomalies, in particular cardiac defects and NTDs, if poorly
pational, or social risks are described in Table 1.5. controlled in the first weeks of pregnancy. The risk of congenital
anomalies is related to long-term diabetic control, reflected in the
Injury prevention level of glycosylated hemoglobin (HgB A1c): <7% = no increased
The second leading cause of death in reproductive-age patients is risk (2–3% baseline); 7–9% = 15%; 9–11% = 23%; >11% = 25% [34].
accidents. Use of seat belts and helmets should be reviewed and It has been estimated that euglycemia (with normal HgB A1c)
strongly encouraged where appropriate. Inquiry should be made during the first trimester, which can only be achieved through
regarding occupational and recreational hazards. Possession and attentive preconception counseling, could prevent >100,000
use of firearms should be evaluated. U.S. pregnancy losses or birth defects per year [2]. Another cost
analysis reported that universal preconception care could lead to
Universal recommendations averted lifetime costs for the affected cohort of children as high as
Preconception recommendations for all patients are listed in $4.3 billion [62, 63]. The benefits of preconception diabetes care
Table 1.6. Reproductive-age patients should be aware of these evi- have been previously demonstrated [64, 65], even in teenagers [66].
dence-based recommendations, both through their doctors and Preconception care is also essential for counseling of the patient
through public awareness campaigns. Several online resources with conditions severe enough to make a successful pregnancy
are available [49–52]. Patients and their partners should take extremely unlikely. The diabetic patient with either ischemic heart
more responsibility for their care and the future health of disease, untreated proliferative retinopathy, creatinine clearance
their offspring, and implement the health and lifestyle changes <50 mL/min, proteinuria >2 g/24 hour, creatinine >2 mg/dL,
recommended. uncontrolled hypertension, or gastropathy should be told not to
get pregnant before these conditions can be improved, and coun-
Specific issues seled regarding adoption if the conditions cannot be improved
[67]. The frequency of fetal/infant and maternal morbidity and
History of preterm birth mortality are reduced in diabetic patients seeking consultation in
There are currently no preconception recommendations for preparation for pregnancy, but unfortunately only about one-third
a patient with a history of preterm birth outside of the general of these patients receive such consultation [68]. The preconcep-
recommendations for patients trying to conceive. Randomized tion consultation affords the opportunity to screen for vascular
controlled trials examining preconception initiation of low- consequences of the diabetes, with ophthalmologic, electro-
dose aspirin did not demonstrate an increase in live birth rate cardiogram (ECG), and renal evaluation via a 24-hour urine
or decrease in PTB [53, 54]. Interval antibiotic treatment with collection for total protein and creatinine clearance, and deter-
azithromycin and metronidazole between pregnancies in patients mine ancillary pregnancy risks. Proliferative retinopathy should
with a prior spontaneous PTB (<34 weeks) has not been associ- be treated with laser before pregnancy. Thyroid-stimulating hor-
ated with decreased risk of preterm delivery [55, 56]. mone (TSH) should be checked, as 40% of young patients with
type 1 diabetes have hypothyroidism. Of note, there is insufficient
Advanced maternal age evidence to treat subclinical hypothyroidism [69].
In recent years, there has been a trend to delay childbearing. This Diabetes evaluation should emphasize the importance of tight
trend is especially prevalent in developed countries, for example, glycemic control, with normalization of the HgB A1c to <7%. To
in the United States where the birth rate in 40- to 44 years old achieve euglycemia, diet, glucose monitoring, and exercise
patients has increased from 5.2 births per 1,000 in 1990 to 10.4 are always stressed. If euglycemia is not achieved with these
births per 1,000 patients in 2013 [57]. It is well established that means, oral hypoglycemic agents or insulins are utilized,
patients of advanced maternal age (AMA) are at increasing risk and their regimens should be optimized preconceptionally. Of
of poor obstetric outcomes, stillbirth, and fetal death [58–60]. the oral hypoglycemic agents, Glucophage (metformin) is the
Patients of extreme AMA (>45 years old) have been found to preferred agent at this time [70] and probably continued during
have an increased prevalence of preexisting chronic disease [61]. pregnancy. The original safety data available for glyburide showed
Although no Level I evidence exists for preconception testing that it did not cross the placenta in appreciable amounts [71],
but recent data have shown a 70% level in umbilical blood com- Seizure disorders
pared to maternal blood [72]. The other oral hypoglycemic agents Conception should be deferred until seizures are well controlled
should not be used for preconception glycemic control, as there is on the minimum effective dose of medication (see Chap. 19 in
no sufficient evidence for their safety and efficacy in pregnancy. A Maternal-Fetal Evidence Based Guidelines). Monotherapy is
common insulin regimen currently used by diabetologists is preferable. Lamotrigine has been reported to be first-line therapy
long-acting (e.g., glargine) and short-acting (e.g., lispro). This for nonpregnant adults for partial seizures [78–80] and associated
is a safe and effective regimen in pregnancy too. Patients compli- with a low incidence of major malformations [81], but not in all
ant with insulin pumps should continue this regimen with the studies [82]. The best choice is the antiepileptic drug (AED) that
understanding of increased insulin requirements in pregnancy. best controls the seizures. The AEDs are usually Food and Drug
If a patient has a history of gestational diabetes, appropri- Administration (FDA) category C (human risk unknown, but
ate postpartum diabetes screening should be performed. none proven yet) except for the following AEDs that are known
Interconception counseling and lifestyle modifications may be potential teratogens: carbamazepine, primidone, phenytoin,
beneficial for future pregnancies [73]. and valproate (Table 1.8). These four AEDs should therefore be
avoided, if possible, by using a different therapy beginning in the
Hypertension preconception period. Patients who have been seizure-free for
Hypertension (see Chap. 1 in Maternal-Fetal Evidence Based ≥2 years with a normal electroencephalogram (EEG) may be
Guidelines) is associated with several maternal and fetal risks in eligible to stop anticonvulsant therapy after consulting with a
pregnancy. Serum creatinine, 24-hour urine for total protein neurologist [83].
and creatinine clearance, ECG, and ophthalmologic exam are
suggested, especially in patients with long-standing or severe Medications/Teratogens
hypertension. It is important to identify cardiovascular risk fac- Detailed discussion regarding prescribed and over-the-counter
tors, identify any reversible causes of hypertension, and assess medications should occur at the preconception visit. The indi-
for target organ damage or cardiovascular disease. If hyperten- cation, safety, effectiveness, and necessity of each drug need to
sion is newly diagnosed and has not been evaluated previously, be reviewed. Often, patients and their doctors stop efficacious
a medical consult may be indicated to assess for any of these and necessary medications as soon as the patient finds out she
factors. Secondary hypertension, target organ damage (left ven- is pregnant, compromising the health of both the patient and
tricular dysfunction, retinopathy, dyslipidemia, microvascular her baby. The vast majority of prescribed medications are safe
disease, and prior stroke), maternal age >40, previous pregnancy in pregnancy, even in the first trimester. Only a few drugs,
loss, systolic blood pressure ≥180 mmHg, or diastolic blood pres- chemicals, infections, or radiations are proven teratogens
sure ≥110 mmHg are associated with higher risks in pregnancy. (Table 1.8) [84, 85]. These should be avoided, except in rare cir-
Abnormalities should be addressed and managed appropriately. cumstances (e.g., the patient with mechanical cardiac valves
If, for example, serum creatinine is >1.4 mg/dL, the patient should who accepts the teratogenic risk of warfarin). This medication
be aware of increased risks in pregnancy (pregnancy loss, reduced counseling is often a crucial part of preconception care and can
birth weight, PTB, and accelerated deterioration of maternal save and ameliorate significantly the health of a future offspring.
renal disease). Even mild renal disease (creatinine 1.1–1.4 mg/dL) Great resources exist on the Web for up-to-date teratologic
with uncontrolled hypertension is associated with 10-fold higher information [86–88].
risk of fetal loss. Preconception prevention can be enormously
effective. Thirty minutes of exercise three times per week in all Substance use disorder/Environmental
patients with hypertension and weight reduction if overweight hazards/Toxins
are recommended. Restriction of sodium intake to <2.4 g sodium Tobacco use during pregnancy is associated with increased
daily intake recommended for essential hypertension is beneficial risks of several complications (see Chap. 22 in Maternal-Fetal
in nonpregnant adults. If antihypertensive medical therapy is Evidence Based Guidelines). The benefits of smoking cessation are
necessary, angiotensin-converting enzyme (ACE) inhibitors tremendous: prevention of 10% of perinatal deaths, 35% of low-
and angiotensin II (AII) receptor antagonists should be dis- birth-weight births, and 15% of preterm deliveries [89]. Smoking
continued, as they are associated with birth defects, fetal growth only one to five cigarettes per day is associated with a 55%
restriction, oligohydramnios, neonatal renal failure, and neonatal higher incidence of low-birth weight compared to nonsmokers.
death in pregnancy. All other antihypertensive agents should be Reproductive-age patients should be informed of other smoking-
used at the lowest effective dose, and are probably safe if started related diseases, such as ischemic heart disease, cancer, lung dis-
preconceptionally and continued in pregnancy. eases, pneumonia, stroke, and congestive heart failure. Patients
at greatest risk for smoking are those <25 years old with less than
Abnormal body mass index a high school education. Smoking makes a major contribution
Obesity rates are increasing in the population and can be asso- to disparities in mortality [90]. Smoking cessation programs are
ciated with infertility, miscarriage, and congenital anomalies, as associated with a 6% increase in smoking cessation and decrease
well as other comorbid diseases. Patients should be counseled in incidences of low-birth weight by 19% and PTB by 16% [91].
regarding the benefits of weight reduction in the preconcep- Support and reward techniques to help quit smoking are one
tion period to reduce these risks [74, 75]. If a woman has had of the best forms of evidence-based medicine, supported by over
a recent bariatric surgery, the following 12–24 months can be a 20 high-quality randomized trials. The “5 As” for screening and
time of rapid weight loss, and it is recommended that pregnancy interventions to prevent smoking in pregnancy are Ask, Advise,
be avoided during this time [76]. Assess, Assist, and Arrange [71]. Counseling with behavioral
Patients who are underweight are at risk for having low-birth- and educational interventions is associated with the highest
weight infants and should also be counseled about attaining cessation rates. If necessary, most pharmacotherapies are
weight optimization before pregnancy [77]. effective preconception, but contraindicated or with uncertain
safety and efficacy during pregnancy. Nicotine replacement 18. Bernstein PS, Sanghvi T, Merkatz IR. Improving preconception care. J
therapy (e.g., patch, gum, and bupropion) is safe and effective in Repro Med 2000; 45:546–552. [Review]
19. Brown HC, Smith HJ, Mori R, Noma H. Giving women their own
reproductive-age patients, but there is insufficient evidence for case notes to carry during pregnancy. Cochrane Database Syst Rev
recommending them in pregnant smokers. Nicotine replacement 2015;2015(10):CD002856. [Meta-analysis]
therapy is associated with known adverse fetal effects, and nico- 20. American College of Obstetricians and Gynecologists and American
tine is detected in breast milk. Possibly the best prevention of the College of Medical Genetics.Preconception and prenatal carrier screen for
cystic fibrosis: clinical and laboratory guidelines. Washington, DC: ACOG/
adverse effects of smoking on pregnancy is achieved by avoiding
ACMG, 2001. [Guideline]
sale of tobacco to young people, prohibition of smoking in public 21. American College of Obstetricians and Gynecologists. The importance
places, increase in tobacco taxation, workplace smoking cessation of preconception care in the continuum of women’s health care. ACOG
programs, and banning of tobacco sponsorship of sporting and Committee opinion no. 313. Obstet Gynecol 2005; 106:665–666. [Review]
cultural events. 22. Zhu B-P, Rolfs RT, Nangle BE, et al. Effect of interval between pregnancies
on perinatal outcomes. N Engl J Med 1999; 340:589–594. [II-2]
Numerous recreational drug exposures have adverse pregnancy 23. Smits LJ, Essed GGM. Short interpregnancy intervals and unfavourable
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recreational drugs such as alcohol, cannabinoids, cocaine, her- 24. Moos MK, Bangdiwala SI, Meibohm AR, et al. The impact of a precon-
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oin, and methamphetamines. Patients with substance use disor-
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2
PRENATAL CARE
Gabriele Saccone and Kerri Sendek
Key points any time in pregnancy, and should be recommended.

Influenza vaccine is recommended for pregnant women
• Prenatal care is of benefit to pregnant women, espe- during flu season and TDaP (tetanus, diphtheria, per-
cially those with modifiable risk factors. tussis) vaccine is recommended for all pregnant women,
• Most women should be offered midwife-led models of regardless of the immunity status, after 28 weeks. Partners
care. Continuity of care by midwives has been associated and family members should be encouraged to be vacci-
with improved patient satisfaction. nated as well.
• Group prenatal care should be promoted, as it has been • Prenatal education directed at specific objectives has
associated with a reduction in preterm birth, greater satis- been demonstrated to be effective.
faction, and higher breastfeeding initiation. • Implementation of community-based interventional
• Prenatal care usually consists of 7–12 visits per preg- care packages is associated with a trend for reduction in
nancy, with a first visit soon after the pregnancy test is maternal mortality and with significant reductions in
positive and in time to establish the location and number maternal morbidity, neonatal mortality, stillbirths, and
of embryo(s), usually at around 6–8 weeks, then at 11–14 perinatal mortality.
weeks for aneuploidy screening, followed by visits about • Perineal massage with sweet almond oil for 5–10 minutes
every 4 weeks approximately at 16, 20, 24, and 28 weeks, daily from 34 weeks until delivery is associated with a sig-
about every 2 weeks from 34 to 36 weeks, and weekly until nificantly higher chance of an intact perineum in nullipa-
delivery. In settings with limited resources where the rous women.
number of visits is already low, reduced-visit programs of • Antenatal classes with training to prepare for labor and
antenatal care (<5) are associated with an increase in delivery are associated with arriving to the labor and
perinatal mortality. delivery ward more often in active labor and less use of
• Early ultrasonography should be used to determine epidural analgesia.
the estimated date of delivery if there is any uncertainty • Identifying mothers at risk for postpartum depression
regarding the last menstrual period. assists in prevention compared to intervening on the
• Regular exercise is beneficial to overall maternal fitness general population.
and sense of well-being, as well as associated with pre- • Breastfeeding is the best feeding method for most
vention of excessive weight gain and prevention of preterm infants and should be strongly encouraged. Continued
birth and gestational diabetes. counseling and education facilitate breastfeeding success.
• Sexual activity in pregnancy is associated with better • Unsensitized RhD-negative women should be offered
outcomes. anti-D immunoglobulin prophylaxis at 28–30 weeks.
• Balanced nutrition and protein supplementation is asso- • Sweeping or “stripping” of membranes during cervical
ciated with modest increases in maternal weight gain and exam at ≥37 weeks reduces the rate of postterm delivery.
in mean birth weight and reduction in risk of small-for- • Magnesium lactate or citrate chewable tablets 5 mmol
gestational-age, stillbirth, and neonatal death. High- in the morning and 10 mmol in the evening for 3 weeks
protein and isocaloric protein supplementation should be for women with leg cramps are associated with significant
avoided, as they are associated with increased risk of small improvement in persistent leg cramps.
for gestational age (SGA). • Water gymnastics for 1 hour weekly starting at <19 weeks
• Suggested weight gain in pregnancy is shown in Figure 2.1. reduces back pain in pregnancy and allows more women
Women who are underweight are at increased risk for low to continue to work, with no adverse effects. Both physio-
birth weight and preterm birth and have better outcomes therapy and acupuncture starting <32 weeks for 10 ses-
with a higher total weight gain. sions might reduce back and pelvic pain.
• Folic acid supplementation is recommended for neural • Exercise, increase in water intake, dietary counseling,
tube defect (NTD) prevention, with 400 µg/day for most and certain foods (e.g., prunes) have shown relief in con-
women and 4 mg/day for women with prior children with stipation. If these self-help measures are inadequate, the
NTD or women taking certain medications that rapidly pregnant woman should then try daily bran or wheat fiber
metabolize folate. All reproductive-age women should supplements.
be on folic acid supplementation.
• Women should be allowed to carry their record. Definition
• Immunity to rubella, varicella, hepatitis B, influenza,
tetanus, and pertussis should be assessed at the first Prenatal care is the care provided to pregnant women with the
prenatal visit. Ideally, needed vaccinations should be aim to prevent complications and decrease the incidence of peri-
provided preconceptionally. COVID vaccine is safe at natal and maternal morbidity and mortality [1]. This care consists
DOI: 10.1201/9781003102342-2 15
30 Singleton
Twin
25
20
Kg
15
10
15 20 25 30
Prepregnancy BMI
FIGURE 2.1 Institute of Medicine Recommended Total Weight Gain in Pregnancy by Prepregnancy BMI [kg (lb)]; see also
Table 2.6. (Data from Ref. [58].)
of health promotion, risk assessment, and intervention linked to demonstrate a reduction in poor outcomes in high-risk preg-
the risks and conditions uncovered. These activities require the nancies with enhanced prenatal care at no added cost (see
cooperative and coordinated efforts of the patient, family, pre- the section “Number and Timing of Visits”) [4]. In addition,
natal care providers, and other specialized providers. Prenatal women are dissatisfied with a reduced schedule of prenatal
care begins when conception is first considered and continues visits, indicating a perceived benefit by women [4].
until labor begins. The objectives of prenatal care for the mother,
infant, and family relate to outcomes through the first year fol-
lowing birth [1].
Organizational issues
Health care provider
Purpose There is no evidence that physicians need to be involved in the
prenatal care of every woman experiencing an uncomplicated
Prenatal care developed, historically, to reduce the incidence of pregnancy. The effect of midwife-led care compared to physician-
low-birth-weight (LBW) and preterm infants [2]. It has evolved led care or to other provider-led care has been evaluated mostly
to encompass a broader purpose: To identify pregnancies with for the whole pregnancy, including both antepartum care
maternal or fetal conditions associated with increased risk of and care during labor and delivery (see also Chaps. 7 and 8).
morbidity, to provide interventions to prevent or treat such com- Therefore it is somewhat difficult to assess the effect of midwife-
plications, and to provide education support and health promo- led care just on antepartum care. From the evidence from both
tion that can have lasting effects on the health of an entire family [3]. antepartum and labor and delivery (L&D) care, most low-risk
Care should be systematic and evidence based, and should women can be offered midwife-led models of care, and women
result in informed shared decision-making between the patient should be encouraged to ask for this option. Women with sub-
and the provider. stantial medical or obstetric complications should consult
with a physician. In a meta-analysis, women—the vast majority
Effectiveness low risk—who had midwife-led models of care were less likely to
experience antenatal hospitalization and less likely to expe-
Prenatal care benefits pregnant women; however, there are no rience fetal loss before 24 weeks’ gestation (RR 0.79, 95% CI
randomized controlled trials (RCTs) of prenatal care versus no 0.65–0.97), although there were no statistically significant differ-
prenatal care, and most studies are observational. Selection bias ences in fetal loss/neonatal death of at least 24 weeks (RR 1.01,
(women who self-select to prenatal care usually are more inclined 95% CI 0.67–1.53) or in fetal/neonatal death overall (RR 0.83, 95%
to have better outcomes) leads to confounding bias (e.g., risk fac- CI 0.70–1.00) (see also Chap. 7) [5].
tors associated with LBW and neonatal death are also risk factors
for inadequate prenatal care). Group prenatal care
There are, however, several RCTs on the number of prenatal In a meta-analysis, educational interventions were the focus of
care visits, which indirectly demonstrate the beneficial effects of group prenatal care. No consistent results were found, and sam-
prenatal care. There is a higher incidence of perinatal mortality ple sizes were very small to moderate. No data were reported
(relative risk [RR] 1.14, 95% confidence interval [CI] 1.00–1.31) concerning anxiety, breastfeeding success, or general social sup-
in programs with significantly less (<5) numbers of prenatal port. Knowledge acquisition, sense of control, factors related to
visits, compared to the usual 8–12. This is particularly sig- infant-care competencies, and some labor and birth outcomes
nificant for low- and middle-income countries [4]. Also, studies were measured. The largest of the included studies (n = 1275)
Prenatal Care 17
examined an educational and social support intervention to 28 weeks, about every 2 weeks from 32 to 36 weeks, and then
increase vaginal birth after cesarean delivery. This high-quality weekly until delivery (Table 2.1). Uncomplicated multiparous
study showed similar rates of vaginal birth after cesarean delivery women may need fewer visits than uncomplicated nulliparous
in “verbal” and “document” groups (RR 1.08, 95% CI 0.97–1.21) ones. Individual patient needs and risk factors should be assessed
[6]. One large RCT demonstrated significant reduction in pre- at the first prenatal visit and reassessed at each appointment
term birth (PTB), greater satisfaction with care, and higher thereafter. Telemedicine can be considered for some visits. The
breastfeeding initiation at no added cost for group prenatal care patient should be encouraged to obtain a home blood pressure
over standard care in a group of medically low-risk (but socially monitor and a weight scale to track important vital signs.
at-risk) women in an urban clinic [7]. In this study, group care A small reduction in the traditional number of prenatal visits
included, among other interventions, continuity of care from a in both developed and developing countries has not been asso-
single provider, patient keeping copies of their records, no waiting ciated with adverse biological maternal or perinatal outcomes,
time at visits, about 20 hours of provider/patient time, and 8–10 but women may feel less satisfied with fewer visits [4]. In set-
women in each group session. In the developing world, partici- tings with limited resources where the number of visits is
patory intervention with women’s groups is associated with already low, reduced antenatal visits (<5) are associated with
decreased maternal and neonatal mortality in several large an increase in perinatal mortality compared to standard care,
cluster-randomized trials [8–10]. In one of these studies, partici- although admission to neonatal intensive care may be reduced
patory care involved a female facilitator convening nine women’s [4]. Women prefer the standard visits schedule. Where the
group meetings every month. The facilitator supported groups standard number of visits is low, visits should not be reduced
through an action-learning cycle in which they identified local without close monitoring of fetal and neonatal outcomes [4].
perinatal problems and formulated strategies to address them In addition, women in high-resource settings were more often
[8]. This strategy holds great promise in decreasing maternal and dissatisfied with a reduced schedule of visits (defined as eight).
perinatal deaths among the most vulnerable in our world. The schedule of visits should be determined by the purpose of
Group prenatal care may even be utilized in a higher-risk the appointment. A minimum of four prenatal care visits is
population. In a non-RCT study, group prenatal care for recommended even for low-risk women [4].
women with gestational diabetes mellitus (GDM) was asso-
ciated with decreased progression to A2 gestational diabetes Structure
and improved postpartum follow-up for appropriate diabetes
screening without significantly affecting obstetrical or neona- Initial visit
tal outcomes [11]. Ideally, this visit should occur at around 6–8 weeks. Women
Group prenatal care should be promoted and further studied should receive written information regarding their pregnancy
among more diverse populations. care services, the proposed schedule of visits, screening tests that
will be offered, and lifestyle issues, such as nutrition and exercise.
Prenatal record Major parts of the visit include history, risk identification, physi-
A formal, structured record should be used for documenting care cal exam, laboratory testing, education for health promotion, and
during the pregnancy. Structured records with reminder aids a detailed plan of care for any risks identified (see Table 2.1) (see
help ensure that providers incorporate evidence-based guide- also Chap. 1, Tables 1.2–1.5).
lines into clinical practice. There is no trial comparing different
records. Women should be allowed to carry their record. A History
meta-analysis of three trials showed that carrying the record is A comprehensive history should be performed, preferably using
associated with increased maternal control and satisfaction standardized record forms (e.g., www.acog.org). Risk assessment
during pregnancy, increased availability of antenatal records should be performed with detailed review of systems. Patients
during hospital attendance, and with more operative deliveries. who may benefit from additional care or referral should be identi-
Importantly, all of the three trials included in the meta-analysis fied. Early ultrasonography should be used to determine the
report that more women in the case notes group would prefer to estimated day of delivery (EDD) if there is any uncertainty
hold their antenatal records in another pregnancy [12]. regarding last menstrual period (LMP) [13]. Accuracy of EDD
is critical for timing of screening tests and appropriate interven-
Number and timing of visits tions, managing complications, and consideration of delivery
There is insufficient evidence to recommend an ideal schedule of timing. It also provides early identification and chorionicity of
prenatal visits for all pregnant women. The most important visit multiple pregnancies (see “Ultrasonography” later and Chap. 4).
to optimize pregnancy outcomes is the preconception visit (see Topics such as lifestyle, nutrition, supplements, drugs, environ-
Chap. 1). A visit early, soon after the pregnancy test is positive, ment, vaccinations, prenatal education, and others should be dis-
and in time to establish location and number of embryo(s), usu- cussed (see “Content of Prenatal Care”). Prenatal diagnosis and
ally around 6–8 weeks, is also desirable. For women with prior screening for aneuploidy (Chap. 5) and genetic screening (Chap. 6)
cesarean delivery in particular, this early ultrasound is important should be reviewed.
also to rule out the risk of cesarean scar pregnancy.
At this early visit, each woman should be assessed for risk fac- Physical exam
tors (see Tables 1.3 and 1.4 in Chap. 1). The frequency of subse- The physical exam should be both general (Table 2.1) and directed
quent visits can be determined based on risk factors. by any risks identified in the history (see Chap. 1).
In developed countries, prenatal care usually consists of 7–12 Weight and height should be determined at the initial pre-
visits per pregnancy, with a prenatal visit ideally at 10–14 natal visit in order to determine body mass index (BMI) [BMI =
weeks for aneuploidy screening (see Chaps. 5 and 6), followed weight (kg)/height squared (m2)]. BMI should be based on weight
by visits about every 4 weeks approximately at 16, 20, 24, and at time of conception or the earliest known weight in pregnancy.
TABLE 2.1: Suggested Prenatal Care Counseling, Screening, and Intervention

Initial Visit ≤14 wk Visits at 14–24 wk 24–28 wk 28–34 wk 34–41 wk
Assessments/Procedures
• Complete history and risk • Fetal heart tones • Fetal heart tones • Fetal heart tones • Fetal heart tones
identification • Fundal height • Fundal height • Fundal height • Fundal height/ EFW
• Assessment of EDB by LMP and • Fetal movement • Fetal movement • Fetal movement • Fetal movement
sizing; ultrasound if indicated • BP • BP • BP • Fetal presentation
• Baseline BP screening • Weight • Weight • Weight • BP
• Weight and BMI • Screening • Rh immunoglobulin • Weight
• Screening for domestic abuse ultrasound for if indicated • Sweeping of membranes
• Vaccines according to risk status and anatomy • Screening for starting at ≥37–38 wk
season domestic abuses
• Referral for specialist care according
to history
• Offer 11–13 6/7 wk aneuploidy
screening ultrasound
Laboratory Tests
• Multiple-marker aneuploidy screen • Multiple-marker • Gestational diabetes • Urine dipstick for • Group B strep
• CBC; Blood type, Rh, antibody aneuploidy screen screen; repeat CBC protein • Urine dipstick for protein
screen; Rubella IgG; RPR; HBsAg; • Urine dipstick for and antibody screen • HIV
HIV protein if indicated • Antibody screen if
• Urine dipstick for protein and indicated
glucose • Urine dipstick for
• Urinalysis and urine culture protein
• Gonorrhea/Chlamydiaa
• Papa
• Additional testing as directed by
history and PEa
Education/Counseling
• Cessation of harmful substances • Review and discuss • Preterm labor s/sx • Preterm labor s/sx • Labor symptoms/ when
• Exercise/Activity results of testing • Preeclampsia s/sx to call
• Nutrition • Preeclampsia s/sx
• Nutrition • Postdates management
• Weight gain • Breastfeeding
• Supplements
• Food safety
• Breastfeeding
Education/Counseling Not Limited to Specific Weeks Gestation
• Danger signs
• Dental care
• Family planning
• Labor preparation, options, s/sx to report
• Travel
• TOLAC
Assessments/Procedures
• Complete history and risk • Fetal heart tones • Fetal heart tones • Fetal heart tones • Fetal heart tones
identification • Fundal height • Fundal height • Fundal height • Fundal height/ EFW
• Assessment of EDB by LMP and • Fetal movement • Fetal movement • Fetal movement • Fetal movement
sizing; ultrasound if indicated • BP • BP • BP • Fetal presentation
• Baseline BP screening • Weight • Weight • Weight • BP
• Weight and BMI • Screening • Rh immunoglobulin • Weight
• Screening for domestic abuse ultrasound for if indicated • Sweeping of membranes
• Vaccines according to risk status and anatomy • Screening for starting at ≥37 wk
season domestic abuses
• Referral for specialist care according
to history
• Offer 11–13 6/7 wk aneuploidy
screening ultrasound
Prenatal Care 19
TABLE 2.1 (Continued): Suggested Prenatal Care Counseling, Screening, and Intervention
Initial Visit ≤14 wk Visits at 14–24 wk 24–28 wk 28–34 wk 34–41 wk
Laboratory Tests
• Multiple-marker aneuploidy screen • Multiple-marker • Gestational diabetes • Urine dipstick for • Group B strep
• CBC; Blood type, Rh, antibody aneuploidy screen screen; repeat CBC protein • Urine dipstick for protein
screen; Rubella IgG; RPR; HBsAg; • Urine dipstick for and antibody screen • HIV
HIV protein if indicated • Antibody screen if
• Urine dipstick for protein and indicated
glucose • Urine dipstick for
• Urinalysis and urine culture protein
• Gonorrhea/Chlamydiaa
• Papa
• Additional testing as directed by
history and PEa
Education/Counseling
• Cessation of harmful substances • Review and discuss • Preterm labor s/sx • Preterm labor s/sx • Labor symptoms/ when
• Exercise/Activity results of testing • Preeclampsia s/sx to call
• Nutrition • Preeclampsia s/sx
• Weight gain • Postdates management
• Supplements • Breastfeeding
• Food safety
• Breastfeeding
Education/Counseling Not Limited to Specific Weeks Gestation
• Danger signs • Labor preparation,
• Dental care options, s/sx to
• Family planning report
• Travel
• TOLAC
Source: Adapted from a review of current prenatal care guidelines from four major groups: U.S. Veterans Health Administration, Department of Veteran Affairs, and Health
Affairs, Department of Defense; Institute for Clinical Systems Improvement; the American Academy of Pediatrics and the American College of Obstetricians and
Gynecologists; and the American Academy of Family Physicians [146].
Abbreviations: EDB, expected date of birth; LMP, last menstrual period; BP, blood pressure; BMI, body mass index; EFW, estimation of fetal weight; RPR, rapid plasma regain;
HIV, human immunodeficiency virus; CBC, complete blood count; PE, physical exam; TOLAC, trial of labor after cesarean; s/sx, signs and symptoms; wk, weeks.
a See text, only in certain circumstances.
Categories of BMI are in Table 2.2. Women with obesity are at blood pressure over time. Blood pressure should be taken in the
increased risk for diabetes, shoulder dystocia, cesarean section, sitting position using an appropriately sized cuff and correct tech-
and other complications and have better outcomes with a lower nique (see Chap. 1 in Maternal-Fetal Evidence Based Guidelines).
(or no) total weight gain. Women who are underweight (<50 kg
or <120 lb) also are at increased risk for LBW and PTB and have Pelvic exam
better outcomes with a higher total weight gain (see “Nutrition”). Routine pelvic exam early in pregnancy is not as accurate for
Blood pressure is recommended at each prenatal visit. Initial assessment of gestational age as ultrasound (see Chap. 4) and is
blood pressure evaluation may help to identify women with not a reliable predictive test of PTB or cephalopelvic disproportion
chronic hypertension, while subsequent blood pressure read- later in pregnancy (see also Chaps. 7 and 18), and so it is not rec-
ings aid in preeclampsia screening. A diastolic blood pressure ommended for these assessments. Abdominal and pelvic examina-
of >80 at booking is associated with later risks of preeclampsia tion to detect gynecologic pathology can be included in the initial
[14]. Significant risks are associated with both hypertension and examination, and women should be asked about cervical cancer
preeclampsia in pregnancy. This simple, inexpensive, and widely screening. In this setting, cervical cancer screening can be recom-
accepted screening tool may help identify abnormal trends in mended according to guidelines if not current (Chap. 34).
TABLE 2.2: Body Mass Index (BMI) Categories Laboratory screening

Recommended initial universal laboratory screening is listed in
Weight Category BMI
Table 2.1. Other lab testing may be ordered if other risks or condi-
Underweight <18.5 tions are present.
Normal weight 18.5–24.9
Overweight 25–29.9 ABO/Rh (D) type and antibody screen
Obesity (class I) 30–34.9
Testing for blood group, Rh status, and atypical red cell antibod-
ies at the initial visit is recommended. Unsensitized RhD-negative
Obesity (class II) 35–39.9
women should be offered anti-D immunoglobulin at 28 weeks
Extreme obesity (class III) >40
(see Chap. 55 in Maternal-Fetal Evidence Based Guidelines).
Anti-D immunoglobulin should also be offered for any invasive creatinine (P/C) ratio may be used as a screening test as a good
procedure (e.g., amniocentesis, chorionic villus sampling [CVS], predictor for remarkable proteinuria, since it seems to be highly
percutaneous umbilical blood sampling [PUBS]); for bleeding; for predictive for diagnosis to detect proteinuria over 1 gram but
partial molar pregnancies, spontaneous abortion, and elective inadequate in detecting lower levels (see Chap. 1 in Maternal-
termination; and for any condition that might be associated with Fetal Evidence Based Guidelines) [16].
fetal-maternal hemorrhage, such as abdominal trauma, external
cephalic version, or placental abruption. It may also be offered Urine dipstick for glucose
for threatened abortion and for ectopic pregnancy, although the Glycosuria ≥250 mg/dL (equivalent to 1+) on urine dipstick in
evidence is not as strong. Du-positive women do not need anti-D the first or second trimester is associated with abnormal GDM
immunoglobulin (see Chap. 55 in Maternal-Fetal Evidence Based screening later in pregnancy. The presence of significant glycos-
Guidelines). uria before 24–28 weeks is an indicator for earlier gestational glu-
cose screening (see Chaps. 4 and 5 in Maternal-Fetal Evidence
Complete blood count Based Guidelines).
Recommended at the first prenatal visit to identify anemia (hemo-
globin and hematocrit) and to screen for thalassemia (mean Urine culture for asymptomatic bacteriuria
corpuscular volume [MCV]). Pregnant women identified with Screening for bacteriuria is recommended at the first prenatal
anemia (Hgb <11.0 g/dL in the first trimester) should be treated as visit for all women. Pregnant women with asymptomatic bacteri-
per Chap. 14 in Maternal-Fetal Evidence Based Guidelines. Initial uria are at an increased risk for symptomatic infection and pyelo-
determination of platelet count (optimally also before pregnancy) nephritis. There is also a positive relationship between untreated
may help identify chronic thrombocytopenias and aid in the bacteriuria and LBW/PTB. Treatment of asymptomatic bacte-
diagnosis of gestational thrombocytopenia or HEELP (hemolysis, riuria prevents these complications (see Chap. 18 in Maternal-
elevated liver enzyme levels, and a low platelet count) syndrome Fetal Evidence Based Guidelines).
later in pregnancy.
Cervical cancer screening
Rubella antibody Cervical cancer screening should be obtained if not current
Screen all women at first encounter. Nonimmune pregnant according to guidelines. Pap smear screening should be initiated
women should be counseled to avoid exposure and seek immu- at age 21, regardless of onset of sexual activity. Routine screen-
nization postpartum (see Chap. 40 in Maternal-Fetal Evidence ing intervals have also been extended to every 3 years for women
Based Guidelines). in their 20s without human papillomavirus (HPV) co-testing and
every 5 years in women over 30 with the addition of HPV co-test-
Syphilis screening ing. Colposcopy can be performed during pregnancy, and a plan
All pregnant women should be screened with a serologic test for can be made for treatment postpartum (see Chap. 34).
syphilis at the first prenatal visit. Women who are at high risk,
live in areas of high syphilis morbidity, or are previously untested Selective (only women with risk
should be screened at 28 weeks and again at delivery (see Chap. 37 factors) laboratory screening
in Maternal-Fetal Evidence Based Guidelines). Hepatitis C serology
A test for hepatitis C antibodies should be performed in pregnant
HBsAg women at increased risk for exposure, such as those with a history
Screen at initial encounter, and rescreen high-risk populations of intravenous (IV) drug abuse, exposure to blood products or
in the third trimester. Postnatal intervention is recommended transfusion, organ transplants, kidney dialysis, etc. (see Chap. 33
in all hepatitis B surface antigen (HBsAg)–positive women to in Maternal-Fetal Evidence Based Guidelines).
reduce the risk of viral transmission to the neonate. Pregnancy
and breastfeeding are not contraindications to immunization in Chlamydia screening
women who are at risk for acquisition of the hepatitis B virus (see All women of age <25 years (strongest risk factor), multiple sex
Chap. 32 in Maternal-Fetal Evidence Based Guidelines). partners, new partner within the past 3 months, single marital
status, inconsistent use of barrier contraception, previous or con-
HIV serology current sexually transmitted infection (STI), vaginal discharge,
Screening is recommended for all pregnant women. The “opt-out” mucopurulent cervicitis, friable cervix, or signs of cervicitis on
approach is recommended. It should be emphasized that testing physical examination should be screened. Some agencies advo-
not only provides the opportunity to maintain maternal health, cate universal chlamydia screening. Rescreen in the third trimes-
but interventions can be offered to dramatically reduce the risk ter if at increased risk for infection. Screening using polymerase
of viral transmission to the fetus (see Chap. 34 in Maternal-Fetal chain reaction (PCR) technology is most accurate (see Chap. 36 in
Evidence Based Guidelines). Maternal-Fetal Evidence Based Guidelines).
Urine dipstick for protein Gonorrhea screening

Screening for proteinuria should occur at the initial visit and rou- All women of age <25 years, prior STI, multiple sexual partners,
tinely after 20 weeks in women at risk for preeclampsia. Urine having a partner with a past history of any sexually transmitted
dipsticks for protein do not reliably detect the variable elevations disease (STD), sex work, drug use, and inconsistent condom use
in albumin that may occur in preeclampsia and may not be indi- should be screened for gonorrhea. Some agencies advocate uni-
cated at each visit in low-risk women [15]. In women at high risk versal gonorrhea screening. Rescreen in the third trimester if at
for preeclampsia, the 24-hour collection is a reasonable screen for increased risk for infection. Screening using PCR technology is
proteinuria as a baseline at the first prenatal visit and when other most accurate (see Chap. 33 in Maternal-Fetal Evidence Based
signs or symptoms of preeclampsia are present. The proteinuria/ Guidelines).
Prenatal Care 21
Bacterial vaginosis • Ongoing assessment of risk factors and plan for interven-
There is no benefit to routine screening and treatment for asymp- tion as indicated
tomatic bacterial vaginosis. Consideration can be given to screen- • Education and health promotion directed to individual
ing and treating women with a prior PTB, but given the inconclusive plan of care
evidence, we do not recommend it as routine. However, those • Opportunity for discussion and questions
women who are symptomatic should be screened (see Chap. 18).
Follow-up physical exam
Genital herpes
Routine serologic or other screening for herpes simplex virus (HSV) • Weight: Weight is usually taken at each visit, as optimal
in asymptomatic pregnant women is not recommended. In the weight gain (Figure 2.1) is associated with better out-
absence of lesions during the third trimester, routine serial cultures comes. Excessive, unexplained weight gain can be a sign of
are not indicated for women with a history of recurrent genital her- preeclampsia.
pes (see Chap. 52 in Maternal-Fetal Evidence Based Guidelines). • Blood pressure: Blood pressure should be taken and
recorded at each visit.
Varicella • Fetal heart tones: Fetal heart rate should be assessed and
Screening is indicated if a woman has had neither past infection recorded at each visit after the first trimester.
nor vaccination. Varicella vaccine (live attenuated) is not recom- • Symphyseal-fundal height measurement: Fundal height
mended during pregnancy, but sero-negative women should be can be performed at each visit after 20 weeks. Fundal
advised to take appropriate precautions (see Chaps. 40 and 53 in height measurement may help detect fetal growth restric-
Maternal-Fetal Evidence Based Guidelines). tion (FGR) and macrosomia, but there is poor intrauser and
interuser reliability. There is probably some value in evalu-
Tuberculosis
ating trends, and although it will not affect the underlying
QuantiFERON Gold or purified protein derivative (PPD) can be
condition, it may affect decision-making on fetal surveil-
offered to high-risk women at any gestational age in pregnancy
lance. There is insufficient evidence to show whether
to screen for tuberculosis, and follow-up chest x-ray is recom-
this measurement has any impact, beneficial or not,
mended for recent converters. High-risk factors include human
on pregnancy outcomes, with no effect in the only one
immunodeficiency virus (HIV) disease, homeless or impover-
trial (see also Chap. 47 in Maternal-Fetal Evidence Based
ished women, prisoners, recent immigrants from areas where
Guidelines) [18]. The best screening tool for diagnosing
tuberculosis is prevalent, and others (see Chap. 26 in Maternal-
FGR is ultrasound biometry (see Chap. 4).
Fetal Evidence Based Guidelines).
• Cervical examination: Routine digital examination of the
Cytomegalovirus cervix is not recommended as a screening measure for pre-
Routine testing is not recommended. Good hand washing and vention of PTB (see Chap. 18).
practicing universal precautions are recommended to prevent
transmission (see Chap. 49 in Maternal-Fetal Evidence Based Sweeping or “stripping” of membranes during cervical
Guidelines) [17]. exam at ≥37 weeks reduces the rate of late-term delivery (see
Chap. 22). Cervical examination may assist in the identification
Parvovirus of abnormal presentation, and therefore the opportunity to offer
Routine screening is not recommended, but can be considered for appropriate intervention (i.e., version).
high-risk groups (see Chap. 51 in Maternal-Fetal Evidence Based
Guidelines). • Fetal movement: There is no evidence that formalized kick
counts reduce the incidence of fetal death in the healthy
Toxoplasmosis singleton (see Chap. 58 in Maternal-Fetal Evidence Based
Universal screening is not recommended in the United States, Guidelines) [19]. Nonetheless, women may be instructed to
where the prevalence is low. Education regarding prevention be aware of daily fetal movements from at or around 28
of the disease should be addressed (Table 2.3) (see Chap. 50 in weeks.
Maternal-Fetal Evidence Based Guidelines). • Leopold maneuvers: Historically, this set of maneuvers
was performed at each visit from 34 weeks on to estimate
Follow-up visits fetal weight and determine presentation. Ultrasound
Follow-up visits should provide for the following: should be used instead as necessary.
• Clinical pelvimetry: Measurement of the bony birth canal
• Follow-up physical exam, laboratory screening, and testing is of limited, unproven value in predicting dystocia during
as indicated delivery (see Chap. 7).
TABLE 2.3: Prevention of Foodborne Illnesses

Foodborne Illness to Avoid Preventive Strategy
Listeriosis Cook meat thoroughly, including luncheon meats; avoid raw or smoked meats or fish, pates, unpasteurized cheese,
and raw milk.
Toxoplasmosis Cook meat and wash fruits and vegetables thoroughly; avoid cat litter; wear gloves when gardening outdoors.
Escherichia coli and Salmonella Follow food-handling guidelines noted earlier.
Methylmercury Avoid consumption of large, mercury-containing fish.
• Routine evaluation for edema: Edema has traditionally allergic) in labor or with rupture of membranes (see Chap. 39
been a part of the evaluation for preeclampsia, but by itself, in Maternal-Fetal Evidence Based Guidelines).
it is neither specific nor sensitive.
Ultrasonography (see Chap. 4)
Follow-up laboratory screening Ultrasound has not been proven harmful to the mother or fetus.
• 10 6/7–13 6/7 weeks: Serum aneuploidy screening, with • First-trimester “fetal dating” ultrasonography (before
nuchal translucency screening by ultrasound (combined 14 weeks): First-trimester ultrasound is more accurate
screening) (see later), should be offered to every pregnant than LMP to determine gestational age. First-trimester
woman. Consider cell-free DNA aneuploidy testing (also ultrasound also allows earlier detection of multiple preg-
called noninvasive prenatal testing [NIPT]) in high-risk or nancies, aneuploidy screening with nuchal translucency,
intermediate-risk women. A policy of universal screening and diagnosis of nonviable pregnancies. In women with
for fetal aneuploidy with NIPT as first-line screening may prior cesarean section, ultrasound performed before 10
be also considered even if the cost-effectiveness is still a weeks, ideally at around 6–8 weeks, should be performed
subject of debate. Randomized controlled trials showed to rule out the risk of cesarean scar pregnancy.
that first-trimester risk assessment for trisomy 21 with • Second-trimester “fetal anatomy” ultrasound: An ultra-
a detailed ultrasound examination followed by cell-free sound to screen for structural anomalies is ideally per-
DNA was associated with a significant reduction in false- formed between 18 and 22 weeks. Routine use of ultrasound
positive rate [20] and better maternal reassurance and reduces the incidence of postterm pregnancies, induction
better maternal satisfaction [21] compared to the first-tri- of labor for postterm pregnancy, increases early detec-
mester combined screening with nuchal translucency and tion of multiple pregnancies, increases earlier detection of
biochemistry (see Chap. 5) (Table 2.1). major fetal anomalies when termination of pregnancy is
• 14–21 weeks: The second part of serum aneuploidy screen- possible, increases detection rates of fetal malformations,
ing (best done at 16–18 weeks) should be offered to all preg- and decreases admission to the special care nursery [22,
nant women interested in prenatal diagnosis of aneuploidy 23]. Given the benefits mentioned, all pregnant women
(see Chap. 5). Counseling regarding the variety of screen- should be offered a second-trimester ultrasound. No sig-
ing options and the limitations of testing should be made nificant differences are detected for substantive clinical
available to all pregnant women. outcomes such as perinatal mortality, possibly because of
• 24–28 weeks: Women with risk factors for GDM should insufficient data (see Chap. 4). Transvaginal ultrasound
be screened with either one-step or two-step tests, since cervical length (TVU CL) screening of all singleton ges-
intervention (diet, exercise, glucose monitoring, and, as tations, even those without a prior spontaneous preterm
necessary, medical therapy) prevents maternal and peri- birth, and is recommended [24]. Institutions prepared to
natal morbidities (see Chap. 5 in Maternal-Fetal Evidence intervene for a short cervix of a patient carrying multiple
Based Guidelines). The one-step approach is associ- gestations should offer TVU CL to these patients as well
ated with better perinatal outcomes, including lower (see Chap. 18).
incidence of large for gestational age (LGA) and neonatal • Third-trimester “fetal growth” ultrasound: In low-risk
intensive care unit (NICU) admission to neonatal hypogly- or unselected populations, routine third-trimester ultra-
cemia, compared to the two-step approach (see Chap. 5 in sound has not been associated with improvements in
Maternal-Fetal Evidence Based Guidelines). Universal glu- perinatal mortality [25]. Selective ultrasound in later preg-
cose challenge screening for GDM is the most sensitive nancy is of benefit in specific situations [26], such as cal-
approach, but the following women are at low risk and less culation of interval growth for suspected FGR, assessment
likely to benefit from testing (must meet all of the follow- of amniotic fluid index for suspected oligohydramnios
ing criteria): Age <25 years; ethnic origin of low risk (not or hydramnios, and assessment of malpresentation (see
Hispanic, African, Native American, South or East Asian, Chap. 4). Gestational age for third-trimester “fetal growth”
or Pacific Islander); BMI <25; no previous personal or fam- ultrasound is also a subject of debate. For example, an
ily history of impaired glucose tolerance; and no previ- ultrasound at 28–30 weeks may detect early-onset FGR,
ous history of adverse obstetric outcomes associated with but would miss late-onset FGR, which may be detected at
GDM. Antibody screening and hemoglobin and hematocrit 34–36 weeks.
are also repeated. Repeat syphilis and HIV screening in the • Routine umbilical artery or other Doppler ultrasound in
early third trimester and at delivery can be considered for low-risk or unselected patients has not been shown to be
high-risk populations (see Chaps. 34 and 37 in Maternal- of benefit.
Fetal Evidence Based Guidelines).
• 36–37 weeks: Group B streptococcus (GBS) is a sig- Content of prenatal care
nificant cause of morbidity and mortality in neonates.
Approximately 10–30% of pregnant women are asymp- The content of prenatal care is extensive and reviewed in detail
tomatically colonized with GBS in the vagina or rectum. not only in this chapter but also in most other chapters in this
Vertical transmission of this organism from mother to book, as well as its companion, Maternal-Fetal Evidence Based
fetus occurs most commonly after the onset of labor or Guidelines. In Chap. 1, see Table 1.2 for topics to be reviewed,
rupture of membranes. All women should be screened Table 1.3 for screening, Table 1.4 for laboratory tests, Table 1.5
for GBS colonization by rectovaginal culture at 36–37 for vaccinations, Table 1.6 for interventions for all women, and
weeks of gestation. Colonized women should be treated Table 1.7 for interventions for women with risk factors. Prenatal
with IV antibiotics (penicillin is the first choice if not care usually incorporates, among other things, the following:
Prenatal Care 23
• Prenatal education and reassurance (regarding drugs, radiation (>5 rad), heavy repeated lifting, prolonged (>8 hours)
environment, lifestyle, nutrition, supplements, vaccina- standing, excessive (>80/week) work hours, and high fatigue
tions, preventive measures, preparation for L&D, depres- score, may be associated with pregnancy complications, but there
sion, breastfeeding, etc.) is insufficient evidence on the effect of avoidance of these risks
• Provision of evidence-based screening tests at appropriate (see also Chap. 17). There are insufficient safety data for paint,
intervals (Table 2.1) solvents, hair dyes, fumes, anesthetic drugs, etc., with no absolute
• Risk assessment evidence of harm. Hot tubs, saunas, etc., should avoid tempera-
• Problem-oriented visits as needed tures >102°F to avoid risk of dehydration, especially in the first
• Condition-specific care for high-risk patients trimester.
Content issues that should be included in prenatal care such Domestic violence
as drugs and environment, lifestyle, nutrition, supplements, vac- Domestic violence during pregnancy is associated with increased
cinations, prenatal education, and others are described next. risk of PTB, LBW, second- and third-trimester bleeding, and fetal
injury. Domestic violence may escalate during pregnancy. As
Drugs and environment such, providers need to be alert to signs and symptoms of abuse
Substance abuse and provide opportunities for private disclosure. However, so far,
Screening for use and counseling for cessation of tobacco, alco- there is insufficient evidence to assess the effectiveness of inter-
hol, and recreational or illicit drug use is recommended (see ventions for domestic violence on pregnancy outcome [35].
Chaps. 22 and 23 in Maternal-Fetal Evidence Based Guidelines).
Maternal smoking, as well as exposure to secondhand smoke, Lifestyle
is dangerous to both the woman and her fetus. Provider sup- Work
port and educational material tailored to pregnancy are shown There is insufficient evidence to recommend exact work hours
to increase smoking cessation by 70% and reduce LBW and PTB and when to take off from work before delivery (if at all). Work
[27–29], as well as the number of women who continue to smoke accommodations are often necessary and helpful to allow a
in late pregnancy [29]. pregnant woman to continue working and earning an income.
Alcohol use at any level in pregnancy cannot be supported, Pregnant women should not be discriminated against by employ-
although deleterious effects at low-to-moderate levels are difficult ers. The website www.pregnantatwork.org provides online tools
to quantify [30]. The evidence from the limited number of stud- health care professionals can use to prepare notes drafted using
ies suggests that education and psychological interventions may language that increases the likelihood that a patient will receive
promote abstinence from alcohol or reduce alcohol consump- the accommodations she needs to continue doing her job safely.
tion among pregnant women. However, results were not consis- Occupational lifting guidelines have been published [36].
tent, and the paucity of studies, the number of total participants,
the high risk of bias of some of the studies, and the complexity of Exercise
interventions limit our ability to determine the type of interven- Regular exercise during low-risk pregnancies is beneficial, as
tion that would be most effective in increasing abstinence from, it increases overall maternal fitness and sense of well-being.
or reducing the consumption of, alcohol among pregnant women Aerobic training is an effective tool in maternal weight gain
[31]. Counseling may be effective in reducing substance abuse in control in pregnancy [37] and decreases the risk of GDM [38].
pregnancy, although women with addictions will need special- Moreover, regular exercise during pregnancy appears to modestly
ized interventions. Screening and brief intervention (SBI) for increase the chance for vaginal delivery among healthy preg-
unhealthy alcohol use has demonstrated efficacy in some trials. nant women [39]. Structured physical exercise programs appear
There is some evidence regarding the acceptability and efficacy also to be safe for the neonate [40] and reduce the risk of having
of computer-delivered SBI plus tailored mailings in women who a large newborn without a change in the risk of having a small
screened positive for alcohol risk [32]. There is insufficient evidence newborn [41]. Furthermore, there is some evidence that exer-
to recommend the routine use of home visits for women with a cise may be effective in treating depression during pregnancy
drug or alcohol problem [33]. However, a cluster RCT among urban [42]. Healthy diet and exercise during pregnancy can reduce the
South African mothers showed that a home-visiting intervention risks of excessive gestational weight gain, cesarean section,
improved the emotional health of low-income mothers and that maternal hypertension, and macrosomia, as well as neonatal
relative to standard care, intervention mothers were significantly respiratory morbidity, particularly for high-risk women receiv-
less likely to report depressive symptoms and alcohol abuse [34]. ing combined diet and exercise interventions [38]. However, most
of the studies included in the meta-analysis were carried out in
Over-the-counter, alternative/Complementary, developed countries and therefore it is not clear if these findings
and prescription medications are widely applicable [43]. In another meta-analysis, exercise was
Due to the possibility of adverse fetal effects, medication use, associated with a lower (by 600 g) gestational weight gain [44].
including alternative remedies, should be limited to circum- Possible maternal benefits include improved cardiovascular
stances where benefit outweighs risk. Beneficial medications function, limited pregnancy weight gain, decreased musculo-
should be continued in pregnancy when safe for both the mother skeletal discomfort, reduced incidence of muscle cramps and
and fetus (see specific disease guidelines in Maternal-Fetal lower limb edema, mood stability, and attenuation of GDM
Evidence Based Guidelines). and gestational hypertension. Fetal benefits include decreased
fat mass, improved stress tolerance, and advanced neurobe-
Environmental/Occupational risks and exposures havioral maturation [45]. For most pregnant women, at least
In general, working is not associated with poor pregnancy out- 30 minutes of moderate exercise is recommended on most
come. Some workplace exposures, such as toxic chemicals, days of the week. There is no target heart rate that is right for
TABLE 2.4: Examples of Safe and Unsafe Physical Activities the pregnancy, which can lead to decreased frequency of sexual
during Pregnancy intercourse during pregnancy [49]. Most women desire more
communication regarding sex in pregnancy from their care pro-
The following activities are safe to initiate or continuea:
viders. Provider counseling should be reassuring in the absence
• Walking of pregnancy complications. Semen is a source of prostaglandin,
• Swimming and pyospermia is associated with preterm prelabor rupture of
• Stationary cycling membranes (PPROM). Also, female orgasm and nipple stimula-
• Low-impact aerobics tion can increase contractions [50]. Therefore, intercourse may
• Yoga, modifiedb have adverse effects for pregnancies with preterm cervical dila-
• Pilates, modified tation and/or shortening, but this is not well studied. PTB and
• Running or joggingc other complications of pregnancy do not seem increased in most
• Racquet sportscd studies of sex in pregnancy. Most studies report that sexual
• Strength trainingc activity is associated with better pregnancy outcomes, proba-
bly because women who are sexually active are healthier to begin
The following activities should be avoided: with compared to women with less sexual activity [51].
• Contact sports (e.g., ice hockey, boxing, soccer, and basketball)
Nutrition
• Activities with a high risk of falling (e.g., downhill snow skiing, water
skiing, surfing, off-road cycling, gymnastics, and horseback riding)
Energy (calorie)/Protein supplementation
A meta-analysis of 17 RCTs provided evidence that antenatal
• Scuba diving
nutritional education, with the goal of increasing energy and
• Sky diving
protein intake in pregnant women, appears to be effective in
• “Hot yoga” or “hot Pilates”
reducing the risk of PTB and of LBW and effective in increas-
Source: Adapted from Physical activity and exercise during pregnancy and the ing the head circumference at birth and the birth weight among
postpartum period. Committee Opinion No. 650. American College of undernourished women [52]. Balanced energy and protein
Obstetricians and Gynecologists. Obstet Gynecol 2015; 126:135–42.
supplementation seems to improve fetal growth and may
[Guideline].
reduce the risk of stillbirth and infants born small for ges-
a In women with uncomplicated pregnancies in consultation with an obstetric care
provider.
tational age (SGA). However, high-protein supplementation
b Yoga positions that result in decreased venous return and hypotension should be does not seem to be beneficial and may be harmful to the fetus,
avoided as much as possible. increasing the risk of SGA. Balanced-protein supplementation
c In consultation with an obstetric care provider, running or jogging, racquet sports, alone has no significant effects on perinatal outcomes [52].
and strength training may be safe for pregnant women who participated in these
activities regularly before pregnancy. Cholesterol-lowering diet
d Racquet sports wherein a pregnant woman’s changing balance may affect rapid A cholesterol-lowering diet with omega-3 fatty acids and dietary
movements and increase the risk of falling should be avoided as much as possible. counseling does not affect cord or neonatal lipids but is associ-
ated with a 90% reduction in PTB <37 weeks in one trial (see also
every pregnant woman. Walking, swimming, and other sports Chap. 18) [53]. More evidence is needed for a recommendation.
with low chance of loss of balance are recommended (Table 2.4)
[46]. Avoidance of contact sports and sports with high chance of Low–glycemic index diet
loss of balance or injury should be recommended. Special consid- A low–glycemic index diet appears to be beneficial to both the
erations may be made for professional athletes at the discretion of mother and child in reducing the incidence of abnormal glucose
the patient and provider. Hypoglycemia and dehydration should tolerance tests, LGA infants, and ponderal indices. The numbers
be avoided. It is important to advise women to be careful while of studies and subjects are small, however, and therefore consid-
stretching, as the hormone relaxin can leave joints vulnerable to ered inconclusive [54]. Studies evaluating the effects of different
overstretching and injury [46]. It is important for clinicians to types of dietary advice for women with GDM did not find any
keep emphasizing that exercise is medicine [47]. significant benefits for the diets investigated [55].
Yoga Antigen avoidance diet
Yoga in pregnancy is associated with lower pain and discomfort, Prescription of an antigen avoidance diet (e.g., avoiding chocolate
as well as lower perceived stress and improved quality of life in or nuts) to a pregnant woman is unlikely to reduce her child’s risk
physical domains in the three RCTs evaluating its effects [48]. of atopic disease, and such a diet may adversely affect maternal or
fetal nutrition [56].
Travel
Counseling should include the proper use of passenger restraint Probiotics
systems in automobiles with the lap belt below the abdomen, A probiotic capsule intervention among women with abnormal
reduction of risk of venous thromboembolism during long-dis- glucose tolerance had no impact on glycemic control [57].
tance air travel by walking and exercise, and provision of care and
prevention of illness during travel abroad. Food safety
Food safety and prevention of foodborne illness and infection are
Sex and sexuality suggested in Tables 2.3 and 2.5.
Intercourse has not been associated with adverse pregnancy
outcomes. Some women have a progressive decrease in sexual BMI and weight gain
desire during the pregnancy, most markedly in the third tri- BMI is utilized in counseling a woman on optimal weight gain in
mester. Couples are often concerned that intercourse may harm pregnancy (Table 2.2) [58–70].
Prenatal Care 25
TABLE 2.5: Food Safety in Pregnancy

Clean: Wash hands thoroughly with soap and water, before and after handling food, using the bathroom, changing diapers, or handling pets. Wash
cutting boards, dishes, utensils, and countertops with soap and water. Rinse raw fruits and vegetables well under running water.
Separate: Separate raw meats and seafood from fresh or prepared foods. Use a separate cutting board for raw meats and seafood. Place prepared food
on a clean plate.
Cook: Cook foods thoroughly. Avoid allowing foods to sit at temperatures between 40°F and 140°F (4°C and 60°C). Discard foods left out at room
temperature for more than 2 hours. Avoid foods made with raw eggs.
Chill: Maintain refrigerator temperature at 40°F (4°C) or below and the freezer at 0°F (−18°C).
Suggested weight gain in pregnancy is shown in Figure 2.1 [71]. of regular coffee drinkers (3+ cups/day) during the second and
Women who are underweight are at increased risk for LBW third trimester did not affect PTB or SGA rate [74].
and PTB and have better outcomes with a higher total weight
gain [66]. Excessive weight gain in women with a normal BMI Supplements
can be prevented with dietary and lifestyle counseling [61– Multivitamin
68]. For example, a program of education on recommended ges- There is insufficient evidence to suggest replacement of iron and
tational weight gain (GWG), application of a personalized weight folate supplementation with a multiple-micronutrient supple-
graph, formalized prescription of exercise, and regular monitor- ment. A reduction in the number of LBW and SGA babies and
ing of GWG at every antenatal visit is associated with a significant maternal anemia has been found with a multiple-micronutrient
reduction in GWG [69]. Obesity is associated with cardiovascu- supplement compared to supplementation with two or fewer
lar disease; diabetes; hypertension; stroke; osteoarthritis; gall- micronutrients or none or a placebo, but analyses revealed no
stones; endometrial, breast, and colon cancer; cardiomyopathy; added benefit of multiple-micronutrient supplements compared
fatty liver; obstructive sleep apnea; urinary tract infections; other with iron and folic acid supplementation [75, 76]. These results
complications; and most importantly, mortality. Pre-pregnancy are limited by the small number of studies available. There is also
obesity and excessive gestational weight gain are associated with insufficient evidence to identify which micronutrients are more
increased risk of childhood obesity for the fetus. Obese pregnant effective, to assess adverse effects, and to say that excess multiple-
women are specifically at increased risk for miscarriage, congeni- micronutrient supplementation during pregnancy is harmful to
tal malformations, GDM, hypertension, preeclampsia, stillbirth, the mother or the fetus [75, 76]. Therefore, there is insufficient
cesarean birth, labor abnormalities, macrosomia, anesthesia evidence to recommend routine multivitamin supplementation
complications, wound infection, and thromboembolism. These for all women, or even only for women who are underweight, have
women have better maternal outcomes with lower (or no) poor diets, are smokers, are substance abusers, are vegetarians,
total weight gain (Table 2.6) (see also Chap. 3 in Maternal-Fetal have multiple gestations, or others. Excess (>1) prenatal vitamin
Evidence Based Guidelines) [59, 60, 66, 67, 70]. Some studies have intake per day should be avoided. No prenatal multivitamin
reported a small increased risk of SGA with weight loss in obese supplement has been shown to be superior to another. Use
women; however, this is not really an increase from the popu- of multivitamin supplements not specific for pregnancy should
lation baseline risk. Obese women who gain weight have larger be discouraged, as often excess doses can pose risks to the preg-
babies (incidence of SGA <5%), while those who lose weight nancy. Each supplement, including each vitamin supplement,
have a normal incidence of SGA (i.e., ≤10%) [72]. Moreover, all should be studied for safety and efficacy individually.
other neonatal outcomes are the same or better, with no weight
gain or some moderate weight loss in obese pregnant women Folic acid
(Table 2.6) [60, 72]. Folic acid supplementation is recommended, with a minimum of
400 mcg/day for all women (93% decrease in neural tube defects
Caffeine [NTDs]) and 4 mg/day for women with prior children with
Moderate caffeine consumption (less than 200 mg per day) does NTD (69% decrease in NTDs) [77, 78]. Supplementation should
not appear to be a contributing factor in miscarriage or PTB. start at least 1 month before conception and continue until
Reducing the caffeine intake of regular coffee drinkers (3+ at least 28 days after conception (time of neural tube closure).
cups/day) during the second and third trimester by an average Given the unpredictability of conception and that 50% of preg-
of 182 mg/day did not affect birth weight or length of gestation nancies are unplanned, all reproductive-age women should be on
in one RCT [73]. A meta-analysis from two RCTs concluded that folic acid supplementation. Because in several countries the base-
there is insufficient evidence to confirm or refute the effective- line serum folate level is only 5 ng/mL and increases in this level
ness of caffeine avoidance on birth weight or other pregnancy are directly proportional with a decrease in the incidence of NTD,
outcomes; moreover, they found that reducing the caffeine intake some experts have advocated 5 mg of folic acid per day as optimal
TABLE 2.6: Weight Gain Suggestions for Overweight and Obese Women
Pre-Pregnancy Weight Category Our Suggested Total Weight Gain Range (lb) IOM Recommendations (lb)
Overweight (BMI 25–29.9 kg/m ) 2 6–20 (2.7–9.0 kg) 15–25 (6.8–11.4 kg)
Class I obesity (BMI 30–34.9 kg/m2) 5–15 (2.3–6.8 kg) 11–20 (5–9.1 kg)
Class II obesity (BMI 35–39.9 kg/m2) −9–9 (–4.0–4.0 kg) 11–20 (5–9.1 kg)
Class III obesity (BMI >40 kg/m2) −15–0 (–6.8–0 kg) 11–20 (5–9.1 kg)
Abbreviation: IOM, Institute of Medicine.
supplementation [79]. No increase in ectopic pregnancy, miscar- as Diclegis, which is the only FDA-approved treatment for nausea
riage, or stillbirth has been associated with folate supplementa- and vomiting of pregnancy. Studies done for FDA approval of the
tion, but it might increase (nonsignificant trend) the incidence of drug showed no adverse outcomes and demonstrated safety and
multiple gestations by 40% [77–82]. However, a multicenter pro- good tolerance by women when used in the recommended dose of
spective cohort study showed that children whose mothers used up to 4 pills (10 mg/10 mg) per day (see Chap. 9 in Maternal-Fetal
folic acid supplement dosages higher than 5 mg/mL had a lower Evidence Based Guidelines).
mean psychomotor scale score than children whose mothers used
a recommended folic acid supplement dosage (i.e., 400 mcg/day) Vitamin C
[82]. Folic acid supplementation has been associated (one non- The data are insufficient to assess if vitamin C supplementa-
RCT study) with a decrease in severe language delay at 3 years of tion, either alone or in combination with other supplements, is
age [81]. Fortifying basic foods such as grains with added folate beneficial during pregnancy for either low- or high-risk women.
is associated with an increase in supplementation of only 140– There may be an associated increased risk of PTB with vitamin C
200 mcg/day and with only a 20–50% decrease in the incidence of supplementation (RR 1.38, 95% CI 1.04–1.82, 3 trials, 583 women)
NTDs, with the potential for large-scale prevention [80]. Women [87]. No other difference in outcome is noted between vitamin C
taking antiseizure medications, other drugs that might interfere supplementation versus no treatment or placebo. There are very
with folic acid metabolism, those with homozygous methylene- limited trials available to assess whether vitamin C supplementa-
tetrahydrofolate reductase (MTHFR) enzyme mutations, or those tion may be useful for all pregnant women. Usually the women
who are obese may need higher doses of folate supplementation. involved in the trials were either at high risk of preeclampsia
Women with first-trimester diabetes mellitus or exposure to val- or PTB or the women had established severe early-onset pre-
proic acid or high temperatures might not experience a decrease eclampsia (see also Chap. 1 in Maternal-Fetal Evidence Based
in NTD risk with folate supplementation due to these risks (see Guidelines). No difference is seen between women supplemented
also Chap. 1). with vitamin C alone or in combination with other supplements
compared with placebo for the risk of stillbirth, neonatal death,
Vitamin A LBW, or intrauterine growth restriction [87].
In pregnancy, some extra vitamin A is required for growth and
tissue maintenance in the fetus, for providing fetal reserves, and Vitamin D
for maternal metabolism. However, vitamin A in its synthetic There is insufficient evidence to evaluate the effects of vitamin
form as well as in large doses as retinol (preformed vitamin D supplementation during pregnancy [88–92]. Vitamin D 1000
A found in cod liver oil and chicken or beef liver) is teratogenic. IU/day in the third trimester is associated with no consistent
It is recommended that pregnant women ingest vitamin A as effect on incidence of LBW [88]. Neonatal hypocalcemia is less
β-carotene and limit the ingestion of retinol during pregnancy. common with vitamin D supplementation compared to placebo
In vitamin A–deficient populations (where night blindness is [88]. Vitamin D supplementation during pregnancy is associated
present) and in HIV-positive women, vitamin A supplementation with increased circulating 25(OH)D levels, birth weight, and
reduces maternal night blindness and anemia. Excess vitamin A birth length but with no effects on maternal-fetal outcomes [89].
intake can cause birth defects and miscarriages at doses There are limited data to assess any benefit of vitamin D supple-
>25,000 IU/day. Vitamin A supplements should be avoided, ments for complete vegetarians and women with extremely lim-
with maximum daily intake prior to and during pregnancy ited exposure to sunlight. Vitamin D supplementation of vitamin
probably 5000 IU and certainly ≤10,000 IU, respectively. D–deficient pregnant women prevents neonatal vitamin D defi-
Vitamin A supplementation may be beneficial in women with ciency [90]. Vitamin D plus calcium has no effect on duration of
vitamin A deficiency, especially in prevention of night blind- pregnancy, type of delivery, and infant anthropometric indicators
ness, in developing countries. Optimal duration of supplement [91]. However, low maternal vitamin D levels in pregnancy ≤50
use cannot be evaluated. One large population-based trial in nmol/l may be associated with an increased risk of preeclampsia,
Nepal shows a possible beneficial effect on maternal mortality gestational diabetes, PTB, and SGA [92].
after weekly vitamin A supplements. Night blindness, associated
with vitamin A deficiency, was assessed in a nested case-control Vitamin E
study within this trial and found to be reduced but not elimi- There is insufficient evidence to assess if vitamin E supplemen-
nated. There is insufficient evidence to support vitamin A supple- tation, either alone or in combination with other supplements, is
mentation as an intervention for anemia [83, 84]. beneficial during pregnancy [93]. All evidence tested women at
high risk of preeclampsia or with established preeclampsia and
Vitamin B6 (pyridoxine) assessed vitamin E in combination with other supplements (usu-
There is insufficient evidence to evaluate pyridoxine supple- ally vitamin C) (see Chap. 1 in Maternal-Fetal Evidence Based
mentation during pregnancy [85]. There are few trials reporting Guidelines). There is no convincing evidence that vitamin E sup-
few clinical outcomes, and mostly with unclear trial methodol- plementation alone or in combination with other supplements
ogy and inadequate follow-up. There is not enough evidence to results in other important benefits or harms [93].
detect clinical benefits of vitamin B6 supplementation in preg-
nancy and/or labor other than one trial suggesting protection Magnesium
against dental decay [86]. For the aim of decreasing dental decay Numerous studies demonstrate an association between magne-
or missing/filled teeth, pyridoxine supplementation 20 mg/day sium supplementation and decreased incidences of LBW, SGA,
(lozenges or capsules) is associated with a decreased incidence antenatal hospitalization, and antenatal hemorrhage. The major-
of these outcomes in pregnant women [86]. Pyridoxine has been ity of RCTs are of poor quality, except one judged to be of high
used in the management of nausea and vomiting in pregnancy. quality, which did not support these associations. There is insuf-
It is now considered category A in combination with doxylamine ficient high-quality evidence to show that dietary magnesium
Prenatal Care 27
supplementation during pregnancy is beneficial [94]. Including differences detected between groups of women who had zinc
high- and low-quality trials, oral magnesium treatment from supplementation and those who had either placebo or no zinc
before the 25th week of gestation is associated with a lower fre- during pregnancy. There is insufficient evidence to assess the
quency of PTB, a lower frequency of LBW, and fewer SGA infants best dose, gestational age and duration, and population for zinc
compared with placebo [87]. In addition, magnesium-treated supplementation in pregnancy [97].
women have less hospitalization during pregnancy and fewer
cases of antepartum hemorrhage than placebo-treated women. Iodine
Incidences of preeclampsia and all other outcomes are similar. In Iodine is essential for normal fetal thyroid and brain develop-
the analysis of one high-quality trial, no differences between mag- ment. Iodine supplementation in populations with low iodine
nesium and placebo groups are seen. Poor-quality trials are likely intake and high levels of endemic cretinism results in an
to have resulted in a bias favoring magnesium supplementation. important reduction in the incidence of the condition with no
apparent adverse effects. Iodine supplementation is associated
Calcium with a reduction in deaths during infancy and early child-
Calcium supplementation is associated with a reduction of the hood, decreased endemic cretinism at the age of 4 years, and
incidence of preeclampsia in pregnancy in all women, partic- better psychomotor development scores between 4 and 25
ularly for women at high risk of hypertension and in women months of age [98]. There are little data, however, on the safety
with low dietary calcium intake (e.g., <600 mg/day) [95]. The of routine iodine supplementation in populations with normal or
minimum dose in the Cochrane review was 1 g/day. Further low-normal iodine levels. Some data suggest an increased risk of
research is needed to determine whether dietary sources of cal- fetal and maternal hypothyroidism from iodine supplementation.
cium confer the same benefit and at what amount. There is insuf- The upper levels of safety have not been established [98, 99].
ficient evidence to determine optimum dosage and the effect on
other important maternal and fetal outcomes. There is no overall Omega-3
reduction in PTB, although there is a reduction in PTB among Pregnancy is a time of increased risk for omega-3 deficiency, as
women at high risk of developing hypertension. Benefits are omega-3 is used for the developing fetus. Thirty-four RCTs have
considered to outweigh an anomalous increase in the risk of been performed to assess whether omega-3 supplementation dur-
HELLP syndrome, which was small in absolute numbers. There is ing pregnancy affects maternal-fetal outcomes. Meta-analyses of
no evidence of any effect of calcium supplementation on stillbirth RCTs [100] show a lack of evidence to support the routine use of
or death before discharge from hospital. In women at high risk of omega-3 supplementation during pregnancy, as omega-3 supple-
hypertension, calcium supplementation is associated with fewer mentation did not affect PTB, preeclampsia, fetal growth restric-
babies with birth weight <2500 g. In one study, childhood systolic tion (FGR), gestational diabetes, SGA, postpartum depression,
blood pressure >95th percentile was reduced (see also Chap. 1 in child development, or other maternal or fetal outcomes. Meta-
Maternal-Fetal Evidence Based Guidelines) [95]. analyses also found that omega-3 supplementation during preg-
nancy did not prevent PTB in low-risk women [101] or in women
Iron with prior PTB [102] and did not prevent recurrent FGR [103].
There is no evidence to advice against a policy of routine iron
and folate supplementation in pregnancy. Iron supplementation Oral health care
is associated with the prevention of low hemoglobin at birth Oral health care is an important component of general health and
or at 6 weeks postpartum [96]. Iron supplementation, however, therefore should be maintained during pregnancy and through a
has no detectable effect on any substantive measures of either woman’s lifespan. However, although some studies have shown a
maternal or fetal outcome. One trial, with the largest number of possible association between periodontal infection and pregnancy
participants of selective versus routine supplementation, shows outcome such as PTB and preeclampsia, the evidence shows no
an increased likelihood of cesarean section and postpartum improvement in obstetric or perinatal outcomes after den-
blood transfusion, but a lower perinatal mortality rate (up to 7 tal treatment during pregnancy. A meta-analysis from 13 RCTs
days after birth). There are not a lot of data derived from commu- showed that providing periodontal treatment to pregnant women
nities where iron deficiency is common and anemia is a serious was not associated with a reduction in PTB or perinatal mortality,
health problem. There is limited evidence for daily versus inter- except for a significant reduction in PTB and LBW in populations
mittent supplementation. High-dose supplementation (80 mg with a high occurrence (>20%) of PTB and LBW [104].
daily) has no clinical advantage over low-dose supplementation
(20 mg daily) and is associated with more gastrointestinal (GI) Vaccinations
side effects. One RCT suggests adverse effects of hemoconcen- COVID vaccine is safe in pregnancy and should be recom-
tration from iron supplementation in nonanemic women. For mended, as in non-pregnant adults. Immunity to rubella, vari-
iron supplementation for women with anemia, see Chap. 14 in cella, hepatitis B, influenza, tetanus, and pertussis should be
Maternal-Fetal Evidence Based Guidelines. assessed at the first prenatal visit [105]. Ideally, needed vacci-
nations would be provided preconception. There is no vaccine
Zinc that is more dangerous to a pregnant woman or her fetus than
There is insufficient evidence to evaluate fully the effect of the disease it is designed to prevent. Recombinant, inactivated,
zinc supplementation during pregnancy [97]. Zinc supplemen- and subunit vaccines, as well as toxoids and immunoglobulins,
tation is associated with a significant reduction in PTB (RR pose no threat to a developing fetus. Inactivated influenza vac-
0.86, 95% CI 0.76–0.98; 13 RCTs; 6854 women). These studies cine should be given by injection, as killed virus to all pregnant
were primarily from a low socioeconomic population and may women during the influenza season. The live attenuated form of
reflect overall poor nutrition. Reductions in induction of labor the vaccine (intranasal spray) should not be given during preg-
and cesarean delivery are from small studies, with no other nancy. Hepatitis B vaccine can be safely given in pregnancy.
Tetanus, diphtheria, and acellular pertussis vaccine, also known no massage in nulliparous, but probably not multiparous, women
as TDAP or “whooping cough” vaccine, is recommended for all [114–116]. The type of oil used during the second stage of labor
pregnant women after 28 weeks (see Table 1.5 in Chaps. 1 and 40 for the prevention of perineal tears has no effect on the integrity
in Maternal-Fetal Evidence Based Guidelines). of the perineum; accordingly it seems that there is no perfect oil
[117]. For perineal massage in labor, see Chap. 9.
Prevention of complications Women should be provided with written information and
Please see specific diseases in each chapter of this book and its instruction regarding what to expect during L&D, how to obtain
companion, Maternal-Fetal Evidence Based Guidelines. Here are care when labor begins, and the value of a support person during
reported only some general, nonspecific interventions. the labor process (see Chaps. 7 and 8).
Antibiotic prophylaxis of pregnant women with no specific risk L&D classes should be encouraged. Compared to no such
factor or infection is associated with similar incidence of PPROM, training, 9 hours of antenatal classes with training to prepare
PTB, and postpartum endometritis (see also Chap. 18) [106, 107]. for L&D are associated with arriving to the L&D ward more
Programs offering additional social support (caring family often in active labor (RR 1.45, 95% CI 1.26–1.65) and using less
members, friends, and health professionals) for at-risk (e.g., for epidural analgesia (RR 0.84, 95% CI 0.73–0.97) [118].
PTB and LBW) pregnant women are not associated with improve- Compared to standard antenatal education, antenatal educa-
ments in any perinatal outcomes, but there is a reduction in the tion focusing on natural childbirth preparation with training in
likelihood of antenatal hospital admission (RR 0.79, 95% CI breathing and relaxation techniques is not associated with any
0.68–0.92) and cesarean birth (RR 0.87, 95% CI 0.78–0.97) [108]. effects on maternal or perinatal outcomes, including similar inci-
For issues such as mild hypertension or preeclampsia, small dences of epidural analgesia, childbirth, or parental stress, in nul-
studies suggest that there are no major differences in clinical out- liparous women and their partners [119].
comes for mothers or babies between antenatal day units or hos- Compared to conventional therapy, intensive counseling
pital admission, but women may prefer day care (see also Chap. 1 therapy for fear of childbirth does not affect the incidence of
in Maternal-Fetal Evidence Based Guidelines) [109]. cesarean sections, but is associated with reduced pregnancy-
and birth-related anxiety and concerns and shorter labors in
Prenatal education one RCT [120].
There is insufficient evidence to assess the effectiveness of formal In a small RCT, a specific antenatal education program is
prenatal education programs. Prenatal education directed at associated with a reduction in the mean number of visits to
specific objectives (e.g., promoting breastfeeding and avoid- the labor suite before the onset of labor [4]. It is unclear whether
ing planned induction of labor) has been demonstrated to be this results in fewer women being sent home because they are not
effective [110–113]. Individualized prenatal education directed in labor (see also Chap. 7) [120, 121].
toward avoidance of a cesarean delivery does not increase the
rate of vaginal birth after cesarean section. As a part of prenatal Depression in pregnancy and the postpartum period
care, women should be provided with information and instruc- Between 14% and 23% of pregnant women will experience a
tion regarding their health, including risk avoidance, breastfeed- depressive mood disorder while pregnant [122–129]. Maternal
ing, what to expect during labor and birth (see “Preparation for anxiety, life stress, history of depression, lack of social support,
Labor and Delivery”), how to obtain care when labor begins, and unintended pregnancy, public insurance, domestic violence,
the value of a support person during the labor process (see Chaps. 7 lower income, lower education, smoking, single status, and poor
and 8). relationship quality were associated with a greater likelihood
of antepartum depressive symptoms in bivariate analyses. Life
Community interventions stress, lack of social support, and domestic violence continued
There is encouraging evidence of the value of integrating mater- to demonstrate a significant association in multivariate analy-
nal and newborn care in community settings through a range ses [123, 124]. Identification of risk factors and screening for
of interventions that can be packaged effectively for delivery depression will facilitate referral for treatment (see Chap. 21 in
through a range of community health workers and health promo- Maternal-Fetal Evidence Based Guidelines).
tion groups. Such evidence-based available interventions such as Between 5% and 7% of women will experience postpartum
immunization to mothers, clean and skilled care at delivery, new- depression. Risk factors include antenatal depressive symptoms,
born resuscitation, exclusive breastfeeding, clean umbilical cord a history of major depressive disorder, or previous postpartum
care, and management of infections in newborns require facility- major depression [123]. If left untreated, postpartum major
based and outreach services. Implementation of community- depression can lead to poor mother–infant bonding, delays in
based interventional care packages is associated with a trend infant growth and development, and an increased risk of anxi-
for reduction in maternal mortality (RR 0.77, 95% CI 0.59–1.02) ety or depressive symptoms in the infant later in life. Identifying
and with significant reductions in maternal morbidity (RR mothers at risk assists in the prevention of postpartum depres-
0.75, 95% CI 0.61–0.92), neonatal mortality (RR 0.76; 95% CI sion compared to intervening on the general population. The
0.68–0.84), stillbirths (RR 0.84, 95% CI 0.74–0.97), and perina- provision of intensive postpartum support provided by public
tal mortality (RR 0.80; 95% CI 0.71–0.91). It also increases the health nurses or midwives is associated with 32% less postpar-
referrals to a health facility for pregnancy-related complications tum depression. Interventions with only a postnatal compo-
by 40% and improves the rates of early breastfeeding by 94% [113]. nent appeared to be more beneficial than interventions that
also incorporated an antenatal component. Individual-based
Preparation for labor and delivery interventions may be more effective than those that are group-
Perineal massage with sweet almond oil for 5–10 minutes based. Women who received multiple-contact intervention are
daily from 34 weeks until delivery is associated with a sig- just as likely to experience postpartum depression as those who
nificantly higher chance of an intact perineum compared to received a single-contact intervention [125]. There is insufficient
Prenatal Care 29
evidence to assess the effectiveness of antidepressants given Leg cramps

immediately postpartum in preventing postnatal depression Leg cramps are reported to occur in 34% of pregnant women
in all women or just in high-risk women [126]. A pilot RCT in the mid-trimester [136, 137]. Magnesium lactate or citrate
showed that prenatal yoga may be of benefit in the prevention chewable tablets 5 mmol in the morning and 10 mmol in the
of postpartum depression in low-risk women [128]. Moreover, evening for 3 weeks are associated with one-third of women
prenatal yoga was also found to be a feasible and acceptable inter- not having persistent leg cramps compared to 94% of placebo
vention and was associated with reductions in symptoms of anx- controls having persistent cramps. A multivitamin with a mineral
iety and depression in women (see Chap. 21 in Maternal-Fetal supplement might decrease leg cramps, but it is unclear which
Evidence Based Guidelines) [129]. one of the 12 ingredients (or combination) is beneficial. Sodium
chloride is associated with a slight reduction, although consid-
Breastfeeding eration must be given to the potential effect on blood pressure.
Breastfeeding is the best feeding method for most infants Calcium supplements do not decrease leg cramps compared
and should be strongly encouraged (see Chap. 31). Counseling to placebo. However, it is unclear whether any of the interven-
and education during pregnancy have been shown to facili- tions studied (i.e., oral magnesium, oral calcium, oral vitamin B,
tate breastfeeding success [130]. Breastfeeding education and/ or oral vitamin C) provide an effective treatment for leg cramps
or support increased exclusive breastfeeding rates and decreased due to poor study design and trials being too small to address the
no-breastfeeding rates at birth and at 1–5 months. Combined question satisfactorily.
individual and group counseling appeared to be superior to either Calf stretching prior to bedtime does not decrease nocturnal
individual counseling alone or group counseling alone. Attitudes leg cramps in nonpregnant patients [137].
of the health care provider are highly associated with breast-
feeding success. An antigen avoidance diet during lactation by Back and pelvic pain
high-risk women may reduce the child’s risk of developing atopic Back pain is common in pregnancy, given weight gain and its
eczema and may reduce atopic eczema in children who already uneven distribution, as well as the softening effects of pregnancy
have it during the first 12–18 months, although more trials are hormones on the musculature.
needed. There is evidence that exercise (any exercise on land or in
water) may reduce pregnancy-related low back pain, improve
Interventions for common functional disability, and reduce sick leave. Water gymnastics
pregnancy complaints for 1 hour weekly starting at <19 weeks reduces back pain in
pregnancy and allows more women to continue to work, with
Itching no adverse effects [138].
The differential diagnosis of itching in late pregnancy (>32 Pregnancy-specific exercises, physiotherapy, and acu-
weeks) is presented in Chap 10 in Maternal-Fetal Evidence puncture starting <32 weeks for 10 sessions appear to reduce
Based Guidelines. If the itching is not due to liver disease, back and pelvic pain; individual acupuncture sessions are more
and if there is no rash, aspirin (600 mg qid) has been reported beneficial than group physiotherapy sessions. Education, other
to decrease itching [124], but because of potential detrimen- exercises, massage, heat therapy, support belts, analgesic ther-
tal fetal effects (closure of ductus arteriosus and oligohy- apy, etc., have not been studied in a trial in pregnancy for back
dramnios), it should not be used. If there are both itching pain relief.
and a rash, chlorpheniramine 4 mg tid decreased itching in a
small trial [131]. However, aspirin 600 mg four times a day— Constipation
which is not safe during parts of pregnancy—appears to be Constipation is common in pregnancy, probably because of
more effective than chlorpheniramine 5 mg three times a day decreased bowel peristalsis (possibly related to increased pro-
for relief of itching when no rash is present in a small cross- gesterone). Constipation is reported by nearly 70% of women in
over trial [132]. the mid-trimester. In nonpregnant adults, exercise, increase
in water intake, dietary counseling, and certain foods (e.g.,
Stretch marks prunes) have been shown to relieve constipation. If these self-
Some stretch marks (striae gravidarum) develop in about 50% of help measures are inadequate, the pregnant woman should then
women by the end of pregnancy. There is no high-quality evi- try daily bran or wheat fiber supplements. There is insufficient
dence to support the use of any topical preparation in the pre- evidence to comprehensively assess the effectiveness and safety
vention of stretch marks during pregnancy [133, 134]. There is of interventions (pharmacological and nonpharmacological) for
also no proven treatment for stretch marks once they have devel- treating constipation in pregnancy, due to limited data (few stud-
oped [134]. Olive oil is not effective in preventing the occur- ies with small sample size and no meta-analyses). Compared with
rence of striae gravidarum or affecting its severity [134]. There bulk-forming laxatives, stimulant laxatives (e.g., senna 14 mg or
is no available product that has been shown to prevent the for- dioctyl sodium succinate 120 mg and dihydroxyanthraquinone
mation of striae gravidarum. Massage with either Trofolastin 100 mg—Normax) appear to be more effective in improving con-
cream or Verum ointment is associated in small RCTs with a stipation (moderate-quality evidence), but are accompanied by
decrease in the development of striae gravidarum [134]. A small, an increase in diarrhea and abdominal discomfort. Docusate
randomized trial showed that a specific anti–stretch mark cream sodium is a similar stimulant laxative, and it is widely available.
(emollient and moisturizer containing hydroxyprolisilane C, Additionally, dietary fiber supplements (e.g., 10 mg/day of either
rosehip oil, Centella asiatica triterpenes, and vitamin E) had a corn-based biscuits—Fibermed—or 23 g wheat bran) increase
small effect in reducing severity (but not the incidence) of striae the frequency of defecation and are associated with softer stools
gravidarum during pregnancy (see Chap. 45 in Maternal-Fetal [139]. These findings in pregnant women are consistent with non-
Evidence Based Guidelines) [135]. pregnant evidence.
Varicosities and leg edema and/or at hospital admission in both women who had COVID-19
A small RCT (n = 69) shows that rutoside capsules improve leg infection and those who had the vaccine to assess risk and guide
edema symptoms; however, there are insufficient data to confirm management.
rutoside safety in pregnancy. Another small RCT (n = 43) demon-
strates a reduction in leg edema with reflexology. Compression
stockings are not effective compared to simple resting, but studies References
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rutosides decrease symptoms compared to a placebo group
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3
PHYSIOLOGIC CHANGES
Jason Baxter and Julia Burd
Key points pregnancy. In most cases, it is not possible to consider the effect
of pregnancy on laboratory values in a simplistic or formulaic
• The normal physiologic changes of pregnancy are sev- way. Rather, it is the understanding of the underlying physiology
eral and listed in part in Table 3.1. that these laboratory values reflect that is the most important in
• Normal laboratory values for pregnant women are pre- their evaluation during pregnancy.
sented in Table 3.2.
• Failure to understand these physiologic changes of Cardiovascular/Hemodynamic
pregnancy may result in both undue alarm and costly
evaluation of normal symptoms of pregnancy or in the An understanding of pregnancy-related hemodynamic changes
neglect of pathologic conditions whose presentation is is crucial in the management of both benign and life-threatening
dismissed as another “discomfort of pregnancy.” complications of pregnancy, ranging from near-syncopal epi-
• The physician should carefully address the pregnant sodes experienced by many pregnant women to hypotension
patient, keeping in mind the question: “How is this pre- from obstetric hemorrhage and hypertension, both of which
sentation affected by the physiology of pregnancy?” are leading causes of maternal intensive care unit admissions
and mortality [6]. Even the ultimate clinical emergency of car-
Background diac arrest is complicated by hemodynamics that are unique to
pregnancy.
Over the course of human pregnancy, the significance of physi- Hemodynamic changes in pregnancy that have been well estab-
ologic changes that occur is such that it often becomes no longer lished include an increase in cardiac output and a decrease in
appropriate for the physician to evaluate her according to stan- both systemic and pulmonary vascular resistance. There is an
dards that have been set through the observation and study of overall increase in heart rate and a decrease in blood pres-
men and nonpregnant women. Some of these physiologic changes sure. Blood volume, plasma volume, and erythrocyte volume
are advantageous to the growth and survival of the fetus. Others all increase, with a greater relative increase in plasma volume,
enhance the ability of the maternal system to compensate for resulting in a dilutional lowering of hematocrit and other
demands of pregnancy, prepare for stress of delivery, and recover blood indices. There is also a redistribution of cardiac output
from delivery. with an increase in flow to the uterus, kidneys, skin, and breasts
Understanding physiologic changes in pregnancy is important [1]. The renin–angiotensin–aldosterone system is activated in step
in evaluating common symptoms associated with pregnancy, with estrogen increases and assists in maintaining blood pressure
interpreting laboratory values in the parturient, and understand- and retaining water and salt despite increased renal excretion [7].
ing pathologic conditions to which pregnant women are suscep- The increase in stroke volume and cardiac output creates a more
tible. Failure to understand the normal physiologic changes of audible physiologic flow murmur and splitting of the S2 sound
pregnancy may result in both undue alarm and costly evalu- during pregnancy, which may be striking upon physical exam.
ation of normal symptoms of pregnancy or in the neglect of One longitudinal study followed maternal hemodynamics as
pathologic conditions whose presentation is dismissed as measured by thoracic electrical bioimpedance monitoring in 50
another discomfort of pregnancy. The patient will most likely be healthy pregnant women [8]. The results showed an increase in
better served by the physician who carefully addresses her symp- mean heart rate from 87 ± 2 beats per minute (bpm) at 10–18
toms while keeping in mind the questions: “How is this presen- weeks to 92 ± 1 bpm at 34–42 weeks. Mean arterial pressure
tation affected by the physiology of pregnancy?” and “What (MAP) decreased significantly after 14 weeks and increased after
pathologic conditions may be represented by this scenario?” than 29 weeks. Systemic vascular resistance (SVR) increased during the
by the physician who uncritically memorizes laboratory values last trimester. This study also found a significantly higher mean
and makes a diagnosis without considering the interplay between cardiac output in nulliparous women compared to multiparous
pregnancy and underlying pathophysiology. women. Mean cardiac output and stroke volume, which show
Two summary tables are provided. Table 3.1 summarizes the an overall increase during pregnancy, were found to decrease in
commonly accepted pregnancy-related changes in various physi- the third trimester in this study [8]. A meta-analysis of 39 stud-
ologic parameters and their importance in the evaluation and ies examining cardiac output in pregnancy indicated that cardiac
management during pregnancy [1]. Table 3.2 provides a sum- output peaks in the early third trimester at 31% higher than non-
mary of laboratory values in each trimester of pregnancy versus pregnant values and quickly returns to baseline in the early post-
in the nonpregnant state based on a recent systematic review and partum period [9].
other resources [2–5]. The reader will note that some values show Another longitudinal study performed serial echocardiogra-
significant overlap between pregnant and nonpregnant states. phy studies on 35 healthy pregnant women from the early sec-
Some show little change between pregnant and nonpregnant ond trimester to 6–12 weeks postpartum [10]. This study showed
states. Others show trends that clearly increase or decrease with a significant increase in cardiac output that peaked in the early
34 DOI: 10.1201/9781003102342-3
Physiologic Changes 35
TABLE 3.1: Summary of Physiologic Adaptations during Pregnancy

Parameter Expected Change Comments
Cardiovascular System
Heart size Increases 12% Increases diastolic filling and muscle hypertrophy
Murmurs Physiologic systolic Ejection murmurs attributable to increased stroke volume
usually occur in early or midsystole and are best heard
along the left sternal edge
ECG Positional heart shifts result in changes that resemble Heart is pushed upward and forward, deviating electrical
ischemia axis to the left by 15–20 degrees, causing flattened or
inverted T in lead III
Cardiac output Increases 30%–50% Greatest increase occurs immediately after delivery with
From 4.5 to about 6.0 L/min (by 1.5 L/min) redistribution of blood flow from uterus. Cardiac output
Influenced by maternal position then decreases.
Rhythm Increases atrial and ventricular extrasystole SVT not infrequent
Heart rate Increases Onset of change is first trimester
Stroke volume Increases Significant change in second half of pregnancy
Mean arterial pressure Decreased soon after beginning of pregnancy and Supine hypotension—decreased venous return due to
midpregnancy (100–110/60–70 mean levels); then compression from gravid uterus; increased blood flow
returns to pre-pregnant values by third trimester and through alternative pathways such as paravertebral
term azygous veins
Pulse pressure Increases
Venous pressure Increases in femoral system; unchanged in arms
Systemic vascular resistance Decreases
Pulmonary BP Unchanged
Blood flow to uterus Increases by 500 mL/min No autoregulation
Increases from 1%–3% of CO to 17%–20%
Blood flow to kidneys Increases by 400 mL/min
Blood flow to skin Increases by 300–400 mL/min
Blood flow to breasts Increases by 200 mL/min
Respiratory System
Anatomy Increases subcostal angle from 68 to 103 degrees → Increased upper respiratory capillary engorgement can cause
3-cm increase in transthoracic diameter increased congestion, epistaxis, and intubation trauma
Tidal volume Increases by 300 mL or 40%
Expiratory reserve volume Decreases by 200 mL Cephalad displacement of diaphragm
Inspiratory capacity Increases by 300 mL
Functional residual volume Decreases by 500 mL
Minute volume Increases by 40% or 3 L/min beginning in first trimester Increased rate of induction of, and emergence from,
inhaled anesthetics
Maximum breathing capacity Unchanged
Forced expiratory volume Unchanged
Peak expiratory flow rate Unchanged
Pulmonary diffusing capacity Decreases by 4 mL/min/mmHg
Oxygen requirement Increases by 30–40 mL/min
Carbon dioxide output Increases; expressed as respiratory quotient
Carbon dioxide pressure Decreases from 35–40 mmHg to 28–30 mmHg
Oxygen pressure Increases
pH Mild increase (7.40–7.44 is normal) Compensated respiratory alkalosis
PCO2 Decrease (30–31 mmHg is normal)
PO2 Mild increase (100–104 mmHg is normal)
Renal System and Homeostasis
Glomerular filtration rate Increases from 97 mL/min to 128 mL/min by 10 wk Increased renal clearance of certain drugs and vitamins
Glucose excretion Increased Random glycosuria
Protein excretion Increased (up to 300 mg/24 hr is normal)
Renin, angiotensin I and II Increased Diminished vascular response causes less pressor effect
from angiotensin
Anatomic changes Dilation of renal calyces and ureters to pelvic brim; Increased risk of pyelonephritis; screen for asymptomatic
“physiologic” hydronephrosis, right > left bacteriuria
Potassium Increased retention
(Continued)
TABLE 3.1 (Continued): Summary of Physiologic Adaptations during Pregnancy

Sodium Increased retention
Urine output No significant change
Vitamin excretion Increased loss of folate, B12, and ascorbic acid
Osmolality Decreases 10 mOsm/kg first trimester, then stable
Sodium Decreases 3 mEq/L first trimester, then stable
Potassium Decreases 0.5 mEq/L
Calcium Decreased total and ionized Increased intestinal absorption of calcium and increased
bone turnover
Magnesium Decreases 10%–20% in first half of pregnancy
Chloride Unchanged
Bicarbonate Decreases markedly (18–22 mEq/L is normal) Compensates for decrease in PCO2
Total protein Decreases from 72 g/L to 62 g/L
Albumin Decreases from 47 g/L to 36 g/L
Urea, creatinine, and uric acid Decrease in first trimester; stabilize in second trimester;
increase toward term
Vitamin B6 Decreases
Blood glucose Fasting levels decrease in first trimester, then Postprandial levels remain elevated longer, prolonging
unchanged return to fasting state. Increased glucose levels allow
passive diffusion across placenta to fetus
Folate Decreases 50% toward term
Vitamin B12 Decreases 50% or more B12 levels in folate-deficient women will increase with
folate supplementation alone
Endocrine System
Pituitary gland Increases to 50% greater than adult male Attributable to increase of prolactin-secreting cells in
anterior lobe
Prolactin Increases from 300 mIU/L to 5000 mIU/L Estrogen stimulates hyperplasia and hypertrophy of
pituitary lactotrophs
Follicle-stimulating hormone Decrease to nearly undetectable
and luteinizing hormone
Melanocyte-stimulating Increased Likely responsible for linea nigra, chloasma, and increased
hormone areolae pigmentation
Thyroid-stimulating hormone Normal range is unchanged May be suppressed during late first to early second
trimester due to hCG-mediated increase in TH
production—subtle effect may be exacerbated by
conditions that increase hCG levels, such as hyperemesis,
molar pregnancies, and multiples
Thyroid-binding globulin Increases—doubles by end of first trimester; triples by term Due to estrogen effect on liver
Thyroxine (T4) and Increased total circulating amount; unchanged free Fetal thyroid hormone production commences at 18 wk
triiodothyronine (T3) fraction
Reverse T3 Unchanged in maternal circulation; increased in cord blood
Cortisol Increased to 3 × nonpregnant values Episodic pattern of release is maintained.
Aldosterone Increased twofold by term
Deoxycorticosterone Increased by 20–100 ×
Testosterone Increased total amount; decreased free fraction
Androstenedione Increases Tenfold increase rate of transformation to estradiol and
estrone
DHEA Unchanged or small decrease Precursor for steroid hormone synthesis by placenta
Pancreas Hypertrophy of islets due to hyperplasia of B cells
Insulin Increases fasting levels toward term; hyperplasia of Proportionally less increase of glucagons compared to
pancreatic B cells insulin; so insulin:glucagon ratio is increased
Glucagon Increases fasting levels
Glucose Slight decrease Especially fasting levels
Parathyroid hormone Increased during end of pregnancy Maintains calcium levels in face of increased renal
absorption and transfer to fetus
Progesterone Markedly increases Production originates in corpus luteum over first 7–8 wk;
then placenta takes over
Estradiol Markedly increases
TABLE 3.1 (Continued): Summary of Physiologic Adaptations during Pregnancy

17-Hydroxyprogesterone Increases
Estriol Increases
Human placental lactogen (hPL) Increases 5000-fold from 0.002 μU/mL to 10 mU/mL
hCG Increases to maximum values by 8–10 wk Peak 93 U/mL; term 14 U/mL
Relaxin Peaks at 10 wk
Gastrointestinal System
Appetite Increases
Gastric reflux Increases Cardiac sphincter laxity and anatomic displacement;
treated during labor and delivery/anesthetic procedures
with nonparticulate oral antacids
Gastric secretion Decreased acidity; increased volume “Full stomach” effect increases risk of aspiration
Gastric motility Decreases
Intestinal absorption Increased
Intestinal transit time Delayed
Large intestine Greater absorption; slower transit time
Gallbladder Larger due to passive dilation
Hematologic System
Plasma volume 40%–60% increase from 12 to 36 wk; 70%–100% Offsets blood loss at delivery
increase in multiple gestations
Total erythrocyte volume Increases 15%–30% Greater increase with iron supplementation
Hematocrit Decreases 3%–5% by 36 wk Physiologic anemia due to greater proportionate increase
in plasma volume compared to erythrocyte volume; less
change with iron supplementation
Hemoglobin Decreases
Mean corpuscular volume Unchanged Best indicator of iron status. Slight increase with iron
supplementation.
Erythrocyte sedimentation rate Significantly increased Provides little diagnostic value; combined with increase in
white blood cell (WBC) can cause false suspicion for
infection
WBC count Increases 8% by term and may increase further Predominantly due to increase in neutrophils
postpartum
Serum iron Decreases 35% by term
Serum transferrin Increases by 100% or more by second trimester Total iron-binding capacity (TIBC) markedly increased
TIBC Increases by 25%–100%
Serum ferritin Decreases markedly (even with iron supplementation) Nadir 30% or less of normal values. Best test to assess
iron-deficiency anemia in pregnancy
Erythropoietin Increases fourfold
α-Fetoprotein Increases Larger increase in neural tube defects, abdominal wall
defects, and fetal death
Glutamic-oxaloacetic Unchanged
transaminase and glutamic-
pyruvic transaminase
Alkaline phosphatase Increases Heat stable fraction formed by placenta
Lipids Increase Triglycerides, cholesterol, phospholipids, and free fatty
acids each increase progressively.
Fibrinogen Increases 2 g/L by term Overall increased tendency toward thrombosis
Factors VII, VIII, IX, and X Increase
Factors XI and XIII Decrease by about 30%
Antithrombin III Decreases
Fibrin, FDP Increase progressively
Protein C Unchanged
Protein S Decreases Protein S–binding protein levels fluctuate in pregnancy,
making screening more reliable in nonpregnant women
Source: See further Ref. [1].
Abbreviations: ECG, electrocardiogram; min, minute; SVT, supraventricular tachycardia; BP, blood pressure; CO, cardiac output; wk, weeks; hr, hour; hCG, human chorionic
gonadotropin; TH, thyroid hormone; DHEA, dehydroepiandrosterone; FDP, fibrin degradation products.
TABLE 3.2: Normal Reference Ranges in Pregnant Women

Nonpregnant Adult First Trimester Second Trimester Third Trimester
Hematology
Erythropoietin (U/L) 4–27 12–25 8–67 14–222
Ferritin (ng/mL) 10–150 6–130 2–230 0–116
Folate, red blood cell (ng/mL) 150–450 137–589 94–828 109–663
Folate, serum (ng/mL) 5.4–18 2.6–15 0.8–24 1.4–20.7
Hemoglobin (g/dL) 12–15.8 11.6–13.9 9.7–14.8 9.5–15
Hematocrit (%) 35.4–44.4 31–41 30–39 28–40
Iron, total binding capacity (μg/dL) 251–406 278–403 359–609
Iron, serum (μg/dL) 41–141 72–143 44–178 30–193
Mean corpuscular hemoglobin (pg/cell) 27–32 30–32 30–33 29–32
Mean corpuscular volume (μm3) 79–93 81–96 82–97 81–99
Platelet (×109/L) 165–415 174–391 155–409 146–429
Mean platelet volume (μm3) 6.4–11 7.7–10.3 7.8–10.2 8.2–7.4
Red blood cell count (×106/mm3) 4–5.2 3.42–4.55 2.81–4.49 2.71–4.43
Red cell distribution width (%) <14.5 12.5–14.1 13.4–13.6 12.7–15.3
White blood cell count (×103/mm3) 3.5–9.1 5.7–13.6 5.6–14.8 5.9–16.9
Neutrophils (×103/mm3) 1.4–4.6 3.6–10.1 3.8–12.3 3.9–13.1
Lymphocytes (×103/mm3) 0.7–4.6 1.1–3.6 0.9–3.9 1–3.6
Monocytes (×103/mm3) 0.1–0.7 0.1–1.1 0.1–1.1 0.1–1.4
Eosinophils (×103/mm3) 0–0.6 0–0.6 0–0.6 0–0.6
Basophils (×103/mm3) 0–0.2 0–0.1 0–0.1 0–0.1
Transferrin (mg/dL) 200–400 254–344 220–441 288–530
Transferrin, saturation without iron (%) 22–46 10–44 5–37
Transferrin, saturation with iron (%) 22–46 18–92 9–98
Coagulation
Antithrombin III, functional (%) 70–130 89–114 88–112 82–116
D-dimer (μg/mL) 0.22–0.74 0.05–0.95 0.32–1.29 0.13–1.7
Factor V (%) 50–150 75–95 72–96 60–88
Factor VII (%) 50–150 100–146 95–153 149–211
Factor VIII (%) 50–150 90–210 97–312 143–353
Factor IX (%) 50–150 103–172 154–217 164–235
Factor XI (%) 50–150 80–127 82–144 65–123
Factor XII (%) 50–150 78–124 90–151 129–194
Fibrinogen (mg/dL) 233–496 244–510 291–538 373–619
Homocysteine (μmol/L) 4.4–10.8 3.34–11 2–26.9 3.2–21.4
International normalized ratio 0.9–1.04 0.89–1.05 0.85–0.97 0.80–0.94
Partial thromboplastin time, activated (sec) 26.3–39.4 24.3–38.9 24.2–38.1 24.7–35
Prothrombin time (sec) 12.7–15.4 9.7–13.5 9.5–13.4 9.6–12.9
Protein C, functional (%) 70–130 78–121 83–133 67–135
Protein S, total (%) 70–140 39–105 27–101 33–101
Protein S, free (%) 70–140 34–133 19–113 20–65
Protein S, functional activity (%) 65–140 57–95 42–68 16–42
Tissue plasminogen activator (ng/mL) 1.6–13 1.8–6 2.4–6.6 3.3–9.2
Tissue plasminogen activator inhibitor-1 (ng/mL) 4–43 16–33 36–55 67–92
Von Willebrand factor (%) 75–125 121–260
Blood Chemical Constituents
Alanine transaminase (U/L) 7–41 3–30 2–33 2–25
Albumin (g/dL) 4.1–5.3 3.1–5.1 2.6–4.5 2.3–4.2
Alkaline phosphatase (U/L) 33–96 17–88 25–126 38–229
α1-Antitrypsin (mg/dL) 100–200 225–323 273–391 327–487
Amylase (U/L) 20–96 24–83 16–73 15–81
Anion gap (mmol/L) 7–16 13–17 12–16 12–16
Aspartate transaminase (U/L) 12–38 3–23 3–33 4–32
TABLE 3.2 (Continued): Normal Reference Ranges in Pregnant Women

Bicarbonate (mmol/L) 22–30 20–24 20–24 20–24
Bilirubin, total (mg/dL) 0.3–1.3 0.1–0.4 0.1–0.8 0.1–1.1
Bilirubin, unconjugated (mg/dL) 0.2–0.9 0.1–0.5 0.1–0.4 0.1–0.5
Bilirubin, conjugated (mg/dL) 0.1–0.4 0–0.1 0–0.1 0–0.1
Bile acids (μmol/L) 0.3–4.8 0–4.9 0–9.1 0–11.3
Calcium, ionized (mg/dL) 4.5–5.3 4.5–5.1 4.4–5 4.4–5.3
Calcium, total (mg/dL) 8.7–10.2 8.8–10.6 8.2–9 8.2–9.7
Ceruloplasmin (mg/dL) 25–63 30–49 40–53 43–78
Chloride (mEq/L) 102–109 101–105 97–109 97–109
Creatinine (mg/dL) 0.5–0.9 0.4–0.7 0.4–0.8 0.4–0.9
γ-Glutamyl transpeptidase (U/L) 9–58 2–23 4–22 3–26
Lactate dehydrogenase (U/L) 115–221 78–433 80–447 82–524
Lipase (U/L) 3–43 21–76 26–100 41–112
Magnesium (mg/dL) 1.5–2.3 1.6–2.2 1.5–2.2 1.1–2.2
Osmolality (mOsm/kg H2O) 275–295 275–280 276–289 278–280
Phosphate (mg/dL) 2.5–4.3 3.1–4.6 2.5–4.6 2.8–4.6
Potassium (mEq/L) 3.5–5 3.6–5 3.3–5 3.3–5.1
Prealbumin (mg/dL) 17–34 15–27 20–27 14–23
Protein, total (g/dL) 6.7–8.6 6.2–7.6 5.7–6.9 5.6–6.7
Sodium (mEq/L) 136–146 133–148 129–148 130–148
Urea nitrogen (mg/dL) 7–20 7–12 3–13 3–11
Uric acid (mg/dL) 2.5–5.6 2–4.2 2.4–4.9 3.1–6.3
Metabolic and Endocrine Tests
Aldosterone (ng/dL) 2–9 6–104 9–104 15–101
Angiotensin-converting enzyme (U/L) 9–67 1–38 1–36 1–39
Cortisol (μg/dL) 0–25 7–19 10–42 12–50
Hemoglobin A1c (%) 4–6 4–6 4–6 4–7
Parathyroid hormone (pg/mL) 8–51 10–15 18–25 9–26
Parathyroid hormone–related protein (pmol/L) <1.3 0.7–0.9 1.8–2.2 2.5–2.8
Procalcitonin (μg/L)a 0.02-0.06 0.02-0.05 0.01-0.08 0.01-0.15
Renin, plasma activity (ng/mL/hr) 0.3–9 7.5–54 5.9–58.8
Thyroid-stimulating hormone (μIU/mL) 0.34–4.25 0.6–3.4 0.37–3.6 0.38–4.04
Thyroxine-binding globulin (mg/dL) 1.3–3 1.8–3.2 2.8–4 2.6–4.2
Thyroxine, free (ng/dL) 0.8–1.7 0.8–1.2 0.6–1 0.5–0.8
Thyroxine, total (µg/dL) 5.4–11.7 6.5–10.1 7.5–10.3 6.3–9.7
Triiodothyronine, free (pg/mL) 2.4–4.2 4.1–4.4 4–4.2
Triiodothyronine, total (ng/dL) 77–135 97–149 117–169 123–162
Vitamins and Minerals
Copper (μg/dL) 70–140 112–199 165–221 130–240
Selenium (μg/L) 63–160 116–146 75–145 71–133
Vitamin A (retinol) (μg/dL) 20–100 32–47 35–44 29–42
Vitamin B12 (pg/mL) 279–966 118–438 130–656 99–526
Vitamin C (ascorbic acid) (mg/dL) 0.4–1 0.9–1.3
Vitamin D, 1,25-dihydroxy (pg/mL) 25–45 20–65 72–160 60–119
Vitamin D, 24,25-dihydroxy (ng/mL) 0.5–5 1.2–1.8 1.1–1.5 0.7–0.9
Vitamin D, 25-hydroxy (ng/mL) 14–80 18–27 10–22 10–18
Vitamin E (α-tocopherol) (mg/mL) 5–18 7–13 10–16 13–23
Zinc (μg/dL) 75–120 57–88 51–80 50–77
Autoimmune and Inflammatory Mediators
C3 complement (mg/dL) 83–177 62–98 73–103 77–111
C4 complement (mg/dL) 16–47 18–36 18–34 22–32
C-reactive protein (mg/L) 0.2–3 0.4–20.3 0.4–8.1
Erythrocyte sedimentation rate (mm/hr) 0–20 4–57 7–47 13–70
IL-6 (pg/mL)b 13.8–41.1 13.1–44.4
(Continued)
TABLE 3.2 (Continued): Normal Reference Ranges in Pregnant Women

Immunoglobulin A (mg/dL) 70–350 95–243 99–237 112–250
Immunoglobulin G (mg/dL) 700–1700 981–1267 813–1131 678–990
Immunoglobulin M (mg/dL) 50–300 78–232 74–218 85–269
Sex Hormones
Dehydroepiandrosterone sulfate (μmol/L) 1.3–6.8 2–16.5 0.9–7.8 0.8–6.5
Estradiol (pg/mL) <20–443 188–2497 1278–7192 6137–3460
Progesterone (ng/mL) <1–20 8–48 99–342
Prolactin (ng/mL) 0–20 36–213 110–330 137–372
Sex hormone–binding globulin (nmol/L) 18–114 39–131 214–717 216–724
Testosterone (ng/dL) 6–86 26–211 34–243 63–309
17-Hydroxyprogesterone (nmol/L) 0.6–10.6 5.2–28.5 5.2–28.5 15.5–84
Lipids
Cholesterol, total (mg/dL) <200 141–210 176–299 219–349
High-density lipoprotein cholesterol (mg/dL) 40–60 40–78 52–87 48–87
Low-density lipoprotein cholesterol (mg/dL) <100 60–153 77–184 101–224
Very-low-density lipoprotein cholesterol (mg/dL) 6–40 10–18 13–23 21–36
Triglycerides (mg/dL) <150 40–159 75–382 131–453
Apolipoprotein A-I (mg/dL) 119–240 111–150 142–253 145–262
Apolipoprotein B (mg/dL) 52–163 58–81 66–188 85–238
Cardiac
Atrial natriuretic peptide (pg/mL) 28.1–70.1
B-type natriuretic peptide (pg/mL) <167 13.5–29.5
Creatine kinase (U/L) 39–238 27–83 25–75 13–101
Creatine kinase-MB (U/L) <6 1.8–2.4
Troponin I (ng/mL) 0–0.8 0–0.064
(intrapartum)
Blood Gas
pH 7.38–7.42 7.36–7.52 7.4–7.52 7.41–7.53
(arterial) (venous) (venous) (venous)
7.39–7.45
(arterial)
PO2 (mmHg) 90–100 93–100 90–98 92–107
PCO2 (mmHg) 38–42 25–33
Bicarbonate (HCO3-) (mEq/L) 22–26 16–22
Renal Function Tests
Effective renal plasma flow (mL/min) 492–696 696–985 612–1170 595–945
Glomerular filtration rate (GFR) (mL/min) 106–132 131–166 135–170 117–182
Filtration fraction (%) 16.9–24.7 14.7–21.6 14.3–21.9 17.1–25.1
Osmolarity, urine (mOsm/kg) 500–800 326–975 278–1066 238–1034
24-hr albumin excretion (mg/24 hr) <30 5–15 4–18 3–22
24-hr calcium excretion (mmol/24 hr) <7.5 1.6–5.2 0.3–6.9 0.8–4.2
24-hr creatinine clearance (mL/min) 91–130 69–140 55–136 50–166
24-hr creatinine excretion (mmol/24 hr) 8.8–14 10.6–11.6 10.3–11.5 10.2–11.4
24-hr potassium excretion (mmol/24 hr) 25–100 17–33 10–38 11–35
24-hr protein excretion (mg/24 hr) <150 19–141 47–186 46–185
24-hr sodium excretion (mmol/24 hr) 100–260 53–215 34–213 37–149
Source: Adapted from Ref. [2], except as indicated.
a Adapted from Refs. [4, 5].
b Adapted from Ref. [3].
Abbreviations: sec, second; hr, hour; min, minute.

third trimester and was maintained until term. The detected loss of consciousness or postictal confusion, carotid or subcla-
46%–51% increase in cardiac output was attributed to a 15% vian bruits, a pathologic cardiac murmur, or electrocardiogram
increase in heart rate and a 24% increase in stroke volume [10]. (ECG) or laboratory abnormalities [12].
The changes in heart rate occur early in pregnancy, whereas The events that are precipitated by a decrease in venous return
those of stroke volume occur later, with the net effect of a pro- can also explain the occurrence of supine hypotension in preg-
gressively increasing cardiac output as gestation progresses. nancy. The commonly recommended “leftward tilt” position is
Again, significant variation in cardiac output changes in the late intended to displace the uterus off of the inferior vena cava, which
third trimester was attributed to patient factors, precluding con- runs to the right of midline. This position should be used to avoid
fident conclusions regarding the behavior of cardiac output at the supine hypotension when recumbent, as well as when perform-
very end of pregnancy. Maternal cardiac output was found to cor- ing surgery on the parturient in the second half of pregnancy. A
relate with maternal body surface area and with fetal birth weight. more extreme application of this physiology comes in the perfor-
Left ventricular mass and left ventricular mass index increased mance of perimortem cesarean section during maternal cardiac
to maximal levels at term but remained well below the cutoff for arrest. The procedure is purported not only so to allow fetal sur-
a diagnosis of left ventricular hypertrophy. This increase corre- vival but also so that the evacuation of the uterus may allow an
sponded to an increase in mean blood pressure at term, as well increase in venous return and cardiac output that may increase
as to an increase in left atrial size and a decrease in left ventricu- the chance for maternal survival [13]. In order to optimize mater-
lar diastolic filling value. These changes may explain some of the nal and fetal survival, it is recommended that the procedure be
variations in cardiac output in the third trimester and may be performed within 4 minutes of cardiac arrest due to the inade-
relevant to the vulnerability of pregnant women to pulmonary quacy of chest compressions in producing adequate cardiac out-
edema during hypertensive crisis [10]. Recent research has indi- put during pregnancy and the susceptibility of both mother and
cated that these changes in left ventricular mass on echocardio- fetus to anoxic brain injury (see also Chaps. 1 and 2 in Maternal-
gram are associated with increased dyspnea in pregnancy [11]. Fetal Evidence Based Guidelines) [13].
Perhaps the most common hemodynamic complaint that
must be evaluated during pregnancy is that of syncope or near- Respiratory
syncope, which provides a useful example of how an under-
standing of pregnancy physiology is useful in clinical evaluation. During pregnancy, the respiratory system undergoes alterations
Syncope is defined as a transient loss of consciousness and pos- that are reflected in pulmonary function tests and in acid–base
ture, caused by decreased cerebral perfusion that may result from balance. These are important in the evaluation of dyspnea in
hypotension, changes in heart rate, or changes in blood volume pregnancy, the management of pregnancy with coexisting pul-
or redistribution. The decreased SVR of pregnancy makes preg- monary diseases such as asthma, and the recognition of acute
nant women particularly susceptible to this condition, with 28% pulmonary complications of pregnancy.
of gravidas experiencing at least one episode of presyncope, 10% Pregnancy is associated with a significant increase in ventila-
experiencing recurrent presyncopal episodes, and 5% experienc- tory drive both at rest and during exercise [14]. Minute ventilation
ing outright syncope [12]. The overwhelming majority of synco- increases mostly due to an increase in tidal volume with little
pal episodes are benign neurocardiogenic syncope, but there are or no increase in respiratory rate [6, 14, 15]. Alveolar ventilation
also several potentially dangerous conditions in the differential increases, along with an increase in arterial partial pressure of
diagnosis of syncope. An understanding of the vasovagal reflex at oxygen (PaO2) and alveolar partial pressure of oxygen (PAO2)
the root of most syncopal episodes helps the clinician to manage and a decrease in arterial partial pressure of carbon dioxide
benign syncopal episodes while being alert for signs and symp- (PaCO2), with a compensatory decrease in serum bicarbonate,
toms that may point to a more serious underlying condition. The with an overall mild increase in pH, reflecting a state of com-
most common trigger of syncope is venous pooling that results in pensated respiratory alkalosis [14]. These changes occur early
a drop in venous return and a subsequent drop in cardiac output. in pregnancy and are almost fully established by 7–8 weeks’ ges-
This results in stimulation of arterial baroreceptors, which trigger tation [14]. This may be due to stimulation of the ventilatory drive
catecholamine stimulation of atria and ventricles. The resultant by progesterone and/or estrogen. Ventilatory equivalents for CO2
vigorous cardiac contraction in volume-depleted chambers stim- and O2 are increased both at rest and during exercise throughout
ulates cardiac mechanoreceptors or C-fibers which, in suscepti- pregnancy. The underlying mechanism for the increased ventila-
ble individuals, can result in paradoxical stimulation of the dorsal tory drive during pregnancy is not fully understood, but theories
vagal nucleus. This stimulation is paradoxical because, in the face have included an increased sensitivity to chemoreflexive drives to
of low SVR and cardiac output, there is a further decrease in sym- breathe (due to hypercapnia or hypoxia) versus a hormone-medi-
pathetic tone and an increase in vagal tone causing vasodilation ated increase in the neural drive to breathe [14].
and bradycardia and the clinical presentation of presyncope or Uterine enlargement and abdominal distension result in a 4- to
syncope [12]. The reflex may be initiated by emotional stimuli in 5-cm cephalad displacement of the diaphragm and a 5- to 7-cm
some individuals or may be initiated by compression of the infe- increase in thoracic circumference. This results in a decrease in
rior vena cava by the gravid uterus causing a decrease in venous expiratory reserve volume, residual volume, and functional
return and intracardiac pressure. Less common conditions that residual capacity. There is a compensatory increase in inspira-
may present with symptoms of syncope include cerebrovascu- tory capacity, while total lung capacity and vital capacity do not
lar accidents, seizures, cardiac arrhythmias or valvular disease, change [14]. Chest wall compliance is increased, but inspiratory
cardiomyopathy, pericardial tamponade, myocardial infarction, muscle strength is preserved with an overall increase in the oxy-
congenital heart defects, thromboembolic phenomenon, anemia, gen cost of breathing [14]. However, it is important to recognize
hypoglycemia, or electrolyte disorders [12]. Further evaluation for that there is no significant change in the parameters of forced
such conditions should be prompted when an apparent syncopal vital capacity, peak expiratory flow rate (PEFR), or forced
episode is accompanied by focal neurologic findings, prolonged expiratory volume in 1 second (FEV1) during pregnancy.
Physiologic dyspnea of pregnancy, experienced by 60%–70% of serum by the time of missed menses and peaks at 10 weeks’ ges-
healthy pregnant women, must be clinically distinguished from tation, then declines over the course of the second and third tri-
more serious respiratory conditions. Physiologic dyspnea tends to mesters [18]. Relaxin is secreted by the corpora lutea of pregnancy
be an isolated symptom that begins in early pregnancy, plateaus and is thought to have an important role in early pregnancy
or improves as pregnancy progresses, and does not interfere with maintenance that has not yet been clearly elucidated [19]. hCG
daily activities [16]. The mechanism for physiologic dyspnea has also peaks at approximately 10 weeks’ gestation. The reproduc-
not been conclusively defined, but pregnant women with dyspnea tive hormones estradiol, progesterone, testosterone, prolactin,
have been demonstrated to have an increase in minute ventilation and 17-hydroxyprogesterone all increase significantly during
and tidal volume and a decrease in end-tidal CO2 pressure com- gestation. Initially the corpus luteum and maternal ovarian tissue
pared to pregnant women who do not report dyspnea [16]. The make the greatest contribution to steroid hormone concentra-
perception of physiologic dyspnea during pregnancy has been tions, but as of 9 weeks’ gestation, aromatization of dehydroepi-
associated with increased sensitivity to hypoxia and hypercapnia, androsterone sulfate by the placenta becomes the predominant
suggesting an increased chemosensitivity causing an increased source of maternal steroids [20]. The elevated estradiol levels
central inspiratory drive in pregnant women who experience dys- stimulate increased hepatic production of sex hormone–binding
pnea. However, the chemical stimuli of hypoxia and hypercapnia globulin and thyroxin-binding globulin. Estrogen also induces
are both reduced in pregnancy, causing others to suggest a neural hypertrophy and hyperplasia of pituitary lactotrophs with a resul-
mechanism [14]. In spite of the common symptom of physiologic tant increase in prolactin levels corresponding to the increase in
dyspnea, pregnancy has not been found to be associated with estradiol levels throughout gestation [20]. Meanwhile, there is a
a decrease in aerobic work capacity or with an increased per- reflexive decrease in follicle-stimulating hormone and luteinizing
ception of breathlessness during exercise [14]. On the contrary, hormone to almost undetectable levels, as would be expected.
exercise in pregnancy has been noted to increase the rate of vagi- One longitudinal study assayed reproductive hormone levels in
nal delivery and decrease rates of gestational diabetes, hyperten- the blood of 60 healthy women drawn during the first, second, and
sive disorders of pregnancy, and preterm birth [17]. third trimesters of uncomplicated pregnancies [20]. Mean proges-
While measurement of FEV1 requires a spirometer, measure- terone levels increased steadily from 49 nmol/L at 5 weeks’ gesta-
ment of PEFR correlates well with FEV1 and can be measured tion to 584 nmol/L at term. Mean 17-hydroxyprogesterone levels
with a relatively inexpensive spirometer (peak flow meter), which are more stable during the first and second trimesters at 12.2
patients can be taught to use at home. Again, these parameters nmol/L but then increase threefold to 36 nmol/L by term. Mean
do not change due to pregnancy, so any detected worsening testosterone increased from 3.3 nmol/L at 5 weeks to 5.7 nmol/L
should be treated appropriately and not attributed to preg- at 40 weeks. Mean serum estradiol levels increased during the first
nancy or to physiologic dyspnea. In the evaluation of severe trimester from 1.64 nmol/L at 5 weeks to 11.13 nmol/L at 16 weeks
acute asthma exacerbations with the potential for impending and then increased fivefold to 53.44 nmol/L at 40 weeks. Mean
respiratory arrest, knowledge of physiologic changes of preg- sex hormone–binding globulin levels increase rapidly during the
nancy is particularly important in the interpretation of blood first half of gestation, from 71 nmol/L at 5 weeks to 392 nmol/L
gases (Table 3.1). The normal parturient lives in a state of com- at 25 weeks, and then remain relatively constant until 40 weeks.
pensated respiratory alkalosis with a lower partial pressure of Mean levels of dehydroepiandrosterone sulfate decreased from
carbon dioxide (PCO2) compared to that of nonpregnant patients. 5.8 mmol/L at 5 weeks to 2.7 mmol/L at midgestation, where they
Thus, significant CO2 retention may be present in spite of values remained rather constant until term. Mean prolactin concentra-
that are high-normal for nonpregnant patients. tion rose from 294 milli-international units (mIU) to 1106 mIU at
While physiologic dyspnea and asthma exacerbation are two 16 weeks. Prolactin levels then continued to increase to a mean of
of the most common causes of dyspnea in pregnancy, the obste- 4092 mIU at 35 weeks and to 4293 mIU at 40 weeks. Mean andro-
trician must also be alert to other pulmonary complications to stenedione levels increase gradually from 8.1 nmol/L at 5 weeks to
which the parturient is susceptible, such as pulmonary embolism 10.6 nmol/L at 40 weeks [14].
and pulmonary edema. Pulmonary edema may occur as a result Other hormonal alterations include an increase in aldosterone,
of preeclampsia, peripartum cardiomyopathy, or the use of cer- cortisol, parathyroid hormone, parathyroid-related hormone,
tain tocolytics. It is important that the prevalence of pulmonary and renin [2]. Deoxycorticosterone increases. Androstenedione
symptoms in pregnancy not be met with complacency by the increases with an increase in the transformation to estrone and
obstetrician, for it may signify a life-threatening condition for the estradiol [1]. Fasting levels of both insulin and glucagon increase [1].
pregnant woman. There is an increase in melanocyte-stimulating hormone to which
can be attributed the pregnancy-related increases in pigmentation
Endocrine seen in the areola and the linea nigra and in chloasma [1].
The function of the thyroid gland is crucial to a healthy gesta-
Pregnancy-related endocrine alterations include the production tion (see also Chaps. 6 and 7 in Maternal-Fetal Evidence Based
of hormones that are specific to pregnancy, an increase in other Guidelines). The interplay between maternal and fetal thyroid
reproductive hormones, and alterations in the level and function function can cause confusion for the obstetrician. Early fetal
of nonreproductive hormones, especially of thyroid hormones. development is dependent on maternal thyroid function, and
There is a significant contribution of steroid hormone secretion both hypothyroidism and hyperthyroidism can have important
by the fetal-placental unit. This section provides a brief descrip- maternal and fetal effects. The risks of thyroid dysfunction extend
tion of the changes in reproductive hormones during gestation well into the postpartum period. The effects of subclinical thyroid
followed by a more in-depth review of the behavior and clinical disease are more controversial. Symptoms of hyperthyroidism
application of thyroid hormones during pregnancy. and hypothyroidism can mimic symptoms of normal pregnancy.
Pregnancy-specific hormones include human chorionic For example, symptoms such as fatigue, muscle cramps, palpita-
gonadotropin (hCG) and relaxin. Relaxin is detectable in maternal tions, thyromegaly, and constipation can be common in normal
pregnancy, but progressive symptoms of insomnia, intellectual pregnancy showed no difference in pregnancy complications or
slowness, or weight loss should be evaluated [21]. in perinatal morbidity and mortality in women with subclinical
Thyroid-binding globulin increases due to stimulation of synthe- hyperthyroidism [24].
sis by estrogen as well as decreased hepatic clearance. Total thyrox-
ine (TT4) and total triiodothyronine (TT3) both increase, while Hematologic
resin triiodothyronine uptake (RT3U) decreases. Structural
similarities between hCG and thyroid-stimulating hormone (TSH) Pregnancy is characterized by both quantitative and qualitative
may result in an hCG-mediated increase in free thyroxine (FT4) changes in the hematologic system. These changes can be adap-
and the free thyroxine index, as well as a decrease in TSH in the tive to normal pregnancy but can also put the pregnant women
first trimester. However, these changes, sometimes referred to as at increased risk for certain pathologic conditions. Anemia and
gestational transient thyrotoxicosis, are typically self-limited and thrombocytopenia are commonly diagnosed during pregnancy,
do not tend to result in values that are outside the normal range as will be discussed later. Measurements of the acute-phase
for nonpregnant individuals. TSH levels normalize in the second response, such as erythrocyte sedimentation rate, C-reactive
trimester and increase again in the third trimester due to increased protein, and white blood cell count, have been found to increase
need for thyroid hormone (see also Chaps. 6 and 7 in Maternal- during pregnancy. This presents a challenge in the evaluation of
Fetal Evidence Based Guidelines) [21]. pregnant women suspected to have various infectious or inflam-
Iodine requirements during pregnancy increase by greater matory conditions, but careful clinical assessment allows the
than 50% due to increased maternal thyroxine production to practitioner to distinguish between physiologic and pathologic
maintain maternal and fetal euthyroidism and increased renal abnormalities in these tests. Pregnancy also has important effects
iodine clearance [22]. Plasma iodine levels decrease. This is on the coagulation system, with the creation of an overall hyper-
associated with an increase in the size of the maternal thyroid coagulable state. This section also reviews the theories and
gland. Longitudinal studies of thyroid ultrasonography in preg- limitations of the evidence surrounding the diagnosis of throm-
nancy show a mean increase in thyroid size of 10%–30%, which is bophilia during pregnancy.
noticeable in most women but not associated with abnormalities Anemia is usually defined as a hemoglobin less than 11 g/
in thyroid function tests [21]. Iodine supplementation results in a dL and hematocrit less than 33% in the first trimester, hemo-
less substantial increase in thyroid gland size [22]. While ultra- globin less than 10.5 g/dL and hematocrit less than 32% in the
sound or laboratory evaluation is not necessary in the pregnant second trimester, and hemoglobin less than 11 g/dL and hema-
patient with a mild diffuse increase in thyroid size, a significant tocrit less than 33% in the third trimester (see also Chap. 14
goiter or thyroid nodule must be evaluated, as in any patient. A in Maternal-Fetal Evidence Based Guidelines). Anemia may be
woman who is marginally iodine deficient may be able to com- caused by decreased production of red blood cells, increased
pensate with increased thyrotropin stimulation of the thyroid to destruction of red blood cells, or blood loss. Anemia in preg-
achieve euthyroidism but become hypothyroid when faced with nancy is complicated by increased iron requirements and an
the increasing iodine requirements of pregnancy [22]. expanded blood volume. Blood volume increases by about 50%,
Thyroid homeostasis is important for healthy fetal develop- while red blood cells increase by only about 25%, resulting in
ment. The fetal thyroid begins to concentrate iodide at 10–12 an anemia of dilution, as measured by hemoglobin and hema-
weeks. Thyroid hormone necessary for fetal brain development tocrit, that is physiologic in pregnancy. Iron requirements
before this time must be provided by the maternal system [21, 23]. increase in order to support the increase in red blood cell mass,
Thyroid hormone synthesis in the fetus is controlled by the fetal to meet the requirements of the fetus and placenta, and to pre-
pituitary gland by 20 weeks. Small amounts of T4 and T3 pass pare for blood loss during delivery. Iron-deficiency anemia is
the placenta, but TSH does not cross the placenta. Thyroid- characterized by microcytosis and hypochromatosis. Iron stud-
releasing hormone (TRH) and iodide do cross the placenta ies reveal a decrease in total iron and ferritin and an increase
[21]. Maternal hypothyroidism has been associated with abnor- in total iron-binding capacity (TIBC). Ferritin levels have the
mal intelligence quotient testing and pediatric neurodevelop- highest sensitivity and specificity for iron deficiency, with levels
ment in offspring, particularly when untreated [23]. While severe less than 10–15 μg/dL being diagnostic of iron deficiency [25].
maternal iodine deficiency can lead to cretinism in the offspring, Iron supplementation, as well as screening for iron deficiency,
it is less clear whether mild-to-moderate iodine deficiency leads during pregnancy is recommended by the Centers for Disease
to more subtle cognitive or neurologic dysfunction. Iodine sup- Control and Prevention (CDC). The typical diet contains 15 mg
plementation in iodine-deficient populations has been found to of elemental iron per day, while the recommended dietary daily
substantially reduce the relative risk of cretinism and to improve allowance during pregnancy is 27 mg/day (see Chap. 14 in
psychomotor and cognitive test scores in the offspring [22]. Maternal-Fetal Evidence Based Guidelines) [26].
Hyperemesis gravidarum is associated with elevated levels Iron-deficiency anemia in pregnancy has been associated
of hCG, an increase in FT4, and a decrease in TSH (biochemical with an increased risk of low birth weight, prematurity, perina-
hyperthyroidism). However, this is largely transitory and rarely tal mortality, postpartum depression, and poor mental and psy-
associated with clinical hyperthyroidism. Thus routine measur- chomotor testing in offspring. Severe anemia (less than 6 g/dL)
ing of thyroid function in hyperemesis is not indicated in the has been associated with abnormal fetal oxygenation, abnormal
absence of other signs of hyperthyroidism such as weight loss or fetal heart rate patterns, reduced amniotic fluid volumes, cere-
persistent tachycardia [21]. Furthermore, treatment of transient bral vasodilation, and fetal death. Transfusion may be indicated
hyperthyroidism associated with elevated hCG and hyperemesis for fetal indications in the case of anemia of this severity [26].
should not be undertaken in the absence of evidence of intrin- Factors that increase the risk for iron deficiency in pregnancy
sic thyroid disease (see also Chap. 9 in Maternal-Fetal Evidence include young maternal age, heavy menses, short interpreg-
Based Guidelines) [21]. A large prospective observational study nancy interval, low socioeconomic status, and non-Hispanic
of 25,765 pregnant women who underwent thyroid screening in black race [26]. Dietary factors can have a significant effect on
iron levels, not only due to levels of consumption of iron-rich less than 50,000/µL [28, 29]. This may result in findings such as
foods but also due to consumption of foods that significantly purpura, ecchymosis, or melena. Less commonly, fetal intracra-
enhance or inhibit iron absorption. nial hemorrhage develops in 1% of deliveries, unrelated to mode
Megaloblastic macrocytic anemia may be caused by defi- of delivery. Therefore, the American Congress of Obstetricians
ciency of folic acid and vitamin B12 and by pernicious anemia. and Gynecologists (ACOG) recommends no change in the route
Nonmegaloblastic macrocytic anemia may be caused by alcohol- of delivery based on ITP alone. However, the use of vacuum
ism, hypothyroidism, liver disease, aplastic anemia, or increased extractors and fetal scalp electrodes should be avoided due to the
reticulocyte count. The most common cause of onset of macro- increased risk of hemorrhage [27].
cytic anemia during pregnancy in the United States is folic acid Onset of thrombocytopenia during the third trimester should
deficiency [26]. During pregnancy, daily folic acid requirements prompt consideration of hypertensive disorders of pregnancy,
increase from 50 μg to 400 μg [26]. Women who have had gastric which are associated with 5%–21% of cases of maternal throm-
surgery and those with Crohn disease may be at risk of vitamin bocytopenia, and decreasing platelet count is considered a sign
B12 deficiency in pregnancy [26]. of worsening of disorders of this spectrum (see also Chap. 1 in
The performance of complete blood counts as a part of routine Maternal-Fetal Evidence Based Guidelines). When combined
prenatal screening results in a frequent diagnosis of thrombo- with hemolytic anemia and elevated liver tests, thrombocyto-
cytopenia in asymptomatic pregnant women. The mean platelet penia is indicative of the diagnosis of hemolysis, elevated liver
count in pregnant women is lower than in nonpregnant women enzymes, and low platelet count (HELLP) syndrome. These dis-
(average 213,000/µL), with 7%–12%% of pregnant women meet- orders are associated with an increase in platelet consumption,
ing criteria for the diagnosis of thrombocytopenia by delivery but the underlying physiology is not known. Platelet function may
[27]. Manifestations of thrombocytopenia include epistaxis, be reduced even if platelet counts are normal, and thrombocy-
petechiae, and ecchymosis, although frequently there are no topenia may occur prior to other manifestations of gestational
clinically significant effects. Clinically significant spontaneous hypertension. Hemorrhage is uncommon in the absence of dis-
bleeding is rare except with exceptionally low platelet counts, and seminated intravascular coagulation. Neonatal thrombocytope-
platelet transfusion is only recommended for surgery if platelet nia following gestational hypertension is increased in premature
count is less than 50,000/µL [27]. The most common cause of infants but not in term infants [27].
thrombocytopenia in pregnancy is gestational thrombocyto- Pregnancy is associated with significant alterations in the
penia, which is an apparently benign condition whose underlying coagulation system. There is a decrease in protein S levels as
physiology is not well understood. However, thrombocytopenia well as in coagulation factors XI and XIII. There is an increase
in pregnancy may also be caused by more severe underlying con- in coagulation factors I, VII, VIII, IX, and X. D-dimer and
ditions such as preeclampsia, human immunodeficiency virus fibrinogen levels also increase. The overall result is the cre-
infection, immune thrombocytopenic purpura (ITP), systemic ation of a hypercoagulable state that is exacerbated by venous
lupus erythematosus, antiphospholipid antibody syndrome, stasis and compression of the inferior vena cava and pelvic veins
hypersplenism, disseminated intravascular coagulation, throm- by the enlarging uterus [30]. This places the pregnant woman at
botic thrombocytopenic purpura, hemolytic uremic syndrome, increased risk for such phenomena as deep venous thrombosis
congenital thrombocytopenia, or medication effect [27]. Most of and pulmonary embolism, which are further elevated when preg-
these conditions can be ruled out by history, physical exam, and nancy is associated with other high-risk states such as obesity,
exclusion of underlying diagnoses. prolonged immobility (bed rest), or surgery (see also Chap. 28
The most difficult differential usually comes down to gestational in Maternal-Fetal Evidence Based Guidelines). Consideration of
thrombocytopenia versus ITP. These conditions cannot be reli- these risks is important in the evaluation of the pregnant patient
ably differentiated with antiplatelet antibody testing or any other with unilateral lower extremity edema or acute dyspnea. They
diagnostic test. A platelet count <100,000/µL is typically more also warrant caution and the responsibility to practice evidence-
concerning for ITP, and a platelet count <50,000/µL is almost based medicine rather than erroneously recommending “bed
certainly ITP as opposed to gestational thrombocytopenia rest” for treatment of conditions ranging from threatened abor-
[27]. In order to be classified as gestational thrombocytopenia, tion, to preterm contractions, to gestational hypertension.
several conditions must be satisfied. Gestational thrombocy-
topenia is mild, with platelet counts typically greater than Gastrointestinal
75,000/µL. There is no history of significant bleeding and no
history of thrombocytopenia prior to pregnancy. Platelet counts Changes in gastrointestinal physiology lead to some of the most
generally return to normal within 4–8 weeks following delivery, commonly described discomforts of pregnancy ranging from
and there is an extremely low risk of fetal or neonatal thrombocy- nausea and vomiting in early pregnancy to more persistent symp-
topenia. ITP is a clinical diagnosis and a diagnosis of exclusion of toms of gastroesophageal reflux and constipation. However, gas-
other systemic disorders known to be associated with thrombo- trointestinal symptoms may reflect coexisting diseases or may
cytopenia. Although it can be associated with elevated antiplate- even herald life-threatening complications of pregnancy such as
let antibodies, this is not a recommended part of the diagnostic severe preeclampsia and HELLP syndrome or acute fatty liver of
evaluation [27]. pregnancy (AFLP). Once again, it becomes crucial for the obstet-
Women with gestational thrombocytopenia are not at risk for ric care provider to be skilled in recognizing signs and symptoms
maternal or fetal hemorrhage or bleeding complications [27], that result from normal pregnancy physiology and distinguishing
whereas immunologic thrombocytopenia such as ITP and neona- those of more serious conditions.
tal alloimmune thrombocytopenia (NAIT) have the potential for There are several recognizable effects of pregnancy on gastro-
fetal complications. Both are characterized by increased platelet intestinal function. Gastric secretion acidity declines but volume
destruction. In retrospective studies, 8%–20% percent of neo- increases, and relaxation of the cardiac sphincter leads to greater
nates born to mothers with ITP may develop platelet counts esophageal reflux [1]. Combined with a decrease in gastric and
intestinal motility, this leads to the “full stomach” effect that uremia, ovarian torsion, kidney stones, and degenerating myoma.
puts pregnant women at increased risk of aspiration. This, com- Nausea and vomiting may also be due to metabolic disorders such
bined with increased airway edema, increases the risks of general as diabetic ketoacidosis, porphyria, Addison disease, and hyper-
endotracheal anesthesia during pregnancy. Thus, for anesthe- thyroidism or neurologic disorders such as pseudotumor cerebri,
sia purposes, all pregnant women are considered to have a full vestibular lesions, migraines, or central nervous system tumors.
stomach. Precautions to reduce aspiration risk include the use of Finally, drug-related toxicity, psychologic factors, or pregnancy-
nonparticulate oral antacids prior to induction of anesthesia, the related complications such as preeclampsia and AFLP may pres-
use of rapid-sequence induction methods, and the use of a cuffed ent with nausea and vomiting [33].
endotracheal tube [1]. Patients who are taking a multivitamin at the time of concep-
During pregnancy, there is a decrease in colonic motility and an tion have reduced rates of nausea and vomiting [33]. There is good
increase in water absorption, leading to constipation as a com- evidence to support the use of vitamin B6 alone or combined with
mon complaint among pregnant women. A prospective study of doxylamine for the treatment of nausea and vomiting in pregnancy.
constipation in pregnancy found that one in two women reports Ginger supplements have also been shown to reduce severity of
constipation at some point in pregnancy, with rates of 24%, 26%, nausea and vomiting [33, 35]. Numerous antiemetics have also
16%, and 24% in first, second, third trimesters, and postpartum, shown acceptable safety and efficacy against nausea and vomiting,
respectively. Constipation is more likely in women with a prior with no antiemetics demonstrating superiority in a meta-analysis
history of constipation and in women taking iron supplements. [36]. A single database study of 1349 patients demonstrated an
The study did not include nonpregnant controls, but historic con- increase in cardiac septum defects with Zofran administered in
trols indicate a constipation rate of 7% in a similar age group [31]. early pregnancy (odds ratio [OR] 1.62, 95% CI 1.04–2.14) [37], but
The most common gastrointestinal symptom of pregnancy this should not stop providers from prescribing Zofran if it effects
is nausea and vomiting (see also Chap. 9 in Maternal-Fetal symptomatic relief. Hospitalization, intravenous fluids, and enteral
Evidence Based Guidelines). As many as 80% of women report nutrition may be used in rare cases of continued weight loss in spite
nausea during pregnancy, and it is also the most common rea- of these therapies (see also Chap. 9 in Maternal-Fetal Evidence
son for hospitalization in the first trimester [32, 33]. Nausea is Based Guidelines). Treating nausea and vomiting earlier in the
generally considered a normal symptom of early pregnancy, and course can help prevent progression to hyperemesis and the need
morning sickness has been associated with improved pregnancy for these more invasive treatments [33].
outcomes such as reduced risk of miscarriage, preterm birth, low
birth weight, and perinatal death. This is theorized to be due to a Renal system and homeostasis
placental etiology for nausea and vomiting, which is increased by
early development of a healthy and robust placenta [33]. However, Pregnancy-related changes in the urinary tract include dilation of
the exact etiology of this symptomatology is not known. It has calyces, pelvis, and ureters. Ureteral dilatation and mild hydrone-
been hypothesized that nausea and restricted intake in the phrosis may be noted as early as the first trimester and is present
mother create an environment that is favorable for early placental in 90% of gravidas by term. Obstructive and humoral mecha-
development [34] or that it confers an evolutionary advantage by nisms have been proposed for this dilatation, with obstruction
causing the mother to avoid the ingestion of foods that may be by the gravid uterus and ovarian venous plexus likely causing the
dangerous to the developing fetus [33]. Numerous psychological dilatation above the pelvic brim [38, 39]. Dextrorotation of the
theories have also been proposed to explain the phenomenon of gravid uterus, likely due to the sigmoid colon on the left and pos-
nausea and vomiting in pregnancy. Nausea in pregnancy is com- terior to the uterus, causes the mechanical obstruction at the pel-
monly attributed to hCG levels, but conclusive evidence of the vic brim on the right more than the left. One important adverse
underlying physiology is lacking. Experience of nausea is also cor- consequence of this ureterocalyceal dilatation is the increased
related with elevated estradiol levels and inversely correlated with incidence of pyelonephritis among gravidas with asymptomatic
prolactin levels [32]. Estrogens in oral contraceptive pills have bacteriuria.
shown a dose-related effect of nausea and vomiting. Smoking There are significant increases in renal blood flow and in
decreases both hCG and estrogen, and a reduced rate of nausea glomerular filtration rate (GFR) in pregnancy [1]. Indeed, GFR
and vomiting of pregnancy has been demonstrated in smokers. increases up to 50% higher than in the nonpregnant state. As a
Increased placental mass, as found in multiple gestations and ges- result, serum urea and creatinine levels decline in pregnancy [40].
tational trophoblastic disease, has been found to increase the risk This can have significant effects on renal clearance of vitamins
of nausea and vomiting and of hyperemesis gravidarum [33]. and pharmaceutical agents. There is a lowering of the threshold
It is important for nausea and vomiting of pregnancy to be for glucose excretion, which may result in significant random
distinguished from that resulting from other pathologic condi- glucosuria even in the absence of gestational diabetes. This gly-
tions. Complacency in the evaluation of pregnant patients with cosuria may also contribute to the increased susceptibility of
nausea and vomiting may result in undertreatment of distressing pregnant women to urinary tract infections.
symptoms, development of hyperemesis gravidarum, or failure There is also a marked increase in ureteral pressure in the third
to diagnose a coexisting underlying disease. Nausea and vom- trimester while standing or sitting that is decreased when in the
iting of pregnancy typically start before 9 weeks’ gestation and lateral recumbent position [38]. This has implications for collec-
are not accompanied by fever, abdominal pain, or headache [33]. tion of 24-hour urine samples, as retention of urine in the dilated
Deviation from this presentation should prompt evaluation for collecting system may result in an incomplete sample. This may
other etiologies. The differential diagnosis includes gastrointes- be alleviated by instructing the patient to lie in the lateral recum-
tinal disorders such as gastroenteritis, gastroparesis, achalasia, bent position for about 45 minutes before the discard void prior
biliary tract disease, hepatitis, intestinal obstruction, peptic ulcer to starting the collection and again before the final void of the
disease, pancreatitis, and appendicitis. Genitourinary condi- sample [38]. Proteinuria is considered abnormal if excessive of
tions that may cause nausea and vomiting include pyelonephritis, 300 mg/24 hours in pregnant patients [38].
Relaxin and nitric oxide (NO) have been implicated as key fac- 3. Curry AE, Vogel I, Skogstrand K, et al. Maternal plasma cytokines in early-
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maternal factors. J Reprod Immunol 2008;77(2):152–60.
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6. ACOG Practice Bulletin No. 211: Critical care in pregnancy. Obstet Gynecol
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average by 3–4 mEq/day, ultimately producing a net balance of dynamics during pregnancy: A series of meta-analyses. Heart 2016;102(7):
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4
ULTRASOUND
L. M. Porche, S. P. Chauhan, and A. Abuhamad
Key points Safety of ultrasonography

• There is no evidence that ultrasound examination dur- The main concern about the safety of ultrasound is based on tis-
ing pregnancy is harmful. Prenatal exposure to ultra- sue temperature elevation from energy transfer and its possible
sound is not associated with adverse influence on school effect of cavitations, or the formation of microbubbles in the tis-
performance, physical, or neurologic function. sues exposed to ultrasound waves. The effect of ultrasound on
• Ultrasound should be performed by trained and experi- tissues has been studied with animal experimentation and has
enced professionals, with continuing education and ongo- suggested an adverse effect. In humans, however, the informa-
ing quality-monitoring programs. tion comes from epidemiologic data and population studies. No
• Routine use of ultrasound in pregnancy increases early epidemiologic studies have shown harmful effects in humans.
detection of multiple pregnancies, major fetal anoma- There is no consistent evidence that ultrasound examina-
lies, abnormalities of amniotic fluid, and fetal growth. tion during pregnancy is harmful. Studies have shown that
• Ultrasound examination is the best method to estimate prenatal exposure to ultrasound is not associated with adverse
accurate gestational dating in pregnancy. effects on children’s physical or cognitive development [1]. Even
• Ultrasound dating in the first trimester is most accurate multiple ultrasound exams during pregnancy were not shown to
for gestational age assessment. Ultrasound examination at adversely affect speech, language, behavior, or neurologic func-
first prenatal visit (usually first trimester) versus at 18–20 tion on postnatal follow-up at 8 years of age [2]. In a randomized
weeks provides more precise estimate of gestational age trial comparing those receiving a second-trimester ultrasound to
and may be associated with less maternal worry. First- those who remained unexposed, there was no significant differ-
trimester ultrasound allows earlier detection of multiple ence in school performance up to age 15–16 [3]. Overall, ultra-
pregnancies, screening for Down syndrome with nuchal sound in pregnancy is not associated with adverse maternal or
translucency, and diagnosis of nonviable pregnancies. perinatal outcome; however, there may be a weak association
• All pregnant women should also be offered a second- between exposure to ultrasound and non-right-handedness in
trimester ultrasound for optimal anatomy evaluation. If boys [4].
only one ultrasound will be done in pregnancy, it should Despite the lack of evidence suggesting harmful effect, ultra-
be done in the second trimester at about 20 (18–22) weeks. sound is a form of energy and may produce secondary effects
• Measurement of cervical length (CL) by transvaginal in the tissues it traverses. Obstetrical ultrasound in pregnancy
ultrasound (TVU) has been shown to be an effective predic- should be considered a medical procedure for the evaluation of
tor of preterm birth. When a short CL ≤25 mm is detected the fetus and maternal pelvic organs. Current expert consensus
before 24 weeks, interventions such as vaginal progester- recommends that ultrasound be only performed with valid
one in singletons without prior preterm birth (PTB) and medical indications, with the shortest duration possible and
cerclage in singletons with prior PTB (these women would at the lowest settings. Adhering to the ALARA principle (As
already be on progesterone, given the prior PTB) have been Low As Reasonably Achievable) helps avoid unnecessary expo-
associated with a decrease in PTB and perinatal morbidity sure to ultrasonic waves. Sonographers and sonologists should
and mortality. familiarize themselves with the mechanical and thermal indices
• In low-risk or unselected populations, routine third- during ultrasound examinations. Exposing the fetus to ultraso-
trimester (>24 weeks) pregnancy ultrasound has not nography with no anticipation of medical benefit is unjusti-
been associated with improvements in perinatal mor- fied [5, 6].
tality, albeit the sample size might lack power to detect a
difference. Quality
• In low-risk or unselected populations, routine Doppler
ultrasound examination in the third trimester does not Levels of expertise vary between different health care centers.
reduce perinatal mortality. Since ultrasound efficiency is operator-dependent, continuing
• In pregnancies with fetal growth restriction, umbilical education and ongoing quality-monitoring programs are
artery Doppler assessment is associated with a reduction important strategies in each center offering ultrasound diagno-
in perinatal deaths and obstetric interventions. sis. The ongoing risks of “false-negative” tests and/or misinter-
• Intrapartum ultrasound can be used to assess fetal head pretation of the images obtained (either false-positives or wrong
position and station in the setting of arrested labor or in diagnoses) can be minimized if those examinations are carried
preparation for operative vaginal delivery. out and interpreted by trained and experienced professionals.
• Suspected placenta accreta spectrum should be referred Sensitivity of ultrasound screening for pregnancy varies widely.
to a center with experience diagnosing and managing Appropriate ultrasound laboratory accreditation, certifi-
patients with this condition. cation of staff, documentation of findings, and continuous
48 DOI: 10.1201/9781003102342-4
Ultrasound 49
careful quality control are important components of ultra- Gestational age dating in pregnancy
sound competency [5, 6].
Precise estimation of gestational age is extremely important for
optimal obstetric care, including evaluation of fetal growth, inter-
Informed consent and patients’ expectations
pretation of maternal screening markers, choosing the appropri-
Even though a formal written informed consent is not always ate gestational age to perform interventions, and management of
needed before the examination, every pregnant woman should preterm and late-term pregnancies.
be informed on expectations about the obstetric ultrasound, For gestational age estimation, cardinal numbers should be
as well as its benefits and risks. Patients should know that ultra- preferred to ordinal numbers to avoid confusion. So week 1 is 1–7
sound evaluation is a screening test with wide variations in detec- days after last menstrual period (LMP), week 2 is 8–14 days, etc.
tion rates for fetal anomalies and that all ultrasound diagnoses, In clinical practice, gestational weeks are used to estimate dating,
especially false-positive and false-negative ones, can put both not months. If a lay person asks, “How many months am I?” then
mother and fetus at risk. 6 weeks of gestation can be equated approximately to 1 month,
Whether the sex of the fetus should be revealed to the patient etc., and 38 weeks = 9 months. Definitions of gestational age,
with a singleton gestation should be addressed. It may be harm- while not uniformly accepted, are shown in Table 4.1 [10].
ful for the physician–patient relationship to withhold this Ultrasound examination is the best method to determine
information, especially if the patient previously requested it. gestational age and estimated due date (EDD) [10]. The first day
Although a moral conflict may exist in some cultures around of the LMP should be asked of all pregnant women to determine
the world where this information is used by the patient for vol- when the dating ultrasound should be performed. Compared
untary abortions based on sex selection and sex preferences with LMP, ultrasound-based gestational age is more precise due
[7], in general disclosing fetal gender during ultrasound can to errors in patient recall and variations in cycle length and tim-
benefit not only the doctor–patient relation but also the ing of ovulation [10, 11]. The error, even with certain LMP, is due
parent–child relationship [8]. often to late ovulation (>14 days after LMP). Some have stated
During high-feedback ultrasound scans, women can see the that there is no reason to use LMP for dating when adequate
screen and they receive detailed explanations of the images. In ultrasound data are available by 24 weeks [10, 11].
low-feedback ultrasound scans, only the operator can see the Ultrasound-based gestational age estimates are lower than
screen and the women are told the results at the end of the scan. LMP-based gestational age estimates and generate a higher
Compared to low-feedback ultrasound, women who had high- rate of preterm birth and lower rate of post-term birth. The
feedback fetal ultrasound are significantly more likely to stop Naegele rule (add 7 days to first day of LMP, add 1 year, take back
smoking and avoid alcohol during pregnancy, with a trend favor- 3 months), manual assessment of uterine size, quickening, etc.,
ing the women’s increased use of positive adjectives to describe should not be used unless ultrasound dating is unavailable.
their feelings after the ultrasound [9]. In general, the earlier the ultrasound, the more accurate
the dating. Multiple parameters and equations have been evalu-
ated to estimate gestational age. The crown–rump length (CRL)
Routine vs. selective use of ultrasound is associated with the most accurate estimation, up to and
Routine (i.e. performed on every pregnant woman) ultrasound including 13 6/7 weeks of gestation with an accuracy of ±2–7
examination is associated with the following, compared to selec- days. For pregnancies in the second trimester, beyond 14 weeks’
tive ultrasound examination (i.e. performed only on women with gestation, the head circumference or biparietal diameter (BPD)
specific indications) [1]: appears to be the best single-measurement predictor of gesta-
tional dating. BPD is most accurate for dating early, between 12
1. Increases the early detection of multiple pregnancies. and 14 weeks. Combining three or more parameters improved
2. Increases the detection of major fetal anomalies. dating slightly over a single biometric parameter [12]. A combi-
3. Reduces the incidence of late-term and post-term preg- nation of BPD, head circumference (HC), abdominal circumfer-
nancies and rates of induction of labor for late-term ence (AC), and femur length (FL) is commonly used for dating
pregnancy by allowing a more precise estimation of ges- by ultrasound in the second and third trimesters [13]. Repeated
tational age. examinations improve the prediction only marginally, and the
4. No significant differences are detected for clinical
outcomes such as perinatal mortality. The effect of TABLE 4.1: Definition of Gestational Age Periods in Pregnancy
ultrasound on perinatal mortality is dependent on the
Period Gestational Age (Weeks)
detection rate of fetal malformations and on the uptake
of pregnancy termination for anomalies in the population First trimester 0–13 6/7
at study. Second trimester 14 0/7–27 6/7
Third trimester 28 0/7 to delivery
If one routine ultrasound examination is done, it is usually Preterm 20 0/7–36 6/7
performed at 18–22 weeks (<24 weeks). Earlier examination pro- Late preterm 34 0/7–36 6/7
vides more accurate assessment of gestational age; later examina- Term 37 0/7–41 6/7
tion (e.g. 20–22 weeks) allows more complete inspection of fetal
Early term 37 0/7–38 6/7
anatomy. In the obese population, transabdominal ultrasound
Full term 39 0/7–40 6/7
screening may have better completion rates if delayed by
Late term 41 0/7–41 6/7
2 weeks (20–22 weeks’ gestation) [10], and transvaginal ultra-
sound at 12–16 weeks may offer better fetal anatomy screening Post term 42 0/7 to delivery
(see later in this chapter). Source: Adapted from Ref. [10].
TABLE 4.2: Gestational Age Dating by Ultrasound TABLE 4.3: Indications for First-Trimester Ultrasound
EDD Changed If • Confirmation of the presence of an intrauterine pregnancy
Gestational Age by Best Ultrasound Discrepancy from LMP • Confirmation of cardiac activity
Ultrasound (Weeks) Parameter(s) Dates More Than (Days) • Estimation of gestational age
• Diagnosis or evaluation of multiple gestations, including
<9 CRL 5
determination of chorionicity
9 0/7–13 6/7 CRL 7
• Evaluation of suspected ectopic pregnancy
14 0/7–15 6/7 BPD, HC, AC, FL 7
• Evaluation of cause of vaginal bleeding
16 0/7–21 6/7 BPD, HC, AC, FL 10 • Evaluation of pelvic pain
22 0/7–27 6/7 BPD, HC, AC, FL 14 • Evaluation of suspected gestational trophoblastic disease
≥28 0/7 BPD, HC, AC, FL 21 • Assessment for certain fetal anomalies, such as anencephaly
Source: Adapted from Ref. [16]. • Measurement of the nuchal translucency when part of a screening
Note: IVF pregnancies can be dated by the date of embryo transfer minus 14 days program for aneuploidy
to obtain LMP and then EDC by Naegele rule. There is no need to ever • Imaging as an adjunct to chorionic villus sampling, embryo transfer,
change dating in these pregnancies. and localization and removal of an intrauterine device
Abbreviations: CRL, crown–rump length; BPD, biparietal diameter; HC, head cir- • Evaluation of maternal pelvic mass and/or uterine abnormalities
cumference; AC, abdominal circumference; FL, femur length.
Source: Adapted from Refs. [5, 6].
EDD should always be set by the earliest ultrasound due to a

smaller prediction error. While prediction of gestational age by from ovulation induction or other assisted reproductive tech-
ultrasound can be very accurate, prediction of date of delivery nologies, first-trimester bleeding, or increased risk of aneuploidy
remains less accurate, with an error of usually ≥7–8 days, given and should be used if transabdominal examination is inconclu-
other biologic factors. sive for diagnosis. First-trimester screening for congenital defects
Other parameters that may play a role in estimating gestational by transvaginal ultrasound is an option for pregnant women
age include trans-cerebellar diameter (TCD) and long bone mea- who meet certain criteria, such as a very high risk for congenital
surements. The TCD is an accurate predictor of gestational age anomalies (e.g. very elevated Hgb A1c) and who may elect termi-
and can be used between 14 and 28 weeks reliably with the use nation based on abnormal results. It should be done by experi-
of nomograms. There is some reliability in gestational age pre- enced sonographers and the findings confirmed at 18–22 weeks
diction even up to 35 weeks, and TCD is spared the effects from [10]. In a randomized controlled trial (RCT), 38% of major mal-
intrauterine growth restriction and so can be used to assess preg- formations and 69% of lethal malformations were detected by a
nancies at risk for this complication [14]. The presence of epiphy- 12- to 14-week ultrasound [18]. In a meta-analysis, 51% of mal-
ses in the lower extremities usually signifies a gestational age of formations were found to have been detected by 11- to 14-week
>32 weeks [15]. ultrasound [19].
The American College of Obstetricians and Gynecologists The NT is a physiologic fluid-filled space at the back of the
(ACOG) has published specific guidelines to guide amendment fetal neck measured for aneuploidy screening between weeks
of dating when ultrasound and LMP are discrepant. Ultrasound 10 6/7 and 136/7 of gestation. Increase in NT has been associated
dating is adopted when discrepancy is noted. Knowledge about with chromosomal and anatomic abnormalities in the fetus.
LMP, regularity of cycles, oral contraceptive (OCP) use, and First-trimester screening for aneuploidy between 10 6/7 and 13
unusual bleeding are clinically helpful but imprecise regarding 6/7 weeks (or CRL 45–84 mm) combines NT measurement with
dating. Ultrasound dating is best and often corrects dating by maternal serum markers to provide individualized risk assess-
even a “certain” LMP [16]. Table 4.2 shows dating criteria based ment. Early risk determination permits choosing the most
on ultrasound results. appropriate definitive diagnostic procedures, like chorionic vil-
lus sampling, allowing women to prepare for a child with health
problems and also providing the option of earlier pregnancy ter-
Ultrasound examinations by trimester mination (see Chap. 5) [6].
First trimester Indications for first-trimester ultrasound as endorsed by the
Ultrasonographic evaluation in the first trimester (0–13 6/7 weeks) ACOG, American Institute of Ultrasound in Medicine (AIUM),
is the most accurate method to determine exact gestational age, Society for Maternal Fetal Medicine (SMFM), American College
as discussed earlier. Ultrasound examination at the first prena- of Radiology (ACR), and Society of Radiologists in Ultrasound
tal visit versus at 18–20 weeks provides more precise estimate (SRU) are shown in Table 4.3, and essential elements of first-
of gestational age and may be associated with less maternal trimester ultrasound are listed in Table 4.4 [5, 6].
worry. First-trimester ultrasound also allows earlier detec-
tion of multiple pregnancies, nonviable pregnancies, certain Ultrasound diagnosis of anembryonic
fetal anomalies, and screening for Down syndrome and other or embryonic demise
aneuploidy with nuchal translucency (NT) [1, 6, 17]. Current
guidelines recommend the routine use of ultrasound in the first Diagnostic criteria for the diagnosis of nonviable pregnancy in
trimester for the appropriate indications (Table 4.3). Guidelines the first trimester is a subject that has undergone recent revision.
for the performance of the detailed-first trimester ultrasound Balancing risk of harming a viable intrauterine pregnancy must
were recently introduced for high-risk pregnancies [5, 10]. be balanced with intervention for a nonviable one. Some crite-
Transvaginal scanning is preferred for dating early in the ria are routinely used (Table 4.5), usually based on transvagi-
first trimester. It is also useful in cases of a pregnancy resulting nal ultrasound: absence of cardiac activity with an embryo of a
Ultrasound 51
TABLE 4.4: Essential Elements of First-Trimester Ultrasound [23], aberrations in this sequence can indicate abnormal preg-
nancy. Abnormal pregnancy should thus be suspected in the
• Gestational sac (location, mean diameter)
absence of an embryo with a heart beat ≥14 days after seeing
• Yolk sac (diameter)
a gestational sac without a yolk sac, or ≥11 days after presence
• Crown–rump length of embryo (CRL)a
of a gestational sac with a yolk sac [20]. The presence of normal
• Development of fetal anatomy in early pregnancy
embryonic cardiac activity in the uterine cavity in the first tri-
• Fetal viability (cardiac activity should be seen in embryo >7 mm)
mester has a >90% prediction for a live birth in both symptomatic
• Fetal number (amnionicity and chorionicity has to be reported for
and asymptomatic pregnancies (See also Chap. 16).
multiples)
• Ultrasound features of early pregnancy failure (e.g. ectopic
pregnancy, hydatidiform mole) Precautions and pitfalls
• Uterus, adnexa, cervix, and cul de sac
• If possible, the appearance of the nuchal region should be assessed Physiologic midgut herniation is normal at 7–11 weeks; it resolves
and specific measurement of nuchal translucency measured as part at ≥12 weeks; do not confuse with omphalocele. The rhomben-
of desired screening cephalon can appear as a cystic mass up until 8–10 weeks and
• Any other abnormalities (e.g. leiomyomata, etc.) should not be confused with a CNS anomaly; ventriculomegaly
cannot be assessed well in the first trimester. The amnion and
Source: Adapted from Refs. [5, 6, 20].
a CRL is a more accurate indicator of gestational age than gestational sac size.
chorion are expected to be fused by 14 weeks.
Second trimester (aka “Anatomy,”

certain length, absence of an embryo with a gestational sac of a “Morphology,” or “Standard” ultrasound)
certain size, and absence of an embryo by a certain time in preg- If just a single exam is to be done during pregnancy, the best
nancy [20]. timing for such ultrasound screening of the fetal anatomy and
A gestational sac is normally noted within the uterus by 5 weeks dating is the early to mid-second trimester (18–22 weeks) [1] to
of gestation. Shortly thereafter at approximately 5 ½ weeks in a obtain an accurate estimation of gestational age and a satisfac-
normal pregnancy, the yolk sac appears, followed by the fetal pole tory inspection of the fetal anatomy. This is therefore usually
at 6 weeks. When measuring the gestational sac, dimensions are called the anatomy, morphology, or standard ultrasound exami-
recorded in three orthogonal planes; the average of the measure- nation (nomenclature such as Level I, II, etc., ultrasound is con-
ments is the mean sac diameter. A mean gestational sac diam- troversial and less descriptive). All pregnant women should be
eter of ≥25 mm without an embryo is diagnostic of pregnancy offered a second-trimester ultrasound, whether or not they
failure (e.g. anembryonic pregnancy, or blighted ovum) with posi- have had a first-trimester ultrasound. The estimated sensitiv-
tive predictive value approaching 100% [21] (See also Chap. 16). ity to detect fetal anomalies varies widely, with higher rates
An intrauterine gestational sac should be visible by transvaginal of detection for major anomalies than for minor anomalies
ultrasound with a serum beta-human chorionic gonadotropin and some organs (e.g. neural tube defect) vs others (e.g. heart)
(B-hCG) of >1500 mIU/mL. If this is not the case, ectopic preg- [19]. The detection of major fetal anomalies is often reported
nancy should be suspected. at about 50%–70% even in the best centers [18]. The detection
Fetal cardiac activity is usually seen once the fetal pole is vis- of fetal cardiac malformations is particularly poor, with often
ible around 6 weeks of gestation. A CRL cutoff of 5 mm without not more than 20%–30% of major heart malformations detected
cardiac activity was previously used to diagnose nonviable preg- [24]. A “detailed” ultrasound can be performed with the aim
nancy, but a literature review showed that there have been preg- to detect anomalies or markers associated with fetal aneuploidy
nancies that met this criterion that went on to be viable [21, 22]. (see later) [25].
Interobserver variability in measurements can also lead to inac- While the best time for detection of most malformations is
curate diagnosis of failed pregnancy. Adopting a CRL cutoff of around 20–24 weeks, it is important for women to obtain this
7 mm with no visible cardiac activity brings the specificity information as early as possible. In some circumstances, more
of this finding for diagnosing failed pregnancy (e.g. embryonic than one second-trimester ultrasound is necessary, especially if
demise, or missed abortion) close to 100% [20]. the initial second-trimester ultrasound is performed at 18–19
Since the presence of intrauterine structures in a viable preg- weeks. Experts have suggested essential elements for the standard
nancy appear in a predictable sequence at standard time intervals second-trimester ultrasound (Table 4.6) [5, 6].
There can be other types of follow-up ultrasounds. Limited
ultrasound examination is performed when a specific question
TABLE 4.5: Criteria for Diagnosis of Embryonic or requires investigation. Examples include assessment of amniotic
Anembryonic Demise fluid volume, fetal viability, biophysical profile, to guide amnio-
Diagnosis Criteria centesis, to localize the placenta in antepartum bleeding, or to
evaluate fetal position. A limited ultrasound is only appropriate
Anembryonic pregnancy Mean gestational sac diameter ≥25 mm
if a prior complete standard ultrasound examination has been
without an embryo
done. A detailed ultrasound examination should be considered
Embryonic demise CRL ≥7 mm with no visible cardiac activity for a patient who, by history, clinical evaluation, or prior scanning
Anembryonic pregnancy No embryo with cardiac activity: evaluation, is at an increased risk for a fetal anatomic or physi-
≥14 days after gestational sac without yolk sac ologic abnormality. This ultrasound examination must be done
Or by personnel with expertise in obstetric ultrasonography and
≥11 days after gestational sac with yolk sac maternal and fetal diseases [25]. Elements of the detailed exam
Source: Adapted from Ref. [20]. (See also Chap. 16.) can be found in the AIUM Practice Parameter for second- and
Abbreviation: CRL, crown–rump length. third-trimester obstetric ultrasounds [25].
TABLE 4.6: Essential Elements of Standard Second-Trimester evaluations in the third trimester generally involve assessments
Ultrasound of fetal growth, amniotic fluid volume, evaluation of the pla-
centa, and evaluation of fetal well-being (possibly biophysical
System Components
profile or Doppler studies). Examples of possible indications for
Head and neck Lateral cerebral ventricles third-trimester ultrasound based on maternal and fetal risk fac-
Choroid plexus tors are shown in Table 4.7.
Midline falx The third trimester is the time when abnormalities of fetal
Cavum septum pellucidi growth and amniotic fluid become more apparent. One study
Cerebellum showed that routine serial ultrasound examinations in the third
Cisterna magna trimester significantly increased detection of amniotic fluid
Face Upper lip abnormalities and abnormal fetal growth in low-risk women
Chest Cardiac activity when compared to fundal height or indicated ultrasound [26].
Heart Four-chamber view In low-risk women, ultrasound examinations at 30–32 weeks
Thorax Left ventricular outflow tract and at 36–37 weeks significantly decrease the likelihood of
Right ventricular outflow tract newborns with growth restriction, though they do increase the
Three-vessel view (if technically feasible) rate of antenatal intervention. This RCT included 1998 women,
Three-vessel trachea view (if technically feasible) and investigators calculate over 30,000 women are required for a
Abdomen Stomach (presence, size, situs) trial to show a significant decrease in neonatal mortality [27]. In a
Kidneys meta-analysis, there was no difference in antenatal, obstetric, and
Urinary bladder neonatal interventions in women screened with >24 weeks (late)
Cord insertion site into fetal abdomen ultrasound vs. those not screened. There was a slightly higher
Umbilical cord vessel number caesarean section rate in women screened with late ultrasound,
Spine Cervical but this difference did not reach statistical significance. Routine
Thoracic late pregnancy ultrasound was not associated with improvements
Lumbar in overall perinatal mortality [28]. In a recent RCT, performing a
Sacral spine growth ultrasound at 36 weeks was more sensitive in detecting
Extremities Legs severe fetal growth restriction (FGR) than a scan at 32 weeks (61%
Arms vs. 32%). But despite increased sensitivity, this was not asso-
Hands ciated with significant differences in perinatal outcomes [29].
Feet Routine screening for FGR in the third trimester has been inves-
Genitalia In multiple gestations
tigated also in a large prospective cohort study and may increase
When medically indicated
detection of fetuses that will go on to be small-for-gestational-age
infants, to 57% in routine screening from 20% in selected screen-
Placenta Location
ing [30]. Currently, there are insufficient data to recommend
Relationship to internal os
routine screening for growth restriction in the third trimes-
Appearance
ter without indication, but many experts advocate its routine
Placental cord insertion
use based on the data just described. There are insufficient data
Standard evaluation Fetal number
about the potential psychological effects of routine ultrasound in
Presentation
late pregnancy and limited data about its effects on both short-
Qualitative or semi-quantitative estimate of
and long-term neonatal and childhood outcome.
amniotic fluid
FGR is defined as sonographically estimated fetal weight or
Maternal anatomy Cervix (transvaginal when indicated)
abdominal circumference of less than the 10th percentile for ges-
Uterus
tational age. Recent guidelines recommend a diagnosis of severe
Adnexa
FGR as estimated fetal weight of less than the third percentile
Biometry Biparietal diameter for gestational age. Population-based fetal weight formula, such
Head circumference as the Hadlock formula, is recommended for use. FGR can be
Femur length categorized as early or late onset. Early-onset FGR is diagnosed
Abdominal circumference prior to 32+0 weeks’ gestation. Late-onset FGR is diagnosed
Fetal weight estimate after 32+0 weeks’ gestation. Detailed anatomic survey should be
Source: Adapted from Refs. [5, 6]. completed and genetic screening confirmed. Diagnostic amnio-
centesis with chromosomal microarray should be offered if FGR
Other specialized examinations include but are not limited and fetal anomaly or polyhydramnios is detected regardless of
to fetal Doppler studies, biophysical profile, cervical length, 3D the age at diagnosis. Suggested ultrasound follow-up, antenatal
imaging, and fetal echocardiography (see later). surveillance, and delivery guidelines can be found in the SMFM
consult series on this topic [31] (see Chap. 47 in Maternal-Fetal
Third trimester Evidenced Based Guidelines).
The potential benefit of a third-trimester ultrasound examina- Large for gestational age (LGA) is defined as an estimated
tion greatly depends on the quality of prior ultrasounds and fetal weight or an actual birth weight (BW) of at least the 90th
maternal indications. If the first and only ultrasound is in the percentile for gestational age. At term a fetus can be LGA without
third trimester, it probably has similar benefits to the routine being macrosomic, defined as birth of 4000 grams or more (i.e.
second-trimester ultrasound, with the exception of accurate BW ≥90th percentile but below 4000 grams). At 37–39 weeks,
dating and early anomaly detection of the latter. Ultrasound about 1% of newborns are LGA without being macrosomic.
Ultrasound 53
TABLE 4.7: Suggested Ultrasound Surveillance for Specific Conditions

Frequency of Ultrasounds
Condition Start of Ultrasounds (Weeks) for Growth (Every X Weeks)
Chronic HTN on medications 24 4
Gestational HTN At diagnosis 4
Preeclampsia At diagnosis 4
GDMA1 30–32 once
GDMA2 At diagnosis 4
Pregestational DM on medications 24 4
Fetal growth restriction At diagnosis 3
Maternal age at delivery ≥35 years 30–32 once
Concordant, non FGR di/di twins 24 4
Mono/di twins 24 4
Mono/mono twins 24 3
Prior unexplained IUFD 28 4
SLE or renal disease 24 4
Organ Transplant 28 4
Hypothyroidism or hyperthyroidism 30–32 once
Maternal cardiac disease 28 4
Oligohydramnios (MVP <2 cm) At diagnosis 3–4
Polyhydramnios (MVP >8 cm) At diagnosis 3–4
Sickle cell disease 24 4
Fetal arrhythmia At diagnosis 4
For expanded suggestions for antepartum fetal testing (e.g. NST, BPs, etc.) and timing of delivery, see Chaps. 23 and 58
in Maternal-Fetal Evidence Based Guidelines.
Abbreviations: HTN, hypertension; GDMA, gestational diabetes mellitus; DM: diabetes mellitus; FGR, fetal growth
restriction; di/di, dichorionic diamniotic; mono/di, monochorionic diamniotic; mono/mono, monochorionic mono-
amniotic; IUFD, intrauterine fetal demise; SLE, systemic lupus erythematosus; MVP, maximum vertical pocket.
Compared to newborns whose weight is between the 10th and noteworthy that the ACOG practice bulletin on the topic has a
89th percentile for gestational age, the nonmacrosomic LGA level B (based on limited or inconsistent scientific evidence) rec-
are at increased risk for adverse outcomes for the mother–new- ommendation that induction for macrosomia should be deferred
born dyad, irrespective of whether the individual has diabetes or until 39 weeks. ACOG’s rationale for awaiting delivery until 39
not. The adverse maternal outcomes among these LGA include weeks, rather than at 38 weeks, is that currently there is insuffi-
increased rate of blood transfusion, ruptured uterus, unplanned cient evidence for the benefits of reducing shoulder dystocia out-
hysterectomy, and admission to the intensive care unit (ICU); the weigh the purported harms of early delivery [36].
complications among nonmacrosomic newborns include still- In summary, if on the sonographic exam the fetus is consid-
birth, Apgar score <5 at 5 minutes, assisted ventilation, seizure, ered to be LGA or macrosomic, induction at 38 weeks can be
and neonatal death [32, 33]. considered (see Chap. 48 in Maternal-Fetal Evidenced Based
In the United States, in 2018, there were upward of 290,000 Guidelines).
newborns that were macrosomic [34]. Compared to those with Placental grading as an adjunct to third-trimester ultrasound
BW below 4000 grams, deliveries of those with a weight of at least examination was associated with a significant reduction in the
4000 grams is associated with a significantly increased likelihood stillbirth rate in one 1987 trial [37]. In one study 15,122 patients
of prolonged labor, chorioamnionitis, cesarean delivery, third- or were evaluated for Grannum grade III placental calcifications
fourth-degree laceration, postpartum hemorrhage, shoulder dys- prior to 28 weeks of gestation. Grade III placental appearance
tocia, peripheral neurologic injury, seizure, need for intubation, prior to term was independently associated with increased risk
and neonatal and infant mortality. To avert these multitude of of stillbirth after controlling for tobacco use [38]. A literature
complications, a third-trimester ultrasound exam combined with review from 2018 examined Grannum grade III placentas in the
delivery at term is reasonable. third trimester and their association with poor fetal and neonatal
A meta-analysis by Magro-Malosso et al. [35], which included outcomes. They found a fivefold increased risk for labor induc-
pooled data from four RCTs, reported on 1190 nondiabetic indi- tion (OR 5.41; 95% CI 2.98-9.82). Negative outcomes associated
viduals who were either induced for macrosomia at 38 weeks with grade III placenta include increased meconium in amniotic
or managed expectantly. Compared to expectant management, fluids (OR 1.68; 95% CI 1.17-2.39), low birth weight (odds ratio
those who were induced had a significant decreased rate of frac- [OR] 1.63; 95% CI 1.19–2.22) and perinatal death (OR 7.41; 95% CI
ture and newborns with actual BW ≥4000 grams or of ≥4500 4.94–11.09). On the other hand, there was no significant differ-
grams. The induction, however, did not decrease the rate of shoul- ence in abnormal fetal heart rate tracing, low Apgar score of less
der dystocia, low Apgar score at 7 minutes, brachial plexus palsy, than 7 at 5 minutes, need for neonatal resuscitation, or admission
and intracranial hemorrhage. While the authors of the meta- to the neonatal ICU [39]. More research is needed in placental
analysis advocate for induction for macrosomia at 38 weeks, it is grading before recommendations can be made for its routine
TABLE 4.8: Polyhydramnios

Risk of Fetal Risk of Neonatal
Amniotic Fluid Index Deepest Vertical Pocket Incidence Abnormalitya Abnormalityb
Polyhydramnios, overall, cm ≥24.0 ≥8 cm 0.3%–1.0%
Mild, cm 24.0–29.9 8–11 65%–70% 6%–10% 1%
Moderate, cm 30.0–34.9 12–15 20% of total 10%–15% 2%
Severe, cm ≥35.0 ≥16 <15% of total 20%–40% 10%
Source: Adapted from Ref. [44].
a Chance that fetal anomaly will be identified prenatally.
b Chance that neonatal abnormality will be identified in cases without a detected prenatal anomaly.
use for the prediction of poor perinatal outcome or interven- differences are detected for substantive short-term clinical out-
tions to improve outcomes. comes such as perinatal mortality [45]. On the other hand, the
Oligohydramnios is sonographically defined as a single deep- use of umbilical artery Doppler ultrasound in pregnancies
est vertical pocket of <2 cm or an amniotic fluid index of <5 cm. with FGR is associated with a reduction in perinatal deaths
It can be caused by ruptured membranes, fetal malformations, and obstetric interventions [46]. Guidelines published by the
or maternal conditions that cause poor placenta perfusion [40]. SMFM confirm a decrease in induction of labor, cesarean deliv-
It is associated with increased risk for stillbirth, cord compres- ery, and perinatal death with use of umbilical artery Doppler
sion, and compromised fetal lung development depending on the assessment in high-risk pregnancies with FGR. Surveillance with
gestational age at onset. One meta-analysis showed that when umbilical artery Doppler studies should be started once growth
compared to women with normal amniotic fluid, those with restriction is suspected in the viable fetus [31, 47]. Guidelines for
oligohydramnios at term had significantly higher rates of labor the technical aspects of Doppler use in pregnancy are available
induction (OR 7.56, CI 4.58–12.48) and cesarean section (OR [48] (see Chap. 47 in Maternal-Fetal Evidence Based Guidelines).
2.07, CI 1.77–2.41). There were higher rates of an Apgar score <7
at 1 and 5 minutes (OR 1.53, CI 1.03–2.26 and OR 2.01, CI 1.3– Middle cerebral artery
3.09, respectively) and admission to the neonatal ICU (OR 1.47, CI Fetal middle cerebral artery (MCA) peak systolic velocity (PSV)
1.17–1.8). They found no difference in cord pH <7.1 or meconium Doppler has been used to evaluate fetal anemia in cases of mater-
[41]. The ACOG recommend starting antenatal surveillance for nal red cell alloimmunization, parvovirus infection, or twin–
diagnosis of oligohydramnios at 28 weeks’ gestation or at the time twin transfusion syndrome in monochorionic twins. Fetal MCA
of diagnosis [42], and delivery is currently recommended between Dopplers are considered a screening test that requires a confir-
36+0 and 37+6 weeks’ gestation [43]. matory test for diagnosis (fetal blood sampling) at the initiation
Polyhydramnios is sonographically diagnosed as a single of therapy (transfusion). MCA-PSV is regarded as the best non-
deepest vertical pocket of ≥8 cm or amniotic fluid index of ≥24 invasive screening test for fetal anemia [49, 50] (see Chap. 55 in
cm (preferred) after 20 weeks’ gestation. Once polyhydramnios Maternal-Fetal Evidence Based Guidelines).
is diagnosed, a detailed ultrasound should be performed to rule
Ductus venosus
out fetal anomaly such as gastrointestinal obstruction, cranio-
The ductus venosus (DV) is a vascular shunt that connects the
facial abnormality, neuromuscular problems, or abnormality
umbilical vein to the inferior vena cava in the fetus. This wave-
leading to high-output heart failure. Results of oral glucose
form is reflective of downstream pressure in the right atrium. In
tolerance testing should also be confirmed, as osmotic diure-
high-resistance states (increased uteroplacental resistance), the
sis from gestational diabetes can also lead to polyhydramnios.
DV shows absent or reversed flow in late diastole. A small retro-
Polyhydramnios is considered mild if the single deepest verti-
spective study showed that reversed flow in the DV in addition to
cal pocket is 8–11 cm or the amniotic fluid index is 24–29.9 cm
increased MCA is associated with perinatal mortality in fetuses
(Table 4.8). Mild polyhydramnios can be monitored, but ante-
less than 32 weeks’ gestation [51]. A meta-analysis including
natal surveillance and early delivery are not recommended.
data from 2267 patients confirmed these data, showing moder-
Moderate to severe polyhydramnios is an indication for ante-
ate predictive value for fetal outcomes in high-risk pregnancies
natal surveillance and delivery between 39+0 and 39+6 weeks’
with placenta insufficiency [52]. A randomized trial did not show
gestation. Ultrasound can also be used to guide amnioreduc-
significant perinatal benefits adding DV screening to fetal heart
tion. Amnioreduction is only recommended for severe poly-
rate monitoring alone for antepartum monitoring of the growth-
hydramnios (deepest vertical pocket ≥16 cm or amniotic fluid
restricted fetus [53]. Therefore, there are insufficient data to
index ≥35 cm) that is associated with significant maternal dis-
currently recommend the use of DV Doppler in the routine
comfort and dyspnea (see Chap. 59 in Maternal-Fetal Evidence
evaluation and management of the fetal growth-restricted
Based Guidelines) [44].
(FGR) fetus [47] (see Chap. 47 in Maternal-Fetal Evidence Based
Guidelines).
Doppler
Uterine artery
Umbilical artery The Doppler waveform of the uterine artery has been shown to
In low-risk or unselected populations, routine Doppler ultra- reflect high-impedance placental circulation by the presence
sound examination, usually of the umbilical artery and fetal of a waveform notch and low diastolic flow in association with
vessels at around 28–34 weeks, does not result in increased hypertension and preeclampsia. Studies have shown an associa-
antenatal, obstetric, and neonatal interventions, and no overall tion between abnormal uterine artery Doppler and early-onset
Ultrasound 55
preeclampsia, but predictive value is low. Current evidence has Three-dimensional ultrasound
not shown a benefit to performing routine midpregnancy utero-
placental Doppler ultrasound for prevention of preeclampsia, Three-dimensional (3D) ultrasound examination is not consid-
FGR, or adverse pregnancy outcome [54, 55] (see Chap. 47 in ered a required modality for all pregnant women at this time [4],
Maternal-Fetal Evidence Based Guidelines). Furthermore, there but it can add accuracy in the assessment of the fetus identified to
is currently a paucity of data to recommend the use of uterine have anomalies by two-dimensional (2D) ultrasound (especially
artery Doppler in the clinical management of hypertensive preg- facial anomalies, neural tube defects, and skeletal malforma-
nancies [55]. tions). Three-dimensional ultrasound allows the acquisition of
volume measurements, which can depict topographic anatomy
Biophysical profile not able to be seen on 2D imaging. New technology allows for 3D
reconstruction of vascular structures, further characterizing ves-
A fetal biophysical profile (BPP) score is a specialized obstetric sel relationship [71], vascular malformations, and vascular inva-
ultrasound consisting of monitoring of fetal movements, tone sion. It has not been shown to have a clear clinical advantage over
and breathing, and assessment of amniotic fluid volume, with or traditional ultrasound in routine settings [6].
without fetal heart rate monitoring. BPP has been used to identify Routine 3D ultrasound (versus the traditional 2D ultra-
babies that may be at high risk of poor pregnancy outcome. While sound) among low-risk women has not shown a significant
information gained from a BPP regarding fetal status can help impact on maternal-fetal bonding [72]. Additionally, 3D/4D
guide clinical management, available evidence from randomized (four-dimensional) ultrasound in women at risk for having
trials does not support the use of BPP as an isolated test of fetal a fetus with congenital anomalies does not reduce maternal
well-being in high-risk pregnancies. Additional evidence from anxiety compared with conventional 2D ultrasound alone [73].
larger trials is needed (see Chap. 58 in Maternal-Fetal Evidence Use of nondiagnostic recreational 3D ultrasound is not recom-
Based Guidelines) [56]. mended in accordance with the ALARA principle [5].
Cervical length Fetal echocardiography

Transvaginal ultrasound (TVU) for the measurement of cervi- The incidence of moderate to severe congenital heart disease
cal length (CL) has been shown to be predictive of spontaneous (CHD) has been reported at 6–13 per 1000 live births [74, 75],
preterm birth (PTB) in all populations studied so far, includ- with most affected infants born to pregnancies without identifi-
ing singletons and multiple gestations, either asymptomatic or able risk factors [76]. Fetal cardiac evaluation is an important part
with symptoms of preterm labor. TVU CL can be effective in of the prenatal ultrasound examination. Basic cardiac screen-
evaluating the need for such interventions as cervical cerclage ing to be completed during the midtrimester ultrasound during
or progesterone supplementation, as well as more effective every pregnancy includes the four-chamber view and evaluation
management of women with symptoms of preterm labor (PTL) of the right and left outflow tracts [5, 10]. An in-depth evaluation
[57–60]. of fetal cardiac structures should be performed if the screening
TVU CL screening is considered universal when offered exam is abnormal or incomplete or when there are maternal or
routinely to all singleton gestations without a prior spontaneous fetal indications (Table 4.9) [77, 78]. Fetal echocardiography is
PTB at the time of the anatomy ultrasound (i.e. 18–24 weeks). usually performed between 18 and 22 weeks. Main areas of evalu-
Both the ACOG and SMFM have published guidelines indicat- ation include visceral situs, atrial and ventricular anatomy, val-
ing that universal TVU CL screening is deemed reasonable, vular structure and function, and orientation and morphology of
but not mandatory [61, 62]. We, as well as other societies, rec- the great vessels. Grayscale, color, and spectral Doppler imaging
ommended it. About 1% of singletons without a prior spontane- are required, while spectral Doppler and M-mode should be used
ous PTB develops a TVU CL ≤20 mm before 24 weeks [63] and as needed to evaluate suspected anomalies [79]. These structures
should be started on vaginal progesterone daily until 36 weeks are usually best seen in the second trimester, but experienced
[64, 65]. Over two-thirds of academic maternal-fetal medicine technicians and sonologists may be able to detect cardiac anoma-
units in the United States perform universal CL screening [66]. lies in the first trimester. One prospective observational study
Women with a history of spontaneous PTB prior to 37 showed a sensitivity and specificity of 88% and 100%, respectively,
weeks’ gestation had routinely been offered progesterone sup- for detection of cardiac anomalies when using the four-chamber
plementation [67]. A statement released by the SMFM in 2019 view, three-vessel view, and three-vessel trachea view to screen an
in response to the PROLONG trial showing no improvement unselected patient population in the first trimester [80].
suggested these findings were due to a difference in study
populations. Given this discrepancy, women at highest risk Intrapartum ultrasound
should still be offered intramuscular or vaginal progesterone
as a component of shared decision-making with their provider Ultrasound during active labor is not routinely used, though
[68]. In addition, current recommendations are for screening studies have shown that it can improve precision and reproduc-
of these high-risk women (history of spontaneous PTB) with ibility over clinical exam alone. The International Society of
serial TVU CL ultrasounds every 2 weeks from 16 to 24 weeks’ Ultrasound in Obstetrics and Gynecology (ISUOG) published a
gestation. In those (about 40%) with TVU CL ≤25 mm, a cer- guideline outlining parameters that can be assessed and how to
clage should be offered (see Chap. 17) [69]. obtain these specific measurements [81].
TVU CL screening of singletons presenting between 24 and Clinical exam of fetal position and station has been proven
34 weeks with symptoms of PTL has been associated with both to be inaccurate with a rate of error from 20% to 70%, with
lower evaluation and triage time and significantly less incidence high interobserver variability [82]. Ultrasound thus can be
of PTB (see Chap. 18) [70]. used to objectively determine fetal head position, station,
TABLE 4.9: Indications for Fetal Echocardiography

Indicated Consider
Fetal Factors Suspected cardiac structural anomaly Systemic venous anomaly
• Persistent right umbilical vein

• Left superior vena cava
• Absent ductus venosus
Suspected cardiac function abnormality
Hydrops fetalis
Persistent fetal tachycardia (>180 bpm)
Persistent fetal bradycardia (<120 bpm)
Frequent or persistent fetal arrhythmia
Major extracardiac anomalies
Nuchal translucency of 3.0 mm or greater or >95th percentile for gestational age
Chromosomal abnormality by invasive testing or cell-free fetal DNA
Monochorionic twins
Maternal Factors Pregestational diabetes Selected teratogen exposure (paroxetine,
carbamazepine, or lithium)
Gestational diabetes dx in the first or early second trimester Antihypertensive medication limited to
angiotensin-converting enzyme inhibitors
In vitro fertilization Autoimmune disorder with SSA antibody
positive without prior affected fetus
Phenylketonuria Second degree relative of fetus with CHD
Autoimmune disorder with SSA antibody with prior affected fetus
First-degree relative of fetus with CHD
First- or second-degree relative of with disease of Mendelian inheritance with
potential cardiac manifestations
Retinoid exposure
First-trimester rubella infection
Abbreviations: DNA, deoxyribonucleic acid; dx, diagnosis; CHD, congenital heart disease; SSA, Sjogren’s syndrome-related antigen A antibodies.
descent, and attitude. All of these parameters contribute to are the pubic symphysis, which appears as an oblong echogenic
assessment of arrested labor and need for obstetric interven- structure anteriorly, and the fetal calvarium. Useful parameters
tions. Indications for intrapartum ultrasound include slower- for assessment of fetal station include angle of progression (AoP),
than-expected labor or arrest of labor in the first stage, slow fetal head direction, head–perineum distance (HPD), and mid-
progress or arrest of descent, evaluation of fetal head position line angle (MLA) (see the ISUOG guideline for details on how to
and station prior to operative vaginal delivery, and objective obtain and interpret these measurements) [81].
assessment of fetal head malpresentation [81]. Ultrasound during active labor may be used as an adjunct
When performing ultrasound during active labor, the equip- to clinical exam to assess fetal position and station. Its use
ment used should be optimal for the information to be obtained. It should be considered in the setting of assessing arrest disor-
is recommended to use an ultrasound machine with a curvilinear ders and planned operative delivery (see Chaps. 8 and 9).
2D probe with a wide sector and low frequency (<4 MHz), as this
yields the best insonation in the laboring patient. Practically, the Placenta accreta spectrum
machine should also turn on quickly, have a battery power option,
have long battery life, and have an efficient recharging time. Placenta accreta spectrum (PAS) represents abnormal adherence
Head position is routinely assessed via transabdominal ultra- of the placenta to the myometrium. It occurs in 3/1000 deliveries
sound. Placement of the probe is transversely on the maternal and has increased in frequency over the last 50 years, likely mir-
abdomen, obtaining an axial view of the fetal trunk. Spine posi- roring the increased cesarean delivery rate [83]. Risk factors for
tion can be ascertained in this view. Suprapubic placement of PAS include number of prior cesarean deliveries, other uterine
the probe will obtain an axial view of the fetal head. Position of surgery, assisted reproduction, and anterior low-lying placenta-
occiput, fetal orbits, or the midline cerebral echo (that represents tion or placenta previa [84]. PAS increases the risk for maternal
the falx cerebri) will indicate fetal head position. morbidity, including intrapartum hemorrhage, need for blood
Transperineal ultrasound is more accurate in determining transfusion, cesarean hysterectomy, and ICU admission. Due to
fetal station and progress into and through the pelvic outlet. It the increased likelihood of adverse maternal outcomes with undi-
can also help to identify caput succedaneum and molding. This agnosed PAS, prenatal diagnosis with ultrasound is of paramount
exam is performed by placing a covered probe vertically or trans- importance.
versely between the labia and applying gentle pressure to bring Ultrasound along with clinical history can be used to identify
anatomic landmarks into view. The major landmarks of interest patients at increased risk for placenta accreta. Ultrasound findings
Ultrasound 57
suggestive of placenta accreta in the first trimester include vas- In summary, PAS is an entity that can be suspected by his-
cular lacunae, implantation into the prior cesarean scar, and low tory and ultrasound findings and is best managed in centers
implantation of the gestational sac. Ultrasound findings sugges- of excellence to decrease maternal and fetal morbidity (see
tive of PAS in the second and third trimester include vascular Chap 29).
lacunae, hypervascularity of the placenta, loss of the retroplacen-
tal clear space, myometrial thinning with bulging of the lower
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5
PRENATAL DIAGNOSIS AND SCREENING FOR ANEUPLOIDY
Sarah Harris, Angie Jelin, and Neeta Vora
Key points pregnancy loss rates in the first trimester contribute to

the high-risk estimates.
• All women, regardless of maternal age, should be coun- • Chromosomal microarray (CMA) analysis should be
seled in regard to screening and diagnostic testing for recommended as the primary test (replacing conven-
aneuploidy, ideally in the first trimester. tional karyotype) to patients undergoing prenatal diag-
• Genetic counseling should include comprehensive nosis in whom a structural abnormality is detected by
information on all modalities, advantages, disadvantages, ultrasound.
and the gestational age for each test prior to screening. All • When CMA is normal, targeted gene panels can be con-
women should receive pre- and post-test counseling, par- sidered if the phenotype is sufficiently defined to select an
ticularly for an “abnormal” result. appropriate panel of genes to sequence.
• Issues of sensitivity, specificity, and positive and nega- • Exome sequencing of both parents and fetus (trio) shows
tive predictive values are vital to the interpretation of a an increased diagnostic yield, especially in fetuses with
screening test. multiple abnormalities or nonimmune hydrops fetalis.
• The positive predictive value of a screening test is greatly • Trisomy 21 is the most common trisomy at birth. Its inci-
influenced by prevalence rates in the population tested. dence increases with increasing maternal age.
• The difference between a screening and a diagnostic test
should be clearly explained prior to any testing. There is
no definitive noninvasive prenatal diagnostic test. The
Screening versus diagnostic tests
only diagnostic tests are invasive (i.e. chorionic villus The aim of a screening test is to identify pregnancies at increased
sampling [CVS] and amniocentesis). risk of being affected by a particular condition. Prenatal genetic
• Cell-free DNA screening is the most sensitive and spe- diagnostic testing is able to definitively identify affected pregnan-
cific screening test for fetal aneuploidy, in particular cies. Prenatal screening tests use noninvasive techniques, such as
trisomy 21, and should be offered regardless of maternal maternal blood sampling or ultrasound measurements, to deter-
age. The detection rate for trisomy 21 is over 99%, with mine risk. Prenatal diagnostic testing requires an invasive proce-
a false-positive rate of <1%. dure, such as amniocentesis or chorionic villus sampling (CVS),
• First-trimester screening (FTS) includes NT, PAPP-A, to obtain a sample from the pregnancy to perform genetic testing.
and B-HCG and is performed from 103/7 to 136/7 weeks. Issues of prevalence, sensitivity, specificity, and positive
The overall detection rate (sensitivity) is 84%–87% (false and negative predictive values are vital to the interpretation
positive rate [FPR]: 5%) for trisomy 21. of a screening test and are critical for interpreting the value of a
• Second-trimester maternal analyte screening (quad test. Table 5.1 lists the characteristics of an ideal perinatal screen-
screen) detects approximately 70%–81% of pregnancies ing test.
with trisomy 21 (FPR 5%).
• Integrated screening has a detection rate of 95% for Sensitivity and specificity
trisomy 21, with a low (1%–4%) FPR, but results are not The sensitivity of a screening test, which can also be called the
provided until the second trimester. Step-wise or contin- detection rate, describes the test’s performance in correctly iden-
gent sequential screening offers the same 95% detection tifying individuals affected by the condition (true positive). For
rate, a reasonable 5% FPR, and initial results are pro- example, if a screening test for trisomy 21 has a detection rate
vided in the first trimester. of 80%, then 80% of fetuses with trisomy 21 will have a positive
• Second-trimester “genetic” ultrasound is an important test result. Importantly, this also means that 20% of fetuses with
screening modality for aneuploidy and anomalies. In addi- trisomy 21 would not be detected with this particular screening
tion to detecting major anomalies (e.g. congenital cardiac test. The specificity of a test describes the test’s ability to correct
defects and duodenal atresia), it can identify soft markers identify individuals without the condition (true negative).
(especially nuchal thickening, short humerus or femur, and
echogenic bowel) that are associated with trisomy 21. Prevalence, positive predictive value,
• Amniocentesis for the diagnosis of fetal aneuploidy is and negative predictive value
typically performed between 15 and 20 weeks’ gesta- High sensitivity and specificity are preferable; however, the prev-
tion. It is associated with a 0.11% (1 in 900) procedure- alence of a condition (based upon the population tested) will
related risk of pregnancy loss. Early amniocentesis ultimately determine the value of a positive or negative result
prior to 15 weeks’ gestation is not recommended. (Figure 5.1). With lower prevalence, the chance of a particular
• CVS can be performed between 10 and 13 weeks’ ges- “positive” test to be a true finding is much less. For example,
tation and is associated with a 0.22% (1 in 455) proce- based upon the numbers from Figure 5.1, if all the women with
dure-related risk of pregnancy loss. Higher background a positive test from group “A” had CVS, there would be 1 positive
60 DOI: 10.1201/9781003102342-5
Prenatal Diagnosis and Screening for Aneuploidy 61
TABLE 5.1: Ideal Prenatal Screening Test rate (FPR) (e.g. first-trimester screening), and some prefer the
highest detection with the lowest FPR (e.g. cell-free DNA screen-
Identify common or important fetal disorder
ing, integrative screening).
Be cost-effective
No matter the sensitivity of available tests, for women under-
High detection rate; low false-positive rate
going screening, detailed discussions regarding the advan-
Be reliable and reproducible tages and disadvantages of screening versus diagnostic
Diagnostic test exists testing should occur. After such counseling, each woman can
Be positive early in pregnancy make the most informed and best choice for their situation. Since
Possible intervention if screening test is positive screening tests will never detect 100% of disease, the option of
diagnostic testing should be offered to all pregnant women [1].
Several studies have shown that most pregnant women prefer
result for every 55 CVSs performed. If all the women in “B” had a early (vs. later) screening for trisomy 21.
CVS, 1 out of every 2.4 tests would yield a positive result.
While complicated, discussion of sensitivity (detection rates) Pretest and posttest counseling
and the 5% screen positive rate of screening tests (highlighted in
Table 5.2) is necessary. Specific resources, including time, exper- The decision to proceed with prenatal screening or testing is
tise, and the availability of genetic counseling, are paramount. personal and based on an individual woman’s reproductive goals
Continuing education of health care providers is necessary. and desires. Pretest counseling should include a discussion of
Some couples might prefer a screening approach with the earli- the conditions being tested for, the expected performance of the
est detection even with a higher—for example, 5%—false-positive test, and the risks and benefits of testing. Counseling should be
FIGURE 5.1 Screening test concepts and effect of prevalence.

62
TABLE 5.2: Comparison of Aneuploidy Testing Options
>10 Weeks First Trimestera Second Trimesterb
Screening Test Screening Test Diagnostic Test Screening Test Diagnostic Test
Name Cell-free fetal NT FTS (NT, CVS Quad screen (AFP, Integrated screen Sequential screen Genetic Amniocentesis
DNA screening PAPP-A, hCG) hCG, uE3, inhibin) (FTS, followed by QS) (FTS followed by QS) ultrasound
Detection rates for >99% 65%–80% 80% >99% accuracy for 70%–81% 95% Stepwise: 95% 50% >99% accuracy for
trisomy 21 chromosome Contingent: 88%–94% chromosome
abnormalities abnormalities
Detection rate for other T18: 98% 70% 74% >99% accuracy for 72% 60%–80% 50%–80% Variable >99% accuracy for
chromosome T13: 99% chromosome chromosome
anomalies SCA: Unknown abnormalities abnormalities
Risk of pregnancy loss N/A N/A N/A 1 in 455 procedure- N/A N/A N/A N/A 1 in 900 procedure-
related risk for related risk for
pregnancy loss pregnancy loss
a Usually 11–13 weeks.
b Usually 15–22 weeks.
Obstetric Evidence Based Guidelines

Abbreviations: NT, nuchal translucency; FTS, first trimester screening; PAPP-A, pregnancy associated plasma protein-A; HCG, human chorionic gonadotropin; CVS, chorionic villus sampling; AFP, alpha fetoprotein; uE3, unconjugated
estriol; FTS, first trimester screening; QS, quad screen; T18, trisomy 18; T13, trisomy 13; SCA, sex chromosome aneuploidy; N/A, not applicable (no risk of pregnancy loss).
Prenatal screening vs diagnosis counseling
Desires non-invasive Desires invasive

screening test diagnostic test
Cell-free DNA at ≥10w CVS (11–12w) or amniocentesis (≥15w)**

FTS or NT at 11–12w*
Anatomy ultrasound at 20w
FIGURE 5.2 General approach to prenatal screening for aneuploidy. *Noninvasive screening test based on patient/provider
preferences. **Test for karyotype and CMA. Abbreviations: FTS, first trimester screening; NT, nuchal translucency; w, weeks.
nondirective and stress that prenatal testing is not mandatory. If an abnormality is identified, the patient can be provided with
Ideally, this counseling should be performed by a certified genetic information specific to her situation. When a patient decides to
counselor or an obstetric provider with expertise in screening carry an affected pregnancy to term, the antenatal, intrapartum,
and testing. and postpartum care can be performed under more ideal circum-
Pretest counseling should include: stances, hopefully altering the outcome and informing care in the
immediate newborn period. A general current approach to prena-
• A discussion of all testing options, including screening tal screening for fetal aneuploidy is shown in Figure 5.2.
tests (cell-free DNA screening, first- and second-trimester
serum screening, ultrasound) versus diagnostic testing
(CVS and amniocentesis); a discussion that all testing is Antenatal noninvasive aneuploidy
optional and that it is acceptable to decline any additional screening (Table 5.2)
testing.
• Review of possible results, including false-positive screen- History
ing results, false-negative screening results, aneuploidy, Langdon Down, in 1866, reported that the skin of individuals
copy number variants, incidental findings, false paternity, with trisomy 21 appeared enlarged. In the 1970s data became
consanguinity, and normal results. available on the relationship between maternal age and increased
• A review of the patient’s goals and values, including a dis- risk for aneuploidy. A statistically relevant difference was seen
cussion of her general attitude toward testing and screen- between the 30- to 34 years old group and the 35- to 39 years old
ing, views and availability of pregnancy termination, and group, so that this difference led to the offering of women 35 years
views on parenting a child with disabilities. of age diagnostic evaluation for karyotype. Maternal serum
• Pregnancy and postpartum management options in the alpha-fetoprotein (MSAFP) was originally found to be elevated
event of an abnormal result, including pregnancy termina- in women carrying fetuses with neural tube defects (NTDs); this
tion versus continuation. led to the realization in 1984 that a low MSAFP was associated
with a higher risk of trisomy 21 [3]. Nuchal translucency (NT)
Posttest counseling should be provided to patients with nega- first-trimester ultrasound screening was introduced in the early
tive or positive results. It is important for patients to understand 1990s [4].
that normal testing results do not eliminate the possibility of an
underlying genetic condition in the pregnancy. For patients with Principles
abnormal results, referral to a genetic counselor or provider with All women should be offered aneuploidy
expertise in the condition is recommended [2]. screening, ideally in the first trimester [3]
The main aims of prenatal aneuploidy screening and testing Historically, the cutoff level for aneuploidy diagnosis and subse-
are to identify pregnancies at risk for genetic conditions and quent public policy was determined over 30 years ago and was
to allow women to make informed decisions regarding the based on a maternal age risk of 35 years at delivery equivalent to
outcome of the pregnancy. Some women may elect to proceed a second-trimester risk of 1:270 or higher (liveborn risk of 1:380).
with pregnancy termination, whereas others may use the infor- Factors considered in determining this value included the preva-
mation to prepare for the birth of an affected child. lence of disease, a perceived significant increase in the trisomy 21
Many still believe that the rationale behind screening for risk after this age, the risk of invasive testing, the availability of
aneuploidy is to provide the option for termination of the preg- resources, and a cost–benefit analysis. Since that time, a number
nancy prior to viability. While couples faced with the reality of of additional screening tests for trisomy 21 have become available
an aneuploid pregnancy may opt for termination, the purpose that challenge the validity of maternal age as a single indication
of prenatal diagnosis and screening is to provide information. for invasive testing. The American Congress of Obstetricians and
TABLE 5.3: Risk for Down Syndrome Based upon Maternal In high-risk populations who have undergone prenatal diagno-
and Gestational Age sis, the sensitivity of cell-free DNA screening for trisomy 21 is
greater than 99%, for trisomy 18 greater than 99%, and for tri-
Gestational Age (weeks)
somy 13 greater than 90% [14–17]. In a mixed population of low-
Maternal Age 12 16 20 Liveborn and high-risk women, the sensitivity of cell-free DNA screening
20 1/1068 1/1200 1/1295 1/1527 for trisomy 21 was reported between 99% and 100%, for trisomy
18 between 90% and 99%, and for trisomy 13 greater than 99%
25 1/946 1/1062 1/1147 1/1352
[18–20]. A recent meta-analysis for cell-free DNA screening
30 1/626 1/703 1/759 1/895
reported a greater than 99% detection range for trisomy 21, 98%
31 1/543 1/610 1/658 1/776
detection rate for trisomy 18, and 99% detection rate for trisomy
32 1/461 1/518 1/559 1/659 13 with a combined false-positive rate of 0.13%. The detection
33 1/383 1/430 1/464 1/547 rate of sex chromosome aneuploidy could not be determined due
34 1/312 1/350 1/378 1/446 to the small sample size [21].
35 1/249 1/280 1/302 1/356 Cell-free DNA screening is the most sensitive and specific
36 1/196 1/220 1/238 1/280 test for screening for aneuploidies. However, it is important that
37 1/152 1/171 1/185 1/218 patients understand the importance of positive predictive value
38 1/117 1/131 1/142 1/167 (PPV) when it relates to a positive result. Understanding the
39 1/89 1/100 1/108 1/128 patient’s a priori risk is essential for helping patients interpret
40 1/68 1/76 1/82 1/97 their results. For example:
42 1/38 1/43 1/46 1/55
• A 45-year-old woman with a 1 in 22 risk for trisomy 21 has
44 1/21 1/24 1/26 1/30
a positive cell-free DNA screening result. The PPV of the
45 1/16 1/18 1/19 1/23
screening test is 98%.
• A 20-year-old-woman with a 1 in 1177 risk for trisomy 21
has a positive cell-free DNA screening result. The PPV of
Gynecologists (ACOG) now recommend that diagnostic testing the screening test is 48%.
for aneuploidy be offered to all women, regardless of their per-
sonal risk factors [1]. Online calculators have been developed to assist with patient
counseling (https://www.med.unc.edu/mfm/nips-calc/; https://
Age www.perinatalquality.org/vendors/nsgc/nipt/). However, these
The risk of fetal aneuploidy increases with maternal age, but calculators have limitations, and providing individual posttest
decreases with the gestational age at assessment in determining risks may be less useful for some patients. It is critical that patients
the risk, secondary to in utero death rates (Table 5.3) [5]. have comprehensive genetic counseling after an abnormal result,
Women older than 35 years of age have a higher individual risk so that they can understand the implications and make informed
than younger women; however, the vast majority of trisomy 21 decisions regarding additional testing options.
pregnancies are born to the <35-year-old age group. Screening Some laboratories also offer screening using cell-free DNA for
programs have been developed to try and detect affected preg- less common microdeletion syndromes. However, this testing is
nancies in both the “higher” and “lower” risk groups. not recommended by ACOG, as it has not been validated, and
because the conditions are so rare, the PPV of this testing is much
Screening in any trimester lower [3].
Cell-free DNA screening First-trimester screening

The discovery of cell-free DNA of fetal origin in maternal plasma
opened up new possibilities for noninvasive maternal prena- Nuchal translucency
tal screening for fetal chromosomal aneuploidy. The methods The NT is a fluid-filled space on the back of the fetal neck. The NT
utilized for detecting fetal aneuploidy differ based on whether can be enlarged in fetuses with aneuploidy and structural anoma-
amplified regions throughout the genome, chromosome-specific lies at 103/7–136/7 weeks (crown–rump length [CRL] about 36–86
regions, or single nucleotide polymorphisms are the targets for mm) [22]. The NT measurement is obtained in a midsagittal plane
sequencing used [6–10]. with the neck of the fetus in a neutral position. The amnion should
Cell-free DNA screening can be used to screen for fetal trisomy be seen separately from the neck. The image should be enlarged
21, trisomy 18, trisomy 13, and sex chromosome abnormalities. >75% of the screen. The measurement is obtained by placing the
This screening can be completed between 10 weeks’ gestation calipers in the inner edges of the nuchal translucency, and mul-
and term. On average, a pregnant woman will have approximately tiples of the medians are used to calculate the risk of Down syn-
3%–13% cell-free DNA of fetal origin in a blood sample [11]. The drome via computer software. An increased NT is >70% sensitive
fetal fraction is derived from placental trophoblast cells. for trisomy 21, trisomy 18, and trisomy 13 (Table 5.2) [3]. Rigorous
Different factors, including gestational age, maternal weight, training, certification, and ongoing quality control are necessary
medication exposure, maternal race, fetal aneuploidy, and mul- to achieve the detection rates published in the literature (www.
tiple gestations, have been shown to influence the fetal fraction fetalmedicine.com; www.ntqr.org). The optimal time to perform
[11–13]. Low fetal fraction is also associated with test failures or NT for aneuploidy screening is about 11 weeks.
uninterpretable results. Due to the increased risk for aneuploidy Compared to a screening policy of amniocentesis for age
in this group, referral to genetic counseling is recommended and ≥35 years and ultrasound at 18 weeks, a policy of NT screen-
diagnostic testing should be offered [13]. ing is associated with similar numbers of births of infants
with trisomy 21 (a nonsignificant 37.5% decrease) and a signifi- sensitive for trisomy 21, but there are insufficient prospective
cant 82% decrease in invasive tests [23]. data for any increase in accuracy over FTS alone [31].
Biochemistry Second-trimester screening

The maternal serum analytes measured in the first trimester
are beta–human chorionic gonadotropin (B-hCG) and preg- Maternal analyte screening had the first reported association
nancy-associated plasma protein-A (PAPP-A). B-hCG normally with trisomy 21 with low MSAFP (MoM 0.75), followed by the
decreases in pregnancy, but is increased in fetuses affected with association of high hCG (MoM 2.3) and a low unconjugated
trisomy 21. Free B-hCG performs better than total hCG as an estriol (MoM 0.7) to form the “triple screen.” The detection rate
independent marker, but there does not appear to be a clini- for women under 35 with a triple screen ranges between 57% and
cally significant difference in sensitivity when either is combined 74%, with a constant 5% FPR [23–25]. For women above 35 using
with NT and PAPPA-A for first-trimester screening (FTS) [24]. similar cutoff values, the sensitivity increases to 87%, but the FPR
PAPP-A normally increases in pregnancy, but is decreased in also balloons to 25% [32]. Inhibin was added to analyte screening
fetuses affected with trisomy 21. hCG discrimination is greatest (quad screen), but since levels correlate somewhat with hCG, it
at 13 weeks, while PAPP-A discrimination is greatest at 10 weeks, is not an independent predictor like the other markers, and the
making 11 weeks the optimal time for first-trimester analyte increase in detection is more limited (7–11 percentage points).
screening. Approximately 70%–81% of cases of trisomy 21 are detected in
the majority of studies, holding the FPR at 5% [24–26]. The detec-
First-trimester screening tion rate for non–trisomy 21 aneuploidies has been estimated at
FTS consists of measuring the NT combined with maternal 72% [28]. This screening test can be performed between 15 and
serum screening (PAPP-A and B-hCG). Over 20 studies in more 22 weeks, with best results obtained at 16–18 weeks. Values need
than 200,000 women have been performed to assess the sensitiv- to be adjusted, as needed, for diabetes, obesity, and other factors.
ity of this screening test [24–28]. Other combinations of markers have been assessed; however,
The gestational age for FTS is about 103/7–136/7 weeks (about with the addition of extra markers, the potential benefit versus the
73–98 days; CRL about 36–86 mm). The usual cutoff risk is 1:270. cost must be balanced. With each additional marker, costs to soci-
The detection rate (sensitivity) is about 84%–87% (95% CI 80%– ety reach into the millions secondary to the numbers of pregnancies
90%) for trisomy 21. For non–trisomy 21 there is an estimated tested each year. The relative cost and value of raising the sensitivity
detection rate of 74% [28]. The best detection rate is achieved or lowering the FPR a few percentage points is an ongoing debate.
at 11 weeks.
FTS should be offered only if the following criteria can be met
Combined first- and second-trimester tests
[24–27]:
Combined screening programs in the first trimester (using both
1. Appropriate training and ongoing quality monitoring pro- ultrasound assessments of the NT as well as maternal analytes)
grams are in place for both ultrasound (NT) and laboratory and the second trimester (using maternal analytes) have been
assays of analytes. described. Patterns of testing include sequential testing (results
2. Sufficient information and resources are available to pro- given after each test) and integrated testing (delaying reporting
vide comprehensive counseling to women regarding the until both tests have been completed).
different options and limitations of these tests.
3. Access to an appropriate diagnostic test (i.e. CVS) is avail- Integrated screening
able when screening results are positive. Integrated screening refers to performing screening tests at dif-
ferent times during pregnancy with a single result provided to the
The Maternal Fetal Medicine Foundation (www.mfmf.org) and patient only after all tests have been completed. A protocol for
the Fetal Medicine Foundation (www.fetalmedicine.com) both integrated screening for trisomy 21 is based upon tests performed
provide NT education and quality review programs. There is suffi- during the first and second trimester (NT, PAPP-A, MSAFP, hCG,
cient evidence to support implementing FTS for Down syndrome estriol, and inhibin). Mathematical models calculated that >85%
provided the previous three requirements are met. Almost 85% of of affected pregnancies would be detected with an FPR of only
women in the United States present for care within 12 weeks and 0.9%. The FASTER trial (First- And Second-Trimester Evaluation
can be offered FTS. FTS can provide high detection, early reas- of Risk) performed integrated screening in 33,557 women (84
surance, more time/diagnostic options, and earlier completion of with trisomy 21) [26]. Cutoff values for the different tests var-
aneuploidy screening. ied (first-trimester combined test cutoff 1:150, second-trimester
Compared to screening programs using second-trimester “quad screen”: 1:300). The authors report a sensitivity of 86% with
screening (STS), the use of FTS is also associated with a signif- FTS (FPR 5%), 85% with second-trimester (FPR high at 8.5%), and,
icant reduction in induction for postterm pregnancy because when combined, a 94% detection of trisomy 21 cases. If results are
of better dating with first-trimester ultrasound [29]. revealed after STS, the FPR is only 4.9%, with the best sensitivity.
If NT is not available, an “integrated serum screening test” has a
Other first-trimester ultrasound markers detection rate of 85% with 3.9% FPR [24]. Disadvantages of inte-
An absent nasal bone has also been associated with trisomy 21. grative screening include the lack of early diagnosis, the physi-
When added to FTS (NT, PAPP-A, and B-HCG), an absent nasal cal and psychological ramifications created if an abnormality is
bone may increase the detection rate and decrease the FPR [30]. found and the woman opts for termination (compared to the first
Possibly because of the difficulty of this exam, these data have not trimester), the increase in costs (compared to either FTS or STS),
been confirmed in all studies. Abnormal ductus venosus Doppler the perception of “hiding” abnormal results, and the limitations it
flow and tricuspid regurgitation have also been found to be >70% places on multiple gestations if discordant karyotypes are found.
Sequential screening TABLE 5.4: Selected Ultrasound Findings Associated with

Sequential screening involves performing different screening Down Syndrome
tests at different times during pregnancy with the results pro- Major Anomalies
vided to the patient after each test. There are three approaches to
Congenital heart defects
sequential testing: Independent, stepwise, and contingent.
Duodenal atresia
Independent Major Markers
This approach involves the independent interpretation of FTS and Increased nuchal thickness
STS. While the sensitivity is as exemplary with this approach as Hyperechoic bowel
with integrative screening (94%–95%), combining screening tests Shortened humerus
and revealing the results after each increases the chance for false- Shortened femur
positive results. The FASTER trial’s FPR was 10.8% with sequen- Echogenic intracardiac focus
tial independent screening [26], far too high for population-based Renal pyelectasis
usage. As a high FPR means higher loss rates due to more invasive Minor Markers
testing, independent sequential screening is the least efficient risk
Shortened or absent nasal bone
assessment strategy and should NOT be used.
Foot length
Stepwise “Sandal gap” of the foot
With this method, both FTS and STS are performed with results Widened ischial spine angle
revealed after FTS. If FTS risk is above a certain cutoff, invasive Hypoplasia of the midphalanx of the fifth digit
testing (i.e. CVS) is offered; if FTS is below a certain cutoff, STS Brachycephaly
is recommended with a final risk revealed at that point. In the
FASTER trial, such an approach (low cutoff 1:150; high cutoff
1:300) had a detection rate of 95% with an FPR of 4.9% [26]. The
advantages of this approach are a very high detection rate (as with on an ultrasound examination. Some of these major structural
integrative screening), with the option of early results in the first congenital anomalies, such as atrioventricular canal or duode-
trimester for the highest-risk women. nal atresia, strongly suggest the possibility of trisomy 21 and are
independent indications to offer invasive testing. Although, when
Contingent present, there is a high risk of trisomy 21, these anomalies have
In contingent testing, both FTS and STS are performed, with low sensitivity and thus are not useful in screening. For example,
results revealed after FTS. If FTS risk is above a certain cutoff when duodenal atresia is identified, there is approximately a 40%
(e.g. 1/150), invasive testing (i.e. CVS) is offered; if FTS is below risk of trisomy 21, yet it is seen in only 8% of affected fetuses.
a certain cutoff (e.g. 1/300), no further screening is necessary; if About 50% of fetuses with Down syndrome have congenital
FTS is in between, STS is recommended with a final risk revealed heart defects.
at that point. Careful determination of risk cutoffs is necessary. Physical characteristics that are not structural anomalies but
This strategy has not been studied prospectively. occur more commonly in fetuses with trisomy 21 are called
markers. By comparing the prevalence of markers in trisomy 21
“Genetic” ultrasound screening for trisomy 21 fetuses to their prevalence in the normal population, a likelihood
An ultrasound of the fetus performed at 18–24 weeks is associ- ratio (LR) can be calculated, which can be used to modify risk.
ated with several important benefits and should be offered to all This is the basis for ultrasound screening for trisomy 21. In order
pregnant women (see Chap. 4). One of the benefits is the ante- for a marker to be useful for trisomy 21 screening, it should be
natal detection of anomalies. The identification of a fetus with sensitive (i.e. present in a high proportion of trisomy 21 pregnan-
an issue allows for directed counseling and optimization of ante- cies), specific (i.e. not commonly seen in normal fetuses), easily
partum, intrapartum, and postpartum care. Whether routine or imaged in standard sonographic examination, and present early
targeted anatomic assessment is being performed, it should be enough in the second trimester that diagnostic testing can be
done by experienced centers with ongoing quality assessment to performed so that results are available when pregnancy termina-
increase detection of anomalies and limit false-positive results. tion remains an option. A list of markers and likelihood ratios are
The in utero diagnosis of trisomy 21 can be suspected when seen in Tables 5.4 and 5.5, respectively [33–35]. Markers com-
anomalies or physical features that occur more frequently in monly sought to assess the risk of trisomy 21 are discussed in the
fetuses with trisomy 21 than in the general population are noted following sections.
TABLE 5.5: Likelihood Ratios and 95% Confidence Limits for Isolated Ultrasound Markers
Isolated Nyberg et al. [10] Smith-Bindman et al. [11] Nicolaides et al. [12]
Sonographic Marker LR (95% CI) LR (95% CI) LR
Nuchal fold/thickening 11 (5.2–22) 17 (8–38) 9.8
Hyperechoic bowel 6.7 (2.7–16.8) 6.1 (3–12.6) 3.0
Short humerus 5.1 (1.6–16.5) 7.5 (4.7–12) 4.1
Short femur 1.5 (0.8–2.8) 2.7 (1.2–6) 1.6
EIF 1.8 (1.0–3) 2.8 (1.5–5.5) 1.1
Pyelectasis 1.5 (0.6–3.6) 1.9 (0.7–5.1) 1.0
Increased nuchal fold be an indication for invasive prenatal diagnosis, since it is associ-
About 35% of trisomy 21 fetuses, but only 0.7% of normal fetuses, ated with a 1%–2% risk of aneuploidy if isolated. If the karyotype
have a nuchal skin fold measurement ≥6 mm (some studies use is normal, mild ventriculomegaly is still associated with about 8%
≥5 mm). When an increased nuchal fold is an isolated finding, the of structural anomalies, 3% of perinatal deaths, and 10%–20% of
LR is strong, at 10–17. Thus the presence of an increased nuchal abnormal neurodevelopment.
fold alone is usually an indication to offer invasive testing. Except for major anomalies and increased nuchal thickness,
isolated “genetic ultrasound” markers should, in general, not
Increased echogenicity of the fetal bowel be used as the sole indication for invasive testing. As with other
When brighter than the surrounding bone, this marker has a tri- screening modalities, “genetic” ultrasound can be used to alter
somy 21 LR of 3.0–6.7. This finding can also be seen with fetal the a priori risk in either direction. A positive LR can be used to
cystic fibrosis, congenital cytomegalovirus (CMV) infection, increase estimated risk. The magnitude of the increase depends
swallowed bloody amniotic fluid, and fetal growth restriction. upon the marker(s) or anomalies seen. While most of the clinical
prospective data justifying this approach have come from a base-
Short long bones line age-related risk, some have advocated using these LRs to adjust
These markers in the second trimester are associated with trisomy whichever baseline risk, even that derived by other screening tests
21 relative to the length expected from their biparietal diameter. (e.g. FTS and/or unconjugated estriol and inhibin [QS], or even
This can be used to identify at-risk pregnancies by calculating a integrative or consecutive approaches). A benign second-trimester
ratio of observed to expected (O/E) femur/humerus length based scan having none of the known markers and no anomalies has been
on the fetus’s biparietal diameter (BPD). An O/E ratio for femur suggested to have an LR of 0.4–0.5, assuming the image quality is
length of <0.91 has a reported LR of 1.5–2.7 when present as an satisfactory when the “genetic ultrasound” is normal. It is doubtful
isolated finding. A short humerus is more strongly related to tri- that the same sensitivity can be achieved in every center.
somy 21, with reported LRs ranging from 4.1 to 7.5.
Ultrasound screening for other
Pyelectasis chromosomal abnormalities
This marker is defined as a renal anteroposterior (AP) diameter of Fetal aneuploidy other than trisomy 21 can be suspected based on
≥4–5 mm and has an LR that ranges from 1.1 to 1.9 as an isolated ultrasound findings [36]. The rates reported are usually in high-
marker. This has been found by some not to be significantly more risk populations and may overestimate the strength of the asso-
frequent in fetuses with trisomy 21 than in euploid fetuses (low ciation when such findings are noted on a screening examination.
specificity).
Trisomy 18
Echogenic intracardiac foci FTS and STS with MSAFP, hCG, and QS have a high detection
This marker occurs in up to 5% of normal pregnancies and in rate for trisomy 18. Second-trimester ultrasound also has a high
approximately 13%–18% of trisomy 21 gestations. The LR for tri- detection rate for trisomy 18.
somy 21 when an echogenic focus is present as an isolated marker Choroid plexus cysts (CPCs) have a very weak association with
has ranged from 1.0 to 2.8. This has been found by most investi- trisomy 18 and should not be the sole indication for invasive
gators not to be significantly more frequent in trisomy 21 preg- testing if isolated. The presence of CPC should be an indication
nancies than in unaffected pregnancies (low specificity). The risk for a detailed second-trimester ultrasound for trisomy 18 major
does not seem to vary if the focus is in the right or left ventricle anomalies, such as cardiac, central nervous system (CNS), hand
or if it is unilateral or bilateral, but may be affected by ethnicity. defects, etc.
Other ultrasound markers Positive screening for aneuploidy

Other markers described include a hypoplastic fifth middle pha- but normal karyotype
lanx of the hand, short ears, a sandal gap between the first and Nuchal translucency
second toes, an abnormal iliac wing angle, an altered foot to An NT above the 95% percentile for gestational age, and especially
femur ratio, short or absent nasal bone, and others. These mark- ≥3.5 mm at 103/7–136/7 weeks, is associated with an increased risk
ers are inconsistently used because of the time and expertise of other anomalies and syndromes, with the risk directly propor-
required to obtain them. Mild ventriculomegaly (10–15 mm) can tional to the increase in NT (Table 5.6) [37]. The list of anomalies
TABLE 5.6: Risk of Chromosome Abnormalities and (If Normal Karyotype) of Fetal Death or Anomalies According to Nuchal
Translucency
Normal Karyotype
NT Chromosomal Defects (%) Fetal Death (%) Major Fetal Anomalies (%) Alive and Well (%) Cardiac Defects (%)
<95th centile 0.2 1.3 1.6 97 0.6
95th–99th centiles 3.7 1.3 2.5 93 0.6
3.5–4.4 21.1 2.7 10.0 70 3.7
4.5–5.4 33 3.4 18.5 50 6.7
5.5–6.4 50 10 24 30 13
≥6.5 65 19 46 15 20
Abbreviation: NT, nuchal translucency.
is long and a detailed second trimester ultrasound is recom- diagnose a karyotypic or genetic abnormality. Both procedures
mended. The incidence of cardiac anomalies is ≥3.7% for NT have been studied extensively. Differences in technique, as well
≥3.5 mm, so that a fetal cardiac ultrasound by an experienced as timing of the procedure, affect loss rates. To fairly compare
operator is recommended. procedure-induced loss rates between the two procedures,
adjustments must be made for the higher background frequency
First-trimester PAPP-A and B-hCG of pregnancy loss earlier in gestation.
Low PAPP-A in FTS in the presence of a normal karyotype is
associated with several adverse pregnancy outcomes, including CVS
fetal loss, premature birth (PTB), and fetal growth restriction CVS is typically performed between 10 and 13 weeks’ gesta-
(FGR). Low free hCG is associated with fetal loss. There are no tion. The procedure should not be completed prior to 10 weeks,
randomized trials assessing any type of intervention or treatment due to an unacceptably high incidence of limb deficiencies. The
for patients with abnormal serum markers [38]. chorionic villi are sampled using ultrasound guidance and a
special catheter to aspirate a sample of the placental cells. The
Second-trimester screening placenta can be accessed through either a transcervical or
High MSAFP is associated with NTDs, as well as abdominal transabdominal approach. There are no significant differences
wall defects and several other fetal abnormalities. High MSAFP, in pregnancy loss between transabdominal and transcervical
negative acetylcholinesterase (AChE), and normal ultrasound CVS, with significant heterogeneity between studies [30, 41].
can be associated with congenital nephrosis or other syndromes, A systematic review of procedure-related losses for CVS and
or a normal pregnancy. Unexplained high MSAFP is associated amniocentesis revealed pooled loss rates for CVS at 14 days, 30
with mild increases in the incidence of preeclampsia, abruption, days, and prior to 24 weeks of 0.7%, 1.3%, and 1.3%, respectively.
placental ischemia, preterm birth, fetal demise, low birth weight, The pooled loss rates for amniocentesis for the same period were
and sudden infant death syndrome (SIDS). No trials have assessed 0.6%, 0.8%, and 0.9%, respectively [42]. In a recent meta-analysis,
specific management to prevent these complications [38]. the procedure-related risk of miscarriage following CVS has been
Low unconjugated estriol is associated with steroid sulfatase reported to be about 2/1000 [43]. Since CVS and amniocentesis
deficiency, Smith-Lemli-Optitz, or other conditions when very are performed at different times, it is difficult to compare these
low, usually <0.3 MOM [38]. procedures due to the higher background loss rate for the period
when CVS is performed. The benefit of earliest diagnosis with CVS
MSAFP screening for NTD
compared to amniocentesis should not be underestimated. With
Elevated (usually ≥2.5 MOM) MSAFP between 14 and 21 weeks is
the advent of FTS, prenatal diagnosis has moved more to the first
associated with a ≥90%–95% sensitivity for NTDs (false-negative
trimester. While the total miscarriage rate is higher following first-
rate 5%). Given that ultrasound is also ≥95% sensitive for NTDs,
trimester CVS because of the higher background rate in early preg-
the routine use of MSAFP screening is most important for preg-
nancy, for experienced centers, the rates of procedure-induced
nancies that will not have a detailed second-trimester ultrasound.
losses secondary to CVS are similar to those of second-trimes-
Screening for aneuploidies in twins ter amniocentesis [43]. In a recent meta-analysis, the weighted-
NT is accurate in estimating risk for fetal aneuploidy in dizygotic pooled procedure-related risk for pregnancy loss associated
twins, using each NT separately for each fetus. In monochorionic with CVS was 0.22% (1 in 455) [44].
twins, the average NT is the most effective screening method. The learning curve for CVS has been estimated to exceed 400
Detection rates comparable to singletons can be achieved. cases, with postprocedure loss rates for operators having per-
Cell-free DNA screening can be used in twin gestations [39]. formed fewer than 100 cases being two to three times higher
Detection rates for trisomy 21 are similar to singleton gestations; when compared to more experienced operators. The importance
however, due to the small number of cases, it is not possible to accu- of operator experience cannot be overemphasized, particu-
rately estimate detection rates for trisomy 18 and trisomy 13 [40]. larly for the route of CVS, with transcervical CVS requiring more
Detection rates of FTS or STS tests are usually lower than in experience.
singletons, with higher rates of false-positive and false-negative
results. Chorionicity does not seem to affect serum analytes in FTS Second-trimester amniocentesis
or STS (see Chap. 44 in Maternal-Fetal Evidence Based Guidelines). For the purpose of genetic testing, amniocentesis is typically
completed between 15 and 20 weeks of pregnancy. The procedure
is performed using a 22-guage needle and direct ultrasound guid-
Diagnostic testing ance to obtain a sample of amniotic fluid.
Second-trimester amniocentesis is associated with a 0.8%
Chorionic villus sampling and amniocentesis
increase in spontaneous miscarriage (2.1% versus 1.3%; rela-
Selected common indications for invasive prenatal diagnosis of
tive risk [RR] 1.60; 95% confidence interval [CI] 1.02–2.52), but
fetal aneuploidy are listed in Table 5.7. Both CVS and amniocen-
similar incidence of perinatal deaths (0.4 vs. 0.7%) [29, 30]. In a
tesis have been performed for many years and can fairly safely
meta-analysis, the procedure-related risk of miscarriage follow-
ing amniocentesis was reported to be about 0.11% (1 in 900) [44].
TABLE 5.7: Selected Common Indications for Invasive Amniocentesis is also associated with vaginal spotting and leak-
Prenatal Diagnosis age of amniotic fluid. Rarely, injury to the fetus from the needle
can occur.
• Abnormal first- or second-trimester aneuploidy screen
• Abnormal ultrasound findings
Early amniocentesis
• Parental concern/anxiety
Early amniocentesis (<15 weeks) is not a safe early alternative
• Parental desire for diagnostic testing
to second-trimester amniocentesis because it is associated with
increased pregnancy loss when compared to traditional amnio- considered if the phenotype is sufficiently defined to select an
centesis (2.5% vs. 0.7%), and higher incidence of talipes equin- appropriate panel of genes to sequence.
ovarus (1.8% vs. 0.2%) compared to CVS [44]. Additionally, there
is an increased rate of culture failure, which may require addi- Exome sequencing
tional invasive procedures [45]. As a result, early amniocentesis is Exome sequencing (ES) represents the next generation of pre-
not currently recommended [1]. natal genetic testing. ES uses massively parallel sequencings to
sequence the entire coding regions of the genome, or the exons,
Genetic testing options for aneuploidy which contains the majority of disease-causing mutations.
Fluorescent in situ hybridization Testing typically involves a trio approach, with testing of the
Fluorescent in situ hybridization (FISH) allows for the rapid and fetus, the mother, and the father, to assist with categorization of
accurate detection of trisomies 21, 18, and 13, as well as sex chro- variants as inherited or de novo.
mosome aneuploidy and triploidy. These common aneuploidies In fetuses with anomalies, it has been estimated to have diag-
account for 80% of clinically significant chromosome conditions nostic rates between 6.2% and 80% [57]. Two large prospective
detected prenatally [46]. In the event of an abnormal FISH result, cohort studies using ES in anomalous fetuses with normal karyo-
confirmatory testing should be completed using a conventional type and CMA showed an overall detection rate for diagnostic
karyotype to determine if a chromosomal translocation is pres- genetic variants in 9%–10% of fetuses and approximately 15%–
ent. If FISH results are normal, then additional testing with con- 20% of fetuses with two or more anomalies [58, 59]. In the case
ventional karyotype or chromosomal microarray (CMA) analysis of nonimmune hydrops fetalis, ES was able to provide a genetic
should be considered to rule out less common aneuploidies or to etiology in approximately 30% of cases [60].
identify smaller deletions or duplications that would be missed Although promising, this new technology has many challenges
using FISH alone. that are still being uncovered, including long turnaround time
for results, incomplete data on prenatal phenotypes and sequence
Conventional karyotype variants, ethical issues related to incidental findings, the large
Traditionally, conventional karyotyping has been the standard for amount of data and need for reanalysis, and a high cost associ-
prenatal diagnosis of fetal aneuploidy. Karyotype analysis allows ated with extensive DNA sequencing [61].
for the detection of whole chromosomal aneuploidies, balanced The decision to proceed with more advanced genetic testing
and unbalanced translocation, and large deletions or duplications. should be made in consultation with a certified genetic counselor
Conventional karyotype has a resolution of 5–10 Mb. Karyotype or medical geneticist.
analysis requires cell culturing, which can delay results and result
in test failures. Common karyotype abnormalities
Chromosomal microarray Trisomy 21 (Down syndrome)
CMA can query the entire human genome for copy number Historic notes
changes such as aneuploidy, deletions, duplications, and unbal- First complete description in 1846 by Seguin. Report by Down in
anced translocations. Unlike traditional cytogenetics, which 1866 established the name of the syndrome. In 1959 LeJeune and
requires dividing cells, CMA does not require cell culture and Jacobs independently described that Down syndrome was caused
can be completed on nondividing cells [47–52]. It can be particu- by trisomy 21.
larly useful in cases of intrauterine fetal demise with congenital
anomalies and culture failure with conventional karyotype [53]. Definition
In a high-risk population referred for prenatal diagnosis, CMA Down syndrome is trisomy 21, or the presence of an extra chro-
was compared to conventional karyotyping. The indications for pre- mosome number 21, either as three number 21s or as a transloca-
natal diagnosis were ultrasound abnormalities, advanced maternal tion between 21 and another chromosome, usually an acrocentric
age, or a positive result on prenatal screening. CMA was similar in a Robertsonian translocation.
to conventional karyotyping in detecting common chromosomal
aneuploidy, but was able to detect clinically significant aneuploi- Epidemiology/Incidence
dies not detected by karyotype [54]. Another study demonstrated About 1 in 800 live births. This is the most common trisomy at
that CMA was more likely to provide genetic results after stillbirth birth. Incidence increases with maternal age.
when compared to conventional karyotype [55]. When structural
abnormalities are detected by prenatal ultrasound, CMA can iden- Embryology
tify clinically significant chromosomal abnormalities in approxi- The Down syndrome critical region on chromosome 21 is being
mately 6% of the fetuses that have a normal karyotype [54]. For studied extensively to identify the genes involved in the Down
this reason, CMA should be recommended as the primary test syndrome phenotype. However, this region is not one small, iso-
(replacing conventional karyotype) to patients undergoing pre- lated spot, but most likely several areas on chromosome 21 that
natal diagnosis in whom a structural abnormality is detected are not necessarily side by side.
by ultrasound. Given its improved detection rates for clinically
significant abnormalities, ACOG also recommends that CMA be Genetics/Inheritance
made available to any patient electing to proceed with an invasive Error in cell division at the time of conception (nondisjunc-
prenatal diagnostic test [56]. tion) is responsible for 92% of Down syndrome cases resulting
in full trisomy 21. Approximately 90% of nondisjunction occurs
Targeted gene sequencing in the eggs. The cause of the nondisjunction error is not known,
In the event of normal karyotype or CMA testing results, addi- but there is a known association with maternal age. The recur-
tional genetic testing can be considered. Targeted panels can be rence risk is empirically 1% or the age-related risk as a woman
gets older. Three to four percent of all cases of trisomy 21 are Diagnosis
due to a Robertsonian translocation, most commonly between CVS or amniocentesis achieves the diagnosis by a study of the
chromosomes 14 and 21. In the balanced state, the individual is fetal chromosomes, which reveal trisomy 21. In the neonate, usu-
healthy and has 45 chromosomes with fusion of the entire long ally peripheral blood is cultured and karyotyped.
arm of chromosome 21 and another acrocentric chromosome
(13, 14, 15, or 22). An individual with Down syndrome due to a Counseling
Robertsonian translocation has 46 chromosomes with an unbal- The major abnormalities are increased risk of FGR, congenital
anced derivative chromosome. Translocations resulting in tri- heart defects, fetal and postnatal death, and developmental delay,
somy 21 may be inherited, so parental chromosomes must be with average IQ 50–75. Congenital heart defects are major con-
checked. A female carrier of a balanced Robertsonian transloca- tributors to mortality.
tion has about a 12% risk of recurrence of trisomy 21 in future
pregnancies, while a male carrier has approximately a 3% risk Workup/Investigations and consultations
of recurrence. Mosaic trisomy 21 occurs when there is a mix- A fetal echocardiogram is recommended. Depending on the
ture of cell lines, some of which have normal chromosomes and lesions detected, specific pediatric subspecialty consultation can
another cell line with trisomy 21. It is impossible to know how be offered. Genetic counseling can be offered as well. Care in a
the normal and trisomy 21 cells are distributed in the different tertiary care center is indicated if there are significant associated
organs; therefore, the percentage of mosaic to normal cells in the anomalies or if they cannot be ruled out adequately.
peripheral blood cannot be used to predict outcome. Another
Fetal intervention
tissue can be examined to help determine the level of mosaicism,
None available
usually skin.
Termination issues
Teratology Termination can be offered as a sole intervention as regulated by
None. local law (usually legal <24 weeks)
Classification Fetal monitoring/Testing

Full trisomy 21, translocation trisomy 21, and mosaic trisomy 21. No specific trials. NSTs weekly at ≥32 weeks can be offered.
Nonreassuring fetal heart rate (NRFHR) is common.
Risk factors/Associations
Advanced maternal age. Individuals who are carriers of balanced Delivery/Anesthesia
Robertsonian translocations involving chromosome 21 have an Mode and management of delivery should not be affected by the
increased risk unrelated to age. diagnosis of trisomy 21. NRFHT is common.
Pregnancy management Neonatology management

Screening (nonultrasound and/or ultrasound) Resuscitation
First- and second-trimester ultrasound, cell-free DNA screening, Providing life support as needed, as in any other infant, is gener-
FTS, STS. ally appropriate.
Ultrasound findings in fetus Transport

Indicated if counseling, general care, and/or major anomalies
• Thickened nuchal translucency at 11–14 weeks (80%) (at cannot be assessed and treated adequately at the birth institution.
times cystic hygroma: 10%)
Testing and confirmation
• Thickened nuchal fold (≥6 mm) at 16–23 weeks
Karyotype is usually confirmed by blood lymphocyte culture.
• Congenital heart disease (CHD) (40%–50%)
• Duodenal atresia (2%) Nursery management
• Omphalocele (2%) Neonatal echocardiogram and physical exam to assess any
• Ventriculomegaly anomaly. Surgery may need to be scheduled for GI or cardiac
• Hydrops or some hydropic changes (pleural effusion, anomalies. Down syndrome presents with a wide variety of fea-
ascites) tures and characteristics. A wide range of intellectual disability
• Several “soft markers,” such as short humerus and femur, and developmental delay is noted among children with Down
echogenic bowel, renal pyelectasis, cardiac (usually left syndrome. There is a great deal of variability in the presence of
ventricular) echogenic focus, short middle phalanx fifth other anomalies such as CHD, GI, and hematologic problems
digit, “sandal foot,” iliac crest >90 degree angle, short ear in these children. Hypothyroidism occurs in a high percentage
length of individuals with Down syndrome and should be monitored
• Biometry may reveal symmetric FGR by the third trimester closely for their lifetime. Early intervention and specialized help
• Amniotic fluid: Polyhydramnios (if gastrointestinal [GI] with education and home rearing have improved the outcome
obstruction or macroglossia present) in children with this condition. Many young adults with Down
• Placenta: Normal syndrome move in to community living arrangements and work
• Ultrasound after 14 weeks only detects ~50% of fetuses regular jobs or in sheltered workshops.
with trisomy 21. CPCs do not increase the risk. Screening
provides the mother and family with a risk for trisomy Future pregnancy preconception counseling
21, but diagnosis can only be achieved with CVS or With full trisomy 21, the recurrence risk is empirically 1% or
amniocentesis. the age-related risk. With Robertsonian translocation, parental
chromosomes should be checked, with genetic counseling regard- Pregnancy management

ing specific future risks. A Robertsonian translocation between Screening
two chromosomes 21, t(21;21) has a 100% risk for trisomy 21 when NT has a sensitivity of >80%; cell-free DNA screening and FTS
transmitted by a carrier parent. Also rare is a non-Robertsonian have a sensitivity of >90%, STS is typically low alpha fetoprotein
translocation formed by the union of two 21s such that the trans- (AFP), low HCG, and low estriol with a sensitivity of about >80%.
location forms a mirror image of the normal 21. Some literature Accurate ultrasound is usually >90% sensitive for trisomy 18.
suggests that in some families where there have been recurrent
trisomies, a relationship exists with their MTHFR status. This Ultrasound findings in fetus
has not been proven in large studies.
• Thickened NT at 11–14 weeks (80%) (at times cystic
Helpful websites hygroma: 15%)
• General: http://www.ds-health.com/ • Thickened nuchal fold (≥6 mm) at 16–23 weeks
• Health care guidelines for the care of individuals with • CHD (90%)
Down syndrome: http://www.denison.edu/collaborations/ • Omphalocele (25%)
dsq/health96.html • NTDs (20%)
• Risk and recurrence risk of Down syndrome: http:// • Clenched hands with overlapping fingers
www.nas.com/downsyn/benke.html • Clubbed or rocker-bottom feet
• CPCs (25%; most commonly isolated and seen in normal
Trisomy 18 (Edward syndrome) fetuses; karyotyping probably not indicated if isolated)
Historic notes • Enlarged (>1 cm) cisterna magna
Trisomy 18 was independently described by Edwards et al. and • Single umbilical artery
Smith et al. in 1960. • Micrognathia
• Cleft lip or palate
Definition • Hydrops or some hydropic changes (pleural effusion,
Edward syndrome is trisomy 18, or the presence of an extra chro- ascites)
mosome number 18. • Biometry may reveal FGR by the third trimester
• Amniotic fluid: Polyhydramnios (25%)
Epidemiology/Incidence • Placenta: Normal
Incidence of 1 in 6600 live births in the United States and the
United Kingdom. This is the second most common trisomy at
birth. Incidence increases with increasing maternal age. Diagnosis
CVS or amniocentesis
Embryology
The presence of three copies of chromosome 18 affects develop- Counseling
ment of all organs. Approximately 95% of concept uses with trisomy 18 die in
embryonic or fetal life. Five to ten percent of affected children
Genetics/Inheritance/Recurrence born alive survive beyond the first year of life. In utero, there are
Extra chromosome 18 is usually (95%) secondary to de novo mei-
decreased fetal movements. Clinical findings the parents should
otic nondisjunction associated with advanced maternal age. In
be informed about include severe psychomotor and growth delay,
approximately 90% of cases, the extra chromosome is maternal
microcephaly, microphthalmia, malformed ears, micrognathia or
in origin, with meiosis II errors occurring twice as frequently as
retrognathia, microstomia, distinctively clenched fingers, rocker-
meiosis I errors. Other human trisomies have a higher frequency
bottom feet, and other congenital malformations. CHD occurs
of nondisjunction in maternal meiosis I. Approximately 80% of
in 90%, with ventricular septal defect (VSD) and polyvalvular
nondisjunctions occurs in females. Mosaicism occurs in approx-
heart disease (pulmonary and aortic valve defects) common.
imately 10% and is due to postzygotic nondisjunction or ana-
Renal anomalies and GI and brain malformations are common.
phase lag. The causes of meiotic and mitotic nondisjunction are
Classical dermatoglyphics with digital arch patterns on finger
unknown. Translocations may also result in trisomy or partial
and toe tips and distal palmar triradius with hypoplastic finger
trisomy 18 with varying phenotype due to monosomy of another
tips and small nails. Central apnea is a frequent cause of death,
chromosome and the variable size of the piece of chromosome 18
along with cardiac, CNS, and renal malformations [62].
involved. The smallest extra region necessary for expression of
If diagnosed prenatally, recommend discussion with parents
serious anomalies of trisomy 18 appears to be 18q11-q12.
about how to proceed in labor and delivery, including option to
Teratology labor without monitoring, level of intervention desired by par-
None. ents, and extent of resuscitation after delivery. Indication for
C-section for fetal indications may be futile. Parents need to
Classification be counseled that some children with trisomy 18 do survive
Trisomy 18 (95%), mosaic trisomy 18, and variable partial trisomy and require lifelong complete care but never achieve any inde-
18 related to translocations. pendence. Few milestones are reached. There is an increased
incidence of Wilms tumor in trisomy 18 children who survive.
Risk factors/Associations Cardiac surgery is controversial. In the first weeks, it may be con-
Advanced maternal age and translocation carriers have sidered a heroic measure, but if the child is surviving, it may make
increased risk. Recurrence risk approximately 1% for full life more comfortable (comfort care). Apnea is a common cause
trisomy 18. of death.
Workup/Investigations and consultations required Genetics/Inheritance

A fetal echocardiogram is recommended. Genetic counseling can Extra chromosome # 13 resulting in full trisomy 13 (80% of
be offered. Neonatal consultation is extremely important to help cases). This is due to maternal nondisjunction, usually in mei-
the couple decide regarding neonatal management; usually just osis I. About 15% of cases are due to translocation, mostly
comfort care for the baby and psychological support for the par- Robertsonian translocation t(13q14). In 5% of cases, translocation
ents are most appropriate. is familial with a recurrence risk of 5% and risk of spontaneous
Fetal intervention: None available. abortion of 20%. The other cases are due to mosaicism (5%) with
trisomy 13 and a normal cell line. Mosaicism cases may have a
Termination issues milder phenotype.
Termination can be offered as the sole intervention as regulated
by local law (usually legal <24 weeks). Teratology
None.
Antepartum testing
As NRFHT is very common and the prognosis poor, fetal testing Classification
is not recommended. Many pregnancies continue without spon- Trisomy 13, mosaic trisomy 13, and translocation trisomy or par-
taneous labor until postterm (>42 weeks). tial trisomy 13.
Delivery/Anesthesia Risk factors/Associations

Fetal heart monitoring is usually declined and not indicated. Advanced maternal age. Individuals who are carriers of balanced
Every attempt should be made to maximize the chances of vagi- Robertsonian translocations involving chromosome 13 have an
nal delivery to minimize maternal morbidity, given the frequently increased risk.
fatal neonatal prognosis. Cesarean delivery for fetal indications is
not recommended and should be discussed. Pregnancy management
Screening
Neonatology management First-trimester ultrasound (with NT). Cell-free fetal DNA screen-
Resuscitation ing. First- or second-trimester multiple marker screening is not
Comfort care only. Allow parents to grieve appropriately. sensitive nor clinically useful for detecting trisomy 13. Accurate
Providing life support is usually not appropriate. ultrasound is usually 90% sensitive for trisomy 13.
Transport Ultrasound findings in fetus

Not indicated.
• Thickened NT at 11–14 weeks (>70%) (at times cystic
hygroma: 20%)
Testing and confirmation
• Thickened nuchal fold (≥6 mm) at 16–23 weeks
Karyotype is usually confirmed by blood lymphocyte culture.
• CHD (80%) (atrial septal defect [ASD] and VSD most com-
mon, but also often complex CHD)
Future pregnancy preconception counseling • Holoprosencephaly (40%)
With full trisomy 18, the recurrence risk is empirically 1% or • Cleft lip and palate (45%)
the maternal age-related risk. With Robertsonian translocation, • Hypotelorism/microphthalmia
parental chromosomes should be analyzed, with genetic counsel- • Polydactyly
ing regarding specific future risks. There are other rare transloca- • Rocker-bottom feet
tions leading to trisomy 18. • Omphalocele (10%)
• Polycystic kidneys (30%)
Helpful website • Enlarged (>1 cm) cisterna magna (15%)
https://rarediseases.info.nih.gov/diseases/6321/trisomy-18 • NTDs
• Hydrops or some hydropic changes (pleural effusion,
Trisomy 13 (Patau syndrome) ascites)
Historic notes • Biometry may reveal symmetric FGR by the third trimester
Patau first identified in a laboratory in 1960 noting three of the • Amniotic fluid: Polyhydramnios or oligohydramnios
group 13–15 chromosomes • Placenta: Normal
Definition
Patau syndrome is trisomy 13, or the presence of an extra chro-
Diagnosis
CVS or amniocentesis achieves the diagnosis by a study of the
mosome number 13.
fetal chromosomes, which reveals trisomy 13. In the neonate,
Epidemiology/Incidence usually peripheral blood is cultured and karyotyped.
1/10,000 live births. Incidence increases with increasing mater-
nal age. Approximately 1% of all first-trimester spontaneous Counseling
losses are due to trisomy 13. Most trisomy 13 conceptions result in spontaneous abortions
(SABs). Median survival is less than 3 days. Mean life expectancy
Embryology is 130 days, with most dying in first month of life—95% die within
Extra chromosome 13 affects development of all organs. 6 months. Apnea is a common cause of death and can happen at
home. The family needs to be prepared for intense care needs and parental chromosomes should be checked, with genetic counsel-
possible sudden death. The most common causes of death are caring regarding specific future risks. There are other rare transloca-
diopulmonary arrest, 69%; CHD, 13%; and pneumonia, 4%. tions leading to trisomy 13. With rare translocation of t(13q13q),
Some infants do survive, and those need complete care and the risk of recurrence or SAB is 100%.
achieve few milestones. Survival depends on associated medical
problems. Survivors with trisomy 13 have severe intellectual dis- Helpful website
ability and developmental delays. For survivors, specific growth https://rarediseases.info.nih.gov/diseases/7341/trisomy-13
charts are available for monitoring growth. Children with tri-
somy 13 are irritable, do not achieve milestones beyond smiling,
Turner syndrome
and most need to be fed by tube. Historic notes
If diagnosed prenatally, recommend discussion with parents In 1938 Turner described the combination of sexual infantil-
about how to proceed in labor and delivery, including option to ism, webbed neck, and cubitus valgus. Ford showed in 1959 that
labor without monitoring, level of intervention desired by parents, this combination of findings was associated with a missing X
and extent of resuscitation after delivery. Parents need to be coun- chromosome.
seled that some children with trisomy 13 do survive and require
Definition
lifelong complete care and never achieve any independence
Turner syndrome is the presence of single X chromosome, or
Workup/Investigations and consultations any karyotype with Xp missing such as isochromosome Xq,
A fetal echocardiogram is recommended. Genetic counseling can ring X, or deletion Xp. Also called 45X0 or 45X syndrome.
be offered. Neonatal consultation is extremely important to help
Epidemiology/Incidence
the couple decide regarding neonatal management; usually just
1/2500 female births (1/5000 total births). Ninety-eight to
comfort care for the baby and psychological support for the par-
ninety-nine percent of Turner fetuses are spontaneously aborted;
ents are most appropriate.
about 20% of all SABs are due to Turner syndrome.
Fetal intervention Embryology
None available.
Lymphedema usually due to congenital hypoplasia of lymphatic
Termination issues channels.
Termination can be offered as the sole intervention as regulated
Genetics/Inheritance
by local law (usually legal <24 weeks).
The presence of a single X chromosome or any karyotype with
Antepartum testing Xp missing, such as isochromosome Xq, ring X, or deletion Xp.
As NRFHT is very common and the prognosis poor, fetal testing The presence of a single X chromosome results from chromo-
is not recommended. Many pregnancies continue without spon- somal nondisjunction. Mosaicism is common (40%) and may
taneous labor until postterm (>42 weeks). include a 46,XY karyotype associated with ambiguous genitalia.
Since features of Turner syndrome are seen in other syndromes,
Delivery/Anesthesia karyotype is essential to make the diagnosis. Chromosome stud-
Fetal heart monitoring is usually declined and not indicated. ies on more than one tissue may be needed to detect mosaicism.
Every attempt should be made to maximize the chances of vagi- Not associated with advanced maternal age.
nal delivery to minimize maternal morbidity, given the almost
universally fatal neonatal prognosis. Teratology
Cesarean delivery for fetal indications is not recommended and None.
should be discussed.
Classification
Neonatology management 45,X in 50%. 46,X,i(Xq) in 17%, mosaicism in 40%.
Resuscitation Risk factors/Associations
Comfort care only. Allow parents to grieve appropriately. Not associated with advanced maternal age. Differentiate from
Providing life support is usually not appropriate. Noonan syndrome by karyotype, which is normal in Noonan
syndrome.
Transport
Not indicated. Pregnancy management
Testing and confirmation Screening
Karyotype is usually confirmed by blood lymphocyte culture. FTS with NT measurement. Cell-free DNA screening, although
detection rates are unknown.
Long-term care Ultrasound findings in fetus
Feeding issues, gastrostomy; irritability; chronic infections, aspi-
ration pneumonia; heart failure; frequent hospitalizations; sei- • Cystic hygroma
zures; blindness and hearing loss; few milestones achieved (smile, • Thickened nuchal fold (≥6 mm) at 16–23 weeks
laugh); parental stress. • CHD (20%; usually left side: Coarctation, aortic stenosis,
bicuspid aortic valve, left hypoplastic heart)
Future pregnancy preconception counseling • Renal anomalies (60%)
With full trisomy 13, the recurrence risk is empirically 1% or • Hydrops or some hydropic changes (pleural effusion,
the maternal age-related risk. With Robertsonian translocation, ascites)
• Amniotic fluid: Occasionally oligohydramnios Neonatology management

• Placenta: Normal Resuscitation
Providing life support as needed, as in any other infant, is gener-
Diagnosis ally appropriate.
CVS or amniocentesis achieves the diagnosis with a study of the
fetal chromosomes, which reveals 45,X or missing Xp. In the neo- Transport
nate, usually peripheral blood is cultured and karyotyped. Indicated if counseling, general care, and/or major anomalies
cannot be assessed and treated adequately at the birth institution.
Counseling
45,X conceptions frequently (>95%) end in SAB. The presence Testing and confirmation
of a cystic hygroma with the diagnosis of Turner syndrome Karyotype is usually confirmed by blood lymphocyte culture.
is associated with an estimated live birth rate of 2.6%, with
only 1% surviving to infancy [63]. If cystic hygroma is not Nursery management
present or resolves and the fetus is still alive >20 weeks, many Neonatal echocardiogram, renal ultrasound, and physical
survive until birth. Female infants with Turner syndrome have exam are indicated to assess any anomaly. Surgery may need to
excess nuchal skin and edema of the hands and feet (80%) due to be scheduled for cardiac anomalies. Early intervention and spe-
lymphedema. CHD, if present, usually most affects the progno- cialized help with education have improved the outcome in chil-
sis and requires surgery and long-term care. In childhood, short dren with Turner syndrome.
stature is apparent. Teenagers have delayed puberty and pri-
mary amenorrhea (>90%) with infertility (>99%). Other clinical Long-term care
findings include shield-shaped chest with widely spaced nipples; Thyroid studies annually; hearing test if otitis and not done
low posterior hairline with webbing or shortness of neck; renal before; speech evaluation, if needed; blood pressure checks
anomalies (60%); cubitus valgus; short fourth metacarpal; nar- routinely (hypertension a complication); annual echocardio-
row, hyperconvex, and deep-set nails; hearing loss; and thyroid gram to measure aortic root; annual urinalysis and culture
dysfunction. Some girls with Turner syndrome have learning if renal anomaly; use Turner growth curve after 2 years old;
difficulties, including difficulty with math and reading maps, monitor diet (calories and calcium); ophthalmology follow-
related to a deficit in spatial ability. Intelligence and verbal up as indicated; psychological support; individual education
skills are usually within the normal range. Mosaicism with a plan (IEP) at school if indicated; refer to endocrinologist in
normal female cell line may result in a milder phenotype and infancy, discuss growth hormone (GH) and hormone replace-
spontaneous puberty with fertility but often early menopause. If ment therapy (HRT): GH treatment can improve growth and
there is a deleted X but the XIST locus is intact, normal random influence a girl’s final adult height. HRT helps the girl with
X-inactivation may occur, and the phenotype may be milder. If Turner syndrome develop the physical changes of puberty. In
XIST is not present in a small X chromosome marker, the phe- vitro fertilization can make it possible for some women with
notype may be more severe. In mosaic 45,X/46,XY individu- Turner syndrome to become pregnant using a donor egg. It is
als clitoral enlargement may be present and virilization may important to discuss at what age to inform the child of her
occur. In these cases there is an increased risk of gonadoblas- diagnosis and its implications.
toma, and the gonad should be removed. Psychological impact
of short stature, infertility, and learning difficulties needs to be Future pregnancy preconception counseling
discussed. Recurrence risk in 45,X is not increased over population risk.
There is an increased risk if associated with a translocation.
Workup/Investigations and consultations
A fetal echocardiogram is recommended. Depending on the Klinefelter syndrome
lesions detected, specific pediatric subspecialty (in particular Historic notes
for cardiac anomalies) consultation can be offered. Genetic In 1942, Dr. Harry Klinefelter described males who had enlarged
counseling can be offered as well. Care in a tertiary care cen- breasts, sparse facial and body hair, small testes, and azoosper-
ter is indicated if there are significant associated anomalies or mia. By the late 1950s these findings were associated initially with
if they cannot be ruled out adequately. Endocrine follow-up is an extra Barr body, and later the extra X chromosome was identi-
indicated. fied with the karyotype 47,XXY.
Diagnosis/Definition
Fetal intervention
Chromosome study for 47,XXY. There are no specific phenotypic
None available.
features to identify Klinefelter syndrome in an infant.
Termination issues Epidemiology/Incidence
Termination can be offered as the sole intervention as regulated 1 in 500 to 1 in 1000 male births.
by local law (usually legal <24 weeks).
Genetics/Inheritance/Recurrence/Future prevention
Fetal monitoring/Testing Advanced maternal age slightly increases the risk for XXY.
No specific trials. NSTs weekly at ≥32 weeks can be offered. Recent studies have shown that half the time, the extra chromo-
some comes from the father.
Delivery/Anesthesia
Mode and management of delivery should not be affected by the Risk factors/Associations
diagnosis of Turner syndrome. Advanced maternal age.
Screening Clinical features

The prenatal phenotype is not well defined. Cell-free DNA screen- Girls with 47,XXX are usually tall. Pubertal development is usu-
ing, although detection rates are unknown. ally normal, and fertility is probably normal, but there may be an
increased incidence of offspring with chromosome abnormalities.
Clinical features
Occasional breast enlargement, lack of facial and body hair, and a Counseling
female-type body configuration. Small testes. Taller than others Girls with 47,XXX are shy and may demonstrate immaturity. The
in their family. Delayed speech occurs in >50%. Poor gross motor support of a loving and understanding family can improve the
coordination is present in ~27%. School difficulties are relatively outcome for these girls. Many have learning difficulties (math
common, and many boys with 47,XXY need assistance at school. and reading), but they are not intellectually disabled. The IQ of
Many are shy and somewhat passive and easy babies to care for. a girl with 47,XXX may be a few points lower than that of her
The average IQ is 90, with verbal IQ higher than performance IQ. siblings. Those diagnosed on amniocentesis or CVS with nor-
XXY boys enter puberty normally, without any delay of physical mal ultrasound, where the indication is Advanced maternal age
maturity. But as puberty progresses, they fail to keep pace with (AMA), have a better prognosis than those diagnosed postnatally
other males. Most XXY boys benefit from receiving an injection because a problem has been noted.
of testosterone every 2 weeks, beginning at puberty.
Selected microdeletions and duplications
Counseling
Regular injections of the male hormone testosterone, beginning DiGeorge syndrome (22q11.2 deletion syndrome)
at puberty, can promote strength and facial hair growth, as well Historic notes
as bring about a more muscular body type. DiGeorge syndrome, described in 1965, and velo-cardio-facial
Psychological support and therapy can help with self-esteem syndrome, described in 1978, are different manifestations of the
issues and interaction with peers. Depression also may be a prob- same deletion of chromosome 22q11.2.
lem in adults.
Boys with 47,XXY have a slightly increased risk of autoim- Diagnosis/Definition
mune disorders such as type 1 (insulin dependent) diabetes, FISH study reveals an interstitial deletion of chromosome 22
autoimmune thyroiditis, and lupus erythematosus. XXY males p11.2. Can be detected on microarray.
with enlarged breasts have the same risk of breast cancer as do
women—roughly 50 times the risk of XY males. XXY males who Epidemiology/Incidence
do not receive testosterone injections may have an increased risk 1 in 2000–4000 births
of developing osteoporosis in later life.
It is unnecessary to share this diagnosis outside of medical pro- Embryology
viders, as the diagnosis may be misunderstood. Defects occur in the third and fourth pharyngeal pouches,
which later develop into the thymus and parathyroid glands.
Rare/Related Developmental abnormalities may also occur in the fourth bran-
Variations include the XY/XXY mosaic, who may have enough nor- chial arch.
mally functioning cells in the testes to allow them to father children.
Genetics/Inheritance/Recurrence/Future prevention
Males with two or even three additional X chromosomes have also
Autosomal dominant inheritance. In 6% of affected individu-
been reported in the medical literature. In these individuals, the
als, one of the parents is affected. Expression is very variable,
classic features of Klinefelter syndrome may be exaggerated, with
so both parents of an affected child should be tested for the
low IQ or moderate to severe mental retardation also occurring.
deletion.
Testosterone injections may not be appropriate for all of them.
Helpful website
Other conditions have been noted to be associated with deleted
https://rarediseases.info.nih.gov/diseases/8705/klinefelter-
22q11.2, including conotruncal anomaly face syndrome (CAFS)
syndrome
(Japan) and sometimes Opitz G/BBB syndrome, CHARGE asso-
47,XXX ciation, and Cayler cardiofacial syndrome.
Diagnosis/Definition Screening
Karyotype shows 47,XXX.
All women with a fetus or neonate with a diagnosis of congeni-
Epidemiology/Incidence tal heart defect, especially if conotruncal, can be offered testing
1:1000 newborn females. (usually FISH) for this deletion. Testing is available from amnio-
cytes or chorionic villi.
Genetics/Inheritance/Recurrence
Sporadic, increased by advanced maternal age. Clinical features
Characteristic facies, cardiovascular defects in 85%, most are
Risk factors/Associations VSD. Cleft of secondary palate, may be submucous cleft or velo-
Advanced maternal age. pharyngeal incompetence. Nasal reflux in infants. Transient
neonatal hypocalcemia. Hypotonia. Immune system dysfunc-
Screening tion. Postnatal growth delay. Developmental delay, learning dis-
No identifying physical features in the fetus. Cell-free DNA ability, and psychological problems, especially in adolescence.
screening, although detection rates are unknown. Hypernasal speech.
Counseling (prognosis, complications, downslanting palpebral fissures, round face with full cheeks, flat
pregnancy considerations) nasal bridge, downturned corners of mouth, micrognathia, low-
Clinical features should be reviewed. Early death due to CHDs set ears, and variable cardiac defects. Renal anomalies have been
before 6 months of age in 8%. Early intervention for speech and described, as have cleft lip and palate, talipes equinovarus, and
motor delays. Special education for older children. Chance of psy- gut malrotation. Treatment is symptomatic.
chiatric disorders in 10%. Very variable phenotype, not predict-
able from laboratory result. Helpful website
http://www.emedicine.com/ped/topic504.htm
5p- (cri-du-chat syndrome)
Historic notes
In 1963, Lejeune et al. described a syndrome of multiple congeni- References
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6
CARRIER SCREENING FOR INHERITED GENETIC CONDITIONS
Whitney Bender and Lorraine Dugoff
Key points This approach is limited due to inaccurate or unavailable

information regarding ancestry, increased intermixing
• The primary goals of carrier screening are to identify indi- between different races/ethnicities, and the presence
viduals and couples who are carriers of disease-causing of carriers for genetic conditions in the nontargeted
variants that place them at increased risk of having a child populations.
with a serious medical disorder and provide them with • Technological advances in next-generation sequencing
information to optimize pregnancy outcomes based on have made it possible to perform expanded carrier screen-
their personal values and preferences. ing, which involves screening for variants associated with
• Preconception carrier screening is preferred to prena- multiple genetic diseases simultaneously irrespective of
tal carrier screening, as it enables couples to consider the ancestry (pan-ethnic screening). Pan-ethnic screening
most complete range of reproductive options. Information can identify more carriers and narrow the equity gap
regarding the risk of having an affected child may influ- inherent in ethnicity-based screening. Although pan-
ence a couple’s decision to conceive or to consider the use ethnic screening is deemed acceptable by medical societ-
of donor gametes, preimplantation genetic diagnosis, or ies, it is currently not recommended.
prenatal genetic testing. • Professional practice guidelines and recommendations are
• Information regarding genetic carrier screening should needed regarding patient and provider education and the
be provided to every pregnant woman. conditions that should be included on expanded carrier
• Most inherited genetic conditions are autosomal recessive. screening panels.
Carriers for these conditions are usually asymptomatic, • Appropriate pre- and posttest counseling regarding
have no significant family history, and are unaware of their prognosis, possible complications, long-term issues,
carrier status. and follow-up should be provided to every couple with a
• Current professional guidelines by the American College pre- or postnatal diagnosis of genetic disorders.
of Obstetricians and Gynecologists (ACOG) and the
American College of Medical Genetics and Genomics Background
(ACMG) recommend pan-ethnic carrier screening for
cystic fibrosis (CF) and spinal muscular atrophy (SMA). Carrier screening for single-gene disorders, also known as
• ACOG recommends that individuals of African, Southeast Mendelian disorders, is an important component of preconcep-
Asian, and Mediterranean ancestry should have screening tion and prenatal care. Carrier screening enables identification
for hemoglobinopathies with a complete blood count in of individuals and couples at risk of transmitting disease-causing
combination with a hemoglobin electrophoresis. genetic variants to their offspring at the time of fertilization.
• Prenatal testing for fragile X syndrome should be offered Preconception carrier screening can increase the reproduc-
to known carriers of the fragile X premutation or full muta- tive autonomy of individuals and couples by providing them
tion. Women with a family history of fragile X–related with knowledge that could lead to the broadest range of available
disorders, unexplained intellectual disability or develop- options, including preimplantation genetic testing for monoge-
mental delay, autism, or premature ovarian insufficiency netic/single gene disorders (PGT-M), adoption, the use of gamete
are candidates for genetic counseling and fragile X premu- donors, and prenatal diagnostic testing.
tation carrier screening. Single-gene disorders result from a disease-causing variant at a
• Carrier screening for Tay–Sachs disease, Canavan dis- single genetic locus. Although single-gene disorders are not very
ease, CF, and familial dysautonomia should be offered to common individually, autosomal recessive and X-linked disor-
Ashkenazi Jewish (one Jewish grandparent) individuals ders collectively occur in up to 1/175 pregnancies [1]. Severe or
before conception or during early pregnancy. The avail- profound single-gene disorders occur in 1 in 545 pregnancies and
ability of genetic carrier screening for mucolipidosis IV, account for 20% of pediatric hospitalizations and 18% of pediatric
Niemann-Pick disease type A, Fanconi anemia group C, deaths [2–4].
Bloom syndrome, and Gaucher disease should be discussed. This chapter will review carrier screening approaches, current
• Patients with a positive family history of a genetic society guidelines, genetic counseling principles, and some of the
condition should be referred for genetic counseling to more common genetic conditions currently included in society
review the family history, provide accurate information screening guidelines.
regarding risk, offer the appropriate genetic testing, and
discuss reproductive options. Carrier screening approaches
• Historically, professional practice guidelines recom-
mended targeted carrier screening for individual condi- Ethnicity-based screening
tions based on race or ethnicity, condition severity, carrier Historically, screening approaches to identify pregnancies at
frequency, prevalence, detection rates, and residual risk. risk for genetic disorders relied upon a patient’s reported race
78 DOI: 10.1201/9781003102342-6
Carrier Screening for Inherited Genetic Conditions 79
or ethnicity. For example, individuals of African American race Carrier screening guidelines
were offered screening for sickle cell disease, while individuals
of Northern European ancestry were offered cystic fibrosis (CF) The American College of Obstetrics and Gynecology (ACOG)
screening. acknowledges that ethnic-specific, pan-ethnic, and expanded
Ethnicity-based screening is limited by the fact that many indi- carrier screening are acceptable strategies for pre-pregnancy
viduals do not have accurate knowledge of their race or ethnic and prenatal carrier screening [10]. ACOG recommends that all
ancestry. In addition, increasing numbers of couples are of mixed pregnant women or women considering pregnancy be offered
race and ethnicity. A recent study of 93,419 individuals undergo- screening for spinal muscular atrophy (SMA), CF, and hemo-
ing a 96-gene expanded carrier screen reported that 9% of indi- globinopathies. Screening for fragile X syndrome, Tay-Sachs
viduals had greater than 50% of genetic ancestry from a lineage disease (TSD), and other genetic conditions commonly affecting
inconsistent with self-reported ethnicity. Limitations of self- individuals of Jewish descent (Canavan disease and familial dys-
reported ancestry led to missed carriers in at-risk populations. autonomia) are recommended on the basis of family history or
In addition, for 7 of the 16 conditions included in current screen- background. ACOG recommends that conditions included on
ing guidelines, most carriers were not from the population the an expanded carrier screening have a carrier frequency of 1
guideline aimed to serve [5]. Therefore, the perpetuation of ethnic in 100 or greater [10]. Of note, the recommendation does not
or racial bias in carrier detection utilizing these approaches is a provide guidance with respect to X-linked disorders, and it does
significant concern. not specify the ethnicities in which the 1 in 100 threshold should
be applied.
Pan-ethnic screening The American College of Medical Genetics and Genomics
In pan-ethnic screening, carrier screening for a panel of dis- (ACMG) also recommends pan-ethnic carrier screening for CF
orders is offered to all individuals regardless of ethnicity. This and SMA. In addition to the conditions recommended by
strategy encompasses screening for specific recommended condi- ACOG for individuals of Ashkenazi Jewish descent, ACMG
tions. This approach satisfies the ethical principle of justice, as recommends offering screening for Fanconi anemia group C,
all individuals are offered the same screening panel regard- Niemann-Pick disease type A, Bloom syndrome, mucolipido-
less of race [6]. sis type IV, and Gaucher disease.
Expanded carrier screening Genetic counseling

Expanded carrier screening involves simultaneous screening
for multiple genetic conditions regardless of a patient’s race/ All individuals and couples considering pregnancy should
ethnicity (pan-ethnic screening). Technological advances in have a basic screen for family history of genetic disorders,
next-generation sequencing have made it possible to efficiently with a pedigree to at least the second prior generation (three-
screen for a large number of conditions simultaneously for the generation pedigree). Questions should also involve history of
same cost as one or two single-gene carrier tests. Screening pan- birth defects, stillbirth, intellectual disability, developmental
els offered by laboratories vary and may include options to screen delay, recurrent spontaneous pregnancy loss, history of a previous
for up to several hundred conditions. fetus or child who was affected by a genetic disorder, and cancer
history. It is optimal to offer carrier screening preconception
Expanded carrier screening has so that women and their partners have the option to consider how
a number of advantages much genetic information they would like to have before starting
It can overcome the limitations associated with the targeted a family. Carrier screening results in the preconception period
ethnicity-based screening approach, including inaccurate may influence a couple’s decision to conceive or to consider the
and unavailable information regarding ancestry, increased use of donor gametes, preimplantation genetic diagnosis, or
intermixing between different races/ethnicities, and the pres- prenatal genetic testing. Additionally, genetic carrier screening
ence of carriers for genetic conditions in the nontargeted should be performed on potential gamete donors.
populations. Data from expanded carrier screening studies Information regarding genetic carrier screening should be
have demonstrated that diseases currently recommended for provided to every pregnant woman. As recommended by ACOG,
screening only in certain populations, such as Canavan dis- screening for CF and SMA should be discussed with every preg-
ease and sickle cell disease, are widely distributed outside of nant woman. Those patients belonging to an ethnic group at
their targeted populations [7, 5]. A modeling analysis based on increased risk for a recessive condition (e.g. sickle cell—African-
data from expanded carrier screening in 346,790 individuals American; TSD and others—Jewish; TSD in Irish, Cajun, and
demonstrated that expanded carrier screening may increase French Canadian; alpha-thalassemia—Southeast Asian; and
the detection of carrier status for a variety of potentially seri- beta-thalassemia—Mediterranean) should be offered specific
ous genetic conditions [8]. Expanded carrier screening may be screening.
the preferred approach for consanguineous couples in which Providers may also offer an expanded carrier screening panel.
both members of the couple may be carriers of the same rare Individuals offered expanded carrier screening should have
autosomal recessive disorder. appropriate pretest counseling. Since expanded carrier screens
Data are emerging regarding the clinical use of expanded can include over 100 conditions, it is not feasible to counsel
carrier screening. Among 391 at-risk couples who underwent patients regarding the specific conditions on the panel. It is
expanded carrier screening and were found to be at risk of having important to discuss the concept of residual risk with patients
an affected fetus, 77% of those diagnosed prior to pregnancy undergoing carrier screening. While sequencing has significantly
planned or pursued action to avoid having an affected off- increased detection rates, the sensitivity is not 100% for any con-
spring. Of those diagnosed in pregnancy, 37% elected to have dition. Table 6.1 lists points to include in the pretest counseling
prenatal diagnostic testing [9]. and consent process [11].
TABLE 6.1: Discussion Points for Pretest Counseling and DMD

Consent Process for Expanded Carrier Screening Female carriers of mutations in the Duchene muscular dys-
1. Carrier screening is voluntary. Patients can choose to participate or
trophy (DMD) gene may develop an abnormal skeletal or car-
decline.
diac muscle phenotype. The muscle disease is quite variable
2. Genetic testing results are confidential and protected in employment
and could include creatine–kinase elevation, exercise intoler-
and health insurance by the Genetic Information Non-Discrimination
ance, muscle cramps, or muscle weakness and wasting [16].
Act of 2008.
Cardiac manifestations are also possible, although their fre-
3. Expanded carrier screening panels include conditions that may vary
quency and features are variable. Myocardial fibrosis, electro-
in severity. The panels include many conditions that are associated
cardiogram (ECG) abnormalities, systolic dysfunction, and
with significant adverse outcomes, including decreased life
dilated cardiomyopathy have been described [16]. A screening
expectancy, cognitive impairment, and the need for medical and/or
echocardiogram is recommended for known female carriers
surgical intervention.
of DMD.
4. Accurate knowledge of paternity is necessary to provide accurate
information regarding risk. DNA (or blood) from the biologic father ATM
is necessary in order to provide risk assessments for autosomal Carriers of pathogenic variants in the ataxia–telangiectasia
recessive conditions. mutated (ATM) gene are at an increased risk of breast cancer
5. There is a residual risk for having an affected offspring even if compared to noncarriers. These individuals are at a twofold
both partners screen negative. This risk may vary depending on higher risk of breast cancer with a cumulative lifetime risk of
ethnicity, the specific condition, and the laboratory performing approximately 30% [17].
the testing.
6. It is common to identify carriers for one or more conditions when GBA
using expanded screening panels. In most cases, being a carrier has Carriers of mutations in the glucocerebrosidase (GBA) gene
no significant medical consequences for the individual. If two are at increased risk for Parkinson disease and other move-
partners are carriers of different autosomal recessive conditions, ment disorders. The risk of Parkinson disease among carriers
offspring are not likely to be affected. is increased between twofold and sevenfold over noncarriers.
7. It is possible that carrier screening will determine that an individual Among patients ultimately diagnosed with Parkinson disease,
has two pathogenic variants for a condition and thus has an those with a GBA mutation had younger onset; greater likeli-
autosomal recessive condition that might affect their health. hood of cognitive impairment; and less prominent tremor, bra-
Expanded carrier screening panels that include autosomal dominant dykinesia, and rigidity [18].
and X-linked conditions may detect individuals affected with one of Women with a specific indication for genetic testing
these conditions. In these situations, individuals should be referred should be referred for genetic counseling and a discussion
for genetic counseling and appropriate medical management. of options available for prenatal diagnosis. Responsibilities
Source: From Ref. [9] under Creative Commons Attribution license.
of clinicians (e.g. ob-gyns, family medicine specialists, and
nurse midwives) caring for pregnant women regarding genetic
screening are shown in Table 6.2 [19]. Possible indications
for genetic consultation for preconception and prenatal
In approximately 1.7%–2.5% of couples undergoing patients are shown in Table 6.3 [20]. Possible indications
expanded carrier screening, both members will be identi- for genetic consultation for adult patients are shown in
fied as carriers of a pathogenic variant for the same condition Table 6.4 [20].
[12–14]. If a patient and her partner both test positive as carri-
ers for the same autosomal recessive genetic condition, or if a
patient tests positive as a carrier for an X-linked condition, they
should be referred to a certified genetics professional to discuss TABLE 6.2: Responsibilities of Clinicians Caring for Pregnant
the implications and reproductive options. Women Regarding Genetic Screening
In addition to implications for a potential fetus, patients under-
1. Clinicians should be able to identify patients within their practices
going expanded carrier screening should be counseled regarding
who are candidates for genetic testing and should maintain
the potential for results that have direct personal health con-
competence in the face of increasing genetic knowledge.
sequences. Some of the genes associated with potential conse-
2. Obstetrician-gynecologists should recognize that geneticists and
quences in the carrier of a disease-causing variant are discussed
genetic counselors are an important part of the health care team and
briefly next.
should consult with them and refer as needed.
FMR-1 3. Discussions with patients about the importance of genetic
Female carriers with the premutation of this FMRP translational information for their kindred, as well as a recommendation that
regulator 1 gene (55-200 CGG repeats) have an increased risk of information be shared with potentially affected family members as
premature ovarian failure. Premature ovarian failure is defined appropriate, should be a standard part of genetic counseling.
as the development of hypergonadotropic hypogonadism prior to 4. Obstetrician-gynecologists should be aware that genetic information
age 40. Male carriers of the premutation are at risk of fragile X– has the potential to lead to discrimination in the workplace and to
associated tremor/ataxia syndrome (FXTAS). This disease may adversely affect an individual’s insurability. In addition to including
develop in as many as 20%–33% of adult male permutation car- this information in counseling materials, physicians should recognize
riers, with increasing age and length of CGG repeats correlated that their obligation to professionalism includes a mandate to
with greater motor impairment [15]. FXTAS may also occur in prevent discrimination.
female carriers due to X-inactivation. Source: From Ref. [19] with permission.
TABLE 6.3: Possible Indications for Genetic Consultation for Preconception and Prenatal Patients
Either Member of the Couple with Reason to Consider Consultation
A positive carrier screening test for a genetic condition such as cystic Discuss additional testing strategies and inheritance, testing of partner and
fibrosisa siblings
A personal history of stillbirths, previous child with hydrops, recurrent Rule out a chromosomal, metabolic, or syndromic diagnosis associated with
pregnancy losses, or a child with sudden infant death syndrome (SIDS) an unexplained neonatal death or SIDS
A progressive neurologic condition known to be genetically Discuss a potential diagnosis, the differential diagnosis, inheritance, and
determined, such as progressive ataxia testing options
A statin-induced myopathy Discuss a potential mitochondrial disorder, inheritance, and testing options
A birth defect such as cleft lip Discuss recurrence risks and testing options
A chromosomal abnormality such as translocation Discuss risks to the fetus and testing options
Significant hearing or vision loss thought to be genetically determined Discuss risks to the fetus and testing options
Intellectual disability, developmental delay or autism Discuss risks to the fetus and testing options
Source: From Ref. [20] with permission.
a If a patient tests positive as a carrier for an autosomal recessive condition, carrier testing should be offered to the patient’s partner. This does not require consultation with
a genetic counselor.
Abbreviation: SIDS, sudden infant death syndrome.
Common genetic disorders CF is an autosomal recessive disorder resulting from patho-

genic variants in the cystic fibrosis transmembrane conductance
Cystic fibrosis regulator (CFTR) protein. The most common mutation is ΔF508,
CF is the most common life-limiting genetic disorder in but >1700 other mutations have been described [21].
Caucasians [21]. Faulty chloride transport leads to increased CF screening should be offered to all women of reproductive
sweat chloride levels and increased viscosity of secretions in the age [18, 21–23]. It is generally more cost-effective and practical to
lungs, pancreas, biliary tree, and intestines. initially perform CF carrier screening for the patient only [21].
TABLE 6.4: Possible Indications for Genetic Consultation for Adult Patients
Personal History of Reason to Consider Consultation
Abnormal sexual maturation or delayed puberty Rule out an intersex condition, chromosomal abnormality, or syndromic
diagnosis
Recurrent pregnancy losses (more than two) Rule out a chromosomal rearrangement such as a balanced translocation
with karyotype
Tall or short stature for genetic background Rule out a skeletal dysplasia, chromosomal, or syndromic diagnosis
One or more birth defects Rule out a chromosomal or syndromic diagnosis, and provide genetic
counseling
Six or more cafe-au-lait macules >1.5 cm in diameter Rule out neurofibromatosis type 1
Statin-induced myopathy Rule out a mitochondrial disorder
A cancer or cancers known to be associated with specific genes or Rule out an identifiable mutation in a gene such as BRCA1; rule out a
mutations in the context of a compelling family history: young age at cancer syndrome (MEN2); discuss surveillance, treatment, testing options,
onset, bilateral lesions, and familial clustering of related tumors and inheritance
Cardiovascular problems known to be associated with genetic factors Rule out a mutation in a causative or contributory gene; discuss
such as cardiomyopathy surveillance, treatment, testing options, and inheritance
Suspected genetic disorder affecting connective tissue Rule out a syndromic diagnosis (Marfan syndrome); discuss surveillance,
treatment, testing options, and inheritance
Hematologic condition associated with excessive bleeding or excessive Confirm or rule out genetic condition; discuss treatment, testing options,
clotting and inheritance
Progressive neurologic condition known to be genetically determined, Confirm or rule out suspected diagnosis; discuss surveillance, treatment,
such as unexplained myopathy testing options, and inheritance
Visual loss known to be associated with genetic factors, such as retinitis Rule out a syndromic diagnosis (Stickler syndrome); discuss testing options,
pigmentosa if applicable, and inheritance
Early-onset hearing loss Rule out a syndromic or nonsyndromic genetic form of hearing loss; discuss
surveillance, testing options, and inheritance
Recognized genetic disorder, including a chromosomal or single-gene Confirm the diagnosis; discuss prognosis, medical management, and
disorder inheritance
Mental illness such as schizophrenia Rule out a genetic condition associated with this history
A close relative with a sudden, unexplained death, particularly at a Discuss diagnosis, inheritance, recurrence risks, and identify syndromes,
young age when possible
TABLE 6.5: Potential Screening Strategies for CF carrier screening for individuals of African, Southeast Asian, and
Mediterranean ancestry. Figure 6.1 outlines a screening strat-
Patient History Testing Considerations
egy [22]. A complete blood count (CBC) in combination with a
No family history • Initial screening of one partner hemoglobin electrophoresis is recommended for screening indi-
Sequential • Other partner tested if first partner is viduals of African ancestry. A CBC with red cell indices is the
positive initial recommended screening test for individuals of Southeast
• Low-risk racial/ethnic groups Asian and Mediterranean ancestry. Individuals with a low mean
Concurrent • Other partner not available corpuscular volume (MCV) and normal iron status should have
• Both partners tested simultaneously a hemoglobin electrophoresis. Southeast Asians with a normal
• Both partners’ results revealed hemoglobin electrophoresis should have molecular testing to
• Assesses couple’s risk rule out alpha-globin gene deletions characteristic of alpha-thal-
• Identifies couples at risk more rapidly assemia. Couples determined to be at increased risk for having
• More precise a child with sickle cell disease or thalassemia should be referred
Known family history • Ideally, test for specific mutation of to a genetic counselor [24]. For additional information regarding
affected family member hemoglobinopathies, refer to Chaps. 14 and 15 in Maternal-Fetal
Source: Adapted from Ref. [21]. Medicine Evidence Based Guidelines.
Abbreviation: CF, cystic fibrosis.
Sickle cell disease
Nonetheless, screening can be concurrent or sequential, and both Sickle cell disease refers to a group of autosomal recessive disor-
strategies are acceptable. Details of these screening strategies are ders involving hemoglobin S. Hemoglobin S differs from hemo-
shown in Table 6.5. If a patient or the patient’s partner has a fam- globin A due to a single nucleotide substitution in the beta-globin
ily history of CF, medical record review should be performed to gene on chromosome 11. The most severe form of sickle cell dis-
identify if information regarding the specific CFTR variant in the ease, sickle cell anemia, occurs in individuals with two copies of
affected family member is available. Additionally, if a woman’s hemoglobin S. Sickle cell disorders can also occur in individu-
reproductive partner has apparently isolated congenital bilateral als who have hemoglobin S and another abnormality of B-globin
absence of the vas deferens, the couple should be referred for a structure or production such as hemoglobin C or beta-thalassemia.
genetics consultation to discuss variant analysis for CF. Sickle cell disease occurs most commonly in people of African
The interpretation of CF screening results and recommended origin. One in 12 African Americans has sickle cell trait. Patients
clinical follow-up are detailed in Table 6.6. It is important to with sickle cell disease are prone to distortion, or sickling, of their
remember that screening panels cannot test for all of the possible red blood cells under conditions of decreased oxygen tension.
pathogenic CFTR variants, and, as such, there exists potential These distorted cells can result in increased viscosity, hemolysis,
for undiscovered pathogenic variants to exist in all patients who and anemia, resulting in interrupted blood supply to vital organs.
undergo screening. This concept is called the residual risk. The These vasoocclusive crises can cause interruption of normal
exact residual risk will differ depending on the patient’s ethnicity, perfusion and function of several organs, including the spleen,
with ethnicities with lower prevalence typically having a higher lungs, kidney, heart, and brain. See Chap. 15 in Maternal-Fetal
residual risk, and the exact screening test utilized. A sample residual Medicine Evidence Based Guidelines.
risk table for the most common 23-mutation CF panel is shown in
Table 6.7. It is important, however, to note the specific residual risk Beta-thalassemia
listed in a patient’s results report and use this for patient counseling. Beta-thalassemia is also caused by a mutation in the beta-globin
gene on chromosome 11. This results in the inability to produce
Hemoglobinopathies hemoglobin A. Individuals who are heterozygous for this muta-
Hemoglobinopathies are a diverse group of inherited single- tion have beta-thalassemia minor. Depending upon the amount
gene disorders that result from variations in the structure and/ of normal beta-globin chain production, disease severity varies.
or function of hemoglobin. The most common hemoglobinopa- Typically, asymptomatic mild anemia is present. Individuals who
thies—sickle cell disease, beta-thalassemia, and alpha-thalassemia— are homozygous for this mutation have beta-thalassemia major,
are all autosomal recessive conditions. A brief discussion of or Cooley anemia. This disease is characterized by severe anemia
each of these disorders is included next. ACOG recommends with extramedullary hematopoiesis, delayed sexual development,
TABLE 6.6: Interpretation of Cystic Fibrosis Test Results and Recommended Follow-Up
Partner One Carrier Testing Partner Two Carrier Testing Recommended Follow-Up
Negative Negative Review residual risk
Diagnostic testing not indicated
Negative Screening not completed Can utilize ethnic-specific carrier risk
Positive Negative Review residual risk
Positive Screening not completed Genetic counseling
Efforts made to screen partner
Positive Positive Genetic counseling
Offer prenatal diagnostic testing or PGT-M (if preconception)
Abbreviation: PGT-M, preimplantation genetic testing for monogenetic/single gene disorders.
TABLE 6.7: Incidence and Carrier Risk for CF Based on Race or Ethnicity
Estimated Carrier Estimated Carrier Risk
Racial or Ethnic Group Detection Rate (%) Risk before Test after a (–) Test
Ashkenazi Jewish 94 1/24 ~1/380
Non-Hispanic white 88 1/25 ~1/200
Hispanic white 72 1/58 ~1/200
African American 64 1/61 ~1/170
Asian American 49 1/94 ~1/180
and poor growth. Although elevated levels of Hb F are produced to moderate hemolytic anemia. Alpha-thalassemia major (Hb
in an attempt to compensate for the absence of Hb A, this condi- Bart disease) results from the absence of functional alpha-globin
tion is universally fatal in late childhood unless treatment with genes. Fetal hydrops and intrauterine fetal demise is the expected
periodic blood transfusions is initiated early. See Chap. 14 in outcome in these cases due to the inability to produce functional
Maternal-Fetal Medicine Evidence Based Guidelines. HbF. Hemoglobin Bart disease does not usually occur in fetuses
of alpha-thalassemia carriers of African origin, since individuals
Alpha-thalassemia of African descent usually have the trans-configuration geno-
Alpha-thalassemia results from a gene deletion of two or more type. See Chap. 14 in Maternal-Fetal Medicine Evidence Based
copies of the four alpha-globin genes on chromosome 16. It is Guidelines.
common among individuals of Southeast Asian, African, West
Indian, and Mediterranean ancestry. Deletion of two genes, alpha- Fragile X syndrome
thalassemia trait, causes a mild hemolytic anemia. The deletions Fragile X syndrome is the most common inherited cause of
may occur on the same chromosome (cis aa/-) or on two different intellectual disability. The prevalence is 1 in 3600 males and 1 in
chromosomes (trans a-/a-). Individuals of Southeast Asian descent 4000–6000 females [25].
are more likely to carry the cis configuration compared to their Affected males may display a wide range of behavioral and
African counterparts. Individuals with alpha-thalassemia trait cognitive manifestations, but they are never asymptomatic [23].
are at increased risk for having a child with a more severe form of The behavioral phenotype is characterized by autism spectrum
alpha-thalassemia. Hemoglobin H disease is caused by the dele- behaviors such as attention deficit/hyperactivity, expressive delay,
tion of three alpha-globin genes. Affected individuals have mild tactile defensiveness, perseverative speech, and echolalia, as well
CBC and RBC indices
Patients of Southeast Asian or Mediterranean descent Patients of African descent
Anemia (with reduced MCV

No abnormality
and normal iron status)
Hemoglobin electrophoresis
Normal Hb AS, AC, SS, SC, elevated A2, and

other abnormal hemoglobin
If Southeast Asian, evaluate for α-thalassemia
Not a carrier of Carrier of

α-thalassemia α-thalassemia
Offer testing of partner to assess reproductive risk
FIGURE 6.1 Screening strategy for anemia. (From Ref. [24] with permission.) Abbreviations: CBC, complete blood count;
Hb, hemogloblin; MCV, mean corposcular volume; RBC, red blood cells.
as social anxiety and avoidance of eye contact. The cognitive TABLE 6.8: Fragile X: Risk of Full Mutation (and Therefore
phenotype generally is moderate to severe mental impairment. Affected Child) Based on Number of Maternal CGG
Ten to twenty percent have seizures. Physical characteristics are Repeats
more readily identifiable around or after puberty. These findings
No. Maternal CGG Repeats % Risk Expansion to Full Mutation
are similar to a connective tissue disorder, including hyperexten-
sible joints; soft, smooth skin; flat feet; and mitral valve prolapse. 55–59 4
The facial appearance is often described as long and narrow with 60–69 5
prognathism and large ears. Macrocephaly may also be present. 70–79 31
Most develop macroorchidism [25]. 80–89 58
Affected females tend to have more normal cognitive develop- 90–99 80
ment, with approximately 33% of affected females having mental 100–200 98
retardation. The remaining either have mild learning disabilities
or normal intelligence Their physical features are also often less
pronounced than their male counterparts.
Fragile X is an X-linked dominant disorder caused by expan- Prenatal testing for fragile X syndrome should be offered to
sion of a repetition of the CGG trinucleotide segment of the frag- known carriers of the fragile X premutation or full mutation.
ile X mental retardation 1 (FMR-1) gene. This gene is located on Women with a family history of fragile X–related disorders,
the X chromosome at Xq27.3.The full mutation (>200 repeats) FXTAS, unexplained intellectual disability or developmental
results in the reduction or absence of fragile X mental retardation delay, autism, or premature ovarian insufficiency are candi-
protein (FMRP), an RNA-binding protein involved in the matura- dates for genetic counseling and fragile X premutation car-
tion and elimination of synapses. rier screening [25]. Careful assessment of the family history for
The FMR-1 gene is typically composed of a limited number males with cognitive impairment should be performed to identify
(<45) of CGG repeats. This region is usually stable and passes individuals at sufficient likelihood of premutation or full muta-
from one generation to the next. It is possible for this region to tion carrier status to warrant screening.
expand during meiosis in oocytes, reaching either intermedi- Women who accept fragile X premutation screening should be
ate (45–54 repeats) or premutation (55–200 repeats) lengths. As offered FMR-1 DNA mutation analysis after genetic counseling
repeat size increases, stability decreases, and further increases about the risks, benefits, and limitations of screening [25]. All
in the number of repeats become likely. Once the premutation identified carriers should be referred for follow-up genetic coun-
reaches expansion to >90 repeats, the likelihood of expansion to a seling. Diagnostic modalities for prenatal diagnosis (including
full mutation is at least 80% (Table 6.8) [26]. chorionic villus sampling [CVS] and amniocentesis) should be
In addition to the presence of CGG trinucleotide repeats, there discussed.
may be AGG trinucleotide repeats within the FMR-1 gene. The
presence of AGG repeats is associated with increased stability of Spinal muscular atrophy
the permutation allele. In contrast, few or no AGG repeats are SMA refers to a group of diseases that affect the motor neurons
associated with an increased risk of expansion in the next genera- of the spinal cord and brainstem. These neurons are responsible
tion, as seen in Figure 6.2. for supplying electrical and chemical signals to muscle cells.
Only women with a premutation FMR-1 can pass the full muta- Malfunction of these neurons causes improper muscle cell func-
tion to their offspring. Fathers with premutations usually pass the tioning and atrophy, resulting in muscle degeneration and weak-
gene in a stable fashion to all of their daughters and risk having ness. The prevalence of SMA is 1/10,000 infants [27].
affected grandsons. Premutation male and female carriers are at SMA is classified into one of four types depending on the age
risk for FXTAS, usually after age 50 years [25]. Female carriers are of onset and disease severity. See Table 6.9 for details regarding
also at risk of premature ovarian insufficiency. these types [27].
100%
Maternal repeat length
90%
0 AGG
80% 1 AGG
Full Mutation Expansion
70% 2 AGG
60%
50%
40%
30%
20%
10%
0%
45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–90
Maternal CGG Repeat Length
FIGURE 6.2 The likelihood for expansion to a fragile X full mutation. (From http://asuragen.com/products-and-services/clinical-
lab/xpansion-interpreter/, with permission from Dr. Sally Nolin.)
TABLE 6.9: SMA Types

Age of Onset Clinical Findings
Type I (Werdnig-Hoffman) Prior to 6 months of age Never able to sit up
Difficulty breathing and swallowing
Respiratory failure within first 2 years of life
Type II <18 months of age Never able to stand
Death in childhood
Type III >18 months of age Able to stand alone but may have frequent falls
Extremity weakness in legs more than arms
Death in adulthood
Type IV >21 years of age Able to stand alone
Death in adulthood
Abbreviation: SMA, spinal muscular dystrophy.
SMA is an autosomal recessive condition caused by a deletion Importantly, the presence of the variant does not confirm the
of a segment of DNA in exon 7 and exon 8 in the SMN1 (survival 2 + 0 genotype, but rather alters the likelihood of this genotype
motor neuron) gene located on chromosome 5. Rarely, SMA is for an individual undergoing carrier screening, thereby affecting
caused by a point mutation in the SMN1 gene. There does not the residual risk after screening.
appear to be a correlation between the type of SMN1 pathogenic Carrier testing may also report the number of SMN2 cop-
variant and disease severity. SMN2 generates small amounts of ies. While this does not determine carrier status, this number
SMN protein. The number of copies of SMN2 does correlate with may help to predict disease severity in the event of an affected
SMA phenotype. Individuals with fewer copies of SMN2 typically pregnancy.
have more severe forms of SMA (type I or II). See Table 6.10. Historically, treatment for SMA has been mainly supportive.
Pan-ethnic carrier screening for SMA is recommended by More recently, however, disease-modifying agents, including
the ACMG and ACOG [10, 19, 27]. Approximately 1 in 50 indi- nusinersen, onasemnogene abeparvovec, and risdiplam, have
viduals is a carrier for SMA.
Carrier testing for SMA measures the number of copies of the
deleted segment in the SMN1 gene. A noncarrier is expected to Normal
have two copies present (no deletion), while a carrier will have
SMN1
only one copy present (a deletion of one copy). SMA carriers most
commonly have one functional SMN1 gene on one chromosome
and an SMN1 gene deletion on the other chromosome (in trans).
Carriers can also have two functional SMN1 gene copies on one SMN1
chromosome (in cis) and none on the other chromosome (the
“2 + 0” genotype) or one chromosome with a nonfunctional
Carrier
SMN1 gene with a point mutation or a microdeletion. The poten-
tial outcomes of carrier testing can be seen in Figure 6.3. The 2 + SMN1
0 genotype occurs in 5%–8% of the general population, with black
individuals of sub-Saharan African heritage having a higher fre-
quency of this genotype. Polymerase chain reaction (PCR)–based
carrier testing is unable to identify this genotype reliably, and, as SMN1
such, the sensitivity for carrier screening in the black population
is 70% compared to 87%–95% in the nonblack population [28]. Carrier with normal screening test result
More recently, two variants in intron 7 and exon 8 of the SMN1
gene have been found to be more prevalent in carriers of the 2 + 0 SMN1
genotype. In the Ashkenazi Jewish population, these variants
occur in approximately 20% of patients with the 2 + 0 genotype
compared to <1% of noncarriers [29, 30]. Testing for these variants SMN1 SMN1
has been added by some laboratories for routine carrier testing.
Affected
TABLE 6.10: SMN2 Copy Number and SMA Clinical
Phenotype SMN1
SMN2 Copy Number SMA I SMA II SMA III/IV
1 96% 4% 0%
2 79% 16% 5% SMN1
3 15% 54% 31%
≥4 1% 11% 88%
FIGURE 6.3 SMN1 gene in normal, carrier, and affected states.
Source: From Ref. [27] with permission. (From Ref. [27] with permission.)
become options for infants and children <2 years of age who Treatment: The mainstay of treatment is supplementary dietary
are not ventilator-dependent. Older children and adults with cholesterol. Clinical benefits from this therapy include improved
moderate symptoms may also derive benefit from nusinersen or growth, improved developmental progress, and a lessening of
risdiplam. behavioral abnormalities.
Nusinersen is an oligonucleotide that modifies splicing of the Testing: Carrier testing detects 99% of carriers [36].
SMN2 gene to increase production of normal, full-length SMN
protein. It is administered intrathecally with four loading doses Medium-chain acyl-CoA dehydrogenase deficiency
over 8 weeks followed by maintenance dosing every 4 months. In Carrier frequency: The carrier frequency in Caucasians is 1 in 50.
a multicenter, double-blinded trial, improvement in motor mile- Affected gene: ACADM
stones as measured by the Hammersmith Infant Neurological Clinical features: This disorder is caused by a deficiency of
Examination was observed in 37 of 73 (51%) infants receiving medium-chain acyl-CoA dehydrogenase. This disorder is charac-
nusinersen vs. 0 of 37 (0%) infants receiving sham therapy. They terized by an intolerance to prolonged fasting, recurrent episodes
were also less likely to die or receive permanent assisted ventila- of hypoglycemic coma, impaired ketogenesis, and low plasma and
tion (39 vs. 68%) [31]. tissue carnitine levels.
Onasemnogene abeparvovec is a recombinant adeno- Treatment: Treatment includes L-carnitine supplementation
associated viral vector containing complementary DNA encod- and avoidance of prolonged fasting.
ing the normal human SMN protein. This medication is admin- Testing: Carrier testing detects 99% of carriers [36].
istered as a one-time intravenous infusion. The ongoing STRIVE
trial demonstrated that 62% of treated infants had reached the Ashkenazi Jewish ancestry genetic screening
age of 14 months without the need for permanent ventilation and
48% of infants achieved the ability to sit without support [32]. Who to screen
Risdiplam is a small-molecule SMN2 splicing modifier that The family history of individuals considering pregnancy, or who
increases the level of full-length SMN protein. This medication are already pregnant, should determine whether either mem-
is administered daily by mouth using a syringe. The FIREFISH ber of the couple is of Eastern European (Ashkenazi) Jewish
and SUNFISH trials demonstrated a greater number of treated ancestry (one grandparent is Ashkenazi Jewish) or has a rela-
patients without permanent ventilation and an improvement in tive with one or more of the following genetic conditions: TSD,
the 32-item Motor Function measure score in treated individuals, Canavan disease, CF, familial dysautonomia, Fanconi anemia
respectively [33, 34]. group C, Niemann-Pick disease type A, mucolipidosis IV, Bloom
syndrome, and Gaucher disease [37].
Additional disorders
In addition to the conditions described earlier and the conditions What to screen for
listed under “Ashkenazi Jewish Ancestry Genetic Screening,” the The ACOG and ACMG guidelines differ with respect to the
ACOG includes the following three conditions in consideration conditions that should be included when performing carrier
for a proposed expanded carrier screening panel [35]. screening in individuals of Ashkenazi Jewish descent. ACOG
recommends that carrier screening for TSD, Canavan disease,
Phenylketonuria CF, and familial dysautonomia should be offered to Ashkenazi
arrier frequency: Unknown in general population. The carrier
C Jewish individuals before conception or during early pregnancy.
frequency in Caucasians is 1 in 50. If the woman is already pregnant, simultaneous screening can
Affected gene: PAH be considered based upon gestational age, partner ethnicity, and
Clinical features: This disorder is caused by a deficiency in patient/partner preference so that results are obtained in a timely
PAH, which catalyzes conversion of phenylalanine to tyrosine. fashion to ensure that prenatal diagnostic testing is an option.
Insufficient enzyme activity results in an elevated blood and ACOG acknowledges that carrier screening is available also for
urine concentration of phenylalanine. Newborn infants are mucolipidosis IV, Niemann-Pick disease type A, Fanconi
asymptomatic prior to the initiation of feeds containing phenyl- anemia group C, Bloom syndrome, and Gaucher disease. The
alanine. In untreated patients, hallmark of the disease is irrevers- ACMG recommends screening for these five additional disorders,
ible intellectual disability, seizures, behavioral abnormalities, and for a total of nine [38]. ACMG provides criteria for adding new
microcephaly. diseases to the panel of Jewish genetic diseases based on signifi-
Treatment: The mainstay of therapy is dietary restriction of cant burden of the disorder, carrier rate >1/100, and/or test sen-
phenylalanine. sitivity >90%.
Testing: Carrier testing detects 99% of carriers [36]. In all cases, a general description of the disorders for which
screening is planned should be provided to the patient and part-
Smith-Lemli-Opitz syndrome ner. Thorough counseling should also include a discussion on the
Carrier frequency: The carrier frequency in Caucasians is 1 in 70. variable phenotype of many of these conditions and a discussion
Affected gene: DHCR7 on the concept of residual risk. Formal genetic counseling should
Clinical features: This disorder is caused by a deficiency of be made available to anyone desiring it.
7-dehydrocholesterol reductase. Smith-Lemli-Opitz syndrome Currently 19 diseases are available for screening on Jewish
has been associated with low maternal serum unconjugated genetic disease panels. In addition to those mentioned previously,
estriol levels less than 0.25 MoM on second-trimester maternal the following diseases are included: maple syrup urine disease,
serum screening. The clinical manifestations of this disorder glycogen storage disease type 1a, dihydrolipoamide dehydroge-
include intellectual disability, poor growth, and characteristic nase (DLD) deficiency, familial hyperinsulinism, Joubert syn-
phenotypic abnormalities, including microcephaly, characteristic drome, nemaline myopathy, SMA, Usher syndrome type 1F,
facies, hypospadias, and polysyndactyly. Usher syndrome type III, and Walker-Warburg syndrome [37].
How to screen Familial dysautonomia

All the disorders on the Ashkenazi Jewish genetic disease panel Carrier frequency: 1/32 with disease incidence of 1/3700.
are autosomal recessive. A carrier is unaffected, but if two carri- Affected gene: ELP1
ers of a mutation in the same gene have a child together, they have Clinical features: This is a disorder of the sensory and autonomic
a 25% risk with each pregnancy of having an affected child. nervous system. Malfunction of these systems affects the regula-
When only one partner is of Ashkenazi Jewish descent, tion of body temperature, blood pressure, and stress response and
that individual should be screened first. If it is determined may also cause decreased sensitivity to pain. Frequent pneumo-
that this individual is a carrier, the other partner should be nia and poor growth may occur. Survival into adulthood is pos-
offered screening for that disorder. However, the couple should sible with careful medical care.
be informed that the carrier frequency and the detection rate in Treatment: Supportive
non-Jewish individuals are unknown for many of these disorders. Testing: Carrier testing for one major pathogenic variant and one
Therefore, it is difficult to accurately predict the couple’s risk of additional variant accounts for 99.5% of carriers [36].
having a child with the disorder, and gene sequencing may be nec-
essary to determine if a non-Jewish partner is a carrier. Referral to Canavan disease
a genetic counselor is recommended in these cases. arrier frequency: 1/40 with a disease incidence of
C
Individuals with a positive family history of one of these disor- 1/3000–1/6000.
ders should be offered carrier screening for the specific disorder Affected gene: ASPA
utilizing the family’s known variant. If possible, genetic counsel- Clinical features: This is a severe degenerative neurologic dis-
ing should be offered in these cases. ease caused by a variant in the gene for aspartoacylase. The phe-
When an individual is found to be a carrier, his or her rela- notype is variable, but presentation typically occurs in the first
tives are at risk for carrying the same disease-causing variant. The few months of life with delayed motor milestones. Thereafter,
patient should be encouraged to inform his or her relatives of they may demonstrate macrocephaly, hypotonia, and intellectual
the risk and the availability of carrier screening. The provider disability. Life expectancy is variable.
should not contact these relatives because there is no provider– Treatment: Supportive
patient relationship with the relatives, and confidentiality must Testing: Carrier testing detects 98% of carriers [36].
be maintained [37].
When both partners are carriers of one of these disorders, Bloom syndrome
they should be referred for genetic counseling and offered Carrier frequency: 1/100 with a disease incidence of 1/48,000.
prenatal diagnosis. Carrier couples should be informed of the Affected gene: BLM
disease manifestations, range of severity, and available treatment Clinical features: This disorder is caused by increased chro-
options. Prenatal diagnosis by DNA-based testing can be per- mosomal breakage. Affected individuals may demonstrate short
formed on cells obtained by CVS and amniocentesis. stature; a sun-sensitive skin rash; an increased susceptibility to
Brief descriptions of selected disorders with increased preva- infections; and higher incidence of leukemia and other cancers,
lence in the Ashkenazi Jewish population are listed next. The listed infertility, and immunodeficiency. Individuals often survive into
carrier frequencies apply to the Ashkenazi Jewish population. adulthood.
Treatment: Supportive
Tay-Sachs disease Testing: Carrier testing detects 95%–97% of carriers [36].
arrier frequency: 1 in 30. The carrier frequency is also increased
C
in individuals of French Canadian and Cajun descent. Fanconi anemia type C
Affected gene: HEXA Carrier frequency: 1/89 with disease incidence of 1/32,000.
Clinical features: This is the most well-known disorder affecting Affected gene: FANCC
the Ashkenazi Jewish population. In this lysosomal storage dis- Clinical features: This disease is caused by disruption to normal
ease, GM2 gangliosides accumulate throughout the body due to DNA repair mechanisms, resulting in genomic instability, abnor-
functional deficiency in hexosaminidase A. The accumulation of mal cell cycle regulation, and cell death. Clinical features include
these gangliosides in the central nervous system results in pro- congenital anomalies such as thumb or other radial ray anoma-
gressive functional decline. An apparently healthy child begins to lies, microcephaly, and facial or renal abnormalities. Affected
lose skills around 4–6 months of age, and there is a progressive children are predisposed to short stature, bone marrow failure,
neurologic decline leading to blindness, seizures, and unrespon- and leukemia and other cancers.
siveness. Death usually occurs by the age of 4–6. Treatment: Pancytopenia can be treated with stem cell
Treatment: Supportive transplantation.
Testing: Carrier testing can be performed using DNA-based Testing: Carrier testing detects 99% of carriers [36].
testing and hexosaminidase enzymatic activity testing [37].
Labs that use a sequencing approach may detect 99% of car- Gaucher disease type 1 (non-
riers regardless of ethnicity [36]. Historically, genotyping was neuropathic Gaucher disease)
used to determine carrier status in individuals of Ashkenazi Carrier frequency: 1/15 with disease incidence of 1/900.
Jewish descent and enzyme testing was used to evaluate indi- Affected gene: GBA
viduals of non- Ashkenazi Jewish descent, as the enzyme assay Clinical features: This condition is a lysosomal storage disease
detects all carriers, regardless of ethnicity [30]. Enzyme test- caused by a deficiency in glucocerebrosidase. Onset of symptoms
ing in pregnant women and women taking oral contraceptives can occur at any time, with approximately 50% of patients not
should be performed using leukocyte testing, as serum test- presenting until late adulthood. It may present with a painful
ing is associated with an increased false-positive rate in these hepatosplenomegaly, anemia, and leukopenia. Bone deterioration
populations. and fractures are a major cause of pain and disability.
reatment: Treatment options include enzyme replacement

T linical features: This disease is caused by an inability to break
C
therapy and substrate reduction therapy. down specific amino acids and a resultant buildup of lactic acid.
Carrier testing: Seven pathogenic variants account for >96% of It presents in early infancy with hypotonia and lethargy. Affected
cases [36]. individuals ultimately develop seizures and hepatomegaly. Many
individuals succumb to this disease in early childhood. Survival
Mucolipidosis type IV into adulthood is associated with intellectual disability, spastic-
Carrier frequency: 1/100 with disease incidence of 1/40,000. ity, ataxia, and seizures.
Affected gene: MCOLN1 Treatment: Supportive with dietary modifications.
Clinical features: This disorder is caused by the accumulation Carrier testing: Carrier testing detects 99% of carriers [36].
of lipids and polysaccharides in cell lysosomes due to abnormal
endocytosis. This results from a lack of functional mucolipin-1 Familial hyperinsulinism
protein. It is a progressive neurologic disorder characterized by Carrier frequency: 1 in 68 with disease incidence of 1/18,000.
physical and developmental delays, severe intellectual disability, Affected gene: ABCC8
corneal clouding, and retinal degeneration. Language and motor C linical features: This syndrome is characterized by exces-
skill function beyond that of a 1 or 2 year old is typically not sive insulin secretion. One-third of infants are macrosomic
achieved. at delivery due to hyperinsulinemia in fetal life. Persistent
Treatment: Supportive hypoglycemia is often recognized within the first few days
Carrier testing: Carrier testing detects 99% of carriers [36]. of life.
Treatment: Treatment options include diazoxide or surgery
Glycogen storage disease, type 1a (pancreatic resection).
Carrier frequency: 1 in 64 with disease incidence of 1/16,000. Carrier testing: Carrier testing detects 90% of carriers [36].
Affected gene: G6PC
Clinical features: This disease is caused by the accumulation of Joubert syndrome
glycogen in various organs. Symptoms, including hypoglycemia Carrier frequency: 1 in 92 with disease incidence of 1/34,000.
and hepatomegaly, typically develop during the first year of life. A ffected gene: TMEM216 is more prevalent in the Ashkenazi
Growth restriction, delayed puberty, and hepatic adenomas can Jewish population (30 additional pathogenic variants in >30 genes
be seen in later years. that affect the structure and function of primary cilia have been
Treatment: Disease management involves lifelong diet identified).
modification. Clinical features: This syndrome is characterized by abnormal
Carrier testing: Carrier testing detects 99% of carriers [36]. structure and function of cilia, resulting in abnormal develop-
ment of the brainstem and cerebellar vermis. Polydactyly and
Maple syrup urine disease prominent cerebellar peduncles, known as the “molar tooth sign,”
arrier frequency: 1 in 81 with disease incidence of 1/50,000
C may be seen on prenatal imaging. Cystic renal dysplasia is seen
(type 1b). in approximately 25% of cases. Affected individuals have ataxia,
Affected gene: BCKDHB (type 1b) hypotonia, abnormal eye movements, and developmental and
Clinical features: This disorder is caused by an inability to break intellectual disability.
down specific amino acids. The disease is associated with ketonu- Treatment: Supportive
ria within 48 hours of life that, if left undiagnosed and untreated, Carrier testing: Detection rate is 99% for the TMEM216 variant
can progress to lethargy, dystonia, seizures, cerebral edema, and [36].
death. It is named for the characteristic maple syrup smell of
urine in those with the disorder. Nemaline myopathy
Treatment: Disease management involves lifelong diet Carrier frequency: 1 in 168 with a disease incidence of 1/50,000.
modification. A ffected gene: NEB (accounts for 50% of total cases of nemaline
Carrier testing: Carrier testing detects 99% of carriers [36]. myopathy)
Clinical features: This disease causes disorganization of the
Niemann-Pick disease type a proteins found in sarcomeres in skeletal muscles and is the most
Carrier frequency: 1 in 90 with disease incidence of 1/32,000. common congenital myopathy. There are different types based
Affected gene: SMPD1 on the degree of severity. Proximal muscle weakness is the most
C linical features: This disease is a lysosomal storage disorder common and may worsen over time.
caused by a deficiency of sphingomyelinase. Affected infants Carrier testing: Carrier testing detects 99% of carriers of NEB
will appear normal at birth but develop hepatosplenomeg- variants [36].
aly, feeding difficulty, and motor regression within the first
few months of life. Macular cherry red spots on fundoscopic Usher syndrome type 1F
exam can be seen in 50% of patients. Death typically occurs by Carrier frequency: 1 in 147 with disease incidence of 1/86,000.
2–3 years of age. Affected genes: PCDH15, USH1F
Treatment: Supportive Clinical features: This syndrome is characterized by profound
Carrier testing: Carrier testing detects 99% of carriers [36]. hearing loss beginning at birth. Affected individuals achieve
walking at later ages due to vestibular areflexia and develop reti-
Dihydrolipoamide dehydrogenase nitis pigmentosa in childhood, which results in progressively
deficiency (DLD deficiency) constricted visual fields.
Carrier frequency: 1 in 107 with disease incidence of 1/35,000. Treatment: Supportive, hearing aids or cochlear implant
Affected gene: DLD Carrier testing: Carrier testing detects ≥75% of carriers [36].
Usher syndrome type III ethnically diverse clinical sample of 24,453 individuals. Genet Med
2013;15:178–186.
Carrier frequency: 1 in 120 with disease incidence of 1/57,000.
8. Haque IS, Lazarin GA, Kang HP, et al. Modeled fetal risk of genetic diseases
Affected gene: CLRN1 identified by expanded carrier screening. JAMA 2016;316(7):734–742.
Clinical features: This syndrome is associated with the same fea- 9. Johansen Taber KA, Beauchamp KA, Lazarin GA et al. Clinical utility of
tures as Usher syndrome type 1F. In contrast to type 1F, however, expanded carrier screening: Results guided actionability and outcomes.
hearing loss develops later in childhood and retinitis pigmentosa Genet Med 2019;21:1041–1048.
10. Committee on Genetics. Committee Opinion No. 691: Carrier screening for
develops in the second decade. genetic conditions. Obstet Gynecol 2017;129:e41–e55.
Carrier testing: Carrier testing detects 99% of carriers [36]. 11. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening
in reproductive medicine – Points to consider. A joint statement of the
Walker-Warburg syndrome American College of Medical Genetics and Genomics, American College of
Carrier frequency: 1 in 149 with disease incidence of 1/60,000. Obstetricians and Gynecologists, National Society of Genetic Counselors,
Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
A ffected genes: Over a dozen genes that prevent glycosylation
Obstet Gynecol 2015;125:653–662.
of alpha-dystroglycan have been associated, including POMT1, 12. Haque IS, Lazarin GA, Wapner RJ. Prenatal carrier screening. JAMA
POMT2, CRPPA, FKRP, and LARGE1. 2016;316(24):2675–2676.
Clinical features: This syndrome is caused by abnormal glyco- 13. Ben-Shachar R, Svenson A, Goldberg JD, et al. A data-driven evaluation
sylation of alpha-dystroglycan. This abnormal protein causes of the size and content of expanded carrier screening panels. Genet Med
2019;21(9):1931–1939.
progressive weakness of skeletal muscles and abnormal migration 14. Guo MH, Gregg AR. Estimating yields of prenatal carrier screening and
of neurons. Affected individuals have hypotonia and can never implications for design of expanded carrier screening panels. Genet Med
walk. Cobblestone lissencephaly results in development and 2019;21(9):1940–1947.
intellectual disability. Microphthalmia is also common. Most 15. Brussino A, Gellera C, Saluto A, et al. FMR1 gene permutation is a fre-
quent genetic cause of late-onset sporadic cerebellar ataxia. Neurology
individuals do not survive past age 3.
2005;64(1):145–147.
Carrier testing: Detection rate is unknown (not enough data). 16. Finsterer J, Stollberger C, Freudenthaler B, et al. Muscular and cardiac
manifestations in a Duchenne-carrier harboring a dystrophin deletion of
Summary exons 12–29. Intractable Rare Dis Res 2018;7(2):120–125.

17. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause
ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet
Preconception carrier screening maximizes patients’ repro- 2006;38(8):873–875.
ductive choices and planning. Current society guidelines 18. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocere-
recommend universal carrier screening for CF, SMA, and hemo- brosidase mutations in Parkinson’s disease. NEJM 2009;361(17):1651–1661.
globinopathies. Although historically, additional genetic testing 19. American College of Obstetricians and Gynecologists. ACOG Committee
Opinion No. 410: Ethical issues in genetic testing. Obstet Gynecol
has been recommended based on a patient’s race, ethnicity, or 2008;111:1495–1502.
family history, more recent data have highlighted the limita- 20. Pletcher BA, Toriello HV, Noblin SJ, et al. Indications for genetic referral: A
tions of this strategy and demonstrated the benefits of expanded guide for healthcare providers. Genet Med 2007;9:385–389.
carrier screening, particularly in individuals of uncertain ethnic 21. American College of Obstetrics and Gynecology. Committee Opinion
No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol
backgrounds or consanguineous couples. The widespread use
2011;117:1028–1031.
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future consideration, including which conditions to include on screening: 2004 revision of American College of Medical Genetics muta-
the panel and the best method for providing pretest and post- tion panel. Genet Med 2004;6:387–391.
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for cystic fibrosis carrier status practice guidelines: Recommendations of
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creation of a repository of these findings and their associated [Level III]
phenotype is also an area of future interest as expanded carrier 24. American College of Obstetricians and Gynecologists. ACOG Practice
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25. American College of Obstetrics and Gynecology. ACOG Committee
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7
PREPARATION BEFORE LABOR
Daniele Di Mascio and Leen Al-Hafez
Key points setting decreased the likelihood of epidural analgesia, oxy-

tocin augmentation of labor, and episiotomy.
• Barometric pressure is not an effective method to predict • Women who had midwife-led continuity models of care
spontaneous onset of labor in pregnancies at term. Diurnal were less likely to receive some medical interventions,
rhythms seem to show a higher rate of starting labor, with such as amniotomy, episiotomy, and intrapartum anal-
maximal frequency of labor starting in the evening and gesia/anesthesia; had shorter labors, less instrumental
night hours. vaginal birth, preterm birth <37 weeks, less fetal loss/
• Transvaginal ultrasound cervical length (TVU CL) eval- neonatal death before 24 weeks, less overall fetal/neo-
uation is a good predictor of the onset of spontaneous labor natal death; and were more likely to experience sponta-
in women at ≥37 weeks: a woman with a CL of 30 mm has neous vaginal birth.
a <50% chance of delivering within 7 days, while one with • Continuous support during labor by a doula is associ-
a CL of 10 mm has an over 85% chance of delivering within ated with a higher rate of spontaneous vaginal birth,
7 days. lower rates of cesarean and instrumental vaginal deliv-
• Antenatal classes to prepare for labor and delivery are eries, less likely negative feelings about the childbirth
associated with arriving to the labor and delivery unit experience, less intrapartum analgesia, shorter labors,
more often in active labor, using less epidural analge- and lower rates of low 5-minute Apgar score.
sia, and fewer mean number of visits to the labor ward • Training of traditional birth assistants in middle- and
before the onset of labor. low-income countries is associated with a trend for less
• Mind–body relaxation, yoga, and music might play a role maternal mortality and significantly less perinatal mortality.
in decreasing pain and increasing satisfaction with pain • There is insufficient evidence to assess the effects of
relief. training and teamwork education for labor and delivery
• Mindfulness-based childbirth education is associated personnel.
with lower postcourse depression symptoms and with a • Delayed admission until active labor is associated with
trend toward a lower rate of opioid analgesia use in labor. less time in the labor ward, less intrapartum oxytocics,
• Intensive counseling in women with fear of childbirth and less analgesia. Women in the labor assessment and
reduces anxiety and concerns related to pregnancy and delayed admission group report higher levels of control
birth and is associated with shorter labors. during labor. Suggested criteria for admission are a cer-
• Antenatal perineal massage is associated with a reduc- vix of at least 3–4 cm dilatation and regular painful
tion in the incidence of trauma requiring suturing and contractions.
the rate of episiotomy, particularly in women without pre- • Women allocated to admission cardiotocography (CTG)
vious vaginal birth. have an increase in the incidence of cesarean deliv-
• Pelvic floor muscle training is associated with a lower ery than women allocated to intermittent auscultation.
risk of reporting urinary incontinence in continent Obtaining an amniotic fluid index in early labor is associ-
women either in late pregnancy and in the mid-postnatal ated with a higher incidence of cesarean delivery and simi-
period from 3–6 months postpartum. lar neonatal outcomes.
• Routine use of sweeping of membranes from 37 to 38 • Enemas do not have a significant beneficial effect on
weeks of pregnancy onwards is significantly associated infection rates such as perineal wound infection or other
with reduced duration of pregnancy and reduced fre- neonatal infections and women’s satisfaction.
quency of pregnancy continuing beyond 41 weeks. • There is no support for routine perineal shaving for
• Women undergoing x-ray pelvimetry are more likely to be women prior to or in labor.
delivered by cesarean delivery.
• Planned home birth is usually associated with a higher
risk of perinatal and neonatal deaths, compared to hos- Introduction
pital or hospital-like (hospital-attached birth center).
This chapter will review the evidence in preparation to labor. A
• The hospital is the safest setting for labor and delivery,
summary of recommendations is reported in Table 7.1.
and women with risk factors for an abnormal outcome
should deliver in a hospital setting.
• Allocation to an alternative hospital setting (e.g. birth Prediction of the onset of spontaneous labor
center alongside the hospital) increased the likelihood of
the following: no intrapartum analgesia/anesthesia, spon- Weather effects
taneous vaginal delivery, breastfeeding at 6–8 weeks, and There is no strong association between changes in barometric pres-
very positive views of care. Allocation to an alternative sure and spontaneous onset of labor in pregnancies at term [1].
DOI: 10.1201/9781003102342-7 91
TABLE 7.1: Summary of Recommendations

Preparation before Labor Issues Evidence
Prediction of the onset of spontaneous labor
• Transvaginal ultrasound cervical length Good predictor of the onset of spontaneous labor in women at ≥37 weeks
• Weather effects No association between changes in barometric pressure and spontaneous onset of labor in pregnancies
at term
Antenatal classes Associated with arriving to labor and delivery unit more often in active labor and using less epidural
analgesia
Antenatal perineal massage Lower incidence of trauma requiring suturing and the rate of episiotomy
Pelvic floor muscle training Lower risk of reporting urinary incontinence in continent women either in late pregnancy and in the
midpostnatal period
Sweeping of membranes Lower duration of pregnancy and lower frequency of pregnancy continuing beyond 41 weeks, when
started from 37 to 38 weeks
Pelvimetry Likely associated with higher rates of cesarean delivery
Place of birth
• Home birth Higher risk of perinatal and neonatal deaths

• Hospital Safest setting for labor and delivery, particularly for women with risk factors for abnormal outcome
• Alternative hospital settings Increased likelihood of the following: no intrapartum analgesia/anesthesia, spontaneous vaginal
delivery, breastfeeding at 6–8 weeks, and very positive views of care
Attendant at birth
• Midwife-led care Less likely to receive amniotomy, episiotomy, and intrapartum analgesia/anesthesia; shorter labors,
less instrumental vaginal birth, preterm birth <37 weeks, less fetal loss/neonatal death before 24
weeks, less overall fetal/neonatal death
• Doulas Higher rate of spontaneous vaginal birth, lower rates of caesarean and instrumental vaginal deliveries,
less likely negative feelings about the childbirth experience, less intrapartum analgesia, shorter labors
and lower rates of low 5-minute Apgar score
Training of birth assistants Trend for less maternal mortality and significantly less perinatal mortality
Teamwork training Conflicting evidence, likely to improve team performance and medical technical skills, and therefore
quality of care
Delayed admission to labor and delivery unit Less time in the labor ward, less intrapartum oxytocic, and less analgesia
Fetal assessment tests upon admission
• Fetal heart rate tracing Higher incidence of cesarean delivery than women allocated to intermittent auscultation
• Amniotic fluid index evaluation Higher incidence of cesarean delivery and similar neonatal outcomes
Enemas No significant beneficial effect on infection rates such as perineal wound infection or other neonatal
infections and women’s satisfaction
Perineal shaving No evidence to support shaving
Time of day the quality of the relationship between her and the birth atten-
Diurnal rhythms seem to show a higher rate of starting labor, dant, and her involvement in labor management [4].
with maximal frequency in the evening and night hours [2]. Antenatal classes include types of educational programs to
help the mother get familiar with labor and delivery. Compared
Transvaginal ultrasound cervical length to no such training, 9 hours of antenatal training to prepare for
The majority of women at term desire to know roughly the timing labor and delivery are associated with arriving to the labor and
of the onset of labor, and this information might be useful also for delivery unit more often in active labor (relative risk [RR] 1.45,
clinicians, mostly when further care is needed at the time of deliv- 95% CI 1.26–1.65) and using less epidural analgesia (RR 0.84,
ery. Transvaginal ultrasound cervical length (TVU CL) evalu- 95% CI 0.73–0.97) [5].
ation is a good predictor of the onset of spontaneous labor in Specific antenatal education programs are also associated with
women at term: a woman with a CL of 30 mm has a <50% chance a reduction in the mean number of visits to the labor ward
of delivering within 7 days, while one with a CL of 10 mm has an before the onset of labor (mean difference [MD] –0.29, 95% CI
over 85% chance of delivering within 7 days [3]. –0.47 to –0.11) [6].
Another typical key issue during antenatal classes is the education
Antenatal classes and education regarding the management of pain during labor. In this scenario,
regarding self-diagnosis of active labor there is a lack of high-quality evidence to assess whether specific
approaches are more effective than others to reduce labor pain.
A woman’s satisfaction with her birth experience is mainly related Compared to no such education, antenatal education focus-
to the personal expectations, the amount of support she receives, ing on natural childbirth preparation with training in breathing
Preparation before Labor 93
and relaxation techniques is not associated with any effects on Evidence is weaker when considering the effect of antenatal
maternal or perinatal outcomes, including similar incidences of PFMT on the incidence of fecal incontinence. In women with or
epidural analgesia, childbirth, or parental stress, in nulliparous without fecal incontinence, antenatal PFMT is associated with
women and their partners [7]. little or no difference in the prevalence of fecal incontinence
However, evidence from low-quality randomized controlled in late pregnancy. Similar results have also been found for the
trials (RCT) showed that some relaxation techniques for pain role of postnatal PFMT on fecal incontinence in the postnatal
management, such as mind–body relaxation, yoga, and music, period and beyond 12 months postpartum [17].
might assume a role in decreasing pain and increasing satis-
faction with pain relief [8].
Moreover, a complementary medicine technique program
Sweeping of membranes
containing six items (acupressure, visualization and relaxation, Sweeping of membranes usually involves inserting one finger
breathing, massage, yoga techniques, and facilitated partner sup- between the cervix and the membranes and sweeping 360
port) is associated with a significant reduction in epidural use degrees at least two to four times to potentially increase the
(RR 0.37 95% CI 0.25–0.55), cesarean delivery (RR 0.52 95% CI local production of prostaglandins [16].
0.31–0.87), and perineal trauma (RR 0.88 95% CI 0.78–0.98), Routine use of sweeping of membranes from 38 weeks of
compared to standard antenatal care [9]. pregnancy onwards is significantly associated with reduced
Mindfulness-based childbirth education is associated with duration of pregnancy and reduced frequency of pregnancy
lower postcourse depression symptoms and with a trend continuing beyond 41 weeks (RR 0.59, 95% CI 0.46–0.74) and
toward a lower rate of opioid analgesia use in labor [10]. 42 weeks (RR 0.28, 95% CI 0.15–0.50), with no difference in
The aim of antenatal classes is also to help women cope better cesarean delivery and maternal or fetal infection rates. Women
with the fear of labor and childbirth. Fear of childbirth is associ- allocated to sweeping more frequently experienced discomfort
ated with a 47-minute longer duration of labor, compared to no during vaginal examination and other adverse effects, such as
fear of childbirth [11]. Intensive counseling in women with fear bleeding or irregular contractions [18]. Women randomized to
of childbirth reduces anxiety and concerns related to preg- membrane sweeping may also be more likely to experience spon-
nancy and birth and is associated with shorter labors [11–13]. taneous onset of labor and less likely to experience induction
Finally, there is no conclusive evidence supporting any antena- of labor [19]. These results are concordant with those found in
tal breastfeeding education for improving initiation and continu- a subsequent RCT on 742 low-risk pregnant women assigned to
ation of breastfeeding, at least in high-income countries [14]. serial sweeping of the membranes every 48 hours until labor at
41 weeks of gestation [20] and in a recent meta-analysis of seven
Antenatal perineal massage trials involving 2252 women that confirmed membrane sweep-
ing as an effective method to promote spontaneous labor and to
Perineal trauma is often related to vaginal birth, usually due to reduce the need for induction of labor, starting from 38 weeks of
episiotomies, perineal lacerations, or both, and might be associ- gestation [21].
ated with both short- and long-term complications, such as peri-
neal pain, discomfort, and dyspareunia.
Antenatal digital perineal massage with sweet almond oil for Pelvimetry
5–10 minutes daily, starting from approximately 35 weeks of gesta-
There is not enough evidence to support the use of x-ray pelvim-
tion, is significantly associated with a reduction in the incidence
etry in women whose fetuses have either a cephalic or nonce-
of trauma requiring suturing (RR 0.91 95% CI 0.86–0.96) and in
phalic presentation. Women undergoing x-ray pelvimetry are
the rate of episiotomy (RR 0.84 95% CI 0.74–0.95), particularly in
more likely to be delivered by cesarean delivery. No significant
women without previous vaginal birth. Conversely, women with a
impact is detected on perinatal outcome, but the numbers are
previous vaginal birth experience significant less pain at 3 months
small, insufficient for meaningful evaluation (e.g. perinatal mor-
postpartum (RR 0.45 95% CI 0.24–0.87). No significant differences
tality 1% vs. 2%). The results are similar for women with or with-
are observed in the incidence of instrumental deliveries; sexual sat-
out a prior cesarean delivery (CD) [22]. There are insufficient data
isfaction; or incontinence of urine, feces, or flatus for any women
regarding MRI or clinical pelvimetry.
practicing perineal massage before childbirth [15].
Pelvic floor muscle training Place of birth

Urinary incontinence and involuntary loss of flatus or feces might Planned home birth
be debilitating problems in both the late pregnancy and the post- The American College of Obstetricians and Gynecologists
partum period. (ACOG) recommend counseling women planning to deliver at
Pelvic floor muscle training (PFMT) usually involves more than home that hospitals and accredited birth centers (especially those
one daily set of repeated voluntary contractions of the pelvic floor alongside a hospital) are the safest settings for birth, although
muscles, performed several times per day, for at least 8 weeks each woman keeps the right to make an informed decision about
[16]. A structured PFMT antenatal program is associated with a her place of delivery [23].
lower risk of reporting urinary incontinence in continent women There is limited evidence to assess the safety and efficacy
either in late pregnancy (RR 0.38, 95% CI 0.20–0.72) or in the mid- of planned home birth for low-risk pregnant women, as there
postnatal period (RR 0.71, 95% CI 0.54–0.95) from 3 to 6 months is only one RCT with only 11 women ever published [24, 25]. In
postpartum. There is not enough evidence to ascertain whether healthy low-risk women, compared to planned hospital birth,
PFMT might be effective also as an intervention in incontinent planned home birth is associated with a higher risk of neona-
women in late pregnancy or in the mid- and late postpartum period. tal deaths (0.2% vs. 0.09%) in a meta-analysis of nonrandomized
TABLE 7.2: Level of Maternal Care

Level of Care Example (Not Requirement)
Accredited birth center Women with an uncomplicated term singleton vertex fetus who are expected to have an uncomplicated birth
Level I Low-risk women with uncomplicated pregnancies and women with higher-risk conditions such as the following:
uncomplicated twin gestation, labor after cesarean, uncomplicated cesarean delivery, preeclampsia, well-controlled
gestational diabetes
Level II Any patient appropriate for level I care, plus higher-risk conditions such as the following: placenta previa with no previous
uterine surgery; maternal medical conditions that require additional monitoring such as pregestational diabetes, poorly
controlled asthma, or poorly controlled or complicated chronic hypertension; anticipated complicated cesarean delivery
Level III Any patient appropriate for level II care, plus higher-risk conditions or complications such as the following: moderate
maternal cardiac disease; suspected placenta accreta or placenta previa and previous uterine surgery; suspected placenta
percreta; adult respiratory distress syndrome or other conditions that require ventilatory support antepartum or
postpartum; acute fatty liver of pregnancy; coagulation disorders; complex hematologic or autoimmune disorders;
expectant management of preeclampsia with severe features remote from term
Level IV Any patient appropriate for level III care, plus higher-risk conditions or complications such as the following: severe maternal
cardiac conditions; severe pulmonary hypertension; pregnant women who require neurosurgery or cardiac surgery;
pregnant women in unstable condition and in need of an organ transplant
studies including over 500,000 births [26]. In a large (>79,000 associated with home births or births in free-standing birth cen-
women with singletons, term, cephalic, and nonanomalous preg- ters compared to hospital births [28, 29]. Some of these studies
nancies) retrospective cohort study, planned out-of-hospital included free-standing (not alongside—very nearby or inside—a
births were associated with a higher rate of perinatal deaths (3.9 hospital) birth centers with home births. This means, therefore,
vs. 1.8 deaths per 1000 deliveries; Adjusted odd ratio (aOR) 1.52, that the hospital is the safest setting for labor and delivery, and
95% CI 0.51–2.54) than planned in-hospital deliveries, as well as women with risk factors for abnormal outcome should deliver
more neonatal seizures [27]. in a hospital setting [30].
There are diverging opinions even in Western countries, with Tables 7.2 and 7.3 show ACOG and Society for Maternal-Fetal
about >15% of Dutch births occurring at home versus <1% of U.S. Medicine (SMFM) recommendations for a standardized and
births. Data from U.S. births showed a significantly increased integrated system of risk-appropriate maternal care and perinatal
risk of neonatal deaths, low Apgar scores, and neonatal seizures care [31, 32].
TABLE 7.3: Level of Neonatal Care

Level of Care Capabilities
Level I well newborn nursery Provide neonatal resuscitation at every delivery; evaluate and provide postnatal care to stable term
newborn infants; stabilize and provide care for infants born at 35–37 weeks of gestation who remain
physiologically stable; stabilize newborn infants who are ill and those born before 35 weeks of
gestation until transfer to a higher level of care
Level II special care nursery Level I capabilities plus: provide care for infants born at 32 weeks of gestation or later and weigh
1500 g or more who have physiologic immaturity or who are moderately ill with problems that are
expected to resolve rapidly and are not anticipated to need subspecialty services on an urgent basis;
provide care for infants convalescing after intensive care; provide mechanical ventilation for brief
duration (less than 24 hours) or continuous positive airway pressure or both; stabilize infants born
before 32 weeks of gestation and weigh less than 1500 g until transfer to a neonatal intensive care
facility
Level III neonatal intensive care unit Level II capabilities plus: provide sustained life support; provide comprehensive care for infants born
before 32 weeks of gestation and weigh less than 1500 g and infants born at all gestational ages and
birth weights with critical illness; provide prompt and readily available access to a full range of
pediatric medical subspecialists, pediatric surgical specialists, pediatric anesthesiologists, and
pediatric ophthalmologists; provide a full range of respiratory support that may include conventional
ventilation and/or high-frequency ventilation and inhaled nitric oxide; perform advanced imaging,
with interpretation on an urgent basis, including computed tomography, magnetic resonance
imaging, and echocardiography
Level IV regional neonatal intensive care unit Level II capabilities plus: located within an institution with the capability to provide surgical repair of
complex congenital or acquired conditions; maintain a full range of pediatric medical subspecialists,
pediatric surgical subspecialists, and pediatric anesthesiologists at the site; facilitate transport and
provide outreach education
Freestanding birth center CI 0.83–0.97), preterm birth less than 37 weeks (RR 0.76, 95%
There are no RCTs of freestanding (far from any hospital) birth CI 0.64–0.91), and less overall fetal/neonatal death (RR 0.84,
centers, and therefore the evidence is insufficient to recommend 95% CI 0.71–0.99) [34]. Women who have midwife-led continu-
this setting [33]. For non-RCT evidence, see “Planned Home Birth.” ity models of care are more likely to experience spontaneous
vaginal birth (RR 1.05, 95% CI 1.03–1.07). There are no differ-
Planned hospital birth: alternative setting ences between groups for cesarean births or intact perineum. In
(homelike, e.g. hospital or alongside birth addition, women assisted by midwives are less likely to receive
center) vs. conventional hospital ward setting some medical interventions, such as amniotomy (RR 0.80, 95%
Several RCTs have evaluated the option of “alternative setting” ver- CI 0.66–0.98), episiotomy (RR 0.84, 95% CI 0.77–0.92), and
sus the conventional hospital ward setting for labor and delivery. intrapartum analgesia/anesthesia (RR 1.21, 95% CI 1.06–1.37).
For the alternative setting, most trials included care by mid- Women who have midwife-led continuity models of care are less
wives in a location in the hospital, close to the regular labor and likely to experience longer mean length of labor (hours) (MD
delivery ward, that did not look like a usual labor and delivery 0.50, 95% CI 0.27–0.74), to be attended at birth by a known mid-
setting. There no RCTs of freestanding birth centers. Some RCTs wife (RR 7.04, 95% CI 4.48–11.08), and have less fetal loss/neo-
randomized women in labor, while others at the beginning of preg- natal death before 24 weeks (RR 0.81, 95% CI 0.67–0.98). There
nancy. So continuity of care was usually higher in the alternative were no differences between groups for fetal loss or neonatal
setting group. Usually about 40%–50% of patients randomized death more than or equal to 24 weeks, induction of labor, antena-
to alternative setting (often about 60% for nulliparous women, tal hospitalization, antepartum hemorrhage, augmentation/arti-
20%–30% for multiparous women) need to be moved in labor to ficial oxytocin during labor, opiate analgesia, perineal laceration
the conventional labor and delivery ward. requiring suturing, postpartum hemorrhage, breastfeeding ini-
Compared to the conventional hospital ward, allocation to an tiation, low-birth-weight infant, 5-minute Apgar score less than
alternative hospital setting increased the likelihood of the fol- or equal to 7, neonatal convulsions, admission of infant to special
lowing: no intrapartum analgesia/anesthesia (RR 1.18, 95% CI care or neonatal intensive care unit(s), or mean length of neona-
1.05–1.33), spontaneous vaginal delivery (SVD) (RR 1.03, 95% tal hospital stay (days). The majority of included studies report a
CI 1.01–1.05), breastfeeding at 6–8 weeks (RR 1.04, 95% CI 1.02– higher rate of maternal satisfaction in midwife-led continuity
1.06), and very positive views of care (RR 1.96, 95% CI 1.78–2.15). models of care [34].
Allocation to an alternative setting decreased the likelihood of
epidural analgesia (RR 0.80, 95% CI 0.74–0.87), oxytocin aug- Doulas
mentation of labor (RR 0.77, 95% CI 0.67–0.88), and episiotomy A doula is a continuous support person that a woman may choose for
(RR 0.83, 95% CI 0.77–0.90) [26]. There was no apparent effect on emotional support and advice about coping techniques and comfort
maternal morbidity and mortality, serious perinatal morbidity/ measures (comforting touch, massage, warm baths/showers) [16].
mortality (RR 1.17, 95% CI 0.51–2.67), perinatal mortality (RR 1.67, Compared to usual care without continuous support, continu-
95% CI 0.93–3.00), other adverse neonatal outcomes, or postpartum ous support during labor (mostly performed by a doula, but
hemorrhage. The 4% increase in SVD may be secondary to less epi- also by midwives or nurses) is associated with a higher rate of
dural anesthesia, which may in turn be secondary to less availability spontaneous vaginal birth (RR 1.08, 95% CI 1.04–1.12), lower
in homelike settings and/or to less intrapartum monitoring. The rates of cesarean delivery (RR 0.75, 95% CI 0.64–0.88) and
trend for a 67% higher perinatal mortality should be weighed instrumental vaginal deliveries (RR 0.90, 95% CI 0.85–0.96),
against the significant 4% increase in SVD and 96% higher sat- less likely negative feelings about the childbirth experience
isfaction during counseling. No firm conclusions can be drawn (RR 0.69, 95% CI 0.59–0.79), less intrapartum analgesia (RR
regarding the effects of variations in staffing, organizational mod- 0.90, 95% CI 0.84–0.96), shorter labors (MD −0.69 hours, 95%
els, or architectural characteristics of the alternative settings [33]. A CI −1.04 to −0.34), and lower rates of low 5-minute Apgar score
birth center in the hospital is a safe location for birth [30]. (RR 0.62, 95% CI 0.46–0.85) [35].
Attendant at birth Training of birth assistants

Midwife-led care Training of traditional birth assistants in middle- and low-
In many parts of the world, midwives are the primary providers income countries is associated with a trend for less maternal
of care for childbearing women. Elsewhere it may be medical mortality and significantly less perinatal mortality [36]. There
doctors or family physicians who have the main responsibility are no trials in high-income countries.
for care, or the responsibility may be shared. The underpinning
philosophy of midwife-led care is normality, continuity of care, Teamwork training
and being cared for by a known and trusted midwife during labor.
There is an emphasis on the natural ability of women to experi- Evidence is conflicting when focusing on the effects of train-
ence birth with minimum intervention [34]. ing and teamwork education for labor and delivery personnel.
The effect of midwife-led care compared to physician-led care In a 2007 RCT, a standardized teamwork training curriculum
or to other provider-led care has been evaluated mostly for the based on crew resource management that emphasized commu-
whole pregnancy, including both antepartum care and care dur- nication and team structure was not associated with a significant
ing labor and delivery. Therefore it is difficult to assess the effect effect on adverse maternal and perinatal outcomes compared to
of midwife-led care just on labor and delivery. no such training [37]. Conversely, two subsequent RCTs showed
Women who have midwife-led continuity models of pregnancy that team performance and medical technical skills may signifi-
care are less likely to experience regional analgesia (RR 0.85, cantly improve after multiprofessional obstetric team training in
95% CI 0.78–0.92), instrumental vaginal birth (RR 0.90, 95% a simulation center and that a simulation-based training program
may improve the use of evidence-based practices at birth, thus infections and women’s satisfaction. Compared to no enema,
improving the quality of care [38, 39]. enema in labor is associated with no significant differences for
infection rates in puerperal women (RR 0.66, 95% CI 0.42–1.04)
Admission to a labor and delivery unit and no significant differences in neonatal umbilical infection
rates (RR 3.16, 95% CI 0.50–19.82). No significant differences
Delayed vs. early hospital admission are found in the incidence of neonatal lower or upper respiratory
Labor assessment programs, which aim to delay hospital admis- tract infections [45].
sion until active labor, may benefit women with term pregnan- One RCT described labor to be significantly shorter (50 minutes)
cies. Active labor was defined as regular painful contractions with enema versus no enema. A second RCT found labor to be
and cervical dilatation >3 cm in these studies. In one RCT, com- significantly longer (112 minutes) with an enema compared to no
pared to direct admission to hospital, delayed admission until enema. No significant differences in the duration of labor were
active labor was associated with less time in the labor ward, found in the third RCT that scored as having a low risk of bias and
less intrapartum oxytocics, and less analgesia [40]. Women in were adjusted for parity. One RCT that researched women’s views
the labor assessment and delayed admission group report higher found no significant differences in satisfaction between groups.
levels of control during labor. CD rates are similar, with a The routine use of enemas during labor should be discouraged
nonsignificant 30% decrease. A 30%–40% decrease in CD has [45]. This intervention (enema) generates discomfort in women
been reported in retrospective studies with delayed versus direct and increases the costs of delivery.
admission. There is insufficient evidence (a larger trial is needed)
to assess the true effects on the rate of CD and other important Perineal shaving
measures of maternal and neonatal outcome. Potential risks of There is no supportive level 1 evidence for routine perineal shav-
delayed admission include unplanned out-of-hospital births and ing (shaving with a razor) for women prior to or in labor. In a very
the potentially harmful effects of withholding caregiver support old trial, 389 women were alternately allocated to receive either
and attention to women in early or latent-phase labor. skin preparation and perineal shaving or clipping of vulvar hair
In another RCT, compared to no use of algorithm, use of an only. In the second old trial, which included 150 participants, peri-
algorithm by midwives to assist in their diagnosis of active labor neal shaving was compared with the cutting of long hairs for proce-
(painful regular contractions with at least one of the following: dures only. In the third trial, 500 women were randomly allocated
3 cm dilated, rupture of membranes [ROM], or “show”) was asso- to shaving of perineal area or cutting of perineal hair. Compared
ciated with more women being discharged after their first labor to no shaving, shaving was associated with a similar incidence of
ward assessment and no effect of oxytocin augmentation and maternal febrile morbidity (RR 1.14, 95% CI 0.73–1.76), perineal
other medical interventions in labor [41]. wound infection (RR 1.47, 95% CI 0.80–2.70), and perineal wound
Suggested criteria for admission based on these studies are dehiscence (RR 0.33, 95% CI 0.01–8.00). In the smaller trial, fewer
a cervix of at least 3–4 cm dilatation and regular painful con- women who had not been shaved had gram-negative bacterial colo-
tractions. Pregnant women should be informed of these data nization compared with women who had been shaved (OR 0.43,
during prenatal care. 95% CI 0.20–0.92). There were no differences in maternal satisfac-
tion immediately after birth [46]. The potential for complications
(redness, multiple superficial scratches, burning and itching of the
Fetal assessment tests upon admission vulva, and embarrassment and discomfort afterward when the
hair grows back), which often occur later, suggests that shaving
Fetal heart rate tracing for 20 minutes should not be part of routine clinical practice. The first two trials
Women allocated to admission CTG have an increase in the are old (1922 and 1965) and included the clipping of long hairs in
incidence of cesarean delivery compared with women allo- their control groups to aid in operative procedures, which is itself
cated to intermittent auscultation (RR 1.20, 95% CI 1.00–1.44). usually unnecessary and can lead to complications.
There is no significant difference in instrumental vaginal birth
(RR 1.10, 95% CI 0.95–1.27) and fetal and neonatal deaths (RR
1.01, 95% CI 0.30–3.47) [42]. References
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8
FIRST STAGE OF LABOR
Leen Al-Hafez
Key points • For women making slow progress in the first stage of
spontaneous labor, the use of oxytocin augmentation
• Vaginal chlorhexidine irrigation is not recommended. is associated with a reduction in the time to delivery of
• Universal prenatal maternal screening with anovaginal approximately 2 hours.
specimen at 36–37 weeks and intrapartum antibiotic • Early intervention with oxytocin and amniotomy for
treatment are the most efficacious of the current strategies the prevention and treatment for dysfunctional or slow
for prevention of neonatal early-onset group B streptococ- labor is recommended.
cus (GBS) disease. • The routine use of intrauterine pressure catheter (IUPC) in
• Prophylactic antibiotics in term prerupture of mem- the first stage of labor is not recommended.
branes (PROM) with latency longer than 12 hours can be • The routine use of ultrasound during a normally evolving
considered. first stage of labor is not recommended.
• Aromatherapy with essential oils through inhalation or • Dystocia cannot be diagnosed unless rupture of mem-
back massage in labor can be considered. branes (ROM) has occurred and adequate oxytocin to
• Water immersion during the first stage of labor slightly achieve at least three to five adequate contractions per
reduces the use of analgesia, without adverse maternal or hour has been instituted. Dystocia also cannot be diag-
neonatal outcomes. nosed reliably before the first stage of labor has entered
• There is little justification for the restriction of fluids the active phase, which has been defined, especially in
and food in labor for women at low risk of complications. nulliparous patients with epidurals in place, as at least
• In the setting of oral restriction, intravenous (IV) fluids 6 cm of cervical dilatation. Before performing a cesarean
at 250 mL/hour containing dextrose are associated with delivery (CD) for active-phase labor arrest, labor should
shorter duration of labor and fewer cesarean deliveries be arrested for a minimum of 4 hours (if uterine activ-
compared to 125 mL/hour. ity is greater than 200 Montevideo units as documented
• Upright positions (either standing, sitting, kneeling, or with IUPC) or 6 hours (if greater than 200 Montevideo
walking around) for women without regional anesthesia units could not be sustained).
in the first stage of labor reduces the length of labor by
approximately over 1 hour and are associated with less Please also see Chaps. 7 and 9 for other guidance during labor.
epidural analgesia. Women with regional anesthesia can
take up whatever position or ambulate as they please. Introduction
• Ambulating should be recommended in the first stage
of labor in women without regional anesthesia. Women For management of induction, meconium, oligo/polyhydram-
with regional anesthesia can ambulate or not ambulate nios, intrapartum monitoring (including amnioinfusion for
in the first stage. variables), operative vaginal delivery, shoulder dystocia, trial of
• Continuous bladder catheterization cannot be recom- labor after cesarean (TOLAC), fetal growth restriction (FGR),
mended in labor. macrosomia, abnormal third stage, etc., see appropriate dis-
• There is insufficient evidence to recommend any par- tinct guidelines in this book and its companion, Maternal-Fetal
ticular frequency of vaginal cervical exams in labor. Most Evidence Based Guidelines. This chapter discusses interventions
studies, including those with active management, perform in the first stage of labor that can influence labor and delivery
cervical exams every 2 hours in active labor, but the risk of outcomes (Table 8.1) [1].
chorioamnionitis increases with increasing number of exams.
• Routine sweeping of membranes in labor cannot be Vaginal chlorhexidine
recommended. There is no evidence to support the use of vaginal chlorhexi-
• The routine use of the partogram is not recommended in labor. dine by either irrigation or vaginal wipes during labor in
• The routine use of a peanut ball cannot be recommended order to prevent maternal and neonatal infections. The effect
in labor. on the incidence of postpartum endometritis is not statistically
• The use of a birthing ball during the first stage of labor can significant (relative risk [RR] 0.83; 95% confidence interval [CI]
be considered. 0.61–1.13) [2]. Chlorhexidine solution is safe and inexpensive,
• Antispasmodics are not recommended for routine use in and vaginal irrigation is easy to perform, but not beneficial. In
the first stage of labor. summary, vaginal chlorhexidine by either irrigation or vaginal
• Routine amniotomy in normally progressing spontane- wipes during labor is not recommended.
ous labor cannot be recommended as part of standard
labor management and care, but early amniotomy (e.g. GBS prophylaxis
after Foley balloon is ejected and so about 3–4 cm of Maternal colonization with group B streptococcus (GBS)
cervical dilation) in labor induction is recommended. increases the neonatal risk of developing early-onset group B
98 DOI: 10.1201/9781003102342-8
First Stage of Labor 99
TABLE 8.1: Summary of Interventions in the First Stage of Labora

Intervention Recommendation
Vaginal disinfection Not recommended
GBS prophylaxis if GBS positive Recommended
Antibiotics in PROM Considerb
Aromatherapy Consider
Water immersion Consider
Oral restriction of fluid or solid foods as tolerated Not recommended
IV fluids with dextrose at 250 mL/hr in the setting of oral restriction Recommended
Upright position in women without regional anesthesia Recommended
Position in women with regional anesthesia As desired by woman
Ambulation in women without regional anesthesia Recommended
Ambulation in women with regional anesthesia As desired by woman
Continuous bladder catheterization Not recommended
Cervical exam/membrane sweeping Insufficient evidence
Routine partogram Not recommended
Routine peanut ball Consider
Routine birthing ball Consider
Antispasmodics Not recommended
Routine use of amniotomy alone Not recommended
Use of oxytocin in slow labor progression Recommended
Early amniotomy and oxytocin in slow labor progression Recommended
Routine use of IUPC Not recommended
Routine ultrasound use Insufficient evidence
Labor dystocia in the first stage should be defined as labor that has been arrested for Recommended
a minimum of 4 hours with adequate uterine activity, or 6 hours with inadequate
uterine activity in a woman with ROM, adequate oxytocin, and ≥6 cm dilated cervix
a Refers mostly to singleton gestations at term, vertex.
b Consider when PROM expected to be >12 hours.
streptococcal disease (EOGBSD), which is defined as vertical low risk for anaphylaxis, cefazolin is the recommended antibiotic.
transmission resulting in sepsis, pneumonia, and, less commonly, For women with a penicillin allergy that are at high risk for ana-
meningitis within 7 days of birth [3, 4]. phylaxis, clindamycin is the recommended antibiotic if the GBS
Universal prenatal maternal GBS screening with ano- isolate is susceptible. If susceptibilities are not available or the
vaginal specimen collected at 36–37 weeks and antibiotic GBS isolate is resistant to clindamycin, vancomycin is the recom-
(penicillin as first line) treatment to GBS-colonized women is mended antibiotic for women with a penicillin allergy at high risk
recommended [3]. Women with GBS bacteriuria in the current of anaphylaxis.
pregnancy or who had a prior infant with GBS sepsis are candi-
dates for intrapartum antibiotic prophylaxis (IAP) and should be Antibiotic prophylaxis for term
the only two groups not screened. Intrapartum treatment for prelabor rupture of membranes
chorioamnionitis is recommended regardless of GBS mater- The administration of routine antibiotic prophylaxis for term
nal status (see Chaps. 24 and 39 in Maternal-Fetal Evidence prelabor rupture of membranes (PROM) is not associated with
Based Guidelines). For those with an unknown GBS culture result either maternal or neonatal beneficial outcomes compared to
in labor, antibiotics should be given to all women with recognized no antibiotic prophylaxis. However, in women with PROM and
risk factors: Previous infant affected by GBS sepsis, GBS bacte- latency longer than 12 hours, prophylactic antibiotics are associ-
riuria during the current pregnancy, preterm labor <37 weeks, ated with significantly lower rates of intraamniotic infection by
prelabor rupture of membranes ≥18 hours and/or fever in labor 51% and endometritis by 88%, and a trend toward a decrease in
≥38°C, or women known to be colonized with GBS in a prior neonatal sepsis, RR 0.34 (0.11–1.04). The most commonly used
pregnancy [3, 4]. There is no intervention shown to be efficacious antibiotics were ampicillin and gentamicin. For women with a
for prevention of late-onset GBS sepsis. penicillin allergy, clindamycin or erythromycin was used [5].
In summary, women with GBS bacteriuria in the current In summary, antibiotic prophylaxis can be considered in
pregnancy or who had a prior infant with GBS sepsis are can- women with term PROM in which >12 hours of latency are
didates for IAP and do not require screening. Universal GBS expected between PROM and delivery.
culture screening is recommended at 360/7 and 376/7 weeks
of gestation. IAP in labor for GBS-positive women is recom- Aromatherapy
mended to reduce neonatal EOGBSD. Penicillin should be Compared to no such intervention, administration of selected
used as the first-line agent: 5 million units loading dose fol- essential oils (such as lavender, jasmine, rose, almond, or a com-
lowed by 2.5 million units every 4 hours, ideally for ≥4 hours bination) through inhalation or back massage during labor is
before delivery. For women with a penicillin allergy that are at not associated with significant effects on cesarean delivery (CD),
instrumental delivery, or use of oxytocin. In a recent meta- of 250 mL/hour are associated with a 1-hour reduction in labor
analysis of 17 randomized trials, it was shown to have a reduc- compared to fluids at a rate of 125 mL/hour where oral intake is
tion in labor pain and duration compared to no aromatherapy. restricted. This review also found a 30% reduction in CDs com-
However, the heterogeneity of the trials included calls for a larger pared to fluids at a rate of 125 mL/hour. These differences were
trial with a more stringent study design in order to provide rec- not significant in the trials where oral intake was not restricted [11].
ommendations for or against aromatherapy [6]. The benefits are substantiated by the fact that several trials
In summary, aromatherapy with essential oils through inha- in nonpregnant adults demonstrate that increased fluid intake
lation or back massage can be considered in labor. improves exercise performance.
Compared to normal saline without dextrose, those containing
Immersion in water dextrose are associated with a 75-minute shorter duration of the
Compared to controls (labor not in water), water immersion dur- first stage of labor where oral intake is restricted [12]. Similarly
ing the first stage of labor reduces the use of epidural/spinal to the results discussed earlier, this meta-analysis did not find a
analgesia by 9% (RR 0.91, 95% CI 0.83–0.99). There is no dif- significantly shorter duration of labor when the trials had a policy
ference in other outcomes: Duration of labor (mean difference of unrestricted oral intake. Five percent dextrose has also been
[MD] –11.53 minutes, 95% CI –45.42 to –22.36), mode of delivery associated with less umbilical cord acidemia compared to lac-
(RR 1.01, 95% CI 0.97–10.4), augmentation of labor by artificial tated Ringer’s solution [13].
rupture of membranes or use of oxytocin infusion (RR 1.02, 95% In summary, in the setting of oral restriction, IV fluids con-
CI 0.90–1.16), perineal trauma or maternal infection, Apgar score taining dextrose at 250 mL/hour are associated with shorter
<7 at 5 minutes (RR 1.58, 95% CI 0.63–3.93), or other neonatal duration of labor and fewer cesarean deliveries compared to
outcomes [7]. There is no evidence of increased adverse effects 125 mL/hour without dextrose and should be preferred. In the
to the fetus/neonate or woman from laboring in water. Laboring setting of liberal oral intake, no specific rate or type of IV fluid
in water is usually linked to midwifery care, which is associated is recommended.
with its own benefits (see Chap. 7). There are no trials evaluating
different baths/pools, immersion in water during pregnancy, or Maternal position
during the third stage of labor. Upright and mobile positions (either standing, sitting, kneel-
In summary, if there is reassuring fetal and maternal status ing, or walking around) in the first stage of labor reduce the
and it is desired by the patient, immersion in water in the first length of labor and do not seem to be associated with increased
stage of labor can be considered. For water birth and immer- intervention or negative effects on mothers’ and babies’ well-
sion in water in the second stage, see Chap. 9. being. Compared to recumbent positions, the first stage of labor
in women without regional anesthesia is approximately 1 hour
Nutrition in labor and 22 minutes shorter when randomized to upright and mobile
Since the evidence shows a shorter duration of labor without an in
positions. Women randomized to upright positions are less likely
increase in harm, there is little to no justification for the restriction
to have epidural analgesia (RR 0.81, 95% CI 0.66–0.99) and CD
of fluids and food in labor for women at low risk of complications.
(RR 0.71, 95% CI 0.54–0.94) [14]. There are no differences between
A meta-analysis of 10 randomized trials assessing various diets
groups for other outcomes, including length of the second stage
versus ice chips, water, or only water, included 3982 low-risk laboring
of labor, or other outcomes related to the well-being of mothers
women. All studies looked at women in active labor and at low risk
and babies, except for a lower incidence of neonatal intensive
of potentially requiring a general anesthetic. Three studies allowed
care unit admission in the upright group. For women who had
women to select from a low-residue diet, one study allowed honey-
epidural analgesia, there were no differences between those ran-
date syrup, and five allowed carbohydrate drinks. All the included
domized to upright versus recumbent positions for any of the
studies allowed patients to have the assigned diet throughout the
outcomes examined in the review [15]. A woman semireclining
entire course of labor until delivery. Compared to only ice, water, or
or lying down on the side or back during the first stage of labor
sips of water, a policy of unrestricted food intake was associated
may be more convenient for staff and can make it easier to moni-
with a significantly shorter duration of labor (MD –16 minutes,
tor progression and check the baby. Fetal monitoring, epidurals
95% CI –25 to –7). There were no significantly different rates of
for pain relief, and use of IV infusions also limit movement.
CD. No events of aspiration occurred in either group [8].
In summary, upright positions in the first stage of labor
Given that no studies found an increased risk of complication,
should be recommended in women without regional anes-
as well as the general rarity of its occurrence (about 15/10,000
thesia. Women with regional anesthesia in the first stage can
CDs) [9], there is no evidence to support food restrictions in
adopt whatever position they find most comfortable.
women in labor.
In summary, oral restriction of fluid or solid food in the first
Ambulation
stage of labor is not recommended.
Compared to remaining in bed, women without regional anesthe-
Acid prophylaxis drugs sia who walk during labor have a 3-hour and 57-minute shorter
There is no good evidence to support the routine administration duration during the first stage, are more likely to have a spontane-
of acid prophylaxis drugs in normal labor to prevent gastric aspira- ous vaginal delivery, are less likely to have operative vaginal deliv-
tion and its consequences [10]. Giving such drugs to women once a ery, and have a lower risk of requiring a CD [14]. For those with
decision to give general anesthesia is made is discussed in Chap. 12. regional anesthesia who ambulate, it is associated with a similar
length of first stage of labor, use of oxytocin, use of analgesia,
Intravenous fluids need for forceps vaginal delivery, or CD [15].
There have been many studies assessing type and rate of intra- In summary, ambulating should be recommended in the first
venous (IV) fluids in labor. A meta-analysis of seven random- stage of labor in women without regional anesthesia. Women
ized trials including 1215 women showed that fluids at a rate with regional anesthesia can ambulate or not ambulate in the
first stage. See also “Maternal Position,” as upright position and intervention with the partogram is early use of oxytocin as soon
mobility have been associated with shorter labors. as the cervical dilatation falls to the right of the partogram, usu-
ally on the 2-hour cervical exams.
Bladder catheterization The use of the partogram cannot be recommended as a rou-
Compared to intermittent bladder catheterization, continuous tine intervention in labor. Compared to no partogram, the use
bladder catheterization during the first stage of labor in patients of the partogram is not associated with significant effects on
with an epidural is associated with no differences in the length of cesarean delivery (RR 0.77, 95% CI 0.40–1.46), oxytocin augmen-
labor or incidence of urinary tract infections (UTIs), but signifi- tation (RR 1.02, 95% CI 0.95–1.10), duration of the first stage of
cantly higher likelihood of CD. However, this finding is based on labor (RR 0.80 hours, 95% CI –0.06 to 1.66), or Apgar score <7
one small trial that was unable to reach the original sample size at 5 minutes (RR 0.77, 95% CI 0.29–2.06), in two RCTs including
from the power analysis. Thus, more research is needed on blad- 1590 women [20].
der catheterization in labor [16]. When compared to a 4-hour action line, women in the 2-hour
In summary, routine continuous bladder catheterization action line group were more likely to receive oxytocin augmenta-
cannot be recommended in labor. tion (RR 2.44, 95% CI 1.36–4.35), with no differences in caesar-
ean delivery rates (RR 1.06, 95% CI 0.88–1.28), duration of first
Frequency of cervical exams stage of labor (RR 0.81 hours, 95% CI 0.32–2.04), or Apgar score
Only one randomized controlled trial (RCT) assessed different <7 at 5 minutes (RR 0.93, 95% CI 0.61–1.42) [20].
frequencies of cervical assessment in labor. Comparing two- In summary, the use of a partogram cannot be recommended
hourly with four-hourly vaginal examinations in labor, there was as a routine intervention in labor.
no difference in length of labor (MD in minutes –6.00, 95% CI
–88.70 to 76.70; 1 RCT, n = 109). There were no data on maternal Peanut ball
or neonatal infections requiring antibiotics and women’s overall A peanut ball, which is an enlarged and elongated exercise ball
views of labor. There were no differences in augmentation, epi- that is placed between the women’s legs, has long been used
dural for pain relief, CD, spontaneous vaginal birth, and operative with the aim to decrease the amount of time in labor. The rou-
vaginal birth [17]. tine use of a peanut ball during the first stage of labor is asso-
The only other RCT on cervical assessment in labor compared ciated with a nonsignificant 79-minute shorter duration and
routine vaginal examinations with routine rectal examinations no decrease in the total length of time to delivery compared
to assess the progress of labor. There was no difference in neona- to no peanut ball. However, there were also trends toward an
tal infections requiring antibiotics (RR 0.33, 95% CI 0.01–8.07; 1 increased incidence in spontaneous vaginal deliveries and
RCT, n = 307). There were no data on length of labor, maternal lower incidence of CD [21].
infections requiring antibiotics, and women’s overall views of In summary, the use of the peanut ball can be considered
labor. The study did show that significantly fewer women reported in labor.
that vaginal examination was very uncomfortable compared with
rectal examinations (RR 0.42, 95% CI 0.25–0.70). There were Birthing ball
no differences in augmentation, CD, spontaneous vaginal birth, Birthing balls (also known as Swiss balls) are round exercise
operative vaginal birth, perinatal mortality, and admission to balls that women in labor can sit on and perform different
neonatal intensive care. movements such as pelvic rotation and rocking back and forth.
In summary, cervical assessment should be done by cervical They are thought to widen the maternal pelvic outlet to assist in
and not rectal examination, as per patient’s safety and comfort. progression of labor, while also decreasing pain. A recent sys-
There is insufficient evidence to recommend any particular tematic review and meta-analysis of seven RCTs that included
frequency of vaginal cervical exams in labor. Most studies, 533 women demonstrated that the use of a birthing ball ver-
including those regarding active management, perform cervical sus no birthing ball resulted in no significant difference in the
exams every 2 hours in labor. However, the risk of chorioamnion- incidence of spontaneous vaginal delivery, cesarean delivery,
itis increases with increasing number of exams [18]. operative vaginal delivery, or duration of labor. However, it did
significantly reduce pain in the active phase of the first stage of
Membrane sweeping in labor labor [22].
There has only been one RCT on membrane sweeping in labor In summary, the use of a birthing ball during the first stage
with 400 participants. For the intervention group, membrane of labor can be considered.
sweeping was performed twice with every vaginal exam during
the first stage of labor. Sweeping was defined as digital separation Antispasmodics
2–3 cm from the internal cervical os and rotating the finger 360 Antispasmodics (e.g. valethamate bromide, hyoscine butyl-bromide,
degrees between the lower uterine segment and the fetal head. drotaverine hydrochloride, rociverine, and camylofin dihydro-
Women in the control group only received cervical examinations. chloride) have been used with the thought that they could lead to
The duration of labor and mode of delivery did not differ between faster and more effective dilation of the cervix. In a meta-analysis of
the two groups [19]. 17 randomized trials, they were shown to be associated with
In summary, routine membrane sweeping during the first a 74-minute shorter duration of the first stage of labor and an
stage of labor is not recommended. increased rate of cervical dilatation by an average of 0.61 cm/hour.
Antispasmodics are not associated with a significant effect on the
Use of partogram duration of the second and third stage of labor. However, the quality
A partogram is a preprinted form, the aim of which is to provide a of the evidence is low to very low [23].
pictorial overview of labor to plot progress and to alert health pro- In summary, antispasmodics cannot be routinely recom-
fessionals of any problems with the mother or baby. The general mended in labor.
Early artificial rupture of membranes analgesia or neonatal outcomes of Apgar scores, umbilical cord
(aka Amniotomy) pH, or admission to special care baby unit. Many outcomes were
Compared to no amniotomy, routine amniotomy in normally pro- not evaluated, such as perinatal mortality, women’s satisfaction,
gressing spontaneous labor is not associated with significant dif- instrumental vaginal birth, uterine rupture, postpartum hemor-
ferences in length of the first stage of labor (MD –20.43 minutes, rhage, abnormal cardiotocography, women’s pyrexia, dystocia,
95% CI –95.93 to 55.06), CD (RR 1.27, 95% CI 0.99–1.63), mater- and neonatal neurological morbidity [29]. Based mostly on physi-
nal satisfaction with childbirth experience, or low Apgar score ologic studies, an oxytocin dilution of 10 mU/mL and initial dose
<7 at 5 minutes (RR 0.53, 95% CI 0.28–1.00). Other maternal and of 2 mU/minute (12 mL/hour), incremental increase of 2 mU (12 mL)
perinatal outcomes are also not different. There is no consistency every 30–45 minutes until adequate labor, and maximum dose of
between RCTs regarding the timing of amniotomy during labor 16 mU/minute (up to 24 mU) have been proposed [28, 29].
in terms of cervical dilatation [24]. Stopping oxytocin instead of continuing it once the active
However, in the setting of labor induction, early amniotomy phase of labor is reached in women in spontaneous labor is not
(which is defined most consistently as amniotomy prior to the associated with maternal or perinatal benefits. Stopping oxy-
active phase of labor) has been shown to decrease the duration in tocin is associated with a longer (by about 30 minutes) time to
the first stage of labor by approximately 5 hours (MD –4.95 hours; delivery [30].
95% CI –8.12 to –1.78) without an increase in CD rates [25] (see In summary, oxytocin augmentation in women making slow
Chap. 23). progress in the first stage is associated with a 2-hour shorten-
In summary, routine amniotomy in normally progressing ing of labor, without apparent effect on mode of delivery or
spontaneous labor cannot be recommended as part of stan- other maternal and perinatal outcomes. Higher doses of oxy-
dard labor management and care, but early amniotomy in tocin can be considered.
labor induction after cervical ripening and expulsion of the For use of oxytocin in induction, see Chap. 23.
balloon is recommended.
Active management of labor
Oxytocin augmentation Active management of labor was originally devised to shorten
There are no trials to evaluate the timing and dosing of oxyto- labor and therefore prevent prolonged labor. Its components have
cin in labor in women making normal progress in labor. varied somewhat in the literature but generally include antenatal
For women making slow progress in the first stage of spon- classes, admission not before premature rupture of membranes
taneous labor, treatment with oxytocin as compared with no (PROM) or 2 cm dilatation and full effacement (active labor),
treatment or delayed oxytocin treatment does not result in any early amniotomy, support by doula, use of partogram, and vaginal
discernable difference in the number of cesarean deliveries per- exams every 2 hours, with oxytocin started for rate of progress
formed in one meta-analysis. In addition, there are no detect- off the partogram or <1 cm/hour. Oxytocin rate is started at 4–6
able adverse effects for mother or baby [26]. The meta-analysis mU/minute, increased by 4–6 mU every 15 minutes to reach con-
included eight appropriate studies, for a total of 1338 women with tractions every 2–3 minutes (but not more than 7/15 minutes),
low-risk singleton pregnancies at term in the active stage of labor. or 40 mU/minute. Early amniotomy and early use of high-dose
IV oxytocin versus placebo or no treatment (three trials; 138 oxytocin are the two most characteristic interventions of active
women) showed no difference as for CD rates; only three small management of labor.
trials were considered, so the comparison was clearly underpow- Compared to “routine” care (no active management), active
ered to make any firm conclusions. Early use of IV oxytocin management of labor with early oxytocin and amniotomy for
versus delayed use (five trials; 1200 women), however, was much the prevention of dysfunctional or slow labor is associated with a
larger and also showed no effect on CD rates. The early use of shorter duration of the first stage (MD –1.28 hours; 95% CI –1.97
oxytocin did significantly increase uterine tachysystole with fetal to –0.59) and lower rates of CD (RR 0.87; 95% CI 0.77–0.99). For
heart rate changes; however, this did not translate into serious treatment of dysfunctional labor, active management is also asso-
neonatal morbidity or perinatal death. The early use of oxytocin, ciated with a shorter duration in the first stage; however, no dif-
as opposed to its delayed use, did significantly shorten the time ferences in CD rates were found, although it is important to note
to delivery by approximately 2 hours, which might be impor- that the number of trials reporting on treatment intervention and
tant to some women. outcome were only 3, compared to 11 in the prevention group,
In a different meta-analysis, early oxytocin was associated with thus limiting the sample size [31].
a 9% significant increase in the probability of spontaneous vagi- In summary, early intervention with oxytocin and amni-
nal delivery (SVD), but also a tripling of the rate of tachysystole, otomy for the prevention and treatment for dysfunctional or
without apparent perinatal consequences [27]. slow labor is recommended.
There is insufficient evidence to assess how to best use (i.e.
dosing issues) oxytocin for augmentation of labor. There are Use of continuous vs. intermittent monitoring,
four variables to assess: (1) type of dilution, (2) initial dose, (3) amnioinfusion for variables, scalp sampling, etc.
incremental increase, and (4) maximum dose [28]. In a meta- See Chap. 10.
analysis, a higher initial dose (e.g., 2 mU/minute) of oxytocin and
incremental dose (e.g., 4 mU/minute or more) was associated with Epidural or other anesthesia
a significant reduction in the length of labor reported from one See Chap. 11.
trial (MD –3.50 hours, 95% CI –6.38 to –0.62, 1 RCT, n = 40).
There was a decrease in the rate of CD (RR 0.62; 95% CI 0.44– Use of intrauterine pressure catheter
0.86) and an increase in the rate of spontaneous vaginal birth (RR The intrauterine pressure catheter (IUPC) can measure more
1.35; 95% CI 1.13–1.62). There were no significant differences for objectively than external tocomonitor the intensity of uter-
neonatal mortality, tachysystole, chorioamnionitis, or epidural ine contractions. It necessitates rupture of membranes (ROM).
Intensity is usually calculated by Montevideo units, that is, active labor. It must be kept in mind that progression in the ear-
the sum of peak pressures above baseline of all contractions in lier part of “active labor” will typically be slower than 0.6 cm/
10 minutes. hour, while progression in more advanced active labor will typi-
Several RCTs have assessed the effect of IUPC on labor out- cally be more rapid [40].
comes. In the largest RCT, compared to no IUPC, IUPC use is Abnormal progression of labor, including terms such as dysto-
associated with no effect in the rate of operative deliveries, mater- cia, dysfunctional labor, failure to progress, cephalopelvic dispro-
nal or fetal infection, or other maternal or perinatal recorded out- portion, and others, is the most common problem in labor and
come [32]. In the meta-analysis, the neonatal outcome was not the reason for the majority of CDs [41]. Risk factors for dystocia
statistically different between groups: Apgar score <7 at 5 minutes are, among others, as follows: Obesity, induction, Bishop <5 at
(RR 1.78, 95% CI 0.83–3.83), umbilical artery pH <7.15 (RR 1.31, start of labor, station higher than –2, persistent occiput poste-
95% CI 0.95–1.79), admission to the neonatal intensive care unit rior, macrosomia, epidural anesthesia, etc. There are no RCTs on
(RR 0.34, 95% CI 0.07–1.67), and more than 48 hours hospitaliza- interventions for asynclitism [42]. (See also Chap. 24.; for mal-
tion (RR 0.92, 95% CI 0.71–1.20). The pooled risk for instrumental position, see Chap. 24). Dystocia cannot be diagnosed unless
delivery (including CD, vacuum, and forceps extraction) was not ROM has occurred and adequate oxytocin to achieve at least
statistically significantly different (RR 1.05, 95% CI 0.91–1.21). 3–5 adequate contractions per hour has been instituted. Dystocia
Tachysystole was similar between groups (RR 1.21, 95% CI 0.78– also cannot be diagnosed reliably before the first stage of labor
1.88). No serious complications were reported in the trials, and has entered the active phase, which has been defined, espe-
no neonatal or maternal deaths occurred [33]. cially in nulliparous with epidurals in place, as at least 6 cm
In summary, the routine use of the IUPC cannot be recom- of cervical dilatation [38, 39]. The majority (>60%) of women
mended in labor, unless clinically indicated. See also “Criteria for who experience 2 hours of labor arrest despite a sustained uterine
Diagnosis of Failure to Progress in First Stage.” contraction pattern of at least 200 Montevideo units in the first
stage of labor will achieve a vaginal delivery if oxytocin is contin-
Use of ultrasound during labor ued [43]. Before performing a CD for active-phase labor arrest,
There is growing evidence, including RCTs, to assess the effect labor should be arrested for a minimum of 4 hours (if uterine
of using ultrasound during labor and delivery. There are several activity is greater than 200 Montevideo units as documented
potential uses, including as an aid to the diagnosis of malposition, with IUPC) or 6 hours (if greater than 200 Montevideo units
dystocia, etc. [34]. Performing routine ultrasound to assess fetal could not be sustained) [43, 44]. These data are not from an
head position in singleton pregnancies in labor ≥8 cm, compared RCT, and there was a significant higher risk of shoulder dystocia
to digital vaginal assessment alone, is associated with an increase among parturients who had arrest for 4 hours or more. Vaginal
in operative vaginal delivery, with no other effects on maternal or birth after cesarean (VBAC) and women with diabetes were not
perinatal outcomes [35]. included in this study. Please see Chap. 8 for additional evidence
In summary, the routine use of ultrasound during a normally on dystocia.
evolving first stage of labor cannot be recommended. In women at term with singleton gestations and requiring oxy-
tocin by obstetrician because of “dystocia” at 4–6 cm, meperi-
Criteria for diagnosis of failure dine 100 mg IV does not affect operative delivery rates and
worsens neonatal outcomes compared to placebo [45] (see also
to progress in first stage Chap. 8).
According to studies now >60 years old in women without In summary, CD for arrest in the first stage of labor should not
regional anesthesia by Friedman, the active phase began at 2.5 cm be performed unless labor has arrested for a minimum of 4 hours
and ended at complete dilatation, with an average duration of with adequate uterine activity, or 6 hours with inadequate uterine
4.6–4.9 hours, a mean rate of cervical dilation of 3 cm/hour, and activity in a woman with ROM, adequate oxytocin, and ≥6 cm
the slowest acceptable rate (95th percentile) of 1.2 cm/hour [36, cervical dilation.
37]. More recently, investigators found that the active phase of
labor in nulliparous women lasts longer than previously thought. References
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[Meta-analysis; 4 RCTs, n = 1273]
9
SECOND STAGE OF LABOR
Alexis C. Gimovsky
Key points • Traditional coaching during pushing in the second stage

of labor may shorten the second stage, but lack of avail-
• Prophylactic intrapartum maternal oxygen should not able coaching support does not adversely affect labor
be used in the second stage of normal labor, since it is asso- outcomes. Ultrasound-assisted coaching is associated
ciated with more frequent low cord blood pH values (<7.20) with a shorter second stage of labor (by about 15 minutes).
than the control group. • Use of a dental support device/mouthguard has been
• Prophylactic intrapartum betamimetics should not be associated with a shorter second stage of labor and
used in the second stage of normal labor, since their usage reduction in failure to descend requiring operative
is associated with an increase in forceps deliveries. intervention.
• Women without epidural anesthesia should be encour- • Manual fundal pressure, gentle assisted pushing, and
aged to give birth in the position they find most com- belt fundal pressure have not been associated with an
fortable, which is usually upright. Use of any upright or effect on spontaneous vaginal delivery rate. Fundal
lateral position, compared with supine or lithotomy posi- pressure is associated with increased levator ani injury
tions, is associated, in women without epidural analge- and cervical tears. Gentle assisted pushing is associated
sia, with reduction in duration of second stage of labor, with greater discomfort. Belt fundal pressure is associ-
reduction in assisted deliveries, reduction in episioto- ated with a shorter second stage in nulliparas, but over-
mies, increase in second-degree perineal tears, increase all less satisfaction with delivery.
in estimated blood loss >500 mL, reduction in report- • Perineal massage and stretching of the perineum with
ing of severe pain during second stage of labor, and a water-soluble lubricant in the second stage of labor
reduction in abnormal fetal heart rate patterns. are associated with similar rates of intact perineum
• There is insufficient evidence to support the best posi- compared with the control group. The incidence of third-
tion for giving birth in women with epidural anesthesia. degree lacerations is decreased.
• There is insufficient evidence to recommend for or • There is insufficient evidence for or against the use of
against maternal stirrup use in the second stage of labor. perineal hyaluronidase (HAase) injection as a method
• Water immersion in the second stage of labor should be to reduce perineal trauma.
avoided, as the risks have not been adequately assessed. • The use of perineal gel in the second stage of labor does
• In nulliparous women at term with epidural analgesia not appear to have an effect on shortening the duration
and a singleton, cephalic fetus, delayed pushing (wait- or decreasing the risk of perineal lacerations, but there
ing 1 hour or until “urge to push”) is associated with do not appear to be any adverse effects.
similar rate of spontaneous vaginal delivery (SVD) • Use of perineal warm packs in the second stage of labor is
and operative vaginal delivery (OVD) compared with associated with a reduction in third- and fourth-degree
early (immediately upon entering second stage) push- tears, as well as a reduction in pain on postpartum days
ing. Additionally, with delayed pushing, the duration of 1 and 2.
the second stage is increased by about 30 minutes, the • Heating pad use on the perineum may decrease the need
incidence of chorioamnionitis and postpartum hemor- for episiotomy.
rhage is increased, and neonatal cord pH is decreased. • A perineal protection device has been shown to decrease
Careful monitoring of mother and fetus is necessary the risk of first- and second-degree lacerations.
to allow labor to continue safely, and risks and benefits of • In fetuses with persistent occiput posterior, there is insuf-
delayed pushing should be discussed with the patient prior ficient evidence to recommend manual rotation in labor
to decision-making. to improve SVD success.
• In women without epidural anesthesia, compared with • Routine use of the Ritgen maneuver does not appear to
encouraging a woman’s own urge to push (open glottis), be associated with any benefits and may increase post-
pushing using the Valsalva maneuver (closed glottis) partum pain.
is associated with shorter (by 19 minutes) duration of • “Hands-poised” is preferred to the “hands-on” method,
labor, similar incidences of OVDs, need for perineal since they are associated with similar incidences of peri-
repair, postpartum hemorrhage, and similar neonatal neal and vaginal tears, but the hands-on method is associ-
outcomes. Labor attendants should counsel women in ated with a higher incidence of episiotomies.
labor regarding these data and support the parturient in • Routine episiotomy should not be performed during
her own choice of pushing technique. the second stage of labor, as restricting episiotomy use is
• Women with levator ani coactivation, as demonstrated associated with less posterior perineal trauma.
by transperineal ultrasound, have a longer active sec- • Use of ultrasound in the second stage of labor can be
ond-stage duration (by about 32 minutes). valuable in predicting SVD.
DOI: 10.1201/9781003102342-9 105

TABLE 9.1: Summary of Interventions in the Second Stage during the second stage of labor. Compared with placebo, pro-
of Labor phylactic betamimetic therapy is associated with an increase in
forceps deliveries. The trial protocol required forceps to be used
Intervention Recommendation
if the second stage of labor exceeded 30 minutes in both groups.
Prophylactic oxygen Not recommended There are no clear effects of prophylactic tocolysis on postpartum
Prophylactic tocolytic administration Not recommended hemorrhage, neonatal irritability, feeding slowness, umbilical
Upright position without epidural Recommended arterial pH values, or Apgar scores at 2 minutes [3]. In summary,
Upright position with epidural Insufficient evidence routine prophylactic tocolysis should not be performed in the
Maternal stirrup use Insufficient evidence second stage of labor.
Water immersion in the second stage Insufficient evidence
Prophylactic positioning to prevent shoulder dystocia
Water birth Not recommended
See Chap. 25.
Immediate Pushing Recommended
Open versus closed glottis pushing Insufficient evidence
Ultrasound-assisted coaching Insufficient evidence Management
Dental support device Insufficient evidence
Maternal position
Fundal pressure Not recommended There are several benefits for upright posture in women with-
Perineal Massage Recommended out epidural anesthesia during the second stage of labor:
Perineal hyaluronidase injection Insufficient evidence Sitting (obstetric chair/stool), semi-recumbent (trunk tilted back-
Perineal gel Not recommended ward 30 degrees to the vertical), kneeling, squatting unaided or
Perineal Warm Packs/Heating Pad Recommended using squatting bars, and squatting aided with birth cushion are
Perineal protection device Insufficient evidence all considered upright positions for women in labor.
Manual rotation Insufficient evidence Use of any upright or lateral position, compared with supine
Routine Ritgen maneuver Not recommended or lithotomy positions, is associated, in women without epidural
“Hands-Poised” Position Recommended analgesia, with a small (4 minutes) reduction in duration of sec-
Routine episiotomy Not recommended
ond stage of labor, a 20% reduction in assisted deliveries, a 17%
reduction in episiotomies, a 23% increase in second-degree
Ultrasound use in the second stage Not recommended
perineal tears, a 63% increase in estimated blood loss >500
Allow a 4-hour second stage in nulliparas, Recommended
mL, a 23% reduction in reporting of severe pain during second
epidurala
stage of labor, and a 69% reduction in abnormal fetal heart rate
a See Table 9.2. patterns [4]. Use of the birth stool showed no effect, and results
with the birth chair were variable. Estimation of blood loss in the
• Nulliparous women with epidurals should be allowed upright group may be influenced by the fact that blood loss in
to labor for at least 1 additional hour after prolonged the birth chair is assisted by gravity and collected in a receptacle.
(3-hour) second stage of labor, since this results in a 55% Physiologic advantages for upright labor may include lessened
lower chance of cesarean delivery (CD) without a large risk of aortocaval compression, improved acid–base outcomes in
absolute increase in perinatal morbidities. There is insuffi- the neonates, stronger and more efficient uterine contractions,
cient evidence to determine exactly when the second stage improved alignment of the fetus for passage through the pelvis
is considered to be prolonged and associated with enough (“drive angle”), and larger anteroposterior and transverse pelvic
complications as to justify either OVD or CD. outlet diameters, resulting in an increase in the total outlet area
in the squatting and kneeling positions [4].
See Table 9.1 for a summary of suggested interventions. In women with epidural anesthesia, the evidence is mixed;
however, a large RCT supports the lying-down position in nul-
Prophylactic interventions liparas with epidural anesthesia. In the largest trial on position
in the second stage for nulliparous women with epidural anes-
Maternal oxygen thesia, there were 14% fewer spontaneous vaginal births in the
Prophylactic intrapartum maternal oxygen in the sec- upright group in comparison to the lying-down group [5]. In a
ond stage of normal labor is associated with more frequent smaller RCT, compared with a supported sitting position, lateral
low (<7.20) cord blood pH values than the control group in a position was associated with a lower chance of an operative vagi-
Cochrane review [1]. There were no other statistically signifi- nal delivery (OVD) [6]. Kneeling and sitting upright are associ-
cant differences between the groups. There is a tendency toward ated with a similar duration of second stage and other outcomes,
reduced cord arterial blood oxygen content and oxygen satura- except for a more favorable maternal experience and less pain
tion in mothers treated with oxygen compared with controls. In associated with kneeling [7]. In a Cochrane review of eight
a large recent randomized controlled trial (RCT), there was no RCTs, there was no significant difference in OVD, cesarean
difference in cord pH with the administration of oxygen during delivery (CD), postpartum hemorrhage, or duration of second
the second stage of labor in uncomplicated pregnancies [2]. In stage based on position during labor [8]. Maternal satisfaction
summary, routine maternal oxygenation throughout the sec- with the overall childbirth experience was slightly lower in the
ond stage should not be performed. upright group; however, 57% less babies were born with low
cord pH in the upright group [8].
Prophylactic tocolysis In summary, women without epidural anesthesia should
There is no evidence to support the prophylactic use of betami- be encouraged to give birth in the upright position, which is
metics to prevent nonreassuring fetal heart rate tracing (NRFHT) also the position they usually find most comfortable [4]. There
Second Stage of Labor 107
is insufficient evidence supporting the best position for giv- with encouraging a woman’s own urge to push (open glottis),
ing birth in women with epidural anesthesia. The American pushing using the Valsalva maneuver (closed glottis: Taking a
College of Obstetricians and Gynecologists (ACOG) therefore deep breath, holding it, and pushing for as long and hard as pos-
supports position changes as desired to sustain maternal comfort sible two to three times during each contraction) is associated
and to maintain appropriate monitoring during labor of women with shorter (by 19 minutes) duration of labor, similar inci-
with epidural anesthesia [9]. dences of OVDs, need for perineal repair, postpartum hemor-
rhage, and neonatal outcomes [17]. Urodynamic studies done 3
Maternal stirrup use months after delivery are worse in the closed glottis group, but
Routine use of stirrups during labor has had limited study insuf- long-term outcome has not been studied [17]. Labor attendants
ficient to make a recommendation. In one small RCT, women should counsel women in labor regarding these data and support
who delivered in bed with stirrups vs. those who delivered without the parturient in her own choice of pushing technique. ACOG
stirrups had similar perineal lacerations, incidence of prolonged supports an individualized pushing technique as preferred by the
second stage, OVD, and CD incidence [10]. In summary, there patient [9]. In summary, there is insufficient evidence to make
is insufficient evidence to make a recommendation regarding a recommendation regarding pushing method.
use of stirrups in labor.
Coactivation during Valsalva
Epidural or other anesthesia The Valsalva maneuver is ordinarily associated with relaxation of
See Chap. 11. the levator ani muscle, which expands around the presenting fetus;
but in some women Valsalva produces levator ani muscle contrac-
Water immersion tion, which is referred to as levator ani muscle coactivation. This has
Although there is some evidence that water immersion in the first been demonstrated by transperineal ultrasound. In one prospec-
stage of labor may reduce the need for epidural/spinal anesthesia tive study, transperineal ultrasound in the second stage of labor
and decrease the length of the first stage of labor (see Chap. 8), immer- was used to measure levator ani muscle coactivation in a group
sion during the second stage has been insufficiently studied of nulliparous women undergoing labor induction to assess labor
and may be best avoided, given the lack of sufficient safety data. outcomes and duration. Women with levator ani muscle coacti-
Of the three trials that compared water immersion during the vation had significantly longer active second-stage duration
second stage with no immersion, only one trial showed a signifi- (about 32 minutes). There was no significant difference between
cantly higher level of satisfaction with the birth experience (rela- women who underwent operative delivery when compared with
tive risk [RR] 0.24, 95% confidence interval [CI] 0.07–0.70). There the SVD group in the prevalence of levator ani muscle coactivation
are reports of neonatal water aspirations from birth (at the end [18]. In summary, women with levator ani coactivation have a
of the second stage) in water [11, 12]. Both ACOG and National longer second stage but no difference in SVD rate.
Institute for Health and Care Excellence (NICE) conclude that
as the safety has not been well established, water immersion in Coached pushing
the second stage of labor should be avoided. In summary, water Although traditional coached pushing confers the benefit of
immersion in the second stage of labor should be avoided, as a slightly shorter second stage (about 13 minutes), coached
the risks have not been adequately assessed [13, 14]. maternal pushing confers no other advantages, and withhold-
ing such coaching is not detrimental to maternal or fetal out-
Pushing comes [19]. Sonographically coached pushing, i.e. using visual
Delayed vs. early pushing demonstration by transperineal ultrasound of the progression
In nulliparous women at term with epidural analgesia and a sin- of fetal head descent, is associated with a shorter active phase
gleton, cephalic fetus, delayed pushing (waiting an hour or until of the second stage of labor (about 15 minutes) [20]. In sum-
the urge to push) is associated with a similar rate of spontaneous mary, coached pushing is not harmful to women in labor,
vaginal delivery (SVD) compared with early (immediately upon and ultrasound-assisted pushing seems helpful but has been
entering second stage) pushing (RR 0.99, 95% CI 0.96–1.03) [15]. insufficiently studied.
Women who delay pushing have a longer second stage (about
32 minutes) and a shorter duration of pushing (about 10 minutes). Use of a dental support device
Women who push immediately have a 30% lower risk of chorio- In one RCT, wearing a dental support device (mouthguard) is
amnionitis and a 40% lower risk of postpartum hemorrhage, associated with a shorter second stage (19 minutes). In addition,
but a 10% higher risk of third-degree lacerations [15]. Umbilical less operative intervention was used in the dental support group.
cord pH < 7.1 and suspected sepsis were more common in the Further research into optimizing maternal expulsive efforts is
delayed pushing group. In a meta-analysis of 12 RCTs, similar needed to evaluate the overall benefit of dental devices [21]. In
results were noted [16]. Due to the adverse outcomes associated summary, use of a dental support device during the second
with delayed pushing and potentially prolonged second stage, stage of labor is recommended.
careful monitoring of both mother and fetus is necessary to
allow labor to continue safely if desired by the patient and pro- Fundal pressure
vider. (see also “Criteria for Diagnosis of Prolonged Second Stage”). In the second stage of labor, fundal pressure has been evaluated
ACOG is therefore in support of immediate pushing for nulliparas by manual pressure, by gentle assisted pressure, or by use of an
with epidural anesthesia [9]. In summary, immediate pushing is obstetric belt wrapped around the woman’s abdomen above the
recommended upon entering the second stage. level of the uterine fundus.
Compared with no manual fundal pressure, manual fundal
Pushing method: Valsalva vs. spontaneous pressure (Kristeller maneuver) concomitant with each con-
Most women spontaneously choose to Valsalva during the second traction while the patient has the urge to push during the
stage of labor. In women without epidural anesthesia, compared second stage is not associated with any significant changes in
duration of labor or with other maternal and perinatal out- intervention. Data from additional trials that contained a placebo
comes in one RCT [22]. Additionally, manual fundal pressure is injection show no clear evidence of a reduction in the incidence
associated with a higher rate of levator ani muscle injury in of perineal trauma, episiotomy, and third- and fourth-degree
comparison to control [23]. A Cochrane review of manual fundal perineal lacerations. In summary, the potential use of perineal
pressure of nine trials showed that manual fundal pressure was HAase injection as a method to reduce perineal trauma has
not associated with changes in SVD, OVD, CD, duration of sec- yet to be determined [29].
ond stage, or low arterial cord pH. More women who received
manual fundal pressure had cervical tears than in the control Perineal gel
group (RR 4.90, 95% CI 1.09–21.98 [24]. The use of a sterile obstetrical gel (lubricant) without perineal
“Gentle assisted pushing (GAP)” is a method of applying gentle, massage has been assessed in women in the second stage of labor.
steady pressure to a woman’s fundus during the second stage of The rates of OVD and CD were comparable between the gel
labor. In the GAP method, the woman is assisted to assume an group and control. There was no reduction in perinatal lacera-
upright kneeling or squatting position on the bed. The provider tions or in the length of the second stage. No adverse perinatal
kneels on the bed or stands behind the woman, wraps the arms outcomes were noted [30]. A meta-analysis of the use of gel to
around her, and places both open palms, overlapping, on the shorten the second stage of labor supported these findings [31]. In
uterine fundus. Steady pressure is applied in the long axis of the summary, use of a perineal gel as a lubricant without perineal
uterus during contractions for a maximum of 30 seconds, with at massage is not recommended.
least 30 seconds of rest before the next application. One trial of
nulliparous women showed that the duration of the second stage Perineal warm packs
of labor was not different in the GAP group versus control. There Application of perineal warm packs during the second stage
were no differences in secondary outcomes, except that at two of labor was associated with less severe (third- or fourth-
sites maternal discomfort was greater for the GAP group com- degree) tears than was standard management. In addition, pain
pared with control [25]. scores were less on postpartum days 1 and 2 in the intervention
The fundal pressure belt inflates with each contraction to a group. After 3 months, a trend toward decreased symptoms of
maximum of 200 mmHg for 30 seconds. Compared with no belt, urinary incontinence was seen in the intervention group [32].
the inflatable obstetric belt is associated with similar incidence An RCT evaluating the effect of warm compresses on episiotomy
of SVD in nulliparous women with singleton term pregnancies showed a decrease in episiotomy use in primiparous women
and an epidural. All other maternal and neonatal outcomes are in the second stage of labor without analgesia (90% vs. 45%, p <
similar, but women with no belt have greater satisfaction [26]. 0.001) [33]. A Cochrane review also supports a decrease in third-
In a Cochrane review, fundal pressure by inflatable belt did not or fourth-degree lacerations, and a meta-analysis of seven trials
reduce OVD or CD. Duration of second stage was shortened showed that warm compresses were associated with a higher rate
in nulliparous women (mean difference –50.80 minutes, 95% CI of intact perineum, a lower rate of third- and fourth-degree
–94.85 to –6.74 minutes). The inflatable belt did not affect the tears, and episiotomy in comparison to controls [28, 34].
incidence of low arterial cord pH babies, but third-degree Use of a heating pad at the start of the second stage has been
perineal tears were increased in the inflatable belt group (RR evaluated in primiparous women delivered by Ritgen maneuver
15.69, 95% CI 2.10–117.02) [24]. in one RCT and showed that episiotomy risk was lower in the
In summary, manual fundal pressure, GAP, and belt fundal heating pad group [35]. In summary, warm packs should be rec-
pressure have not been associated with an effect on method of ommended in the second stage.
delivery, but they are associated with decreased maternal sat-
isfaction, increase in cervical and third-degree tears, and Perineal protection device
shorter second stage in nulliparas; therefore, all types of fun- A perineal protection device, a plastic device inserted into the
dal pressure should be avoided. perineum when the fetal head is visible at the introitus during
crowning, has been shown to decrease the risk of first- and
Perineal massage second-degree tears in the vaginal and perineum during vaginal
Perineal massage has been evaluated for a decrease in perineal lac- birth in comparison to no device in one trial (34.9% vs. 26.6%, p =
erations. Perineal massage has not been associated with compli- 0.03). The number needed to treat to prevent one laceration was
cations. For perineal massage during pregnancy and before labor, 12 [36]. In summary, the use of a perineal protection device
see Chap. 2. Perineal massage and stretching of the perineum has insufficient evidence to make a recommendation.
with a water-soluble lubricant in the second stage of labor are
associated with a 40% increased rate of intact perineum, a 51% Manual rotation
decreased rate of severe perineal trauma, and a 44% decreased Persistent fetal occiput posterior position is a risk factor for
rate of episiotomy compared with controls [27]. A Cochrane prolonged labor and higher rate of CD. Malposition includes
review also favored perineal massage versus hands off for a 51% occiput transverse or posterior positions. These are often
reduction in third- or fourth-degree tears [28]. In summary, associated with asynclitism, defined often as the “oblique mal-
perineal massage is recommended in the second stage of labor presentation of the fetal head in labor” [37]. In a pilot RCT of 30
to decrease perineal trauma. women with occiput posterior fetuses who were randomized to
manual rotation or sham procedure, operative delivery (CD plus
Perineal hyaluronidase injections OVD) were similar in both groups [38]. In an RCT of 65 nullipa-
Perineal hyaluronidase (perineal HAase) injections have also ras where manual rotation was attempted at the beginning of the
been used to reduce perineal trauma. In a Cochrane review of second stage, the manual rotation group had a shorter second
this strategy, hyaluronidase injection during the second stage of stage (about 13 minutes) and a higher rate of SVD [39]. When
labor had a lower incidence of perineal trauma compared with no assisted by ultrasound, manual rotation and SVD success rate
were improved (see also Chap. 26) [40]. Therefore, there is insuf- episiotomy should not be performed, as restrictive episiotomy
ficient evidence to evaluate the efficacy of manual rotation in policies have many benefits compared with routine episiot-
labor, but limited data are encouraging. omy policies.
Ritgen maneuver Ultrasound

The Ritgen maneuver (originally described by Ritgen in 1855) Transabdominal and transperineal ultrasound have been used
involves reaching for the fetal chin when it reaches the plane as adjuncts in the second stage of labor to predict SVD. In one
between the maternal anus and the coccyx and pulling it anteri- prospective cohort study of nulliparas and second stage >2 hours,
orly while using the fingers of the other hand on the fetal occiput SVD was associated with a higher rate of occiput anterior posi-
to control the speed of delivery and keep flexion of the fetal neck. tion, lower head–perineum distance and head–symphysis dis-
Its aim is to protect the perineum from lacerations. In a meta- tance, narrower midline angle, and wider angle of progression.
analysis, compared with no Ritgen maneuver, Ritgen maneuver At logistic regression analysis, the midline angle and the head–
performed for delivery of the fetal head during uterine contrac- symphysis distance proved to be independent predictors of
tions is not associated with any benefit on the incidence of peri- SVD [46]. In summary, there is insufficient evidence to sup-
neal tears, but may be associated with a higher risk of postpartum port the routine use of ultrasound in the second stage of labor
pain [41]. In summary, Ritgen maneuver does not appear to be for prediction of SVD or management of labor, as outcomes
associated with any benefits and is not recommended. are unchanged by the use of ultrasound as studied so far.
“Hands-on” vs. “hands-poised” Criteria for diagnosis of

The hands-on method (also described by Ritgen) involves employ-
ing pressure on the infant’s head upon crowning and supporting
prolonged second stage
the perineum with the other hand. The aim is to protect against There is insufficient evidence to determine when the second
lacerations. In the hands-poised method, the fetal head and stage is prolonged and associated with enough complications
perineum are not touched or supported by the delivering person- with continuing labor so as to justify either OVD or CD. Some
nel. These two methods are associated with similar incidences of have proposed the criteria in Table 9.2 for the diagnosis of pro-
perineal and vaginal tears, but the hands-on method is associ- longed second stage (or criteria for dystocia or failure to progress),
ated with a 42% higher incidence of episiotomies [28]. A policy but these are not based on level 1 evidence [47–49]. Clinically, the
of hands-poised has also been supported by a meta-analysis of start of the second stage is imprecise and begins when the subjec-
five RCTs. The hands-on method does not protect against severe tively timed cervical exam reveals complete (10 cm) cervical dila-
perineal trauma and was associated with increased risk of third- tion. It is also important to realize that, historically, women often
degree lacerations (RR 3.41, 95% CI 1.39–8.37) [42]. In summary, do not begin to push until 1 hour or more of delayed pushing and
the hands-on method should be avoided in labor. complete dilation has been ascertained.
The second stage can be further divided into passive and active
Episiotomy second stage. According to the Agency for Healthcare Research
Routine episiotomy should not be performed, as restrictive epi- and Quality (AHRQ), passive second stage is defined as full
siotomy policies have a number of benefits compared with routine dilation of the cervix without voluntary or involuntary pushing
episiotomy policies. In a recent large trial there was no difference [14]. Active second stage is defined as when the fetus is visible
in severe perineal laceration between a policy of restrictive epi- or once pushing has started with or without contractions [14].
siotomy and no such policy [43]. Restrictive episiotomy resulted These guidelines suggest that the passive phase in a nulliparous
in more intact perineums in multiparous women, but increased woman can be allowed for up to 2 hours regardless of anesthe-
the risk of vaginal laceration in primiparous and multiparous sia. In a multiparous woman, passive phase is suggested to be
women. Restrictive episiotomy did not lead to more suturing [43]. allowed for 1 hour without an epidural and 2 hours with an epi-
In the most recent Cochrane review, 83% of women had episioto- dural. The active phase of the second stage of labor is suggested
mies in the routine episiotomy group, while the rate in the restric- in nulliparous women to have a time limit of 1 hour without an
tive episiotomy group was 32% (median). Compared with routine epidural and 2 hours with an epidural. In a multiparous woman,
use, restrictive episiotomy is associated with less severe peri- active phase is suggested as 1 hour regardless of anesthesia [14].
neal trauma (RR 0.70, 95% CI 0.52–0.94). Compared to routine Epidural anesthesia is shown to increase the length of the second
episiotomy, restrictive use of episiotomy had a similar rate of stage by 13.66 minutes regardless of parity in a large meta-analy-
blood loss (average of 27 mL less; 95% CI 75 mL less to 20 mL sis [50, 51]. The suggestions regarding length of the active second
increase), similar Apgar score of <7 at 5 minutes, and peri- stage are not supported by level 1 data, and longer second stages
neal infection (RR 0.90, 95% CI 0.45–1.8). There was a similar are allowed if maternal and fetal conditions permit (see Table 9.2).
rate of moderate to severe perineal pain at 3 days postpartum (RR
0.71, 95% CI 0.48–1.05), dyspareunia (RR1.14, 95% CI 0.84–1.53),
TABLE 9.2: Proposed Criteria for Prolonged Second Stage
and long-term (6 months or more) urinary incontinence (RR 0.98,
95% CI 0.67–1.44) [44]. There is insufficient evidence to evalu- Suggested Upper Limit of Length of
ate if there are indications for any use of episiotomy, such as in Maternal Characteristics Second Stage (hour)
OVD, preterm delivery, breech delivery, predicted macrosomia,
Nulliparous, epidural 4
or presumed imminent tears. Episiotomy should be avoided if
Nulliparous, no epidural 3
at all possible, but if used, it is unknown which episiotomy tech-
Multiparous, epidural 3
nique (mediolateral or midline) provides the best outcome. The
restrictive use of episiotomy is supported by practice guidelines Multiparous, no epidural 2
endorsed by both ACOG and NICE [14, 45]. In summary, routine Source: Modified from Ref. [55].
Several non–level 1 studies have compared maternal and peri- comparing outcomes of women in two different periods. Period
natal outcomes between women with shorter versus “prolonged” 1 consisted of a definition of prolonged second stage in nullipa-
second stage. In a review of all studies up to 2004, a strong asso- rous women after 3 hours with regional anesthesia or 2 hours if
ciation between prolonged second stage and OVD was noted no such anesthesia was provided. Period 2 allowed nulliparous
[52], although the definition of prolonged second stage was incon- and multiparous women to continue the second stage of labor an
sistent across studies. In addition, significant associations with additional 1 hour. The primary CD rate in period 2 was decreased
maternal outcomes such as postpartum hemorrhage, infection, in nulliparous women (RR 0.67; 95% CI 0.61–0.74) and in mul-
and severe obstetric lacerations were reported, but again, meth- tiparous women (RR, 0.75; 95% CI 0.67–0.84). The rate of OVD
ods varied widely. Urinary incontinence may also be increased in nulliparous women was higher in period 2 than in period 1
with prolonged second stage [48]. Anal incontinence does not (19.2% vs. 17.7%, p <0.0001). Rates of third- and fourth-degree
seem to be affected [53]. In general, SVD without morbidity lacerations and of shoulder dystocia were also higher in period 2.
decreases with increasing duration of the second stage [54, 55]. The rate of arterial cord pH <7.0 and the rate of admission to the
However, these risks may not be entirely related to the duration neonatal intensive care unit were higher in period 2, but the early
of the second stage and may also be related to management of the neurologic outcome was not different [62].
second stage by the health care provider [55]. Additionally, the If there are no signs of infection (maternal or fetal), no
negative consequences of a prolonged second stage seem to have a maternal exhaustion, and reassuring fetal testing, labor can
low absolute risk difference [55]. No clear associations between be allowed to continue beyond current limits (Table 9.2) as
prolonged second stage and adverse neonatal outcomes have long as some progress has been made. This is supported by the
been reported [52, 56]. The length of the second stage is not AHRQ recommendations [63]. Nevertheless, even if contractions
associated with poor neonatal outcome as long as reassuring fetal are adequate, the chance of vaginal delivery decreases progres-
testing is present. A recent large retrospective study suggested sively after 3–5 hours of pushing in the second stage [64].
that neonatal sepsis (odds ratio [OR] 2.08, 95% CI 1.60–2.70), A mandatory second opinion is associated with 22 fewer
asphyxia (OR 2.39, 95% CI 1.28–4.27), and mortality (OR 5.92, intrapartum CDs per 1000 deliveries without affecting maternal
95% CI 1.43–24.51) were increased in nulliparous women with or perinatal outcomes (see Chap. 13) [65].
prolonged second stage of labor [57]. Nevertheless, these data are In summary, prolongation of the second stage by at least
limited by their retrospective nature. 1 hour (over the 3 hours that define prolonged second stage) in
In a large observational study of 53,285 women, time spent dur- nulliparous women with epidural anesthesia is recommended;
ing active pushing was found to be associated with increases in a mandatory second opinion is beneficial to reduce the CD rate.
postpartum hemorrhage, third- and fourth-degree lacerations, and
composite neonatal adverse outcome. The composite neonatal out- Second-stage duration during a trial
come in nulliparous women with active pushing ≥240 minutes was of labor after cesarean delivery
increased (OR 2.2; 95% CI 1.2–4.2) in comparison to the reference Most women with a previous CD who reach the second stage
group of <60 minutes and was also increased for parous women of labor deliver vaginally (90.6%). As in women without a prior
with active pushing ≥120 minutes (OR 2.7; 95% CI 1.5–4.8) in com- CD, as the length of the second stage increases, the chance of a
parison to the referent group of <60 minutes [58]. successful vaginal birth decreases. The risk of uterine rupture
Long-term outcome data are also lacking in the area of pelvic or dehiscence increases with second-stage length from less than
floor dysfunction (PFD). In one survey of women immediately and 1 hour (0.7%), 1 to less than 2 hours (1.4%), 2 to less than 3 hours
3 months postpartum, all women had a large difference in PFD (1.5%), to 3 hours or greater (3.1%). Risk of neonatal outcomes did
symptoms during pregnancy and 3-month postpartum (p < 0.001). not differ significantly by second-stage length [66]. In summary,
A larger recovery of colorectal and anal dysfunction symptoms was the risk of uterine rupture increases with the length of the
associated with a shorter duration of the second stage of labor [59]. second stage in women with prior CD.
The challenge with the evidence presented here is that these
maternal detriments of prolonged second stage occur when these Possible effects of cesarean delivery
women are compared with women without prolonged second in the second stage of labor
stage. It is evident that a planned CD before labor might decrease In a large retrospective study of second-stage CD, the risk of pre-
some of these complications (e.g. bleeding, infection, lacerations, term birth <37 weeks in the subsequent pregnancy was increased
and incontinence). The clinical issue is different, however. (RR 1.57; 95% CI 1.43–1.73) [67]. Length of time spent in the
Once a woman is having a prolonged second stage, should second stage with resultant CD and risk of preterm birth is a
she be delivered operatively or should she continue labor? CD controversial risk factor, as there are studies both refuting and
performed after prolonged second stage has been associated with supporting this as a potential confounder [68, 69]. In summary,
longer surgery time, increased postoperative fevers, maternal women with a prior CD during the second stage may have an
intraoperative trauma including higher risk of extensions of the increased risk in a future pregnancy for preterm birth.
uterine incision, and higher composite maternal morbidity, but
similar perinatal outcomes compared with CD performed before
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10
THIRD STAGE OF LABOR
Alyssa R. Hersh and Jorge E. Tolosa
interval of greater than 30 minutes is the 97th percentile, which

Part 1: Normal third stage of labor is considered a prolonged third stage of labor.
Key points Pathophysiology

• Oxytocin has historically been the uterotonic of choice for The third stage of labor involves separation of the placenta with
postpartum hemorrhage prophylaxis, as it reduces blood capillary hemorrhage and shearing of the placental surface when
loss and has fewer side effects compared with other agents the uterus contracts after delivery of the infant. Signs of separa-
such as ergot alkaloids and misoprostol. However, recent tion include a gush of blood, cord lengthening, and the uterine
data suggest that oxytocin combined with misoprostol fundus becoming more globular and firmer.
or ergot alkaloids (e.g. methergine), or carbetocin alone,
are more effective in reducing blood loss greater than Complications (see Chap. 28)
500 mL than oxytocin alone. Oxytocin can be given in
several ways, for example, as 20 IU (10–40 IU) IV in 500 cc • Postpartum hemorrhage—classically defined as an esti-
normal saline (NS) or lactated Ringer’s (LR) infused over mated blood loss (EBL) >500 mL after vaginal delivery
1 hour following vaginal delivery, either after delivery of or >1000 mL after cesarean delivery. Most recently, it has
the anterior shoulder or immediately after delivery of the been defined as >1000 mL for both vaginal and cesarean
neonate and before delivery of the placenta. delivery; see Chap. 28.
• Tranexamic acid in addition to oxytocin before skin inci- • Retained placenta—placenta not expelled within
sion at cesarean section or within 10 minutes of vaginal 30 minutes of infant delivery.
delivery is effective in reducing blood loss and improving • Uterine inversion—collapse of uterine fundus into the
obstetric outcomes, compared to oxytocin alone. uterine cavity.
• Delayed cord clamping in preterm neonates by 30–60
(maximum 180) seconds is associated with lower risk of
death before discharge, necrotizing enterocolitis, and
Management
intraventricular hemorrhage (IVH). Delayed cord clamp- Uterotonics and tranexamic acid
ing in term neonates is associated with higher hematocrit An algorithm including management of the third stage of labor is
and lower risk of iron deficiency at less than a year of age, shown in Figure 10.1.
but with an increased risk of hyperbilirubinemia requiring
phototherapy. Oxytocin (Syntocinon®)
• Milking of the umbilical cord is associated with severe Oxytocin binds to specific uterine receptors with immedi-
intraventricular hemorrhage in very preterm infants ate action, causing increasing strength and frequency of con-
and associated with inconsistent evidence of benefit and tractions. The mean half-life is 3 minutes with the plateau
therefore is not recommended for infants of any gesta- reached after 30 minutes. It can either be given as intravenous
tional age. (IV) or intramuscular (IM), though IM injection has a time of
• Controlled cord traction reduces the need for manual onset of 3–7 minutes and the clinical effect is longer, lasting
extraction of the placenta. Uterine massage has not been 30–60 minutes. It is metabolized by the liver and kidneys with
associated with benefits as studied so far during vaginal a known 5% antidiuretic effect of vasopressin. If given in large
delivery. volumes, greater than 40–50 mL per minute, and high concen-
• Vaginal and perineal lacerations should be repaired with tration, or when given without dilution, it may result in hypo-
one continuous absorbable synthetic suture, including natremia and syndrome of inappropriate antidiuretic hormone
continuous subcuticular skin repair. hypersecretion (SIADH) with symptoms of headache, vomiting,
• Oral medications such as nonsteroidal antiinflammatory drowsiness, and convulsions.
agents (e.g. ibuprofen) and acetaminophen, and topical There have been different ways of administering oxytocin for
anesthetics can decrease perineal pain and need for addi- prophylaxis following vaginal delivery, including IM, IV (either
tional pain therapy. undiluted or as a diluted infusion), and intraumbilical. The IM
dose is 5–10 IU, administered at the delivery of the anterior
Definitions shoulder or soon after, before delivery of the placenta (Table 10.1).
Oxytocin can also be given as an undiluted IV bolus (10 IU in
The third stage of labor is defined as the interval between deliv- 1 mL over 1 minute) or as a diluted IV infusion consisting of
ery of the neonate and expulsion of the placenta. The mean 10–40 IU diluted in 500–1000 mL of normal saline or lactated
length of time of the third stage of labor is about 6 minutes. An Ringer’s. A randomized controlled trial (RCT) compared various
DOI: 10.1201/9781003102342-10 113

RCTs. The IM route is favored in some institutions, particularly

Delivery of the infant
(vaginal or cesarean) in resource-poor settings, as it can be administered rapidly by
providers with minimal training [2]. Two recent RCTs have
demonstrated lower rates of PPH with the IV route (10 IU
in 1 mL over 1-minute bolus or 10 IU in 500 mL infusion
Oxytocin IV* saline) compared with the IM route (10 IU in 1 mL bolus)
and no increase in adverse effects [3, 4]. A smaller trial found
+/– Tranexamic acid 1,000 mg**
no significant difference in PPH but reduced need for additional
Delayed cord clamping/cutting*** uterotonics [5]. Therefore, an IV administration of oxytocin (10
IU in 1 mL over 1 minute or 10 U in 500 mL at rate of 12 mL
Controlled cord traction for spontaneous per minute) is safe and effective and is the preferred route for
placental delivery**** oxytocin administration.
Injection of oxytocin into the umbilical cord is not recom-
mended. Compared to IV/IM oxytocin or to injection of saline
alone, the umbilical vein injection of oxytocin does not have a
Delivery of placenta significant effect on postpartum blood loss, need for transfusion,
length of the third stage of labor, or need for manual placental
removal [6].
FIGURE 10.1 Suggested algorithm for management of the Oxytocin is an effective prophylactic uterotonic in the third
third stage of labor. *See dosing and timing options in text. stage of labor. Compared with no uterotonics, prophylactic oxy-
**Consider also, in addition to oxytocin, misoprostol, or tocin may reduce blood loss of greater than 500 mL after vaginal
methergine, in particular in women at high risk for postpartum delivery and the need for therapeutic uterotonics [7]. There are
hemorrhage. *** If no neonatal asphyxia. **** If a skilled birth similar incidences of manual removal of the placenta and rates
attendant is present. of blood transfusion with the use of oxytocin compared to no
uterotonic.
Oxytocin is routinely administered after delivery of the
oxytocin doses (10 IU, 40 IU, and 80 IU IV in 500 mL) given over anterior shoulder or immediately after delivery of the neo-
1 hour after placental delivery for primary postpartum hemor- nate and before delivery of the placenta. Timing of oxyto-
rhage (PPH) prophylaxis at vaginal delivery and showed no differ- cin administration before or after placental delivery did not
ences overall in incidence of PPH. However, the dose of 80 IU was show differences in rates of blood loss, length of third stage
associated with a lower risk of needing additional uterotonics and of labor, and rates of retained placenta [8, 9]. Nonsignificant
lower risk of ≥6% decline in hematocrit [1]. trends for less PPH but more retained placenta are associated
The comparative effectiveness and safety of administration with oxytocin given before compared with after placental
by the IM or IV route have recently been assessed in multiple separation [8].
TABLE 10.1: Commonly Used Uterotonic Agents

Route/Dose Maximum Dose Side Effects Contraindications
Oxytocin 10–80 IU IV infusion in 500–1000 mL NS/LR (or 80–100 IU Hypotension None
5–10 IM if IV not available) Hyponatremia
Fluid overload
Flushing
Nausea/emesis
Misoprostol 200–1000 mcg PO, PR, or PV Unknown Pyrexia None
Shivering
Nausea/emesis
Diarrhea
Ergometrine/methergine 0.2 mg IM or 1 mg Nausea/emesis Hypertension
0.2 mg PO (5 doses) Vasoconstriction Cardiac diseasea
Every 15 minutes × 2 doses then every 2–4 hours Hypertension Peripheral vascular diseasea
Prostaglandin F2α/ 0.25 mg IM 2 mg Bronchoconstriction Asthma
Hemabate Every 15–90 minutes (8 doses) Hypertension Active cardiac, pulmonary,
Nausea/emesis renal, or hepatic diseasea
Diarrhea
Carbetocin 100 mcg IV (single dose) 100 mcg Hypotension None
Flushing
Pruritus
Headache
Nausea/emesis
a Relative contraindication.
Abbreviations: LR, lactated Ringer’s solution; NS, normal saline; IU, international units; IM, intramuscular; IV, intravenous; PR, per rectum; PV, per vagina.
Third Stage of Labor 115
Oxytocin agonists with nausea, vomiting, and diarrhea. Studies suggest that these
Carbetocin is a synthetic analogue of oxytocin; 100 μg IV has side effects are dose dependent, particularly with doses exceed-
been shown to reduce the need for therapeutic uterotonics ing 600 μg [16].
compared to oxytocin for those women who underwent cesar- Compared with placebo, prophylactic oral or sublingual
ean section [10]. Compared with Syntometrine (oxytocin plus misoprostol reduces the risk of severe PPH and need for blood
ergometrine), carbetocin is associated with less blood loss and transfusion [17]. When compared to conventional injectable
fewer side effects when used prophylactically following vaginal uterotonics (oxytocin, Syntometrine, or ergometrine), the risk of
delivery; however, the risk of PPH is not decreased [10, 11]. An PPH is no better [17–19]. Recent RCTs have found conflicting evi-
international randomized, controlled noninferiority trial, which dence for the benefit of misoprostol over oxytocin at vaginal deliv-
enrolled over 29,000 women expected to give birth vaginally, ery [20, 21]. For cesarean delivery, misoprostol combined with
found that heat-stable carbetocin was noninferior to oxytocin for oxytocin may be more effective than oxytocin alone in reducing
the use of additional uterotonics or blood loss of greater than intraoperative and postoperative hemorrhage [22]. Furthermore,
500 mL; however, noninferiority was not demonstrated with a recent network meta-analysis found that oxytocin with miso-
blood loss greater than 1000 mL [12]. There was no difference in prostol was more effective in reducing blood loss greater than
adverse events. As carbetocin is similar to oxytocin in outcomes 500 mL [14]. However, due to the conflicting evidence of its ben-
but not widely available, the decision to use it compared to oxyto- efit, misoprostol may be a more appropriate first-line agent in the
cin should be based on local circumstances. setting of no IV access, patients with contraindications to other
uterotonics, or in resource-poor settings (see Chap. 28).
Ergot alkaloids (Methergine® or ergometrine) Prostaglandin F2α (Hemabate/carboprost) causes contrac-
Ergot alkaloids cause sustained tonic contraction of uterine tion of uterine smooth muscle cells. Administration is either
smooth muscle by stimulation of alpha-adrenergic myometrial 0.25 mg IM or as a direct injection into the myometrium, which
receptors. The dose is 0.2 mg IM injection or PO (orally), with may be repeated every 15–20 minutes for a maximum of eight
a mean elimination half-life of 3.4 hours (range 1.5–12.7 hours). doses or 2 mg. Side effects are secondary to smooth muscle con-
IV administration is not recommended, as it is associated with striction and include bronchoconstriction, venoconstriction, and
more severe side effects. Nausea and vomiting are common side constriction of GI smooth muscle. Common side effects are nau-
effects, although the most concerning side effect is vasoconstric- sea, vomiting, diarrhea, pyrexia, bronchospasm, and case reports
tion of the vascular smooth muscle. This results in elevation of of hypotension and intrapulmonary shunting with arterial oxy-
central venous pressure and systemic blood pressure, increasing gen desaturation. It is contraindicated in patients with cardiac
the risk of pulmonary edema, stroke, or myocardial infarction. and pulmonary disease. There is no high-quality evidence to
Contraindications include cardiac disease, autoimmune dis- support the use of carboprost for PPH prophylaxis.
eases associated with Raynaud phenomena, peripheral vascular
disease, arteriovenous shunts, hypertension, preeclampsia, and Tranexamic acid
eclampsia. Tranexamic acid (TXA) is a synthetic derivative of the amino
Compared with oxytocin, ergot alkaloids used alone as pro- acid lysine that is metabolized in the kidney and functions as
phylactic uterotonics have similar benefits, such as reducing blood an antifibrinolytic that has been studied for use as treatment for
loss, reducing the need for additional uterotonics, and increasing PPH, as well as for prophylaxis. Side effects include nausea, vom-
maternal hemoglobin levels. However, they are associated with iting, and dizziness [23]. A large multicountry RCT called “The
worse side effects, suggesting other agents such as oxytocin may Woman Trial” tested the use of 1 g of TXA initially (100 mg/mL
be preferable as the first-line prophylactic agent [13]. at a rate of 1 mL/minute), followed by 1 g if bleeding contin-
Compared with oxytocin alone, ergot alkaloids in addition to ued, in women diagnosed with PPH compared to placebo; TXA
oxytocin are associated with a statistically significant reduction reduced the rate of maternal death due to bleeding in women
in the risk of PPH when compared to oxytocin alone for blood with PPH (see Chap. 14) [24].
loss of 500 mL or more. A network meta-analysis found a sig- When used for prophylaxis for women undergoing cesarean
nificant difference in blood loss 1000 mL or more [14]. There were delivery, TXA given in combination with routine traditional
no differences in blood transfusion, retained placenta, or other prophylactic uterotonics (e.g. oxytocin) appears to decrease the
neonatal outcomes. Unfortunately, the adverse side effects when risk of postpartum blood loss and need for blood transfusion in
ergometrine is added to oxytocin are important to consider, women at low risk for PPH, with data from clinical trials of mixed
including nausea, vomiting, and hypertension [15]. quality and meta-analysis from such data [23, 25]. For prophylaxis,
Syntometrine is a combination drug containing oxytocin 5 IU it is administered intravenously at a dose of 10 mg/kg (usually a
and ergometrine 0.5 mg and is administered intramuscularly. As maximum of 1 g), 10–20 minutes before skin incision, with rapid
with ergot alkaloids alone, side effects are significant, including onset of action and a mean elimination half-life of 2–10 hours.
nausea, vomiting, and hypertension [7, 15]. We recommend TXA be considered for routine prophylactic
use at cesarean section in addition to prophylactic oxytocin.
Prostaglandins For women planning to have a vaginal delivery, there is vari-
Misoprostol is a synthetic analog of prostaglandin E1 and is ability among published studies. For prophylaxis, it is adminis-
metabolized in the liver. The tablet can be given by the oral or tered intravenously at a dose of 1 g (in 10 mL over 2–3 minutes)
sublingual route at 400–600 μg, or by the vaginal or rectal within 10 minutes of vaginal delivery. In a recent large multicenter
route at 400–1000 μg. It does not require sterile needles and RCT, prophylactic TXA in addition to prophylactic oxytocin did
syringes for administration. It is inexpensive, heat and light not result in a significantly lower rate of PPH >500 mL, although
stable, and has a long shelf-life, making it more accessible and women required fewer additional uterotonic agents [26]. A review
beneficial in low-resource settings. Side effects include shivering, combining this RCT with previously published studies found that
elevated body temperature >38°C, and gastrointestinal (GI) upset prophylactic TXA reduced PPH >500 mL in combination with
prophylactic oxytocin, cord traction, and uterine massage [27]. Timing of cord clamping
Therefore, we recommend TXA be considered for routine pro- In preterm neonates less than 37 weeks’ gestation, delayed cord
phylactic use at vaginal delivery in addition to prophylactic clamping (DCC) by about 30–60 seconds (180 seconds maxi-
oxytocin. mum) is associated with a lower risk of death before discharge,
necrotizing enterocolitis, and intraventricular hemorrhage
Summary (IVH) than early cord clamping (ECC) [32, 33]. This interven-
Recent evidence suggests that numerous regimens of uterotonic tion also benefits very preterm neonates less than 32 weeks’ ges-
agents, including oxytocin with ergot alkaloids, carbetocin alone, tation, with decreased mortality, risk of blood transfusion, and
or oxytocin with misoprostol, are more effective at reducing IVH [34]. In addition, DCC has been shown to be safe and does
blood loss at delivery than oxytocin alone. Furthermore, there is not compromise the preterm infant; there may be small increases
high-quality evidence that oxytocin with TXA is more effective in polycythemia and hyperbilirubinemia, but without increased
in reducing PPH and improves outcomes compared with oxyto- need for exchange transfusion [35, 36]. There are no clear differ-
cin alone. If just one agent is to be used for routine prophylaxis ences in other outcomes, including respiratory distress, death,
during the third stage of labor, oxytocin is recommended. Based initial adaptation phase, or long-term outcomes. There is no cur-
on safety and side effect profiles, TXA with oxytocin is the rec- rent recommendation on positioning of the preterm infant
ommended regimen to be considered to be used routinely during during DCC secondary to insufficient data. One RCT showed
the third stage of labor whenever possible. no differences in neonatal outcomes during DCC by 120 seconds
after vaginal delivery with the neonate held either at the level of
Umbilical cord the vagina or the level of the abdomen or chest, concluding that
Cord gases mothers can safely be allowed to hold their baby on their abdo-
Cord gases are stable in a clamped segment of cord for up to men or chest for skin-to-skin and breastfeeding [37].
60 minutes and in a heparinized syringe for up to 60 minutes. In term neonates, DCC has also been shown to have some
Umbilical artery pH, pCO2, and base deficit may be helpful in benefits, but also some risks. Compared with early clamping,
indicating timing of insult and can be collected in cases of non- DCC is associated with higher birth weight, higher hematocrit,
reassuring fetal heart rate tracings (NRFHTs), meconium, low and a lower risk of iron deficiency at less than a year of age [38].
Apgar scores (defined as below 7 at 5 minutes), growth restric- However, there was an increased risk of the neonate needing pho-
tion, preterm birth, or any sentinel event, including cord pro- totherapy for hyperbilirubinemia. The possible increased risk of
lapse, uterine rupture, or placental abruption. Umbilical vein pH neonatal jaundice requiring phototherapy must be weighed
may be helpful in cases of uteroplacental problems like growth against the physiologic benefit of greater hemoglobin and iron
restriction, placental abruption, asthma, and hypertension. A levels conferred by DCC in term infants, which may be of clini-
recent large prospective trial found that umbilical cord arterial cal value particularly in infants where access to good nutrition
lactate may be more useful than arterial pH in predicting neo- is poor [38]. For women, there are likely no differences in PPH
natal morbidity at term [28]. While there are no RCTs on the or change in hemoglobin levels, but the data are limited [38, 39].
routine sending of umbilical cord gases, this practice is usually Therefore, DCC is recommended instead of ECC (Figure 10.1).
not necessary or recommended for normal labor, delivery, and
Apgar scores, without risk factors. A recent systematic review Cord milking
found that delayed cord clamping (<120 seconds) has little to Milking of the cord refers to the action of an obstetric provider
no clinically significant effect on blood acid–base status among during which the cord blood is manually pushed toward the infant
healthy, term singletons [29], but this has not been thoroughly following delivery and prior to cutting and clamping the cord.
assessed in preterm infants. Numerous studies have assessed the safety and outcomes associ-
ated with cord milking, which have found varying evidence but
Cord blood collection together demonstrated potential benefit [32]. However, a recent
Cord blood is routinely sent for Rh status of the infant, especially large RCT was terminated prematurely for safety concerns; there
in Rh-negative women. Cord blood collection for stem cells has was an increase in severe IVH among very preterm infants (23–
increased in popularity in recent years. Obstetricians should 27 weeks of gestation), likely related to the sudden hemodynamic
support public banking of cord blood [30]. Public banking is changes in a fragile circulatory system [40]. Therefore, there is
recommended over private banks secondary to more strin- evidence of harm with inconsistent evidence of benefit, and
gent Food and Drug Administration (FDA) guidelines, given its this practice is no longer recommended.
increased legal responsibilities, cost-effectiveness, and greater
access to cord blood by the general population. The chance of a Placenta
child requiring an autologous transplant from privately banked Controlled cord traction
cord blood is about 1/2700. Directed donation of cord blood when Controlled cord traction (CCT) refers to the act of pulling the
there is a disease in the family amenable to stem cell transplanta- umbilical cord while applying counter-pressure with the goal of
tion can be arranged through many public banks. delivering the placenta [41]. Cord traction alone has been asso-
For adequate cord blood collection, at least 40 mL must be col- ciated with lower mean blood loss and decreased risk of PPH,
lected. A recent cohort study found that delayed umbilical cord shorter third stage of labor, and lower risk of needing manual
clamping up to 60 seconds did not have a negative impact on placental removal compared to no cord traction after delayed
adequate collection of total nucleated cell count [31]. It is recom- cord clamping (1–3 minutes) and vaginal delivery [41]. However,
mended to counsel women that cord blood collection should not this is a skill that requires training, as there can be complications
compromise maternal and neonatal care and therefore may not such as uterine inversion if applied incorrectly. If a skilled birth
be possible in cases where maternal or neonatal health status is attendant is present, it is recommended to use CCT for these ben-
a concern. efits (Figure 10.1).
After cesarean delivery, cord traction is preferred over manual management, active management may reduce severe blood loss
removal of the placenta, as cord traction is associated with less and anemia [49]. However, numerous adverse effects were iden-
endometritis, less blood loss, less drop in postoperative hemato- tified, including increases in vomiting after birth, increased
crit, and shorter hospital stay [42]. CCT has not been assessed spe- maternal diastolic blood pressure, increased use of analgesia and
cifically in the setting of DCC after cesarean delivery. Therefore, pain, more women returning to the hospital with bleeding, and
in settings where DCC is the standard of care, the decision to use decrease in infant birth weight, possibly reflecting some degree
CCT can be shared between the patient and provider. of lower blood volume from placental transfusion if ECC is per-
formed. There is probably no difference in risk of infant admission
Cord drainage to the neonatal unit or incidence of jaundice requiring treatment.
In the third stage of labor, umbilical cord drainage refers to the While AMTSL is composed of multiple interventions, each ele-
unclamping of the previously clamped cord with drainage of the ment of AMTSL should be assessed separately, as we have done
blood into an appropriate container [43]. Immediate cord drain- in the preceding sections (“Umbilical Cord” and “Placenta”).
age and traction together are associated with a slightly shorter
duration of the third stage of labor and a slightly smaller Obstetric lacerations
decrease in hemoglobin compared to no drainage or traction after Closure and repair
vaginal delivery and ECC [43, 44]. Cord drainage without traction Classifications of laceration types are displayed in Table 10.2.
but with administration of 5 IU oxytocin is associated with lower Compared with nonclosure, closure of first- and second-degree
mean blood loss, shorter duration of the third stage, higher post- perineal lacerations after vaginal delivery has not been shown
delivery hemoglobin, and less need for a blood transfusion [45]. In to be associated with improved wound healing or pain. There is
settings where DCC is the standard of care, the decision to use cord insufficient evidence to recommend surgical closure compared to
drainage can be shared between the patient and provider. nonclosure for first- and second-degree lacerations [50]. The con-
tinuous suturing techniques, compared with the interrupted, are
Massage of the uterus associated with less short-term pain in second-degree and episi-
There is limited evidence to evaluate the effect of massage of the
otomy repairs [51]. Furthermore, approximation (end-to-end) and
uterus alone. Three studies have been conducted comparing uter-
overlap technique for third- and fourth-degree laceration repair
ine massage to no uterine massage in addition to oxytocin and
are associated with similar outcomes in two RCTs [52, 53], while
CCT; uterine massage is not associated with a reduction in PPH,
in the most recent RCT, end-to-end repair was associated with
use of additional uterotonics, or retained placenta [46]. Therefore,
significantly lower rates of anal incontinence, with no difference
uterine massage after delivery of the placenta cannot be rec-
in long-term outcomes [54]. One small, randomized trial showed
ommended as studied so far [46, 47].
that use of antibiotics at the time of third- and fourth-degree
Placentophagy repairs decreased perineal wound complications (wound disrup-
Placentophagy or placentophagia is the consumption of the pla- tion and purulent discharge) [55]. See also Chap. 31.
centa postpartum. There is no evidence for maternal benefit, but
there is evidence for risk of harm, such as increased risk of infec- Suture
tion [48]. Therefore, providers should counsel patients against Absorbable synthetic materials should be used for all layers of the
placentophagy based on currently available data. repair. Compared with catgut (plain or chromic), absorbable syn-
thetic sutures (e.g. Vicryl) used for perineal repair decreased wom-
Active management of the third stage of labor en’s experience of short-term (3-day) pain, less need for analgesia,
Active management of the third stage of labor (AMTSL) usually reduced rate of suture dehiscence up to day 10, and less need for
consists of: repeat suturing at <3 months. There is no significant difference in
long-term pain or dyspareunia experienced by women [56]. More
• Prophylactic oxytocin at delivery of the anterior shoulder women with catgut sutures required repeat suturing compared
or immediately after delivery of the baby with synthetic sutures, while more women in the standard synthetic
• ECC and cutting suture group required suture removal compared with the rapidly
• CCT absorbed group. Clinical experience has shown suture removal is
necessary <5% of the time when using 3-0 or finer sutures and
Expectant management usually consists of: performing subcuticular skin closures [56]. Polyglactin (Vicryl)
and polydioxanone (PDS) have similar outcomes [57].
• No uterotonics
• No ECC, cutting, or traction
• Use of gravity and maternal expulsive efforts for placenta TABLE 10.2: Perineal Laceration Classification
delivery Definition
First degree Injury limited to the skin of the perineum
There is heterogeneity in the literature regarding the definition
Second degree Injury to the perineum; perineal muscles involved
of AMTSL. Presented earlier is the one utilized for evaluation of
the existing RCTs of AMTSL by the Cochrane collaboration [49]. Third degree 3(a) <50% tear of external anal sphincter
Some definitions also consider uterine massage to be a compo- 3(b) >50% tear of external anal sphincter
nent of AMTSL. AMTSL has been used mostly among women 3(c) Tear in both external and internal sphincter
after term, vaginal births, so recommendations are limited to this Fourth degree Injury to perineum, internal and external sphincter,
population. Historically, AMTSL was thought to reduce the risk and anal epithelium
of PPH and was therefore recommended to all women, includ- Source: Modified from ACOG Practice Bulletin No. 198: Prevention and manage-
ing women following preterm birth. Compared with expectant ment of obstetric lacerations at vaginal delivery.
Anal ultrasound anesthesia may be used if complications arise in the manage-

Endoanal ultrasonography with clinical examination of the ment of retained placenta, intractable PPH, uterine inversion, or
perineum immediately after delivery in nulliparous women with assisted vaginal deliveries (see Chap. 12).
second-degree lacerations detected more sphincter tears than
clinical examination alone. Endoanal ultrasonography with Breastfeeding
immediate repair of these tears is associated with less severe Hypertension and headache are associated with misoprostol and
fecal incontinence at 1 year compared with clinical examina- ergotamine use. There are no other known complications with
tion only [58, 59]. breastfeeding after use of other uterotonics. There are limited
data regarding breastfeeding outcomes with TXA, but one small
Perineal pain control study found no increase in adverse long-term outcomes [67].
Oral medications
Delivery note
One dose of oral nonsteroidal antiinflammatory agents
If a complicated delivery occurs with possible fetal compromise,
(NSAIDS) (any dose) is effective in achieving adequate pain relief
a detailed note should address the pertinent and immediate neo-
and reducing the need for additional analgesics compared to pla-
natal status, including Apgar scores, umbilical cord pH, and base
cebo in the postpartum period without serious adverse effects
deficit (if obtained), and assessment of fetal heart testing prior to
[60]. Rectally administered NSAIDs appear to provide effective
delivery.
pain relief in postpartum women. Rectal indomethacin or diclof-
enac are associated with less pain up to 24 hours after birth and
less requirement for additional analgesia in the first 24 hours
and 48 hours postpartum [61]. Limited information is available
Part 2: Care of the pregnant woman
on pain experienced >72 hours after birth or other outcomes of who declines blood products
importance, such as the impact on daily activities, resumption
of sexual intercourse, and impact on the mother–baby relation-
ship. More studies are needed to assess the acceptability of the Key points
rectal route of administration and its direct comparison to oral
• A common reason for declining blood products during
NSAIDs. A single dose of aspirin (300–1200 mg) may reduce pain
pregnancy and childbirth is the identification as a member
after an episiotomy, but the evidence is low quality, and studies
of the Jehovah’s Witness faith.
did not assess for adverse effects [62].
• Members of the Jehovah’s Witness faith may decline blood
transfusions due to their belief that accepting them vio-
Topical anesthetics
lates God’s law and would lead to excommunication and
Compared with placebo, topical anesthetics applied to the
eternal damnation.
perineum are associated with similar pain relief up to 24 hours to
• Refusal of blood can lead to an increased risk of maternal
72 hours postpartum, but women are more satisfied after admin-
death.
istration of an anesthetic [63]. Epifoam (1% hydrocortisone
• All obstetric providers are responsible for asking each
acetate and 1% pramoxine hydrochloride in the mucoadhesive
woman at the preconception visit or first prenatal visit if
foam base) use is associated with less additional analgesia, while
she has any objection to receiving any blood product.
lignocaine/lidocaine showed no difference with regard to addi-
• The woman’s wishes should be respected, following the
tional analgesia use compared with placebo [63]. A lidocaine/
principle of autonomy, and documented well so that every
prilocaine cream appears to be as effective as local mepivacaine
provider understands each patient’s specific beliefs and
injection for pain relief during repair, with improved patient sat-
goals.
isfaction [64]. Compared with indomethacin vaginal supposito-
• After counseling, it is recommended that the patient sign
ries, topical anesthetics have similar mean pain scores.
the consent for refusal of blood products, as well as the
health care power of attorney.
Therapeutic ultrasound for perineal pain
• It is recommended that the third stage of labor be managed
There is insufficient evidence to evaluate the use of ultrasound
in accordance with the general recommendations stated
in treating perineal pain and/or dyspareunia following vaginal
earlier in this chapter, as there are no studies specifically
delivery. Women treated with active ultrasound for acute peri-
assessing these interventions among patients who decline
neal pain are more likely to report improvement in pain and less
blood products.
pain at 10 days and 3 months, but more likely to have bruising at
10 days compared with placebo [65]. Additionally, women with
persistent perineal pain or dyspareunia treated with ultrasound Historic context of objection to blood
are less likely to report pain with sexual intercourse. products by Jehovah’s Witnesses
Local cooling “That is why I have said to the sons of Israel: ‘No soul of you
Local cooling techniques, including ice packs, cold gel packs, or must eat blood and no alien resident who is residing as an alien
ice/cool water baths, may be associated with reduced perineal in your midst should eat blood’” (Holy Bible: Leviticus 17:12).
pain following childbirth [66]. However, the data regarding safety Charles Russell started the Jehovah’s Witness Christian sect
and effectiveness are limited. in Pennsylvania in 1872. Nearly all members of the Jehovah’s
Witness faith decline blood transfusions due to their belief that
Anesthesia in labor/Postpartum accepting blood products violates God’s law, which would lead
An epidural is commonly used during labor for pain control. to excommunication and eternal damnation, as is taken literally
Spinal, epidural, paracervical block, nitrous oxide, or general from the statement reported in the Bible.
Complications I hereby consent to the blood products marked below:

• ___Whole Blood
One study reported the risk of obstetric hemorrhage as approxi- • ___Fresh Frozen Plasma
mately 6% in women who are members of the Jehovah’s Witness • ___Cryoprecipitate
• ___Albumin
faith [68]. The risk of maternal death was estimated to be about • ___Erythropoietin
0.5%, a forty-fourfold increase compared with non–Jehovah’s • ___Immune globulins (blood fraction, Rh immunoglobulin)
Witness controls [68]. • ___Clotting factors
• ___PolyHeme (human hemoglobin), Hemopure products (bovine
• ___hemoglobin).
Management • ___Recombinant Factors
• ___Platelet cell fractions (Platelet Gel)
There are no trials to assess the efficacy of interventions spe- • ___Other surgical procedures, medical tests, or current therapy
cifically in women who are Jehovah’s Witnesses. Therefore, • ___Using my own blood, i.e. tagged red cells, white cells, blood patching
obstetrics providers should refer to the guidelines for third stage • ___Hemodialysis equipment (nonblood primed)
• ___Intraoperative blood salvage ("cell saver")
and abnormal third stage for general recommendations.
• ___Intraoperative hemodilution
• ___None of the above
Preconception counseling Patient's name _________________________________________________
Counsel regarding complications and management in pregnancy. Patient's Signature ______________________________________________
Date __________________________________________________________
Prenatal care
All obstetric providers are responsible for asking each woman FIGURE 10.2 Blood product consent for Jehovah’s Witness
at the preconception visit or first prenatal care visit if she has patients.
any objection to receiving any blood product in case of neces-
sity. Providers should not assume that all patients who identify • A consult with the maternal-fetal medicine service can be
as a Jehovah’s Witness fully endorse refusal of blood products; considered and, if available, with a bloodless surgery and
therefore, each patient’s individual beliefs and goals should be medicine program.
ascertained [69]. The woman who states she would decline blood • An ethics consult is not indicated but can be considered in
transfusion even if medically necessary should be managed as specific cases.
follows:
Antepartum testing
• Counsel the woman and any family member present
regarding the reasons and the risks of blood product No specific antepartum testing is indicated.
refusal, including the possibility of maternal and fetal
death. The counseling should be documented in the
medical record. The patient might want to consult with
Delivery
members of her family and/or community before signing • Consents: Upon admission and prior to the surgery or
informed refusal. Her wishes should be respected, follow- delivery, it is recommended that obstetric providers con-
ing the principle of autonomy. A physician has the right firm all patients who refuse blood products have signed a
of refusing to provide care for a patient who refuses blood consent form, as shown in Figure 10.2, and the previously
products only if an alternative caregiver agrees to accept mentioned health care power of attorney. If consents have
and care for the patient [70]. not been previously signed or are not available, the patient
• Documentation of each conversation in the medical record should be counseled again and consents signed.
will help each provider on the care team understand each • As there are no specific studies among women who refuse
individual patient’s specific beliefs and goals [69]. blood products, providers should refer to the guidance for
• After counseling, it is recommended that the patient sign managing the third stage of labor presented earlier in this
the consent for blood products (Figure 10.2), as well as chapter.
the health care power of attorney [70]. These two con- • If an operative delivery or bleeding disorder is anticipated,
sents should be kept in the medical record and be avail- if the patient has a history of a low-lying placenta or a pla-
able at labor and delivery. Approximately 39% of Jehovah’s centa previa, or if an operative delivery is to occur, a cell
Witness pregnant women accept a variety of donated blood saver can be on standby throughout the patient’s labor and
products, and 55% accept either intraoperative normo- delivery. Use of the cell saver is safe in obstetrics [73].
volemic hemodilution or transfusion of their own blood
obtained by a cell saver [71].
• Consider including a copy of this guideline in the medical Anesthesia
record for reference. An anesthesiology consult should be obtained. The anesthesiolo-
• Selected high-risk patients, for example, those with hemo- gist will review the patient’s medical record and consents, includ-
globin <9 mg/dL, may be considered for appropriate ing consent or refusal for blood products.
replacement of iron, folic acid, and erythropoietin, which
can be coordinated by a maternal-fetal medicine and/or a
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11
INTRAPARTUM FETAL MONITORING
Nandini Raghuraman and Alison G. Cahill
Key points monitoring or EFM are more commonly used in the United
States. Adapted from the 2008 National Institute of Child
• Compared to intermittent auscultation (IA), the use Health and Human Development (NICHD) Workshop [2],
of continuous electronic fetal heart rate monitoring the definitions of EFM patterns and features are described in
(EFM) decreases the likelihood of neonatal seizures and Table 11.1 and depicted in Figures 11.1–11.3. The definitions
perinatal mortality and significantly increases the rate were developed for the specific purpose of intrapartum moni-
of operative interventions (vacuum, forceps, and cesarean toring. No distinction is made between short- and long-term
delivery [CD]). variability [2]. Accelerations, decelerations, bradycardia, and
• Category II EFM is indeterminate for the prediction of tachycardia can be quantified by describing the nadir and the
acidemia. However, certain high-risk category II features duration in minutes and seconds of the FHR change. A recur-
such as prolonged decelerations, recurrent late decel- rent deceleration occurs with >50% of uterine contractions in
erations, and recurrent variable decelerations, may be any 20-minute period.
associated with neonatal acidemia. A three-tier system for categorization of EFM patterns has
• Limited evidence (one randomized controlled trial [RCT]) been recommended [2]. According to this classification, cat-
demonstrates an increase in fetal oxygen saturation with egory I tracings are predictive of normal fetal acid–base status
maternal repositioning, intravenous fluid administra- at the time of observation and may be followed in a routine man-
tion, or maternal oxygen supplementation among patients ner. Category II tracings are indeterminate and not predictive
with reassuring EFM. However, none of these interven- of abnormal fetal acid–base status but require evaluation and
tions have been shown to reduce the risk of acidemia, and continued surveillance and reevaluation. Category III tracings
multiple RCTs have shown no benefit to fetal acid–base are abnormal and predictive of abnormal fetal acid–base status
status with maternal oxygen administration. Therefore, (Table 11.2, Figures 11.4–11.6). These tracings require prompt
maternal oxygen administration for fetal benefit in evaluation and should include efforts to expeditiously resolve the
labor cannot be recommended. abnormal pattern. It is noteworthy that a full description of an
• Continuous EFM should be used to monitor the labor of FHR tracing requires a qualitative and quantitative description of
women at risk for poor peripartum outcomes. the following: (1) uterine contractions, (2) baseline FHR, (3) base-
• Reinterpretation of EFM, especially knowing the neonatal line FHR variability, (4) presence of accelerations, (5) intermittent
outcome, should be avoided. or recurrent decelerations, and (6) changes or trends of FHR pat-
• There is insufficient evidence to recommend universal terns over time [2]. Of the categories and features defined by the
computerized EFM analysis. NICHD, the presence of recurrent late decelerations, recurrent
• For singletons at 36 weeks or more, fetal electrocardio- variable decelerations, more than one prolonged deceleration,
gram (ECG) ST segment analysis (STAN) used as an or tachycardia in the 30 minutes before delivery are associated
adjunct to conventional intrapartum electronic fetal heart with acidemia [3].
rate monitoring does not improve perinatal outcomes. In relation to uterine activity, tachysystole is defined as >5
• Fetal pulse oximetry (FPO) is not associated with sig- contractions in 10 minutes averaged over 30 minutes, whether
nificant maternal or neonatal benefits compared to con- the contractions are spontaneous or stimulated. The terms hyper-
tinuous EFM alone. stimulation and hypercontractility should be abandoned. Terms
such as “asphyxia,” “hypoxia,” and “fetal distress” should not be
Background used in the interpretation of EFM.
Electronic fetal heart rate monitoring (EFM) during labor is pH definitions

the most common obstetric procedure in the United States [1].
Between 1997 and 2003 in the United States, monitoring was Acidemia: Increased concentration of hydrogen ions in blood
utilized in 84% (23,273,458) of the over 27 million births [1]. For Acidosis: A pathologic condition marked by increased concen-
admission tests at the beginning of labor, see Chap. 8. For meco- tration of hydrogen ions in tissue
nium, see Chap. 25. Hypoxemia: Decreased oxygen content in blood
Hypoxia: A pathologic condition marked by decreased level of
EFM definitions oxygen in tissue
Asphyxia: Acidemia, hypoxia, and metabolic acidosis; must
Intrapartum fetal monitoring usually refers to monitoring have all of the following: (1) umbilical arterial pH <7.00; (2) Apgar
of the fetal heart rate (FHR). Outside the United States, this ≤3 at >5 minutes; and (3) neonatal neurologic sequelae (e.g. sei-
monitoring is often referred to as cardiotocography (CTG), zures, coma, and hypotonia) [4]. This term should be used with
while the terms intrapartum electronic fetal heart rate caution and never before birth (see also Chap. 32).
122 DOI: 10.1201/9781003102342-11

Intrapartum Fetal Monitoring 123
TABLE 11.1: Definitions of Fetal Heart Rate Patterns

Definitions
Baseline FHR The mean FHR rounded to increments of 5 bpm during a 10-minute period (excluding accelerations,
decelerations, and periods of marked variability)
The baseline must be for a minimum of 2 minutes.
May need to compare the previous 10-minute segment to determine the baseline
Bradycardia—baseline FHR <110 bpm
Tachycardia—baseline FHR >160 bpm
Sinusoidal pattern—visually apparent, smooth, sine wave–like undulating FHR baseline pattern with cycle
frequency 3–5/minutes, persisting ≥20 minutes
Baseline FHR variability Fluctuations in the baseline FHR that are irregular in amplitude and frequency (excluding accelerations and decelerations)
Variability is quantitated as the amplitude of peak-to-trough in bpm
Absent—amplitude range undetectable
Minimal—amplitude range ≤5 bpm
Moderate (normal)—amplitude range 6–25 bpm
Marked—amplitude range >25 bpm
Acceleration An abrupt (peak within 30 seconds) increase in the FHR from baseline
Acme is ≥15 bpm above baseline, lasting for 15 seconds or more and <2 minutes from the onset to return to baseline
Before 32 weeks, acceleration is acme ≥10 bpm over the baseline and lasting at least 10 seconds but <2 minutes
Prolonged acceleration if it lasts >2 minutes but <10 minutes
If the acceleration is >10 minutes, then it is a baseline change
Deceleration An abrupt or gradual decrease in FHR as characterized:
Recurrent—occur with ≥50% contractions in 20 minutes
Intermittent—occur with <50% contractions in 20 minutes
Prolonged—visually apparent decrease in FHR ≥15 bpm, lasting ≥2 minutes but <10 minutes
Early deceleration (Figure 11.1) In association with a uterine contraction, a visually apparent, usually symmetrical, and gradual (onset to nadir
≥30 seconds) decrease in FHR with return to baseline
Onset, nadir, and recovery of deceleration occur at same time as beginning, peak, and ending of contraction, respectively
Late deceleration (Figure 11.2) In association with a uterine contraction, a visually apparent, gradual (onset to nadir ≥30 seconds) decrease in FHR
Onset, nadir, and recovery of deceleration occur after the beginning, peak, and end of the contraction, respectively
Variable deceleration (Figure 11.3) An abrupt (onset to nadir <30 seconds) decrease in FHR
The decrease in FHR is at least 15 bpm, lasting ≥15 seconds but <2 minutes
Onset, depth, and duration vary with contractions
Abbreviations: bpm, beats per minute; FHR, fetal heart rate.
Fetal heart rate
FIGURE 11.1 Early decelerations of 15, 30, and 45 bpm, respectively. Abbreviation: bpm, beats per minute.
124 Fetal heart rate Obstetric Evidence Based Guidelines
FIGURE 11.2 Late decelerations of 15, 30, and 45 bpm, respectively. Abbreviation: bpm, beats per minute.
Fetal heart rate
FIGURE 11.3 Variable decelerations of 15, 40, 30, and 60 bpm, respectively. Abbreviation: bpm, beats per minute.
TABLE 11.2: Three-Tier FHR Interpretation System

Baseline Variability Acceleration Deceleration
Category I (Figure 11.4a–c) 110–160 bpm Moderate Possible, not necessary Possible early; no variable or late
Category II (includes those 1. Bradycardia without 1. Minimal After fetal stimulation 1. Recurrent variable with minimal
not in category I or III; absent variability 2. Absent without recurrent to moderate variability
Figure 11.5a–i) 2. Tachycardia decelerations 2. Prolonged
3. Marked 3. Recurrent late with moderate
variability
4. Variable with other
characteristics (i.e. slow return to
baseline, overshoots, or
shoulders)
Category III (Figure 11.6a–c) 1. Bradycardia Absent 1. Recurrent late
2. Sinusoidal 2. Recurrent variable
Abbreviations: FHR, fetal heart rate; bpm, beats per minute.
(a)
Fetal heart rate
(b)
Fetal heart rate
(c)
Fetal heart rate
FIGURE 11.4 Category I. (a) Normal baseline, moderate variability, absence of late and variable decelerations, accelerations present.
(b) Normal baseline, moderate variability, absence of late and variable decelerations, early decelerations present. (c) Normal baseline,
moderate variability, absence of late and variable decelerations.
Incidence Risk factors and predictors of abnormal FHR

The prevalence of cesarean delivery (CD) for nonreassuring FHR The risk of CD for NRFHT is >20% in patients with moderate/
tracing (NRFHT) is approximately 3% or more, and it is increas- severe asthma, severe hypothyroidism, severe preeclampsia,
ing [5]. NRFHT is the second most common reason for CD, after postterm pregnancy, or fetal growth restriction (FGR) with
arrest of labor, accounting for 23% of all primary CDs [6, 7]. abnormal Doppler studies [5].
(a)
Fetal heart rate
(b)
Fetal heart rate
(c)
Fetal heart rate
FIGURE 11.5 Category II. (a) Bradycardia with moderate variability. (b) Tachycardia. (c) Minimal variability.
(d)
Fetal heart rate
(e)
Fetal heart rate
(f )
Fetal heart rate
FIGURE 11.5 (Continued) Category II. (d) Absent variability. (e) Marked variability. (f) Recurrent variable decelerations, minimal
variability.
(g)
Fetal heart rate
(h)
Fetal heart rate
(i)
Fetal heart rate
FIGURE 11.5 (Continued) Category II. (g) Prolonged deceleration. (h) Recurrent late decelerations, moderate variability.
(i) Variable decelerations.
(a)
Fetal heart rate
(b)
Fetal heart rate
(c)
Fetal heart rate
FIGURE 11.6 Category III. (a) Recurrent late decelerations, absent fetal heart rate variability. (b) Recurrent variable decelerations,
absent fetal heart rate variability. (c) Bradycardia, absent fetal heart rate variability.
Although there is no formal definition of NRFHT, the diag- and clinicians place on the route of delivery and neonatal out-
nosis is associated with an increased risk of acidemia. The abil- comes. Compared with pregnant patients and mothers, obste-
ity to predict CD for NRFHT remains limited [8]. The available tricians overestimate the burden posed by CD, and contrary to
evidence suggests that fetal movement count, abnormal EFM on obstetricians, women value a newborn with permanent neuro-
admission, vibroacoustic stimulation, amniotic fluid index, con- logic handicap over neonatal death [18].
traction stress test, and modified biophysical profile are limited Clinicians choosing to utilize IA should be aware of some of
diagnostic tests to identify patients at risk of emergent CD for the problems associated with its use. Continuous EFM has a sig-
NRFHT [5]. nificantly better ability to detect acidemia (umbilical arterial
pH <7.15 in this study) than IA: A sensitivity of 97% versus 34%
Fetal heart rate monitoring and a higher positive predictive value of 37% versus 22%, respec-
tively [19]. Continuous EFM was superior to IA for the detection
Continuous electronic FHR monitoring of respiratory, metabolic, and mixed acidosis. It is possible that
vs. intermittent auscultation ominous EFM patterns are poorly assessed by IA. Logistically, it
Despite the ubiquitous use, there is mixed evidence for the util- may not be feasible to adhere to guidelines of how frequently
ity of EFM. As noted by the American College of Obstetricians the heart rate should be auscultated with IA. One prospective
and Gynecologists (ACOG) practice bulletin [9], the efficacy of study noted that the protocol for IA was successfully completed
monitoring is adjudicated by comparing the neonatal and infant among only 3% of the cases [20].
morbidity, including seizure and cerebral palsy, or mortality Not all pregnancies should be monitored with IA because
averted versus the unnecessary interventions (operative vaginal those at risk for adverse outcomes like cerebral palsy, neona-
delivery or CD) undertaken. Since all the randomized clinical tri- tal encephalopathy, and perinatal death should be monitored
als (RCTs) with EFM compare it to intermittent auscultation (IA), with EFM during labor [21]. Thus, high-risk pregnancies that
the efficacy is determined by calculating the relative risks (RRs) of undergo antepartum surveillance should not be evaluated with
interventions, neonatal seizures, cerebral palsy, or death. IA, nor should those who are likely to have CD for NRFHT [5].
Compared with IA, continuous EFM shows no significant These include but are not limited to FGR, oligohydramnios, poly-
improvement in overall perinatal death rate (RR 0.86, 95% hydramnios, placenta previa, postterm pregnancy (≥42 weeks),
confidence interval [CI] 0.59–1.23), but was associated with a multiple gestation, isoimmunized pregnancy, prior intrauterine
halving of neonatal seizures (RR 0.50, 95% CI 0.31–0.80). There fetal demise (IUFD), maternal renal disease, diabetes, preeclamp-
was no significant difference in cerebral palsy rates (RR 1.75, sia, collagen disorders, hemoglobinopathies, and cardiovascular
95% CI 0.84–3.63). The positive predictive value of NRFHT for disease. Additionally, parturients should be monitored with con-
cerebral palsy is approximately 0.1% [10]. The false-positive rate tinuous EFM if they are being induced, are augmented, or have
of NRFHT is extremely high (99%) for abnormal neonatal out- dysfunctional labor. Patients with suspected FHR abnormalities
comes, especially cerebral palsy [11]. with auscultation, abnormal fetal presentation, regional anesthe-
There was a significant increase in CD associated with the use sia, abruption, infection, preterm labor, prior CD (vaginal birth
of continuous CTG (RR 1.63, 95% CI 1.29–2.07). Women were after cesarean [VBAC] attempt), hypertonic uterus, and meco-
also more likely to have an operative vaginal birth (RR 1.15, nium staining of the amniotic fluid should also be monitored
95% CI 1.01–1.33). Data for subgroups of low-risk, high-risk, and with continuous EFM [22]. In these cases, EFM should be contin-
preterm pregnancies, as well as from high-quality trials, were ued until delivery.
consistent with overall results [9, 12]. EFM is associated with one
additional CD for every 58 women monitored continuously; 661 Reviewing electronic FHR monitoring
women need to have continuous EFM during labor to prevent one When EFM is utilized during labor, the nurses or physicians
neonatal seizure [12]. should review it frequently. If the patient is low risk, the FHR
While the efficacy of EFM is debated, it is noteworthy that tracing should be reviewed at least every 30 minutes in the first
there are concerns regarding the 13 RCTs, which enrolled over stage of labor and at least every 15 minutes during the second
37,000 women, on continuous FHR monitoring versus IA [12]. stage. The corresponding frequency for high-risk parturients is 15
Only two of these trials were rated to be of high quality [10, 13], and 5 minutes, respectively. The maternal pulse should be taken
and only three trials reported data in low-risk women [10, 13, 14]. to make sure the FHR is indeed fetal and not maternal. Health
The authors of the meta-analysis on this subject [12] noted that care providers should document that they have reviewed the
to test the hypothesis that continuous monitoring can prevent tracing by a narrative note, use of comprehensive flow sheets, or
1 death in 1000 births, more than 50,000 women would have to by placing one’s initials on the monitor strip [22]. NICHD termi-
be randomized. Inadequate study size may not reflect the out- nology should be utilized in any assessment of intrapartum EFM
comes in contemporary obstetrical practice [15]. However, addi- [2]. Among low-risk patients, it is more feasible to confirm that the
tional observational data have demonstrated that the rising rate strips are reviewed according to the guidelines, whereas among
of continuous EFM use is associated with a decrease in neonatal high-risk patients, compliance during the active phase, and espe-
mortality and reduction in Apgar score <4 at 5 minutes [1, 16]. cially during the second stage of labor, is more demanding and
If IA is available on the labor and delivery unit, shared deci- difficult. The FHR tracing, as a part of the medical chart, should
sion-making should be used to discuss the risks and benefits of be labeled and available for review if the need arises. Alternatives
IA versus continuous EFM in low-risk patients [17]. Admittedly, like computer or server storage of the FHR tracing that do not
both patients and clinicians prefer continuous EFM to evaluate permit overwriting or revisions are reasonable [22].
the fetus during labor [18]. The explanations for the preference Due to the interobserver and intraobserver variability, FHR
include the ease of use, the reassurance women derive from hear- tracing should be interpreted cautiously and preferably without
ing the heartbeat during labor, and the different value patients knowing the neonatal outcome [23–25]. When four obstetri-
cians, for example, examined 50 CTGs, they agreed in only 22%
of the cases. Two months later, during the second review of the (RR 0.40; 95% CI 0.08–2.02), or an Apgar less than 7 at 5 minutes
same 50 tracings, the clinicians interpreted 21% of the tracings (RR 0.50; 95% CI 0.13–1.95).
differently than they did during the first evaluation [24]. Factors Another RCT compared computer analysis of CTG using
that influence the interpretation of CTGs include the clinician’s the Omniview-SisPorto 3.5 to standard clinician analysis of
experience, whether the tracing is normal versus equivocal or pre-recorded cases. Prediction of abnormal umbilical artery
ominous with greater agreement if the tracing is reassuring, and pH was more reproducible and accurate when clinicians had
the time of the day, with possibly greater error at night. With access to the computerized analysis of CTGs [28]. The most
retrospective reviews, the foreknowledge of neonatal outcome recent multicenter RCT investigating computerized inter-
alters the impressions of the tracing. Given the same intrapar- pretation of FHR through the INFANT decision support
tum tracing but opposite neonatal outcomes, the reviewer is software found no difference in neonatal outcomes or devel-
more likely to find evidence of fetal hypoxia and criticize the opmental assessment at 2 years of age with the use of this
obstetrician’s management if the outcome was supposedly poor software [29].
versus good [25]. Therefore, there is insufficient evidence to support routine
The positive predictive value of NRFHT for cerebral palsy is use of computerized evaluation of EFM.
approximately 0.1% [8]. The false-positive rate for prediction of
abnormal neonatal outcomes is high (99%) [11]. Other fetal monitoring tests
External vs. internal FHR monitoring Digital scalp or vibroacoustic stimulation
External FHR monitoring is accomplished via a Doppler ultra- Persistent minimal variability may be associated with fetal acide-
sound device applied to the maternal abdomen. An internal mia. In the setting of minimal variability, digital scalp or vibro-
scalp electrode (“scalp lead”) for FHR monitoring measures the acoustic stimulation can be performed to elicit an acceleration
R-R interval between consecutive beats. This provides an accu- (see the definition in Table 11.1). If there is an acceleration in
rate representation of FHR variability. There are no RCTs com- response to scalp stimulation, labor should continue, as this indi-
paring these two monitoring techniques. Internal monitoring cates that the likelihood of fetal scalp pH <7.19 is 2% [30]. In the
is used, in general, for an FHR that is discontinuous or unre- absence of an acceleration, the likelihood is 38%.
liable transabdominally due to factors such as maternal body Allis clamp and scalp puncture have been used to elicit an
habitus or multiple gestations. Placement of a fetal scalp elec- acceleration but are less safe. Digital scalp stimulation (gentle
trode for internal monitoring requires rupture of membranes stroking of the fetal scalp for 15 seconds) is the test with the best
(ROM) and sufficient cervical dilation to access the fetal scalp. predictive accuracy among these four techniques [30]. There are
Contraindications to internal monitoring include maternal currently no RCTs that address the safety and efficacy of digi-
infections such as HIV, active hepatitis B or C, and fetal throm- tal scalp or vibroacoustic stimulation used to assess fetal well-
bocytopenia. The use of a fetal scalp electrode may be associated being in labor in the presence of NRFHT.
with a decrease in the risk of CD with no associated increase in
infectious morbidity [26]. The risks of internal fetal monitoring Fetal scalp blood sampling
are rare but include scalp injury, infection, and cephalohema- FSBS to measure scalp pH and lactate was introduced in 1962 in
toma [27]. Berlin, Germany, as a standalone fetal status test, before the com-
Given the potential safety risks, routine or universal use of mercialization of EFM machines in 1968 [31].
internal fetal monitoring should be avoided. If CD is performed, It is important to understand fetal intrapartum physiology in
internal scalp monitoring can be continued until delivery, while order to interpret FSBS. The fetus reacts to intrapartum hypoxia
external monitoring can be discontinued when the abdominal by using anaerobic glycolysis, which leads to metabolic acidosis
preparation begins. through conversion of pyruvate to lactate. Low pH can be a com-
bined measure of both metabolic acidosis and the more labile
Computerized EFM analysis component, respiratory acidosis [32].
Due to limited interobserver agreement, computerized evalu- Historically, a pH value >7.25 on FSBS is considered normal,
ation of intrapartum FHT, also called expert systems (ES), has with a low likelihood of fetal hypoxia. Values between 7.25 and
been evaluated as a tool to improve the sensitivity of FHT for 7.20 are considered subnormal, indicating the need for repeat
perinatal morbidity and mortality and decrease false positives sampling within 20–30 minutes. FSBS pH <7.20 (or <7.15 in the
associated with FHT. second stage of labor) requires intervention, such as intrauter-
Two RCTs evaluating the use of CTG with ES in labor have ine resuscitation or operative delivery. As for lactate concentra-
been published, but only one trial (n = 220) provides data for tion, normal values have been described as being <4.2 mmoL/L.
quantitative analysis. There is no strong evidence that CTG Values between 4.2 and 4.8 are defined as intermediate, and
with an ES has an effect on the incidence of CD (RR 0.61; 95% values > 4.8 mmoL require intervention [33]. If the results are
CI 0.35–1.04) when compared with CTG with fetal scalp blood scalp pH <7.20 or lactate >4.8 mm/L, then delivery should be
sampling (FSBS). There is no strong evidence supporting a expedited [34].
reduction in the incidence of neonatal seizures (RR 0.33; 95% The technical aspects of FSBS require ruptured membranes
CI 0.01–8.09) or fetal acidemia (RR 0.50; 95% CI 0.09–2.67) in and a cervical dilatation greater than or equal to 3 cm. An amnio-
women monitored using a CTG with an ES versus a CTG with- scope is then placed vaginally to allow adequate visualization of
out an ES. Perinatal mortality was not reported. No fetal deaths the fetal head. A small blood sample is then taken from the fetal
occurred. There was no strong evidence supporting a reduction in scalp. Usually 30–50 microliters of blood are sufficient to perform
the incidence of forceps-assisted vaginal birth (RR 0.50; 95% CI the test. For testing lactate, a much smaller amount of blood is
0.05–5.43), hypoxic ischemic encephalopathy (RR 0.33; 95% CI required [32]. To be beneficial, the scalp pH machine needs to be
0.01–8.09), admission to the neonatal intensive care unit (NICU) reliable and readily available with prompt results.
Observational data from a Cochrane review on continuous RCTs on FPO are at high risk of bias because of the impracti-
CTG monitoring with or without FSBS demonstrate that use of cal nature of blinding participants and clinicians. In RCTs not
FSBS is associated with a decrease in neonatal acidosis (P = 0.04) requiring FSBS prior to study entry, the use of FPO plus CTG
but at the cost of more instrumental deliveries (P = 0.04) [35]. decreased the risk of cesarean section for NRFHT (RR 0.65, 95%
Retrospective studies have also failed to show a positive effect of CI 0.46–0.90) compared to CTG alone; however, there was no
FSBS on neonatal outcomes [36, 37]. evidence of differences in the overall cesarean section rate
The only level 1 evidence pertaining to FSBS are two RCTs between those monitored with and without FPO or for whom
comparing lactate to pH in FSBS [31]. The two RCTs [38, 39] the FPO results were masked (RR 0.99, 95% CI 0.86–1.13). There
enrolled a total of 3348 women in labor with NRFHT patterns was evidence of a higher risk of cesarean section in the group
and investigated maternal/fetal/neonatal/infant outcomes fol- with FPO plus CTG than in the group with fetal ECG plus CTG
lowing FSBS-obtained pH or lactate. The Cochrane review noted (one study only, n = 180, RR 1.56, 95% CI 1.06–2.29). No studies
that lactate sampling is more likely to be successful than pH reported details of long-term disability [49].
sampling, but there were no differences between the two tests in No differences are seen for endometritis, intrapartum or post-
terms of mode of birth or neonatal outcomes evaluated by umbili- partum hemorrhage, uterine rupture, low Apgar scores, umbili-
cal cord blood gases, Apgar score, encephalopathy, or admission cal arterial pH or base excess, admission to the NICU, or fetal/
to the NICU [33]. neonatal death [49, 50]. Given the evidence presented, routine
Given these data, as well as the several risks of FSBS [31], ACOG use of FPO in labor is not recommended.
has recommended against the use of FSBS [37, 40]. Others have
also cautioned against its use [31, 34]. However, this procedure is Management of abnormal EFM
still frequently performed in some countries.
The frequency with which EFM should be evaluated depends
Fetal electrocardiogram for fetal monitoring in labor on the risk status of the pregnancy (see earlier). To correctly
Use of the fetal electrocardiogram (ECG) has been evaluated as interpret intrapartum EFM, the clinician must be cognizant
an adjunct to continuous EFM in labor [40–47]. Traditionally, of the gestational age, labor progress, medications (Table 11.3)
fetal ECG has been obtained via internal monitoring with a fetal [55], prior fetal assessment, and obstetric and medical condi-
scalp lead. However, recent data suggest the feasibility of transab- tions. Since more than 80% of fetuses demonstrate category II
dominal ECG monitoring [48]. One study assessed PR intervals EFM in labor, a standardized approach to EFM management
but was insufficient to make recommendations [45]. Six RCTs in this group is important (Figure 11.7) [56]. The management
assessed the ST segment [38, 39, 41–44]. of category II EFM, specifically recurrent late or variable FHR
A meta-analysis of six RCTs including 26,529 laboring single- decelerations, is guided by the presence or absence of mod-
tons at 34 weeks or more reported that ST analysis (STAN) plus erate variability or accelerations and intrauterine resuscita-
CTG was associated with no difference in perinatal composite tion. Category III EFM should prompt rapid assessment with
outcome (1.5% vs. 1.6%; RR 0.90, 95% CI 0.74–1.10), neonatal
metabolic acidosis (0.5% vs. 0.7%; RR 0.74, 95% CI 0.54–1.02), TABLE 11.3: Effect of Medications and FHR Patterns
admission to the NICU (5.4% vs. 5.5%; RR 0.99, 95% CI 0.90–1.10),
perinatal death (0.1% vs. 0.1%; RR 1.71, 95% CI 0.67–4.33), neo- Medications Study Design Effect on FHR
natal encephalopathy (0.1% vs. 0.2%; RR 0.62, 95% CI 0.25–1.52), Butorphanol Case control
Transient sinusoidal FHR pattern
CD (13.8% vs. 14.0%; RR 0.96, 95% CI 0.85–1.08), or operative Cocaine Case control
No characteristic changes in FHR
delivery (either cesarean or operative vaginal delivery) (23.9% vs. pattern
25.1%; RR 0.93, 95% CI 0.86–1.01) compared to standard CTG Corticosteroid RCT Decrease in FHR variability with
only [4]. The Cochrane review confirms these findings, but also betamethasone but not
found an 8% decrease in operative vaginal deliveries associated dexamethasone
with STAN [40].
Magnesium sulfate RCT and A significant decrease in the FHR
As there is no difference in perinatal outcomes between
retrospective baseline and variability; inhibits the
STAN with CTG compared with CTG alone, this modality can-
increase in accelerations with
not yet be recommended for routine clinical care. Nonetheless,
advancing gestational age
given the concerns of heterogeneity in inclusion criteria among
Meperidine RCT No characteristic changes in FHR
RCTs, the learning curve for STAN, possible Hawthorne effect in
pattern
the RCTs, different (three vs. four) tier classifications used in the
Morphine Case control Decreased number of accelerations
RCTs, and limited power to address abnormal perinatal outcomes
such as metabolic acidosis, more research is needed before the Nalbuphine RCT Decreased the number of
STAN technology can be deemed of no value for fetal monitoring accelerations, long- and short-term
in labor [46]. variations
Terbutaline Retrospective Abolishment or decrease in
Fetal pulse oximetry frequency of late and variable
The use of fetal pulse oximetry (FPO) has been evaluated as decelerations
an adjunct to intrapartum continuous EFM [49–54]. In Zidovudine Case control No difference in the FHR baseline,
this noninvasive form of monitoring, a fetal oxygen sensor variability, number of accelerations
lies against the fetal cheek. FPO showing fetal oxygen satu- or decelerations
ration (FSpO2) <30% for at least 2 minutes is associated with Source: Adapted from Ref. [55].
an increased risk of declining fetal arterial pH and metabolic Abbreviations: FHR, fetal heart rate; bpm, beats per minute; RCT, randomized clini-
acidosis. cal trial.
FHR
category II or Ill
Intrauterine
resuscitation*
Scalp stimulation
or VAS
FHR
Acceleration category II or Ill
Recurrent late Recurrent variable

Continue labor decelerations decelerations
Amnioinfusion
Resolved Persistent, with Resolved Persistent, with

continue labor absent variability continue labor absent variability
Deliver Deliver
FIGURE 11.7 Algorithm for the management of Category II EFM in labor. (Adapted from ACOG Practice Bulletin 116.) *Uterine
relaxation, hydration, maternal repositioning, and/or amnioinfusion.
scalp stimulation, vibroacoustic stimulation, and intrauterine ACOG recommends amnioinfusion for management of
resuscitation with movement toward expedited delivery if not recurrent variable decelerations [56].
resolved.
In an RCT investigating intrauterine resuscitation maneuvers Uterine relaxation
in patients with reassuring EFM, intravenous fluid (IVF) bolus Tocolysis is a possible tool in the management of recurrent FHR
of 1000 mL, lateral positioning, and oxygen administration at decelerations, particularly in the presence of tachysystole The
10 L/minute via nonbreather face mask were the three tech- rationale behind this is that uterine relaxation improves utero-
niques that increased FSpO2 during labor [57]. However, inter- placental blood flow and therefore fetal oxygenation. Uterine
pretation of these results is limited by a lack of supportive data relaxation can be performed by stopping or reducing the dose
for FSpO2 as a marker of neonatal morbidity and the exclusion of of oxytocin infusions or by administering a tocolytic. The most
patients with NRFHT from this study. commonly studied tocolytics for intrapartum fetal resuscitation
are betamimetic drugs (e.g. terbutaline 0.25 mg IV).
Intrauterine resuscitation There are some important safety concerns regarding these
Amnioinfusion drugs. The most serious side effects of beta-agonists are pulmo-
Amnioinfusion is the process of infusing fluid into the amniotic nary edema and myocardial ischemia [59]. Six RCTs have been
cavity after ROM. The goal of amnioinfusion is to provide fluid performed to evaluate the use of betamimetics for acute intra-
and buoyancy in order to relieve possible umbilical cord com- partum fetal resuscitation [60–66]. When betamimetic admin-
pression, usually during labor after ROM. This technique consists istration was compared with no treatment, neonatal outcomes
of introducing normal saline or Ringer’s lactate transcervically seemed to improve [61, 62]. Four RCTs assessed the efficacy of
through a catheter into the uterine cavity. Intrapartum amnio- betamimetics by comparing these drugs with either magnesium
infusion is used in the setting of repetitive variable decelerations sulfate (4.0 g IV) [63], atosiban (6.75 mg in 4.9 mL saline adminis-
after ROM. Transcervical amnioinfusion can be done by bolus tered IV over a 1-minute period) [60, 64], or nitroglycerin (0.4 mg
or continuous infusion technique, with similar ability to relieve IV) [65]. Betamimetics provided a more effective tocolysis, with
recurrent variable decelerations. Either lactated Ringer’s solution similar successful resuscitation rates [60].
or normal saline can be used to place a crystalloid solution into ACOG recommends the administration of tocolytic medica-
the uterus without altering the neonatal electrolyte balance [58]. tions (e.g. terbutaline) when tachysystole is associated with FHR
In a Cochrane review on use of amnioinfusion for suspected abnormalities [56]. Repetitive use of terbutaline is not recom-
cord compression in labor, transcervical amnioinfusion was mended. There is insufficient evidence (no randomized trial) to
found to significantly reduce the following outcomes: CD (13 assess the effect of labor stimulant discontinuation on fetal status.
trials, 1493 participants, RR 0.62, 95% CI 0.46–0.83); FHR decel- Nonetheless, labor stimulants such as oxytocin should be discontin-
erations (7 trials, 1006 participants, RR 0.53, 95% CI 0.38–0.74); ued in cases of NRFHT, especially in the setting of tachysystole.
Apgar score less than 7 at 5 minutes (12 trials, 1804 partici-
pants; RR 0.47, 95% CI 0.30–0.72); meconium below the vocal Maternal position change
cords (3 trials, 767 participants; RR 0.45, 95% CI 0.25–0.81); and Maternal position change to improve fetal status in cases of intra-
maternal stay longer than 3 days (4 trials, 1051 participants, RR partum NRFHT has not been independently studied in an RCT.
0.45, 95% CI 0.25–0.78) [58]. This intervention has only been studied in combination with IVF
and oxygenation supplementation (see earlier) [57]. Indirect evi- In the absence of benefit and concern for potential harm, rou-
dence for position change comes from studies on maternal posi- tine use of prophylactic or therapeutic maternal oxygen admin-
tioning during normal labor. There are two reports comparing the istration for intrauterine resuscitation should be reconsidered.
effects of right lateral, left lateral, and supine maternal positions
on fetal oxygen status, each suggesting that lateral positioning is Other interventions
more favorable than a supine position [66, 67]. In 2013, a Cochrane Additional steps with the management of NRFHT might include
review was published on the impact of maternal positions during (no trials available) the following:
the first stage of labor on peripartum outcomes. Twenty-five tri-
als with a total of 5218 women were included. Upright and mobile • Cervical examination
positions were associated with a shorter duration of first stage Assessment of cervical status can be helpful to assess rapid
of labor, a reduction in the risk of cesarean birth, less use of epi- dilation or descent and to ensure that the umbilical cord
dural as a method of pain relief, and a lower chance of babies being has not prolapsed.
admitted to the neonatal unit [68]. However, this review does not • Maternal blood pressure assessment
answer directly the question of whether changing maternal posi- Maternal blood pressure monitoring may be helpful, espe-
tion should be considered as a therapeutic measure for NRFHT in cially among those who have received regional anesthesia.
labor. Given that maternal repositioning is a low-risk intervention, If hypotension is present in conjunction with NRFHT pat-
it should be considered as part of routine intrauterine resusci- tern, ephedrine or phenylephrine may be utilized [9].
tation of category II EFM. • Piracetam for NRFHT in labor
Piracetam, a derivative of gamma-aminobenzoic acid, is
Intravenous hydration thought to counteract the effects of hypoxia on the fetal
The rationale for intravenous (IV) fluid administration is that it brain by promoting metabolism. There is not enough
optimizes maternal intravascular volume, thereby improving pla- evidence to evaluate the use of piracetam for NRFHT in
cental perfusion. In one randomized trial comparing 500 mL to labor. In one randomized trial of piracetam versus placebo
1000 mL IVF bolus, the 1000 mL was associated with an increase for fetal distress in labor, the rates of cesarean section,
in FSpO2 [57]. IV fluids are typically administered at the time of low Apgar scores, and neonatal morbidity were similar
epidural placement, given the 10%–12% incidence of hypoten- between groups [81].
sion following neuraxial anesthesia. However, there is no evi- • Operative delivery for NRFHT in labor
dence that routine preload of IV fluids reduces the incidence of There are no contemporary trials of operative delivery ver-
hypotension [69]. Excessive administration of IV fluids may be sus conservative management of suspected NRFHT. In the
harmful in those at risk of pulmonary edema such as patients only outdated (1959) trial, there is no difference in perina-
with preeclampsia or cardiac disease. A 1500-mL IVF bolus may tal mortality [82].
help reduce the risk of FHR abnormalities in patients with nar-
row pulse pressures indicative of hypovolemia [70]. There is no
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12
ANALGESIA AND ANESTHESIA
Michele Mele, Valentina Bellussi, and Laura Felder
Key points • Use of a low-concentration local anesthetic epidural

infusion, prophylactic prehydration, and phenyleph-
• In every hospital providing labor and delivery services, rine or ephedrine can decrease the incidence of mater-
anesthesia personnel must be available on a 24-hour nal hypotension and associated nonreassuring fetal heart
basis, with the ability to perform a cesarean delivery (CD) rate (NRFHR).
within 30 minutes from decision. • Compared with the standard epidural approach, com-
• Intravenous pain relief is inferior to neuraxial analge- bined spinal epidural (CSE) has been shown to produce
sia, less effective, and associated with several maternal and a quicker (by about 6 minutes) onset of analgesia, result
fetal/neonatal side effects. in a lower total dose of local anesthetic over the course
• Neuraxial analgesia provides superior pain relief in of the labor, achieve a lower median visual analog pain
labor and should be available to all laboring women score earlier in labor, increase the incidence of maternal
upon request. satisfaction, and have a lower incidence of incomplete
• Airway complications can occur during induction and block, but is associated with an increased likelihood of
emergence of general anesthesia, as well as in the post- maternal pruritus.
operative period, and constitute the most common • For CD, neuraxial anesthesia is the anesthetic tech-
cause of anesthesia-related death. nique of choice. Spinal (intrathecal) anesthesia has
• Regarding parental opioids, remifentanil is an ultra-short- advantages over epidural anesthesia, including quicker
acting opioid, usually given as patient-controlled analgesia. onset of surgical anesthesia, simplicity, lower total
Patients receiving remifentanil were more satisfied with drug dose, and superior abdominal muscle relaxation.
their pain relief and had better pain relief at 1 hour; how- Compared with epidural anesthesia, the spinal technique is
ever, it is associated with maternal apneic episodes and associated with a similar failure rate, need for supplemen-
should only be administered at institutions with the capa- tal intraoperative analgesia, need for conversion to general
bility of increased maternal respiratory monitoring and anesthesia intraoperatively, maternal satisfaction, need for
appropriate nursing ratios. postoperative pain relief, and neonatal intervention.
• In the absence of a medical condition associated with • Hypotension following spinal analgesia for CD can be
coagulopathy, it is not necessary to obtain a platelet count decreased by crystalloid or colloid administration,
before neuraxial techniques. In general, women with platelet phenylephrine, or ephedrine.
counts of ≥70,000/μL can safely receive neuraxial analgesia. • General anesthesia for CD should be avoided if at all
• As there is no benefit to obstetric outcome from delaying possible, as it is associated with a threefold risk of mater-
neuraxial analgesia until an arbitrary cervical dilation has nal death compared with neuraxial analgesia. Risks include
been reached, the decision of when to initiate neuraxial inability to intubate or ventilate the patient at the induc-
analgesia should be made individually with each patient. tion of general anesthesia, as well as airway complications
• Patients should be counseled regarding the benefits and at emergence from anesthesia. There are no evident advan-
risks of neuraxial analgesia in labor. These include the tages to general anesthesia in the absence of a contraindi-
following: cation to a neuraxial approach.
• Neuraxial anesthesia is associated with superior • Transversus abdominus plane (TAP) block may be used
pain relief compared with any other intervention for at the time of CD in patients unable to receive long-acting
pain relief and with lower risk of umbilical cord pH intrathecal opioids to decrease postoperative pain.
<7.20 compared with systemic opioids. • Postpartum analgesia after vaginal delivery is typically
• Neuraxial analgesia is associated with an increased achieved with a combination of abdominal heating pads,
incidence of hypotension, pruritus, urinary reten- perineal ice packs, topical lidocaine, nonsteroidal anti-
tion, and maternal fever; increased need for oxy- inflammatory drugs (NSAIDS), and acetaminophen.
tocin administration; increased duration of the Opioids should be reserved for severe or breakthrough pain.
second stage (by about 15 minutes); and increased • Following CD, a stepwise multimodal approach should be
risk of operative vaginal birth. employed, with scheduled NSAIDS and acetaminophen
• Complications of neuraxial analgesia include as first-line analgesia, and oral or intravenous opioids
postdural puncture headache (PDPH), respiratory reserved for breakthrough pain. Combination pain medi-
depression from opioid use, and, rarely, epidural or cations, such as oxycodone-acetaminophen, should be
spinal hematoma or abscess. avoided, with acetaminophen administered standing and
• Discontinuation of neuraxial analgesia in the second stage opioids used only as needed. The lowest effective opioid
does not affect obstetric outcome. dose should be used for the shortest necessary duration.
DOI: 10.1201/9781003102342-12 137

• For severe, refractory, postoperative pain, Ketamine may oxygen reserve, and are much more likely to be difficult to intu-
be used as an analgesic adjunct to decrease opioid require- bate than a nonpregnant woman (see also Chap. 3). Centers for
ments. Lidocaine patches, gabapentin, and pregabalin may Disease Control and Prevention (CDC) Surveillance Data on
also improve postoperative pain control. Pregnancy Related Mortality reveal anesthetic-related maternal
mortality decreased nearly 60% when data from 1979 to 1990 were
Historic notes compared with data from 1991 to 2002. Although case-fatality
rates for general anesthesia are falling, rates for regional anesthe-
Three months after the first successful public demonstration of sia are rising. A subgroup comparison of data for CD showed that
the anesthetic properties of ether, on January 19, 1847, Dr. James case-fatality rates for general anesthesia decreased from 16.8 per
Simpson Young of the University of Edinburgh used diethyl ether million in 1991–1996 to 6.5 per million in 1997–2002, whereas for
to deliver anesthesia for childbirth to a woman with a deformed regional anesthesia, there was a slight increase in mortality rates
pelvis [1]. Before this time, pain during labor and childbirth was from 2.5 to 3.8 per million [6].
seen by both medical professionals and the lay community as Whenever possible, pregnant patients should be positioned
a necessary and indeed inseparable part of pregnancy. By 1860 with left uterine displacement when supine after 20 weeks of
anesthesia for parturition had become common practice thanks gestational age. Left uterine displacement prevents aortocaval
to a majority of women demanding it be a part of their medical compression, which can result in a marked decrease in venous
care. The practice of obstetric anesthesia has changed markedly return and a subsequent drop in cardiac output. The ability to
since. Women in labor now receive analgesia, rather than anes- compensate for aortocaval compression is compromised in the
thesia, with the goal of enabling maternal mobility during labor. presence of neuraxial analgesia or anesthesia.
Refined anesthetic techniques for women requiring cesarean When considering anesthesia or analgesia, one must take
delivery (CD) have substantially decreased the number of mater- into account that pregnant women are more sensitive to seda-
nal deaths directly related to anesthesia. tive hypnotics, local anesthetics, and the inhaled anesthetic
agents than nonpregnant women. In addition, the pregnant
Definitions patient should be considered two patients, and occasionally the
needs of one must be prioritized over the other. Informed consent
ain: An unpleasant sensory and emotional experience associ-
P should be obtained early in the course of labor in case of an emer-
ated with actual or potential tissue damage gency, and the patient’s wishes for an unmedicated birth always
Analgesia (from the Greek: “no pain”): Loss of the ability to feel respected. Successful initiation of breastfeeding is not affected by
pain without the loss of consciousness neuraxial analgesia.
Anesthesia (from the Greek: “no sensation”): An induced, tempo-
rary state of analgesia, paralysis, amnesia, and unconsciousness Nonpharmacologic analgesic techniques
General comments Increasingly, many pregnant women are seeking alternative
approaches to labor pain relief such as water immersion, acu-
More than 60% of women in the United States choose to receive puncture, and aromatherapy. While these techniques may not
epidural or spinal anesthesia during labor [2]. While not all labor- provide complete pain relief, they may diminish labor pain, help-
ing women desire the services of an anesthesiologist, maternal ing parturients delay or even avoid the use of pain relief medica-
request is a sufficient medical indication for pain relief in labor tions if that is their goal.
[3]. Hospitals providing labor and delivery services must have anes-
thesia personnel available on a 24-hour basis, with the ability to Acupuncture and acupressure
perform a CD within 30 minutes from decision [4]. Availability of Acupuncture and acupressure are therapeutic techniques based
licensed practitioners to administer anesthetics and support vital on the concept that energy flows throughout the body and strate-
functions in emergencies is recommended [3, 4]. gic placement of needles or pressure can restore its balance and
provide pain relief. Theories on its mechanism of action suggest
Physiology of labor pain it stimulates the release of endorphins in the muscles, brain, and
spinal cord.
Labor is associated with two sources of pain: visceral pain at A Cochrane review including 28 trials with data reporting on
T10–L1 from uterine contractions and cervical dilatation dur- 3960 women compared acupuncture with no intervention or
ing the first stage of labor and somatic pain transmitted by the placebo and found acupuncture for labor pain may be associ-
pudendal nerve at S2–S4 from descent and consequent pressure ated with less intense pain and reduced use of pharmacologic
of the fetal head on the pelvic floor, vagina, and perineum during analgesia. Compared with no intervention or placebo, acupres-
the second stage of labor [5]. This pain is amenable to safe inter- sure may be associated with less pain intensity [7]. Therefore,
vention, as the anesthesiologist can interrupt the transmission of acupuncture and acupressure may have a minor role in reducing
peripheral afferents from the cervix, lower uterine segment, and pain, increasing satisfaction with pain management, and reduced
perineum by use of neuraxial techniques that block spinal cord use of pharmacologic management.
transmission of labor pain.
Water immersion
Maternal physiologic changes Water immersion is a form of hydrotherapy in which water is
used to relieve pain during labor. A Cochrane review suggests
Pregnancy is associated with unique physiologic changes. As a that immersion during the first stage of labor may be associated
result of these changes, after the first trimester, parturients are at with a reduction in the use of neuraxial anesthesia compared
increased risk for aspiration of gastric contents, have decreased to controls [8]. There were no differences in perineal trauma,
Analgesia and Anesthesia 139
need for assisted vaginal deliveries, or CDs. There is no evidence Relaxation

that immersion improves perinatal outcome; however, there are A review of 19 randomized controlled trials, with data reported
case reports of rare but serious adverse effects in the newborn, on 2519 women, found that relaxation techniques, music, and
including respiratory distress, when practiced during the second yoga may help manage labor pain [14].
stage of labor. Given these rare but serious risks to the newborn,
it is the opinion of the American Congress of Obstetricians and Transcutaneous electrical nerve stimulation
Gynecologists (ACOG) and the American Academy of Pediatrics Transcutaneous electrical nerve stimulation (TENS) units emit
that the practice of immersion in the second stage of labor (under- low-voltage electrical impulses and may be used to stimulate acu-
water delivery) should be avoided in routine obstetrical care [9]. pressure points. A systematic review of nine trials including more
See also Chaps. 8 and 9. than 1000 women concluded that TENS did not reduce labor pain
and did not reduce the use of additional analgesic agents [15].
Biofeedback
Biofeedback is a therapy that allows women to gain control over Systemic analgesia
their body’s physiologic response to pain by controlling heart
rate, blood pressure, and muscle tension. Despite some positive Parenteral opioids
results shown in some very small trials, there is insufficient evi- Parenteral opioids continue to have a role in managing labor pain
dence that biofeedback is effective for the management of pain globally and are the most widely used of the systemic medica-
during labor [10]. tions for labor analgesia. Opioids are low cost, easy to use, and
do not require specialized personnel or equipment to be deliv-
Aromatherapy ered safely. There are a variety of opioid agonist-antagonists in
Aromatherapy is the use of plant-derived aromatic essential oils clinical use such as butorphanol (Stadol) or nalbuphine (Nubain)
to promote the sense of physical and psychological well-being. or pure opioid agonists such as meperidine, fentanyl, morphine,
The limited evidence available does not show benefit, or harm, hydromorphone, or their derivatives. More recently, remifentanil,
from aromatherapy for labor pain relief compared to no aroma- an ultra-short-acting opioid without active metabolites, has been
therapy [11]. utilized and is administered only as a patient-controlled intrave-
nous (IV) infusion.
Hypnotherapy Characteristics of some of these drugs are shown in Table 12.1.
Hypnotherapy is the use of hypnosis to deeply relax the body Opioids may be delivered intramuscularly or intravenously.
through focused concentration. For childbirth, hypnosis is often Intramuscular (IM) administration is easy for the health care
used to focus attention on feelings of comfort or numbness, as provider, but painful for the patient. IV administration requires
well as to enhance women’s feelings of relaxation and sense IV access, but allows faster onset of analgesia, predictable magni-
of safety. In a review of nine studies (2954 women) there was tude of peak plasma concentration, and titrating of dose to effect.
no significant difference between women receiving hypnosis IV opioids may be delivered as intermittent boluses or via patient-
versus controls in terms of women’s satisfaction with method controlled analgesia (PCA) technology.
of pain relief or women’s sense of coping with labor. However,
fewer women in the hypnosis group used pharmacologic pain Efficacy
relief [12]. Meperidine is a commonly used opioid for labor analgesia admin-
istered by intermittent boluses intravenously or intramuscu-
Massage larly. In one small study, compared with placebo, meperidine
There is insufficient evidence to assess the effect of massage ther- (Demerol, pethidine) 100 mg IM in early labor is associated
apy on labor pain. However, a meta-analysis involving 326 women with a very modest (17 mm) reduction in the visual analogue
found that women who used massage felt less pain when compared scale (VAS) pain score at 30 minutes [16, 17]. Request for epidural
with women given usual care during first stage of labor [13]. analgesia is delayed to 232 minutes compared with 75 minutes
TABLE 12.1: Intravenous or Intramuscular Opioid Agents for Maternal Pain Relief in Labor
Agent Usual Dose (mg) Frequency (Hour) Onset (Minute) Neonatal Half-Life (Hours)
Tramadol 50–100 mg 4
Pentazocine 30 mg IV or IM 3–4
Meperidine 25–50 IV 1–2 5 13–22
Remifentanil 0.15-0.5 µg/kg Q 2 minutes as PCA 3–4 minute
Fentanyl 50–100 µg IV 1 1 5
Nalbuphine 10 IV or IM 3 2–3 (IV) 4
15 (IM)
Butorphanol 1–2 IV or IM Q 4–6 1–2 (IV) Not known
10–30 (IM)
Morphine 2–5 IV 4 5 (IV) 7
5–10 IM 30–40 (IM)
Abbreviations: IV, intravenous; IM, intramuscular; Q, every; PCA, patient-controlled analgesia.
for parturients receiving placebo, with no further requests for be used for labor analgesia, is metabolized to normeperidine in
analgesia in 32% versus 4% of women receiving meperidine or the liver. This active metabolite has a prolonged half-life in adults
placebo, respectively [17]. In contrast, other studies have shown and a half-life of up to 72 hours in the neonate, which is associ-
that meperidine provides limited labor analgesia and has less ated with neonatal sedation. The normeperidine effect cannot be
labor analgesia efficacy than other systemic opioids such as remi- reversed by naloxone. Because of this, meperidine must be used
fentanil [18]. Additionally, meperidine has an active metabolite, cautiously for intrapartum analgesia. Agonist/antagonists such
normeperidine, which has a prolonged duration of action and as nalbuphine can result in both neonatal cardiac and respiratory
may result in neurobehavioral effects in the newborn. depression, although there are no data that demonstrate adverse
Fentanyl is a synthetic opioid that is 50–100× more potent outcomes. Naloxone is a pure opioid antagonist and is the drug
then morphine [19]. It is most commonly given intravenously by of choice in the treatment of neonatal respiratory and neurobe-
intermittent bolus administration or via PCA. It has a fast onset havioral depression secondary to opioid agonist agents. Repeated
and relatively short duration of action of 45–60 minutes, mak- doses might be necessary, but excess use can be associated with
ing it a good option for labor pain relief. It has no active metabo- neonatal withdrawal seizures. Compared with neuraxial anal-
lites; however, larger doses are associated with longer duration of gesic techniques, systemic medications are much less effective
action and increased needs for neonatal resuscitation compared at decreasing visual analog pain scores (see later).
to remifentanil [20]. When compared to equianalgesic doses of
meperidine, fentanyl is associated with less maternal nausea, Peripheral nerve blocks
vomiting, maternal sedation, and need for neonatal naloxone [21].
Remifentanil, an ultra-short-acting opioid without active Paracervical block
metabolites, has been growing in use as an option for labor anal- During the first stage of labor, pain from cervical dilation (but
gesia. Its pharmacokinetics allow for easy titration and for less not uterine contractions) can be blocked by a paracervical block.
risk of respiratory depression of the newborn. Remifentanil has Studies assessing the effectiveness of paracervical block in labor
a rapid peak analgesic effect <2 minutes after IV administra- are small and of poor quality. The data suggest that this block
tion [22] and a short context-sensitive half-life of 2–3 minutes. is more effective for pain relief than placebo [25]. Risks include
Women who received PCA remifentanil were more satisfied with maternal local anesthetic toxicity from IV injection, fetal local
their pain relief, had better pain relief at 1 hour, and were associ- anesthetic toxicity from inadvertent fetal injection, and a strong
ated with a reduced need for additional analgesia compared to association with fetal bradycardia.
women receiving other opioids either by IV or IM injection [23].
Pudendal block
Maternal safety During the second stage of labor, perineal pain can be blocked
There is not enough evidence to definitively evaluate the compar- with a pudendal block. Studies assessing the effectiveness of
ative safety of the various systemic opioids used to provide labor pudendal block in labor are small and of low quality. The data
analgesia. Maternal side effects are largely dose dependent rather suggest the pudendal block is more effective for pain relief than
than drug dependent. Across all opioids there exists the poten- placebo [25]. There is a small risk of maternal local anesthetic tox-
tial for maternal nausea, histamine release and pruritus, delayed icity in the event of accidental intravascular injection.
gastric emptying, constipation, urinary retention, dysphoria,
drowsiness, apnea, hypoventilation, and hypotension. However, Lumbosacral sterile water injection
in a small randomized controlled trial, maternal apneic episodes For patients who desire nonpharmacologic analgesic techniques,
occurred in 26% of women receiving remifentanil by patient- back pain during the first stage of labor can be reduced with lum-
controlled IV analgesia [24]. Due to concerns of maternal respira- bosacral sterile water injection. In a randomized controlled trial
tory depression, standardized protocols for administration and studying 128 term parturients, women receiving sterile water
monitoring, including one-to-one nursing care, pulse oximetry, injection versus acupuncture reported greater pain relief and
and capnography, as well as the immediate availability of anes- higher degrees of relaxation during labor [26]. In another study,
thesiology personnel, should be standard of care at institutions for women with severe lower back pain, four injections of sterile
where remifentanil PCA is used for labor analgesia [18]. water, either 0.1 mL intracutaneously or 0.5 mL subcutaneously
There is weak evidence of more frequent adverse effects such in the lumbosacral region, has been shown to be effective in
as maternal nausea, vomiting, and drowsiness with meptazinol reducing severe back pain [27].
compared to meperidine. However, both tramadol and pen-
tazocine have fewer maternal side effects when compared with Neuraxial (regional) labor analgesia
meperidine [16], making these two agents the ones with the best (epidural, spinal, or combined)
evidence of both moderate efficacy and lowest incidence of
side effects among the opioid analgesic agents. Respiratory and Background
neurobehavioral depression can be reversed with the use of the Epidural, spinal, and combined spinal-epidural analgesia tech-
pure opioid antagonist naloxone. niques are the most effective methods of providing pain relief to
the laboring parturient. A large meta-analysis looking at over 300
Fetal safety studies comparing neuraxial analgesic techniques to a variety
IV opioids cross the placenta because of their low molecular of other techniques, including systemic opioids, inhaled anes-
weight and lipid solubility and as a result can affect the neonate. thetics, and nonpharmacologic agents, concluded that neuraxial
When compared with neuraxial analgesia, IV opioids are associ- techniques are superior to all other methods in terms of parturi-
ated with increased incidence of nonreassuring fetal heart rate ent pain relief [28]. In a jointly published opinion, both the ACOG
(NRFHR), lower fetal base excess, and decreased fetal respira- and the American Society of Anesthesiologists (ASA) state: “In
tions and tone at birth. Meperidine, the first synthetic opioid to the absence of a medical contraindication, maternal request is
a sufficient medical indication for pain relief during labor” [29]. type of anesthetic used, and several other technical aspects of
As labor results in severe pain for many women, neuraxial anes- epidural anesthesia in labor to recommend one specific drug
thesia, when available, should be offered to all women in labor, combination [31, 32]; however, a meta-analysis of 23 randomized
assuming no medical contraindication. controlled trials comparing epidural ropivacaine and bupivacaine
did not demonstrate significant difference between the two drugs
Overview of techniques in mode of delivery, maternal satisfaction or neonatal outcomes,
Neuraxial labor analgesia is also commonly called regional anal- although the incidence of motor blockade was less in the ropiva-
gesia. It can be provided via the epidural space, the intrathecal caine groups [33].
(spinal) space, or both. The epidural infusion rate can be controlled either by the anes-
Medications injected into the epidural space have a relatively thesiologist or by the patient. Patient-controlled epidural anal-
slow analgesic onset of 8–15 minutes. Block height is determined gesia (PCEA) typically employs a background infusion of local
by the volume of medication injected into the epidural space. anesthetic and opioid together with enabling the parturient to
Injecting low-concentration local anesthetic produces analge- augment the infusion with a bolus dose every 10–15 minutes. This
sia, and injecting high-concentration local anesthetic produces technique can also be used with a spinal catheter with appropri-
anesthesia. ately reduced doses.
By contrast, medication injected into the intrathecal space has
a quick onset of 2–5 minutes. Block height is determined primar- Indications
ily by the baricity (density relative to cerebrospinal fluid [CSF]) of In its 2019 Practice Bulletin, Obstetric Analgesia and Anesthesia,
the drug and, to some extent, the total volume of the drug. ACOG confirmed an opinion published also by the ASA, which
stated that “in the absence of medical contraindication, mater-
Epidural analgesia nal request is a sufficient medical indication for pain relief
Technique during labor” [5]. However, numerous maternal conditions make
The epidural space is located using a loss of resistance (to air or neuraxial anesthesia the prudent choice. Examples of such condi-
saline) technique (Figure 12.1) [30]. A small catheter is placed tions include anticipated difficult intubation, history of malignant
into the epidural space through which local anesthetics and opi- hyperthermia, high risk for CD, the presence of a comorbidity that
oids can be intermittently injected (bolus) or given as a continu- would benefit from the reduced catecholamine levels that result
ous infusion. from adequate labor analgesia (e.g. selected respiratory or car-
The most common local anesthetic choices include low- diac disease), and prophylaxis against autonomic hyperreflexia in
concentration, long-acting amides such as bupivacaine and ropi- the woman with a high spinal cord lesion. Functioning epidural
vacaine in combination with a lipid-soluble opioid such as fentanyl catheters can also be used to provide anesthesia for instrumented
and sufentanil. The addition of opioids to local anesthetics pro- delivery and extraction of a retained placenta.
duces an additive effect that results in a lower concentration of In some cases, an epidural catheter can be intentionally
local anesthetic being required to produce adequate labor anal- inserted into the intrathecal space to provide continuous spinal
gesia. A lower concentration of local anesthetic increases mater- analgesia. However, the resulting postdural puncture headache
nal mobility and decreases the potential for maternal systemic (PDPH) incidence may be high. Nonetheless, this risk may be
toxicity. There is insufficient evidence comparing concentrations, acceptable in certain situations such as the presence of certain
Anterior Superior Posterior
Cerebrospinal
fluid and
Body of intrathecal space
vertebra
Epidural space
Intervertebral
disk
Interspinous
Spinal cord ligament
Spinous
Posterior process
longitudinal
ligament
Ligamentum
flavum
Dura mater
(outer layer) and
subarachnoid
Cauda equina membrane
(inner layer)
Inferior
FIGURE 12.1 The epidural space. (From Pamela E. Macintyre and Stephan A. Schug, Acute Pain Management: A Practical Guide,
Fifth Edition, CRC Press 2021, with permission.)
maternal comorbidities (typically cardiac), the morbidly obese Safety, disadvantages, and complications
parturient with an airway that appears extremely difficult or Compared with non-neuraxial analgesia, epidural analgesia is
impossible to intubate, or following an inadvertent dural punc- associated with an increased risk of mild maternal fever, hypo-
ture during a difficult epidural placement. tension, and urinary retention; increased need for oxytocin
administration; increased duration of the second stage by an
Efficacy and advantages average of 15 minutes; and increased risk of operative vagi-
Compared with nonepidural methods, epidural analgesia both nal birth (forceps or vacuum-assist) [31]. A recent noninferior-
reduces pain during labor and increases maternal satisfaction ity trial assessed the effects of routine epidural analgesia during
with pain relief. However, some women who undergo epidural labor versus epidural upon maternal request and suggests that
versus nonepidural analgesia appear to have an increased inci- routine epidural analgesia was associated with a statistically sig-
dence of assisted vaginal birth. These findings have not been seen nificant increase in the rate of operative deliveries (difference
in more recent studies, suggesting that modern approaches to 8.1%, 95% confidence interval [CI] –0.01 to –16.3) [42].
epidural analgesia with lower concentration of local anesthetics The etiology of the occasional increase in maternal temper-
do not affect this outcome [31]. In more than 85% of cases, the ature associated with epidural use is uncertain. This effect can
pain relief is optimal. As labor results in severe pain for many lead to increased maternal and neonatal antibiotic treatments, as
women, and neuraxial analgesia is the most effective inter- well as neonatal sepsis evaluations, but with no difference in the
vention to decrease or eliminate this pain, neuraxial analge- corresponding rate of neonatal infection or sepsis [43]. In centers
sia should be offered, when available, to all women in labor with structured protocols for neonatal sepsis workups, there are
(assuming no medical contraindication). no increases in the incidence of neonatal sepsis workups in babies
Compared with systemic opioids, epidural anesthesia is asso- born to mothers with epidural analgesia.
ciated with superior pain relief and lower risk of umbilical The incidence of maternal hypotension following neuraxial
cord pH <7.20. There is no evidence of a significant difference analgesia during labor is approximately 14%. Hypotension is asso-
in the risk of CD. In addition, there is no evidence of a signifi- ciated with an increased incidence of nonreassuring fetal heart
cant difference in the risk of long-term backache, and this did not rate tracing (NRFHT) that rarely (1%–2%) necessitates CD. Left
appear to have an impact on neonatal status as determined by uterine displacement should be maintained whenever possible, as
Apgar score or in admissions to neonatal intensive care [31]. No it will increase maternal preload and increase uterine perfusion.
studies reported on rare but potentially serious adverse effects of Measures such as fluid preloading and concurrent administration
epidural analgesia [31]. Neuraxial analgesia is the least depressant of phenylephrine or ephedrine can mitigate or prevent maternal
method of analgesia for the fetus/neonate, and it is important to hypotension.
note that initiation of breastfeeding is not affected by neuraxial Although the risk of long-term backache in women who uti-
analgesia. lize epidural analgesia is similar to controls (IM meperidine), it is
quite common for a woman to experience soreness or tenderness
Timing of initiation of neuraxial analgesia at the site of epidural insertion for 2–3 days [44].
There is no reason to delay epidural placement until an arbitrary Disadvantages of epidural analgesia include a slower onset com-
cervical dilation has been reached. The traditional practice of pared with intrathecal (spinal) injection, incomplete blockade of
delaying the placement of an epidural catheter until the cervix is pain (in about 10%–15% of patients), and inadvertent intrathecal
dilated to 4–5 cm has been disproven. Data suggest that neuraxial or intravascular catheter placement. While the PCEA gives the
analgesia can be offered as early as 2 cm or less without adversely patient more control and requires less intervention from anesthe-
affecting labor outcome or incidence of CD. Epidural placement siologists, this can lead to underdosing and therefore inadequate
at ≤2–5 cm is associated with similar maternal (instrumental analgesia: for example, if the patient does not self-administer a
delivery, CD, etc.) and neonatal outcomes compared with epi- bolus (if she is asleep) or if there is a pump malfunction.
dural placement at ≥3–5 cm in women in spontaneous labor or Other complications include a 1%–2% chance of PDPH fol-
receiving oxytocin [34–38]. Subsequently, in the updated ACOG lowing accidental lumbar puncture and, rarely, epidural hema-
Committee Opinion, it is affirmed that early initiation of neur- toma, respiratory arrest due to the unrecognized injection of an
axial analgesia does not increase the rate of CD [39]. Moreover epidural dose of opioid into the intrathecal space, systemic local
in practice bulletin No. 209 Obstetric Analgesia and Anesthesia anesthetic toxicity due to unrecognized IV injection, or total
ACOG reaffirms that “consideration should be given to early spinal anesthesia from an unrecognized intrathecal injection of
placement of neuraxial catheter that can be used later for women a dose of local anesthetic meant for the epidural space. See sec-
undergoing labor after cesarean” [5]. tions on spinal analgesia and anesthesia emergencies for further
The decision of when to place epidural analgesia should be details on these complications and strategies for their prevention
made individually with each woman [5]. and treatment. Women should be counseled about these risks
PCEA gives the patient control over her analgesia. Patients before labor [43].
receive less local anesthetic overall (and therefore have less
motor blockade) and receive fewer manual boluses from the anes- Interventions to avoid some disadvantages
thesiologist (“top-offs”) [31, 40]. As patient satisfaction is high and complications of epidural analgesia
with epidural analgesia, PCEA is not associated with additional Preloading with IV fluids to prevent hypotension: Preloading
improvement in maternal satisfaction. with IV fluids (500–1000 mL or weight-based formula 10–20 mL/
There is insufficient evidence to support the hypothesis that kg) prior to traditional high-dose local anesthetic blocks may have
discontinuing epidural analgesia late in labor (e.g. at the begin- some beneficial fetal and maternal effects in healthy women [45].
ning of the second stage) reduces the rate of instrumental deliv- When using low-concentration analgesic solutions for epidural
ery. There is evidence that it increases the rate of inadequate pain techniques, preloading with IV fluids is associated with no sig-
relief in the second stage of labor [41]. nificant difference in maternal hypotension, although only a
very large effect was excluded. There is, however, a trend toward to prevent PDPH following inadvertent dural puncture with an
less frequent fetal heart rate abnormalities [45]; therefore, some epidural needle. Conservative early interventions include anal-
fluid preloading may be beneficial. gesics, supine positioning, caffeine, and hydration. In about
Prophylactic ephedrine to prevent NRFHR: Compared with one-third of cases, the headache persists and is severe enough to
no ephedrine, ephedrine 10 mg IV bolus, followed by a 20-mg require an epidural blood patch procedure. An epidural blood
continuous infusion over 60 minutes, started in the first minutes patch is performed by injecting 10–25 mL of autologous blood
after the epidural test dose significantly decreases the incidence into the patient’s epidural space at the level of the dural puncture
of NRFHT from 15% to 3% [46]. However, this evidence is insuf- using meticulous sterile technique. If the level of the dural punc-
ficient to make a recommendation. ture is unknown, a more caudad interspace should be chosen.
In summary, epidural analgesia remains one of the most After the procedure, the patient should rest in the supine position
effective and safe methods of intrapartum analgesia, and, in for 1–2 hours. Resolution of symptoms with blood patch occurs
most cases, maternal request for pain relief is sufficient indi- in 70%–85% of women. Expected side effects following epidural
cation for its placement. A lower-concentration local anes- blood patch include transient backache and leg pain [47].
thetic (e.g. bupivacaine 0.0625%–0.125%) with the addition of
a lipid-soluble opioid (fentanyl 1–2 mcg/mL) allows excellent Respiratory depression or arrest
analgesia while reducing the total dose of local anesthetic and Respiratory depression or arrest due to intrathecal opioids occurs
minimizes the side effects (i.e. the severity of motor block). rarely: 1 in 5000–10,000 patients. Naloxone reverses this compli-
While there is no superior method of dosing (continuous infu- cation and should be readily available, along with airway manage-
sion vs. PCEA), PCEA allows the patient to titrate the neur- ment equipment, when administering labor analgesia.
axial blockade, which can result in less breakthrough pain.
Hematoma
Epidural analgesia can be given in early labor (cervical dila-
Hematoma after epidural or spinal analgesia is an extremely
tion <4 cm) and does not increase the rate of CD or prolong
rare complication of neuraxial anesthesia (1/150,000–250,000).
the duration of labor.
Symptoms include bilateral leg weakness, urinary incontinence,
Spinal analgesia and back pain. Prolonged motor paralysis without regression
Technique of block should raise suspicion. If suspected, the patient should
Using a small-bore spinal needle (typically a pencil-point design undergo prompt definitive imaging (magnetic resonance imaging
that minimizes trauma to the dura, thereby reducing the inci- [MRI]) of her neuraxis, followed by surgical decompression after
dence of PDPH), a dural puncture is made and proper location diagnosis. Surgical decompression within 6 hours following the
confirmed by CSF aspiration (Figure 12.1). A single injection of onset of symptoms often prevents permanent neurologic injury.
an analgesic dose of an opioid such as fentanyl or sufentanil, with The risk of persistent neurologic injury from epidural is about
or without a local anesthetic such as bupivacaine or ropivacaine, 1/240,000 [30].
is administered.
Combined spinal epidural
Indications Technique (Figure 12.1)
Indications for single-injection spinals include advanced labor The epidural space is identified with the loss-of-resistance tech-
where delivery is imminent, forceps deliveries in women without nique. A spinal needle is then introduced into the intrathe-
epidurals, and for patients with retained placentas. cal space. An intrathecal dose of local anesthetic and opioid is
injected through the spinal needle, which is then removed, leav-
Advantages ing the epidural needle in place. An epidural catheter is inserted,
Advantages for single-injection spinals include ease and speed of and an epidural local anesthetic and opioid infusion is started.
onset, completeness of block, and lower incidence of PDPH com- The intrathecal dose generally lasts about 2 hours, after which the
pared with epidural analgesia. epidural catheter will provide continuous analgesia.
Disadvantages and complications Indications

The main disadvantage for single-injection spinals is an inability The CSE technique provides the benefit of immediate onset of
to redose. spinal analgesia coupled with the indefinite duration of an epi-
dural catheter technique. This technique is particularly useful for
Postdural puncture headache women in advanced labor requesting pain relief. There are data
PDPH occurs with a frequency of approximately 1%–2% after that associate CSE with an increased rate of cervical dilatation
either spinal or combined spinal-epidural (CSE) analgesia when and shorter length of labor compared with both IV opioid and
administered using a small-gauge pencil-point needle. PDPH is epidural analgesia [48–50]. Indications for a CSE are the same as
thought to be caused by leakage of CSF through the punctured those for both epidural and spinal techniques.
dura. The leak of CSF and subsequent decreased spinal fluid pres-
sure leads to downward traction or stretch on the meninges with Advantages
resulting symptoms. PDPH is characterized by a positional fronto- Both CSE and epidural techniques provide effective pain
occipital headache that is exacerbated by the upright position relief in labor. The type of opioid and concentration of local
(with gravity worsening stretch on the meninges), with improve- anesthetic used in the CSE or epidural technique affect mater-
ment in symptoms when the patient is supine. Diplopia, tinnitus, nal mobilization and other outcomes more than the technique
nausea, and vomiting caused by stretch on the cranial nerves are itself [51]. A CSE results in faster onset of pain relief when
also common symptoms. Although pencil-point-design spinal compared to a traditional epidural [52], and in a randomized
needles have significantly reduced the incidence of PDPH controlled comparison of epidural and CSE analgesia, CSE may
following spinal analgesia, there are no proven interventions provide better subsequent labor analgesia with reduced need for
additional doses for breakthrough pain [53]. There is some evi- there is no other acquired or congenital coagulopathy, the platelet
dence that CSE compared with an epidural is associated with a function is normal, and the patient is not receiving any anticoagu-
faster rate of cervical dilatation in nulliparous women less than lation [54, 55]. In a recent statement by the Society for Obstetric
5 cm [49], and women close to imminent birth may benefit from Anesthesia and Perinatology (SOAP) (endorsed by the American
the speed of onset a CSE offers. There is no difference in ability to Society of Regional Anesthesia and Pain Medicine [ASRA], ACOG,
mobilize, obstetric outcome, or neonatal outcome [51]. However, and Society for Maternal-Fetal Medicine [SMFM]) through a sys-
there is a statistically significant difference in risk of instrumental tematic review and modified Delphi method, they concluded that
delivery between CSE and epidural analgesia, with CSE having the risk of spinal epidural hematoma associated with a plate-
decreased rates of instrumentation (relative risk [RR] 0.81; 95% let count ≥70,000 × 106/L is likely to be very low in obstetric
CI 0.67–0.97) [51]. patients with thrombocytopenia secondary to gestational throm-
bocytopenia, ITP, and hypertensive disorders of pregnancy in the
Disadvantages absence of other risk factors [56].
The disadvantages of CSE are similar to epidural and spinal tech-
niques. Although data are limited, no differences are reported Anticoagulation
between IV preloading and no preloading to prevent hypotension Recently updated guidelines from the ASRA from 2018 address
[45]. Women who receive intrathecal opioids experience more the use of neuraxial anesthesia in the setting of anticoagulation
pruritus than with a standard epidural [51]. However, pruritus is [57]. These updated guidelines now include prophylactic unfrac-
quite common after both spinal and epidural opioids and results tionated heparin in the dosing regimens that are considered to
from mu-opioid receptor stimulation in the brainstem. Naloxone increase the risk for major complications of neuraxial anesthesia.
and nalbuphine are effective interventions. Diphenhydramine These new ASRA recommendations are reflected in the SOAP
and other antihistamines are not effective in treating opioid- consensus statement from 2018 and the updated ACOG Practice
induced pruritus because opioids administered via the intra- Bulletin No. 196 Thromboembolism in Pregnancy [58, 59]. When
thecal or epidural route do not cause histamine release. The administering any form of anticoagulation to a parturient,
significantly higher incidence of urinary retention, instru- whether in the antepartum or postpartum period, in the setting
mental deliveries, and rescue analgesia interventions with of neuraxial anesthesia use, clinicians must be knowledgeable
traditional high-concentration epidurals would favor the use of these recommendations to minimize the risk of major com-
of low-dose epidurals [51]. An additional disadvantage is that the plications from neuraxial anesthesia, including spinal epidural
correct placement of the catheter in the epidural space cannot hematoma.
be verified until the spinal analgesia regresses. It is not possible
to draw any meaningful conclusions as to possible differences
between CSE and epidurals in producing rare complications such Intrapartum recommendations
as nerve injury and meningitis. regarding thromboprophylaxis
In summary, CSE is an ideal technique when rapid-onset
analgesia with good sacral coverage in advanced labor is These recommendations are adapted from the SOAP Consensus
needed. In addition to rapid pain relief, an advantage of this Statement on the Anesthetic Management of Pregnant and
technique is the visualization of CSF flow through the spinal Postpartum Women Receiving Thromboprophylaxis or Higher
needle, which can provide confirmation that the epidural Dose Anticoagulants) [58].
space has been reached successfully. An additional benefit of
Low-dose aspirin
a CSE is the block can be extended with the epidural catheter
Women receiving prophylactic low-dose aspirin are not at
if the duration of the spinal anesthetic is inadequate.
increased risk for spinal epidural hematoma from neuraxial
anesthesia.
Contraindications to regional anesthesia
Coagulopathy Unfractionated heparin
A routine platelet count is not necessary before administering For low-dose unfractionated heparin (UFH) thromboprophylaxis
neuraxial analgesia in the healthy parturient; however, the deci- (i.e., 5000 U SQ twice daily or three times daily), consider holding
sion to order a platelet count should be individualized and based the dose for 4–6 hours before placing the neuraxial anesthetic
on the patient’s history, physical examination, and clinical signs [3]. or assessing coagulation status as per ASRA recommendations.
Indications for platelet count may include hypertensive disorders For intermediate-dose UFH thromboprophylaxis (i.e., 7500 U
of pregnancy, history of thrombocytopenia (gestational, immune SQ twice daily or 10,000 U SQ twice daily), consider holding the
thrombocytopenia [ITP]), abruption, and disorders of coagulation. dose for 12 hours and assessing coagulation status before placing
Thrombocytopenia is a relative contraindication to neuraxial anes- a neuraxial anesthetic.
thesia, but a safe lower limit for platelet count has not been clearly For high-dose UFH thromboprophylaxis (i.e., individual dose
defined. In the absence of disseminated intravascular coagulation >10,000 U SQ per dose, or >20,000 U SQ total daily dose), con-
(DIC), a platelet count of ≥100 × 109/L has historically been consider holding the dose for 24 hours and assessing coagulation sta-
sidered safe; however, there are no data to support a specific mini- tus before placing the anesthetic.
mum platelet count for neuraxial anesthesia. The literature reports For IV heparin, consider stopping the infusion for 4–6 hours
mostly retrospective data on this issue. In a recent retrospective and then assessing coagulation status before placing a neuraxial
cohort study of 84,471 obstetric patients from 19 institutions com- anesthetic.
bined with a review of the medical literature suggests that epi-
dural or spinal anesthesia is considered acceptable, and the risk Low-molecular-weight heparin
of epidural hematoma is low in patients with platelet counts of For low-dose low-molecular-weight heparin (LMWH) thrombo-
70 × 109/L or more, provided that the platelet count is stable and prophylaxis (i.e., enoxaparin ≤40 mg SQ once daily or 30 mg SQ
twice daily, or dalteparin 5000 U SQ once daily), consider hold- Disadvantages

ing the dose ≥12 hours before placing a neuraxial anesthetic, as Patients with gestational hypertension, preeclampsia, and
recommended by the Food and Drug Administration (FDA) and eclampsia are at increased risk for hemodynamic instability dur-
ASRA. ing both labor and surgical anesthesia. Neuraxial techniques can
For intermediate-dose LMWH thromboprophylaxis (i.e. be used safely with increased vigilance for maternal hypotension.
enoxaparin >40 mg SQ once daily or 30 mg SQ twice daily and In one focused review, marked hypotension after spinal anesthe-
<1 mg/kg SQ twice daily, or 1.5 mg/kg SQ once daily or dalteparin sia in women with preeclampsia did not occur, lending support to
>5000 U SQ once daily and <120 U/Kg SQ twice daily, or 200 U/ the safety of the technique in these women [60].
kg SQ once daily), there are insufficient published data to recom- Women with preeclampsia may have thrombocytopenia, which
mend a specific interval between 12 and 24 hours to wait before increases the risk of neuraxial hematoma formation. A recently
proceeding with neuraxial anesthesia. published SOAP consensus statement considers a platelet count
For higher-dose LMWH (i.e. enoxaparin 1 mg/kg SQ twice above 70,000/mm3 to be adequate for the administration of neur-
daily or 1.5 mg/kg SQ once daily; dalteparin 120 U/kg SQ twice axial anesthesia in patients with thrombocytopenia secondary to
daily or 200 U/kg SQ once daily), consider holding the dose hypertensive disorders of pregnancy [56].
≥24 hours before placing a neuraxial anesthetic as recommended
by the FDA and ASRA. Cautions
Caution must be taken in fluid management in this patient popu-
General considerations lation, as there is altered vascular leaking, decreased oncotic pres-
The safest way to prepare the pregnant patient on thrombopro- sure, and a higher incidence of pulmonary edema. Also, there can
phylaxis for delivery is through advanced planning and thorough be an exaggerated hypertensive response to ephedrine and phen-
communication between the obstetric and anesthesia teams. ylephrine. The prevention, rather than treatment, of hypotension
Consideration should be given to converting women who require has been associated with better outcomes for the fetus. Women
anticoagulation from LMWH to UFH as they approach term. with severe preeclampsia who must undergo general anesthesia
The coagulation status of parturients with medical condi- are at risk for an exaggerated hypertensive response to intubation
tions associated with coagulopathy, such as the HELLP syn- and often benefit from pretreatment with an antihypertensive
drome (hemolysis, elevated liver enzyme levels, and low platelet such as labetalol immediately prior to induction. Treatment with
levels), should be thoroughly evaluated before initiating a neur- magnesium sulfate for preeclampsia/eclampsia can potentiate
axial block. Patients with thrombocytopenia should be exam- neuromuscular blockade in patients receiving general anesthe-
ined for stigmata of coagulopathy (easy bruising, bleeding from sia, so care must be taken when using nondepolarizing muscle
the IV site, etc.) before instrumentation. A fibrinogen level and relaxants.
a d-dimer level are useful to assess the presence of DIC if sus-
pected. A bleeding time is not indicated. Patients with known Maternal cardiac disease
platelet dysfunction, including those on antiplatelet medication Heart disease in the parturient is the leading cause of maternal
(e.g. clopidogrel), should not receive neuraxial analgesia. Aspirin mortality outside of obstetric complications. Understandably,
therapy is considered an acceptable risk [57]. the risk increases with severity of maternal disease. The normal
changes in maternal cardiac physiology resulting from pregnancy
Infection can either unmask subclinical disease or worsen clinical cardiac
Systemic: Patients with suspected meningitis (bacterial or viral)
disease. Every effort should be made to care for these patients in
or sepsis should not receive neuraxial blockade. Patients with sus-
facilities equipped to provide the multidisciplinary approach that
pected chorioamnionitis can receive neuraxial analgesia/anes-
is required to ensure the best possible outcome for mother and
thesia following the administration of appropriate IV antibiotics.
neonate. Goals of anesthetic management for parturients with
Chronic herpes simplex virus (HSV) outbreak is not a contrain-
heart disease are: (1) maintain a normal heart rate, sinus rhythm,
dication to neuraxial techniques. However, a primary outbreak
and adequate systemic vascular resistance (SVR); (2) maintain
places the parturient at risk for herpetic viremia and the theoreti-
intravascular volume and venous return; (3) avoid aortocaval
cal risk for central nervous system (CNS) infection and should be
compression; and (4) avoid myocardial depression during general
weighed against the risk of alternative methods of analgesia. HIV/
anesthesia.
AIDS is not a contraindication to spinal or epidural anesthesia or
epidural blood patch. Valvular heart disease
Localized: Patients with localized skin or soft tissue infections Patients with acquired valvular disease (rheumatic fever, mitral
should not be instrumented at those sites. valve prolapse, artificial valves, and endocarditis) are at increased
risk for arrhythmias, pulmonary edema, and cardiac ischemia
Anesthesia and maternal comorbidities from the increased heart rate, cardiac output, metabolic demand,
and decreased oxygen reserve associated with pregnancy and the
Hypertensive disorders pain of labor. Patients with arrhythmias or artificial valves may
Advantages of neuraxial analgesia also be on heparin or LMWH.
Pregnant women with hypertension may benefit from neuraxial Advantages of neuraxial analgesia: Epidurals and CSE block
analgesia, as it may improve uterine perfusion through several the pain and stress of contractions, therefore reducing tachy-
pathways (localized neuraxial vasodilatory effect, reduced cat- cardia and increased cardiac output. Ablation of the bearing-
echolamine release). Neuraxial analgesia is the analgesia of down reflex can be advantageous in patients with aortic or mitral
choice in hypertensive pregnant women, as it allows clinicians regurgitation.
to avoid the possibility of difficult intubation and the severe Disadvantages: Hypotension is the largest disadvantage with
hypertension that accompanies endotracheal intubation. neuraxial analgesia; even transient hypotension can lead to
coronary hypoperfusion, ischemia, arrhythmias, or arrest. This and anesthesia with initial epidural failure as high as 42%.
is especially dangerous in patients with moderate to severe aor- Despite this increase in technical difficulty, neuraxial anesthesia
tic stenosis. However, parturients with aortic stenosis have safely is the technique of choice in the obese parturient.
undergone both neuraxial labor analgesia and anesthesia for CD.
Meticulous anesthetic technique and allowing adequate time to Cesarean delivery anesthesia
slowly administer the requisite medication is the key to safe pro-
vision of neuraxial anesthesia in these patients. Inadvertent IV Current guidelines recommend a fasting period for solids of
injection of local anesthetics is also a significant risk in patients 6–8 hours prior to scheduled CD. Parturients without compli-
with underlying arrhythmias due to impairment of cardiac auto- cations may drink clear liquids for up to 2 hours before induc-
maticity and conduction (especially with bupivacaine). tion of anesthesia for planned CD [3]. For laboring patients with
additional risk factors (i.e. morbid obesity, diabetes mellitus) or
Congenital heart disease patients at increased risk for CD (NRFHR pattern), consider fur-
Women with congenital heart disease (e.g., tetralogy of Fallot, ther restrictions of oral intake [3]. See also Chap. 8 for food intake
hypoplastic left ventricle, transposition of the great vessels, in labor.
and septal defects) are now surviving to childbearing years.
Depending on the adequacy of their surgical repair, pregnancy Epidural
may or may not severely affect these patients with underlying cya- Epidural anesthesia can be used for CD and for most urgent or
notic heart disease. The increased cardiac output, oxygen con- emergent deliveries if a functioning catheter is in place. Patients
sumption, changes in systemic and pulmonary resistance, and with existing labor epidurals can have their block extended to an
aortocaval compression can exacerbate preexisting right-to-left adequate level for surgery using a large volume of high-concentration
shunts, increasing the risk of maternal cyanosis and death. local anesthetic solution containing opioids and epinephrine
Advantages of epidural analgesia: Although the hypotension (which is thought to produce analgesia via α2 receptors in the
of large-dose spinal anesthesia can be associated with risk of spinal cord).
shunting and cyanosis, slowly administered epidural, low-dose
spinal, and continuous spinal analgesia are advantageous to these Advantages
patients by reducing catecholamine levels and preventing mater- There are numerous advantages to using epidural anesthesia for
nal expulsive reflexes. Additionally, if an instrumented delivery CD, including avoiding instrumentation of the maternal airway,
or CD is required, a surgical anesthetic level can be slowly pro- the ability to redose the epidural in the event of a delayed or pro-
duced, avoiding the risks of general anesthesia in these patients. longed surgery, the ability to administer long-acting epidural
Disadvantages: The largest disadvantage of neuraxial analgesia opioids to augment postoperative pain control, and the avoid-
is the risk of hypotension. Hemodynamic management of these ance of a dural puncture. Opioids administered via the neuraxial
patients should be aggressive and tailored to the underlying car- approach are associated with a 35%–55% incidence of maternal
diac defect. pruritus severe enough to require treatment [65]. An additional
advantage is that the patient is awake and can experience the
Previous lumbar surgery birth. The epidural catheter should be removed after 24 hours to
Previous lumbar surgery (e.g., discectomy, placement of reduce urinary retention, pruritus, and infection risks.
Harrington rods) is not a contraindication for lumbar epidural
or spinal analgesia or anesthesia. One case series found that suc- Disadvantages
cessful block can be achieved, although at a lower rate (55%) than Disadvantages of an epidural for CD include longer onset time
in the control population. There were no cases of spine infection, for surgical block compared with spinal anesthesia and the pos-
low back pain, or headaches [61]. sibility of incomplete or patchy block, making epidural anesthe-
sia a less attractive option than spinal anesthesia in emergent
Maternal obesity situations (when an epidural catheter is not already in place). The
The incidence of maternal obesity has been rapidly increasing higher doses of local anesthetics used in epidural blocks (com-
worldwide. Obese parturients have higher rates of hypertension, pared with spinal) increase the risk of maternal systemic toxicity.
diabetes, preeclampsia, chorioamnionitis, and cesarean section
compared with normal-weight women. Obese patients are also Spinal
more at risk for hypoventilation and apnea after administration Spinal anesthesia can be used for both planned CDs and in most
of opioids, complicating postpartum and postoperative pain emergencies. Intrathecal opioids can be added to augment post-
control. Relative immobility also increases the risk of thrombo- operative pain control.
embolic events [62]. Most importantly, obesity increases the risk
for death during pregnancy. The report of Confidential Enquiries Advantages
into Maternal Deaths in the United Kingdom for the 2006–2008 Spinal anesthesia is a reliable form of anesthesia that is techni-
triennium showed that 49% of maternal deaths were overweight cally easier to perform and produces adequate anesthesia signifi-
or obese [63]. The risks of low Apgar scores, neonatal intensive cantly faster than epidural anesthesia [66]. Other advantages are
care unit admission, fetal death, and perinatal death are increased its simplicity, lower drug doses, and superior abdominal muscle
[64]. Respiratory, gastrointestinal, and anatomic changes of preg- relaxation. Compared with epidural, spinal technique is asso-
nancy significantly increase the risk of a failed intubation and ciated with similar failure rate, need for additional intraop-
aspiration, which is as high as 15%–33% in obese pregnant erative analgesia, need for conversion to general anesthesia
women. Venous access can be difficult, increasing the need for intraoperatively, maternal satisfaction, need for postopera-
central venous access. Bony landmarks and increased adipose tive pain relief, and neonatal intervention [66]. Compared with
and soft tissue can complicate placement of neuraxial analgesia epidural, spinal anesthesia for cesarean section is associated with
reduced time, by about 8 minutes, from start of the anesthetic to 30 minutes of surgery and/or metoclopramide. Time permitting,
start of the operation. an H2 blocker can be given 30–50 minutes before induction of
Compared with general anesthesia, women with neuraxial anesthesia to confer additional protection. Airway protection
anesthesia have less intraoperative blood loss but significantly with endotracheal intubation is mandatory.
more nausea. In a review of randomized clinical trials, no dif- There is insufficient evidence to assess prevention of aspiration
ferences in umbilical cord arterial blood pH were found among during general anesthesia. When compared with no treatment or
general and neuraxial anesthetic techniques [67]. placebo, there is a significant reduction in the risk of intragastric
pH <2.5 with antacids, H2 antagonists, and proton pump antago-
Disadvantages nists [71]. H2 antagonists are associated with a reduced risk of
Hypotension, possibly profound, is increased in incidence 23% intragastric pH <2.5 at intubation when compared with proton
with spinal versus epidural anesthesia [66]. A number of strate- pump antagonists, but compared with antacids, the findings were
gies can be used to mitigate hypotension. No intervention reliably unclear. The combined use of “antacids plus H2 antagonists” is
prevents hypotension due to spinal anesthesia for CD, but five associated with a significant reduction in the risk of intragas-
interventions have been found to reduce the incidence of hypo- tric pH <2.5 at intubation when compared with placebo or com-
tension: (1) crystalloid preload, (2) preemptive colloid admin- pared with antacids alone (RR 0.12, 95% CI 0.02–0.92, 1 trial, 119
istration, (3) ephedrine, (4) phenylephrine, and (5) lower limb women). In general, the quality of the evidence is insufficient to
compression [45, 68, 69]. No differences were detected for dif- make a recommendation. None of the studies assessed potential
ferent doses, rates, or methods of administering colloids or crys- adverse effects or substantive clinical outcomes [71].
talloids. High doses of ephedrine may increase the incidence of
hypertension and tachycardia and are associated with fetal acido- Advantages
sis of uncertain clinical significance. Patients who receive intra- There are few advantages to general anesthesia in the absence of
thecal bupivacaine with prophylactic IV phenylephrine infusion a contraindication to a neuraxial approach. One possible advan-
have less hypotension than those without phenylephrine [68]. tage is the relaxation properties halogenated anesthetics have on
One systematic review showed that phenylephrine is as safe as uterine muscle. This property can be useful in the management of
ephedrine; in fact, fetal pH is higher and the incidence of mater- uterine inversion, fetal entrapment, or retained placenta. IV nitro-
nal nausea is lower with phenylephrine [70]. Given the efficacy glycerine and terbutaline are other options in these situations.
of phenylephrine and better umbilical cord pH, many anesthesia
providers now use phenylephrine as a first-line agent for the treat- Disadvantages
ment and prevention of maternal hypotension. Different methods Compared with neuraxial anesthesia, general anesthesia is asso-
of compression appeared to vary in their effectiveness. In sum- ciated with a threefold risk of maternal death [72]. The greatest
mary, interventions such as crystalloids, colloids, ephedrine, risk is from the inability to intubate or ventilate the patient.
phenylephrine, or lower-leg compression can reduce the inci- Parturients have increased upper airway edema, lower pulmo-
dence of hypotension, but none have been shown to eliminate nary functional residual capacity, increased metabolic oxygen
maternal hypotension during spinal anesthesia for CD. consumption, decreased lower esophageal sphincter tone, and
Limited duration is another disadvantage of spinal anesthesia. delayed gastric emptying. These conditions increase the risk of
CSEs and spinal catheters combine the advantages of the rapid both hypoxemia and aspiration. Airway edema can also make
onset of spinal anesthesia with the ability to redose in the case of anesthetizing the airway for awake fiber-optic intubation more
prolonged surgical time. difficult. The incidence of failed intubation in the obstetric popu-
The rate of PDPH after spinal anesthesia ranges between 1.5% lation is approximately 1 in 300, nearly eight times that of the
and 11.2%. To reduce this risk, this technique should be per- general population [72, 73].
formed using a small-gauge (24 g or smaller), pencil-point spinal CD is considered a high-risk procedure for intraoperative
needle when possible. recall. Concern about neonatal depression and uterine atony has
In summary, both spinal and epidural techniques are shown led to minimal use of benzodiazepines and low-dose intraopera-
to provide effective anesthesia for cesarean section. Both tech- tive halogenated anesthetics intraoperatively. Compared with
niques are associated with moderate degrees of maternal satisfac- nonobstetric surgery, the risk of maternal awareness under
tion. Spinal anesthesia has a shorter onset time, but treatment for general anesthesia is increased (0.4% vs. 0.2% for nonobstetric
hypotension is more likely if spinal anesthesia is used. Because of surgery) [74]. Although benzodiazepines and opioids can depress
its safety and effectiveness, spinal anesthesia has evolved as the the fetus, they are pharmacologically reversible, and administra-
regional technique of choice for CD due in particular to rapid- tion should be considered if their use would benefit the mother.
ity of anesthetic onset, quality of anesthesia, and ease of perfor- For instance, the judicious use of preintubation opioids can be
mance of block. considered to blunt the sympathetic response to direct laryngos-
copy in the hypertensive parturient. The ultra-short-acting syn-
General anesthesia thetic opioid remifentanil can provide this benefit with minimal
While neuraxial techniques are clearly the preferred anesthetic effect on the neonate.
for CD, general anesthesia is indicated in the case of failed General anesthesia is also associated with higher incidence of
regional anesthesia, an obstetric emergency preventing place- postoperative nausea and vomiting, maternal sedation, and
ment of a neuraxial technique, a contraindication for regional increased time to breastfeeding.
anesthesia, or objection by the patient to regional anesthesia. General anesthesia’s effect on the fetus depends on the length
of time from induction to umbilical cord clamp; length of time
Precautions from hysterotomy to cord clamp is also important. Fetal exposure
If a general anesthetic is chosen, patients must receive aspiration to inhaled anesthetics of >5–8 minutes is associated with neo-
prophylaxis that may include a nonparticulate oral antacid within natal depression. General anesthesia compared with neuraxial
anesthesia has been shown to increase the incidence of fetal aci- tolerate oral intake. Women should be aware of an FDA advi-
dosis, drug exposure, and lower Apgar scores. IV induction sory warning not to breastfeed when using tramadol or codeine
agents, opioids, and hypnotics readily cross the placenta, while [98]. Opioid PCA may be required by some individuals, such as in
neuromuscular blocking agents do not [75]. cases where regional anesthesia with a long-acting opioid was not
used. An opioid PCA is not required for most patients and should
Post–vaginal delivery analgesia not be the default order in the postoperative period.
After a vaginal delivery, women may experience pain from uter- These methods may not be effective for adequate post-cesarean
ine cramping or perineal laceration. Typical first-line analgesic pain control in some situations. This includes women with aller-
methods include abdominal heating pads for uterine cramps, per- gies to NSAIDs and acetaminophen, women with substance
ineal ice packs, and topical lidocaine applied to the perineum. The use disorder, and those undergoing cesarean hysterectomy.
data to support these methods is limited [76–78]. Oral analgesics Ketamine is an adjunct that has been shown to improve post-
such as nonsteroidal antiinflammatory drugs (NSAIDs) and acet- operative pain scores and decrease opioid use that may be used
aminophen may be used as needed or scheduled. NSAIDs have when pain is not optimally controlled [99]. Additional analgesics,
been shown to be superior to acetaminophen [79]. Oral or IV such as a lidocaine patch, pregabalin, and gabapentin, are also
opioids should be reserved for severe or breakthrough pain, and options; however, there are limited data on their efficacy follow-
these medications should be limited to the lowest effective dose ing CD [100–103]. Finally, an epidural catheter may be left in
for the shortest necessary duration. place for women at risk of poor pain control or those undergo-
ing more extensive surgery. This can be titrated for an analgesic
Post-CD analgesia effect, rather than anesthesia.
Pain management following CD is important for patient and
provider experiences, bonding with the newborn, minimizing Anesthetic emergencies
the risk of postpartum depression, and improving breastfeeding
[80–82]. However, studies have shown that a significant num- An anesthetic emergency in the obstetric patient necessitates
ber of women become persistent users after opioid prescription clear and precise communication and cooperation between the
at the time of CD [83]. Optimizing alternative analgesic meth- anesthesia and obstetric teams. The goal is to stabilize the mother
ods after CD is therefore a priority. Preservative-free morphine while, if necessary, safely and quickly delivering the neonate.
hydrochloride administered at the time of spinal anesthesia or
following cord clamp when using epidural anesthesia provides Total spinal
effective pain relief in the first 12–24 hours after surgery and has A total spinal occurs with cephalad spread of local anesthetic
been shown to limit opioid use in this period [5, 84]. to the breathing centers of the brainstem. This can result from
For patients unable to receive regional anesthesia with long- unintentional intrathecal placement of an epidural dose of local
acting opioids, the transversus abdominis plane (TAP) block anesthetic or from subdural catheter placement with subsequent
may be utilized. It is performed by injecting local anesthetic migration of the catheter. Agitation, difficulty speaking, and
between the internal oblique and transversus abdominis muscles profound hypotension are signs of a total spinal. Control of the
to block the plexus of nerves supplying the anterior abdominal airway with endotracheal intubation, blood pressure support
wall. In a randomized controlled trial comparing intrathecal opi- with fluid, vasopressors, and left uterine displacement should
oid to TAP block after CD, intrathecal opioid was superior, and be performed immediately. Once the airway has been secured,
patients receiving TAP block had increased opioid consumption assessment of the fetus should be facilitated. If the fetus is stable,
in the immediate postoperative period [85]. The TAP block is a delivery can safely await maternal recovery.
reasonable alternative in a patient with a contraindication to a
neuraxial block [86, 87]. Local anesthetic systemic toxicity
Following surgery, scheduled NSAIDs and acetaminophen IV injection of local anesthetics can lead to systemic toxicity,
have been shown to decrease opioid use and improve pain scores including seizures and cardiovascular collapse. The mother’s air-
[88–90]. While the optimal dose and route of these medications way should be controlled immediately, and delivery of the fetus is
are unclear, IM or IV administration of NSAIDs does appear to often indicated because of maternal instability. Seizures can be
be more effective than oral administration [91]. Acetaminophen quickly terminated with administration of diazepam. The phar-
may also be administered intravenously, although there is con- macologic treatment of local anesthetic systemic toxicity (LAST)
flicting data on the efficacy of the IV route when compared to is different from other cardiac arrest scenarios. Management
oral or rectal administration [92–96]. Because IV acetaminophen of cardiac arrest includes treatment according to the American
is significantly more expensive than other formulations, many Heart Association/Advanced Cardiac Life Support (AHA/ACLS)
institutions opt to use oral acetaminophen. In general, medi- guidelines with adjustment of medications and possibly pro-
cations that combine acetaminophen with an opioid should be longed effort as per ASRA guidelines [104]. Administration of
avoided. Compared to scheduled acetaminophen, combination Intralipid, a 20% fat emulsion, has been shown to increase the
medications, such as oxycodone-acetaminophen (Percocet), have survival rate of patients who experience cardiac arrest secondary
been shown to increase opioid consumption overall [97], and such to LAST [104, 105].
medications are known to have higher associated street value,
making them more prone to abuse by other community members. Failed intubation
Opioids should be reserved for breakthrough pain that is The risk of failed intubation is increased in the parturient at
not controlled with around-the-clock acetaminophen and approximately 1 in 300—nearly eight times that of the gen-
NSAIDs. In general, the lowest possible dose of opioids, if eral population (1:2330) [72, 73]. Increased edema in the upper
needed, should be used on an as-needed basis, and these med- airway, increased breast size, and increased friability of the
ications should be administered orally if the patient is able to mucosa increase chance of failure. In addition, parturients have
decreased functional residual capacity that decreases their apneic 5. American Congress of Obstetricians and Gynecologists. ACOG Practice
oxygen reserve and are at higher risk for aspiration secondary to Bulletin No. 209: Obstetric Analgesia and Anesthesia. Washington, DC:
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13
OPERATIVE VAGINAL DELIVERY
Adeeb Khalifeh and Megan Piacquadio
Key points implies a mechanism for facilitating vaginal delivery of a healthy

infant while minimizing maternal risk.
• Vacuum- and forceps-assisted deliveries have the same In modern obstetrics, OVD, whether forceps or vacuum, is used
indications. There are no circumstances where opera- to expedite safe vaginal delivery for maternal or fetal indications.
tive vaginal delivery is definitely indicated. Alternatives, Despite wide variations in different countries [1], in appropriate
including allowing the patient to labor longer, oxytocin circumstances, OVD has a crucial role in safely avoiding primary
augmentation, and cesarean delivery, should always be cesarean delivery (CD). Emphasis should be placed on indica-
considered. tions, contraindications, and prerequisites for an OVD, with
• When used by experienced operators, operative vaginal instrument choice based on clinical circumstances and operator
delivery is safe for both mother and baby and effective in skill to minimize maternal and neonatal morbidity.
obtaining vaginal delivery, with forceps having slightly
higher success rates. Incidence
• Ultrasound before operative vaginal delivery is more accu-
rate than digital examination (>99% versus 80% accuracy, Rates of OVD (forceps and vacuum) have been declining in the
respectively). United States. The rate of OVD decreased from 9.01% in 1992 to
• Forceps achieve a vaginal delivery more often than vac- 3.30% in 2013. In 2013, forceps-assisted deliveries accounted for
uum, 91% versus 86%, respectively. Complication rates only 0.59% of live births [2].
differ between vacuum and forceps, with the predomi-
nant differences being that maternal third- and fourth-
degree perineal (14% versus 7.5%) and vaginal wall (26%
Indications
versus 8%) injuries are more common with forceps- Both forceps and vacuum have the same indications. Use should
assisted delivery. Neonatal facial injury is uncommon depend mostly on proper evaluation of the patient’s labor, risk
with operative delivery, 1.7% with forceps and 0.2% with factors, clinical pelvimetry, estimated fetal weight, and operator
vacuum. The choice of instrument is decided after appro- experience. There are no circumstances where OVD is definitely
priate counseling and depends also on operator experience. indicated. Alternatives, including allowing the patient to labor
• There is insufficient evidence to compare different types of longer, oxytocin augmentation, and CD, should always be con-
forceps. sidered. OVD is usually considered for the following [3]:
• Soft vacuum cups fail at attaining vaginal delivery more
often than by rigid cups but have a lower rate of sig- • Maternal:
nificant fetal scalp trauma. Rigid cups may be better for • Prolonged second stage: At least 3 hours in nullipa-
occiput posterior and other more difficult deliveries, while rous women and at least 2 hours in multiparous women
soft cups may be better suited for less complicated, routine (longer duration are possible on individualized basis, e.g.
deliveries. with the use of epidural analgesia) [4] (See also Chap. 9)
• If attempted, delivery with a vacuum should ideally be • Shortening of the second stage of labor for maternal
achieved within 5 minutes from vacuum application benefit (e.g. underlying medical condition preclud-
and, in general, should be discontinued if the vacuum cup ing pushing)
pops off the fetal head three times. • Inefficient maternal effort (e.g. exhaustion or under-
• Attempting to use a different extraction instrument lying medical condition precluding pushing)
after failing with one should be avoided due to increased • Fetal:
incidence of fetal injury. • Suspicion of fetal compromise
“Elective” forceps delivery, that is, without an indication, is

Historical perspectives associated with increased maternal perineal trauma and, given
Operative vaginal delivery (OVD) has been practiced for centu- the other potential maternal and neonatal complications, should
ries. Its initial function was fetal extraction during prolonged not be preferred to spontaneous vaginal delivery [5].
dysfunctional labor in an attempt to preserve the life of the labor-
ing woman. The invention of modern forceps can be traced back Contraindications to operative
to the Chamberlain family in Europe during the 16th century. vaginal delivery
Vacuum extraction was first described by Dr. James Yonge in
1705. The modern evolution of vacuum delivery (also called ven- Contraindications to OVD are listed in Table 13.1. Severe scalp
touse) can be attributed to Malmström’s metal cup vacuum sys- trauma and unexplained active bleeding may be relative con-
tem developed in 1954. OVD has evolved significantly and today traindications in individual cases. OVD should be used with
152 DOI: 10.1201/9781003102342-13

Operative Vaginal Delivery 153
TABLE 13.1: Contraindication to Operative Vaginal Delivery blades and overlapping shanks), and Elliot forceps (fenes-
trated blades, overlapping shanks, and largest cephalic cur-
• Nonvertex presentation
vature). Many of these forceps have been modified with a
• Unengaged fetal head
Luikart pseudofenestration of the blade.
• Unknown fetal head position
• Rotational forceps: These have a cephalic curvature but lack
• Fetal prematurity such as <34 weeks (vacuum) a pelvic curvature. Also have a sliding lock to allow forceps
• Known fetal coagulation disorders (e.g. hemophilia, NAIT, to slide to correct asynclitism of the fetal head if present.
von Willebrand disease) After rotation of the fetal head is accomplished, classical for-
• Known fetal bone demineralization conditions (e.g. osteogenesis ceps should be used to complete the delivery. Types include
imperfecta) Kielland, Luikart, Barton, and Salinas forceps.
Source: From data in Ref. [3]. • Forceps for breech delivery: These are indicated to help
Abbreviation: NAIT, neonatal alloimmune thrombocytopenia. with the aftercoming head in a breech delivery. These forceps
lack a pelvic curvature and have blades that are beneath the
extreme caution in women with maternal diabetes, prolonged plane of the shank. Types include Piper and Laufe forceps.
labor, and fetal macrosomia, with appropriate preparations due
to an increased risk of shoulder dystocia. Types of vacuum extractors
Vacuum extractors were originally designed with a rigid metal
Risks for failed operative vaginal delivery cup. Subsequently, soft cups have been developed. Several types
Risks for failed vacuum or forceps vaginal delivery include of rigid (metal or plastic) and soft (silicone plastic or rubber)
increased maternal age, increased body mass index, diabetes, vacuums are in clinical use [10–12]. Among different types of
polyhydramnios, macrosomia, occiput posterior (also increases vacuums, the metal cup is more likely to result in a success-
rates of third- and fourth-degree perineal lacerations), dysfunc- ful vaginal birth than the soft cup (9% versus 17%), with more
tional labor, and prolonged labor [6, 7]. cases of scalp injury (41% versus 30%) and cephalohematoma
(14% versus 8%). The handheld ventouse is associated with more
failures than the metal ventouse and a trend to fewer than the soft
Classification of operative ventouse [10–13].
vaginal delivery [3] Rigid cups may be better for occiput posterior and other
more difficult deliveries, while soft cups are better suited for
• Outlet: Scalp is visible at introitus without separating the less complicated, routine deliveries [10]. Maternal injury, low
labia, fetal skull has reached pelvic floor, sagittal suture is Apgar scores at 1 or 5 minutes, umbilical artery pH <7.20, hyper-
anteroposterior (AP) diameter or right or left occiput ante- bilirubinemia/phototherapy, retinal/intracranial hemorrhage,
rior or posterior position, fetal head is at or on perineum, and perinatal death do not differ between soft and rigid vacuum
and rotation ≤45 degrees. cups [10, 13]. Soft vacuum cups have largely replaced the rigid
• Low: Leading point of the fetal skull is at station ≥+2 cm and cup in routine clinical practice. For a comprehensive review of
not on the pelvic floor, rotation is ≤45 degrees (left or right vacuum delivery, see Ref. [14].
occiput anterior to occiput anterior or left or right occiput
posterior to occiput posterior), or rotation is >45 degrees. Possible complications of operative vaginal deliveries
• Mid: Station is above +2 cm but head is engaged.
1. Maternal
Originally devised for forceps, this classification is valid for any • Forceps use is associated with a sixfold increase in
OVD, including vacuum [8]. third- and fourth-degree perineal tears compared to
a spontaneous vaginal delivery [15].
Types of forceps • Vacuum use is associated with a twofold increase in
third- and fourth-degree lacerations compared to
There are many different designs for forceps, but all consist of two spontaneous vaginal deliveries [15].
separate halves that each have the same four basic components: • Forceps delivery has an increased risk of anal sphinc-
Blade, shank, lock, and handle. There is insufficient evidence to ter injury compared to vacuum delivery [10].
compare different types of forceps, and it is recognized that • Urinary, flatus, liquid, and solid incontinence is
the choice is often subjective. In the only small trial performed, similar at 1 year in women who had OVD compared
severe facial abrasion was decreased from 4.1% to 1.9% from the to women who had a second-stage CD [16].
regular forceps compared with soft forceps, as were minimal • Pelvic floor and sexual function do not differ at 1 year
markings (from 61% to 34%, respectively) [9]. Unfortunately, postpartum compared to women who had CD [17].
successful delivery rates for the two different forceps were not • In the absence of anal sphincter injury, anal incon-
reported, and the soft forceps were self-made. Given the paucity tinence rates at 5–10 years are similar to those in
of data, choice of forceps type is operator dependent. women who had a spontaneous vaginal delivery [18].
2. Neonatal
• Classical forceps: These have cephalic and pelvic curva- • Intracranial hemorrhage rate is increased in OVD,
tures. Usually indicated when no rotation of the fetal head but the absolute risk is low [19].
is necessary before delivery. Common types include the fol- • The rates of intracranial hemorrhage and neonatal
lowing: Simpson forceps (fenestrated blades and nonover- encephalopathy compared to second-stage CD are
lapping shanks), Tucker-McLane forceps (nonfenestrated similar [19, 20].
• Cephalohematoma, fetal scalp lacerations, retinal the general population [26]. However, the diagnosis of
hemorrhages, subgaleal hematoma, and intracra- cephalohematoma can be falsely positive in up to 75% of
nial hemorrhages have been reported in vacuum cases [27].
deliveries. • Retinal hemorrhages tended to be less common in forceps
• Facial lacerations, facial nerve palsy, and corneal than vacuum deliveries (5% versus 8%; RR 0.68, 95% CI 0.43–
abrasion are more common with forceps delivery. 1.06) [12]. One study found retinal hemorrhages occurred in
• Long-term cognitive outcomes are similar to spon- 18% in spontaneous vaginal deliveries [28]. The clinical sig-
taneous vaginal deliveries [21, 22]. nificance of retinal hemorrhages remains unclear [26].
• Recent data show that the duration of OVD, more • Rates of scalp/face injury other than cephalohematoma,
specifically vacuum duration, is correlated to a use of phototherapy, perinatal death, readmission to hos-
greater risk of adverse neonatal outcomes [23]. pital, and hearing or vision disability are similar between
forceps- and vacuum-assisted vaginal deliveries [10, 29].
• Other possible uncommon fetal complications associated
Comparison of forceps- versus with OVD include facial nerve injury, corneal abrasions,
vacuum-assisted delivery [10] facial bruising, and lacerations. Very rare findings include
facial nerve palsy, skull fractures, cervical spine injury, and
Safety/Complications intracranial hemorrhage. With vacuum-assisted delivery,
Maternal life-threatening neonatal injuries include subgaleal (sub-
• There is a trend for less regional (37% versus 40%) and aponeurotic) hematoma (0%–4%). Intracranial hemor-
significantly less general anesthesia (1% versus 10%) rhage is a rare complication of OVD (0%–2.5%).
with vacuum-assisted compared to forceps-assisted
deliveries. We do not use general anesthesia for operative Efficacy
delivery. Both vacuum- and forceps-assisted delivery have high deliv-
• Third- and fourth-degree perineal (14% versus 7.5%; rela- ery success rates (with vacuum from 83% to 94% and with for-
tive risk [RR] 1.89, 95% confidence interval [CI] 1.51–2.37) ceps from 78% to 92%) [10, 27]. Forceps are less likely than the
and vaginal wall lacerations (26% versus 8%; RR 2.48, vacuum to fail to achieve a vaginal birth with the allocated
95% CI 1.59–3.87) (maternal trauma) are significantly instrument (9% versus 14%; RR 0.65, 95% CI 0.45–0.94) [10].
increased with forceps compared with vacuum. CD occurred in 4.5% of forceps and 2.6% of vacuum deliveries,
• Severe perineal pain at 24 hours is decreased (9% versus as in these studies unfortunately, failed vacuum would at times
15%) with vacuum- compared to forceps-assisted deliveries. be followed by forceps, which, in general, should not be done [10].
• Flatus incontinence or altered continence is more common
with forceps compared to vacuum in a small trial (59% ver- Alternatives to operative vaginal delivery
sus 33%; RR 1.77, 95% CI 1.19–2.62). In one randomized Alternative management should always be discussed with the
controlled trial (RCT) comparing forceps and vacuum patient. This includes continued expectant management for
delivery, there was no difference in either bowel or uri- prolonged second stage in the presence of a reassuring fetal
nary dysfunction 5 years postpartum [24]. status, oxytocin augmentation, or proceeding with a CD.
• Rates of moderate/severe pain at delivery, endoanal ultra- However, the appropriate use of OVD is encouraged by the
sound abnormalities [24], and other maternal outcomes are American Congress of Obstetricians and Gynecologists (ACOG)
similar. to safely prevent the primary CD [4].
• Rotational forceps does not increase adverse maternal out-
come compared to rotational vacuum delivery [25]. Summary
There is a recognized place for forceps and all types of vacuums in
Fetal/Neonatal clinical practice [10]. The role of operator training with any choice
• Facial injury is more likely with forceps (1.7% versus 0.2%; of instrument must be emphasized. The increasing risks of failed
RR 5.10, 95% CI 1.12–23.25). delivery with the chosen instrument from forceps, to metal cup,
• Using a random effects model because of heterogeneity to handheld, to soft cup vacuum and the trade-offs between the
between studies, there was a trend toward fewer cases of risks of maternal and neonatal trauma (see Table 13.2) need to be
cephalohematoma with forceps (5% versus 9%; RR 0.64, considered when choosing an instrument. Overall, forceps or the
95% CI 0.37–1.11). Rates of cephalohematomas occur in metal cup appears to be most effective at achieving a vaginal
about 10% versus 4% in vacuum and forceps, respectively birth, but with increased risk of maternal trauma with forceps
[10]. Cephalohematomas have an overall rate of 2.5% in and neonatal trauma with the metal cup [10].
TABLE 13.2: Comparison of Forceps versus Vacuum for Operative Vaginal Delivery
Fetal Maternal
Favors Forceps Favors Vacuum Favors Forceps Favors Vacuum
Less facial injury (0.2% versus 1.7%) Less likely to fail to deliver vaginally Fewer third- and fourth-degree perineal tears (7.5%
the baby (9% versus 14%) versus 14%) and vaginal wall (8% versus 26%)
lacerations
Less severe perineal pain postpartum (9% versus 15%)
Source: From data in Ref. [10].
Operative Vaginal Delivery 155
Management 0.11, 95% CI 0.09–0.13) and forceps delivery (OR 0.08, 95% CI
0.07–0.11), compared with no episiotomy. The number of medio-
Preoperative assessment lateral episiotomies needed to prevent one sphincter injury in
Counseling vacuum extractions was 12, whereas 5 mediolateral episiotomies
Review with the patient the indication, risks (possible complica- could prevent one sphincter injury in forceps deliveries [36, 37].
tions) and benefits, and type of instrument to be used for OVD. Episiotomy should not be routinely performed, as it is associ-
The option of CD, including its risks and benefits, should also be ated with perineal lacerations in nonoperative vaginal deliveries.
reviewed. Obtain verbal or written informed consent prior to OVD. However, episiotomy should not be used as an obstetric quality
measure in assisted vaginal deliveries, as this could decrease fur-
Preparation/Documentation (Table 13.3) ther the use of OVD and increase the CD rate [38].
aternal: Sufficient analgesia, clinical assessment of pelvis,
M
lithotomy position, ± empty bladder. Antibiotic prophylaxis
Fetal: Vertex presentation, head engaged (lower part of bony ver- OVD increases the risk for postpartum infection and readmis-
tex—not caput—at or lower than level of ischial spines), knowl- sion to hospital when compared to spontaneously vaginal deliv-
edge of the position of the head, asynclitism, and estimated fetal ery. Two grams of cefotetan IV at the time of vacuum or forceps
weight. Suboptimal instrument placement increases maternal delivery are associated with a nonsignificant decrease (0% versus
and neonatal morbidity [30]. 3.5%) in endometritis [39]. A more recent RCT, the ANODE trial,
U ltrasound: Several studies have investigated the role of ultra- showed patients in the United Kingdom who received a single dose
sound in OVD. In one RCT, the use of ultrasound significantly of co-amoxiclav (1 g amoxicillin/200 mg clavulanic acid) follow-
decreased the incidence of incorrect diagnosis of fetal head ing OVD were at significantly decreased risk for infection within
position [31]. The measurement of ultrasound distance between 6 weeks of delivery. However, aspects of the ANODE trial may
the perineum and fetal skull has been shown to be a reproduc- make these findings ungeneralizable to U.S. patient populations.
ible and predictive measure of the difficulty of OVD [32]. Another For example, 89% of patients in the study received an episiotomy
study demonstrated ultrasound measurements of head circum- (majority mediolateral), which is routinely performed in the United
ference and angle of fetal head progression as predictors of Kingdom [40]. Therefore a single dose of co-amoxiclav at the time
OVD complications, defined as the need for three or more trac- of delivery may be reasonable in patients with OVD and con-
tions, third- and fourth-degree lacerations, hemorrhage during comitant episiotomy. However, antibiotic prophylaxis cannot be
episiotomy repair, and/or neonatal trauma [33]. However, an RCT recommended solely for the indication “operative vaginal deliv-
demonstrated ultrasound did not show any benefits in reducing ery.” Of note, there is an increased risk for wound infections and
the risk of failed operative delivery or maternal and fetal morbid- complications in patients with third- and fourth-degree lacerations;
ity. Moreover, patients randomized to the transabdominal ultra- thus, one may consider prophylactic antibiotics in this setting [3].
sound arm were noted to have a higher rate of episiotomy [34].
See figures in Chap. 9. Vacuum application
Uteroplacental: Cervix completely dilated, ruptured mem- Vacuum application, if performed, should begin with low suc-
branes, absence of placenta previa, or other contraindications. tion and be slowly increased to vacuum of about 0.7–0.8 kg/cc2
Other: Alert nursing, anesthesia, and neonatology of plan for (500–600 mmHg). Compared with stepwise negative pressure for
OVD. Be prepared for possible shoulder dystocia. Willingness to vacuum delivery, rapid negative pressure application is associated
discontinue the procedure if it does not proceed as planned [2]. with reduced duration (by 6 minutes) of vacuum procedure, but no
other maternal or perinatal effects, in a small trial [25]. No torque
Episiotomy or rocking motions should be applied to the vacuum. Traction
There is insufficient evidence (no trials) to assess the benefits and should only be in the direct line of the vaginal canal. The risk
risks of episiotomy in operative deliveries. Lateral episiotomy has of cephalohematoma increases as the time of vacuum application
been shown to be protective against anal sphincter injuries in increases. There is no evidence that reducing pressure between
vacuum deliveries, compared to mediolateral and median episi- contractions decreases the risk of fetal injuries [41]. Most deliver-
otomies, in a meta-analysis [35]. In a large observational study, ies are achieved with one to three pulls, with increased neonatal
mediolateral episiotomy protected significantly against anal trauma (45%) after three pulls [42]. The risk of cephalohematoma
sphincter damage in both vacuum extraction (odds ratio [OR] is increased after 5 minutes of vacuum application [43].
TABLE 13.3: Preoperative Checklist before Operative Delivery

Maternal Criteria Fetal Criteria Uteroplacental Criteria Other Criteria
Sufficient analgesia Vertex presentation Cervix fully dilated Obtain patient’s informed consent
Alert nursing, anesthesia, and neonatology
Patient in the lithotomy position The fetal head must be engaged Membranes ruptured An experienced operator who is fully acquainted
in the pelvis with the use of the instrument
Bladder has been emptied The position of the fetal head No placenta previa Ability to monitor fetal well-being continuously
must be known with certainty;
perform ultrasound before OVD
Clinical pelvimetry must be The station of the fetal head The capability to perform an emergency cesarean
adequate in dimension and size to must be +2 or more delivery if required
facilitate an atraumatic delivery
Failed operative delivery Network. Duration of operative vaginal delivery and adverse obstetric out-
comes. Am J Perinatol. 2020;37(5):503–510.
Attempting to use a different extraction instrument after fail-
24. Fitzpatrick M, Behan M, O’Connel PR, et al. Randomized clinical trial to
ing with one should be avoided, as cephalopelvic disproportion assess anal sphincter function following forceps or vacuum assisted vaginal
may be present, and the highest incidence of neonatal intracra- delivery. Br J Obstet Gynecol. 2003;110:424–429. [RCT, n = 130]
nial hemorrhage, as well as other neonatal injuries, is highest 25. Al Wattar BH, Al Wattar B, Gallos I, Pirie AM. Rotational vaginal delivery
among infants delivered using forceps and vacuum sequentially [29, with Kielland’s forceps: A systematic review and meta-analysis of effective-
ness and safety outcomes. Curr Opin Obstet Gynecol. 2015;27(6):438–444.
44–46]. At that point, cesarean is usually offered and performed. [Meta-analysis; I]
26. Uhing M. Management of birth injuries. Clin Perinatol 2005;32(1):19–38.
Postpartum [II-3]
It is essential to examine carefully both the fetus and the mater- 27. Williams M, Knuppel R, O’Brien W, et al. A randomized comparison of
nal perineum after OVD. assisted vaginal delivery by obstetric forceps and polyethylene vacuum cup.
Obstet Gynecol. 1991;78:789–794. [RCT; I]
28. Williams M, Knuppel R, O’Brien W, et al. Obstetric correlates of neonatal
References retinal hemorrhage. Obstet Gynecol. 1993; 81:688–694. [II-2]
29. Bofill JA, Rust OA, Schorr SJ, et al. A randomized prospective trial of the
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ventions in 12 countries. Paediatr Perinat Epidemiol. 1993;7:45–54. [II-3] 1996;175:1325–1330. [RCT; I]
2. National Vital Statistics. Reports Volume 64, Number 1, Centers for Disease 30. Ramphul M, Kennelly MM, Burke G, Murphy DJ. Risk factors and mor-
Control. January 2015. [Epidemiologic data] bidity associated with suboptimal instrument placement at instrumental
3. Operative vaginal birth. Obstet Gynecol. Committee on Practice Bulletins— delivery: Observational study nested within the Instrumental Delivery &
Obstetrics. ACOG Practice Bulletin No. 154: Operative vaginal delivery. Ultrasound randomised controlled trial. BJOG. 2015;122(4):558–563.[II-1]
Obstet Gynecol. 2020;134(4):149–e159. [Guideline] 31. Ramphul M, Ooi PV, Burke G, et al. Instrumental delivery and ultrasound:
4. Obstetric care consensus. ACOG safe prevention of primary caesarean A multicentre randomised controlled trial of ultrasound assessment of the
delivery. [Guideline] fetal head position versus standard care as an approach to prevent morbid-
5. Yancey MK, Herpolsheimer A, Jordan GD, et al. Maternal and neonatal ity at instrumental delivery. BJOG. 2014;121(8):1029–1038.[RCT; I]
effects of outlet forceps delivery compared with spontaneous vaginal deliv- 32. Kasbaoui S, Séverac F, Aïssi G, et al. Predicting the difficulty of operative
ery in term pregnancies. Obstet Gynecol. 1991;78:646–650. [II-2] vaginal delivery by ultrasound measurement of fetal head station. Am J
6. Gopalani S, Bennett K, Critchlow C. Factors predictive of failed operative Obstet Gynecol. 2017;216(5):507.e1–507.e9. [II-2]
vaginal delivery. Am J Obstet Gynecol. 2004;191:896–902. [II-3] 33. Sainz JA, García-Mejido JA, Aquise A, Borrero C, Bonomi MJ, Fernández-Palacín
7. Elfituri A, Datta T, Hubbard HR, Ganapathy R. Successful versus unsuc- A. A simple model to predict the complicated operative vaginal deliveries using
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Obstet Gynecol Reprod Biol. 2020;244:21–24. [II-3] 34. Ghi T, Dall’Asta A, Masturzo B, et al. Randomised Italian sonography for
8. Weinstein L, Calvin S, Trofatter KR. Operative vaginal delivery: Risks and occiput POSition Trial Ante vacuum (R.I.S.POS.T.A.). Ultrasound Obstet
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9. Roshan DF, Petrikovski B, Sichinava L, et al. Soft forceps. Int J Obstet 35. Sagi-Dain L, Sagi S. Morbidity associated with episiotomy in vacuum deliv-
Gynecol. 2005;88:249–252. [II-2] ery: A systematic review and meta-analysis. BJOG. 2015;122(8):1073–1081.
10. O’Mahony F, Hofmeyr GJ, Menon V. Choice of instruments for assisted vaginal [Meta-analysis]
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11. Attilakos G, Sibanda T, Winter C, et al. A randomized controlled trial risk for anal sphincter injury during operative vaginal delivery. Br J Obstet
of a new handheld vacuum extraction device. Br J Obstet Gynecol. Gynecol. 2008;115:104–108. [II-3]
2005;112:1510–1515. [RCT; I] 37. de Vogel J, van der Leeuw-van Beek A, Gietelink D, et al. The effect of a
12. Groom KM, Jones BA, Miller N, et al. A prospective randomized controlled mediolateral episiotomy during operative vaginal delivery on the risk
trial of the Kiwi Omnicup versus conventional ventouse cups for vacuum- of developing obstetrical anal sphincter injuries. Am J Obstet Gynecol.
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of Child Health Human Development Maternal-Fetal Medicine Units
14
CESAREAN DELIVERY
A. Dhanya Mackeen and Meike Schuster
Key points • Tranexamic acid should be used prophylactically pre-

operatively, particularly in women at increased risk for
• A cesarean delivery on maternal request (CDMR) or a PPH.
planned repeat CD without other indication should not • Gentle cord traction with uterine massage for sponta-
be performed before 39 weeks. neous placental removal is recommended.
• The optimal CD rate is unknown, though ≥19% is the • Continuous, full-thickness, one-layer uterine closure is
CD rate associated with lower maternal and neonatal recommended if the woman is planning no more preg-
mortality. CD rates of less than 15–19% have been associ- nancies (e.g. receives tubal ligation). For women plan-
ated instead with higher neonatal mortality rates. ning future pregnancies, especially after primary CD,
• Prophylactic antibiotics should be administered before the uterus can be closed in two layers.
every CD. The evidence suggests the use of a single dose • Routine intraabdominal irrigation is not recommended.
of cefazolin (e.g. 1 gram) or ampicillin IV be given • Routine use of adhesion preventions barriers is not
30–60 minutes prior to skin incision. Higher doses (e.g. recommended.
2–3 grams) are appropriate for patients with greater • There is no evidence to justify the time taken and the
body mass indexes (BMIs). If performing CD in labor cost of peritoneal closure, so it should be avoided.
or after rupture of membranes (ROM) >4–6 hours, add • Continuous nonlocking fascial closure with delayed
azithromycin. absorbable suture at about 5- to 10-mm intervals should
• All women undergoing CD should receive mechani- be considered.
cal venous thromboembolism (VTE) prophylaxis with • Subcutaneous tissue should be irrigated and closed
either pneumatic compression devices or compres- with sutures, especially if ≥2 cm in thickness. Routine
sion stockings. These should be applied preoperatively drainage should be avoided.
and continued until full ambulation. In women with • The low transverse cesarean skin incision should be
a history of VTE or inherited thrombophilia, phar- closed with suture, regardless of obesity status.
macologic prophylaxis with subcutaneous enoxapa- • Gum chewing after CD, typically three times/day for at
rin 40 mg daily (preferred) or UH 5000 units every least 30 minutes each time, is associated with earlier
8–12 hours should also be initiated and continued for return of bowel sounds, passage of flatus and stool, and
6 weeks postpartum. In women with these risk factors less ileus.
and class III obesity, enoxaparin 40 mg every 12 hours • Early oral fluids and even food within 6–8 hours after
should be considered. CD is recommended.
• Manual displacers may be better than left lateral tilt for • Nonsteroidal anti-inflammatory drugs (NSAIDs) and
maternal positioning. acetaminophen should be administered around the
• If opting to remove pubic hair, an electric clipper applied clock for post-CD pain relief. Wound infiltration with
the morning of the surgery is preferred to shaving. local analgesia and abdominal nerve blocks can also be uti-
• The use of chlorhexidine (preferred) or povidone-iodine is lized. Narcotics should only be used if and when these
recommended for skin cleaning before skin incision at CD. interventions do not control the pain.
• Vaginal cleansing with chlorhexidine or povidone- • Reclosure of the disrupted laparotomy wound with
iodine before CD is recommended. adhesive tape or surgically is associated with success in
• Active warming decreases maternal and neonatal >80% of women, faster healing times, and fewer office visits
hypothermia. as compared to healing by secondary intention.
• Adhesive drapes should be avoided at CD due to their
association with a higher incidence of wound infection. Historic notes
• The fascia can be transversely incised initially with the
scalpel and the incision extended bluntly or sharply The word cesarean is probably derived either from the “Lex
with scissors. Regia,” later called “Lex Cesarea,” which allowed the postmor-
• Routine development of a bladder flap is not necessary tem abdominal delivery of the child in ancient Rome, or from
for CD. the Latin “caesare,” which means “to cut.” Until the late 1800s,
• The uterus should be incised transversely with a scalpel most cesarean deliveries (CDs) were done after maternal death
and the incision expanded bluntly with the fingers in a for attempt at fetal salvage. In 1882, the era of modern CD began
cephalocaudal direction. when Saenger advocated closing all uterine incisions immedi-
• Misoprostol plus oxytocin or carbetocin was more ately after surgery. The lower uterine segment incision was intro-
effective than oxytocin alone at preventing postpartum duced by Kronig in 1912 and popularized in the United States by
hemorrhage (PPH) ≥ 500 mL in the setting of CD. DeLee in 1922. The transverse uterine incision was described by
DOI: 10.1201/9781003102342-14 157

Munro-Kerr in 1926 [1]. CD has been associated with relatively and fear or concerns about vaginal delivery persist. This prac-
low maternal mortality for about 100 years. Safety has improved tice is supported by the American Congress of Obstetricians
in the last 50 years, especially with the introduction of antibiotics and Gynecologists (ACOG), the Society of Obstetrics and
and improvement of surgical techniques. Gynecology of Canada, the Brazilian Medical Association,
and the National Institutes of Health State-of-the-Science
Diagnosis/Definition Conference on Cesarean Delivery on Maternal Request [4–7].
Uniformly, these medical authorities recommend shared
Birth via abdominal route by laparotomy. decision-making between patient and provider and that the
provider explore the patient’s motivation for CDMR to help
determine the most appropriate mode of delivery. Two meta-
Epidemiology/Incidence analyses found increased risks of bleeding, infections, and
CD is now the most common surgical procedure in the United respiratory complications associated with unindicated CD
States, with over 1.2 million performed each year. Its incidence [6, 8], while two other meta-analyses found increased urinary
has increased to 32% of all deliveries in the United States in 2018 incontinence and pelvic organ prolapse, but not anal inconti-
[2]. This increase has been fueled, at least in part, by increased nence [9, 10], associated with vaginal delivery.
multifetal gestations and decreased trial of labor after cesarean There is insufficient evidence to assess the benefits and risks
(TOLAC) and vaginal breech deliveries. of a policy of CDMR compared with trial of labor in women with
term singleton gestations in cephalic presentation. The most
common reason for CDMR is fear of labor pain. CDMR should
Indications not be motivated by the unavailability of effective pain medica-
Commonly accepted indications for CD are failure to progress tion. There is also no randomized controlled trial (RCT) to evalu-
(aka arrest of dilation, arrest of descent, suspected cephalopelvic ate the obstetrician’s recommendation for CD without indication.
disproportion [CPD], dystocia, etc.), nonreassuring fetal heart With the absence of strong trials, the short- and long-term out-
rate tracing, nonvertex presentation, etc. (Figure 14.1). See spe- comes after CDMR versus trial of labor cannot be assessed.
cific chapters for details. There is insufficient evidence on the impact of counseling dur-
ing pregnancy with the aim of reducing the incidence of CDMR,
Cesarean by maternal request but counseling reduces anxiety and concerns related to preg-
Cesarean delivery by maternal request (CDMR) indicates that nancy and birth [11]. A practitioner is not obligated to perform
the sole reason for CD is the woman’s preference for CD and a CDMR, but should appropriately refer the woman as necessary.
her refusal to labor in the case of a cephalic, singleton gestation. Although CDMR and elective CD are commonly used synony-
Although the true rates are unknown, it is estimated that the mously, CDMR is the preferred term and should not be referred
incidence of CDMR is approximately 2% in the United States to as elective CD.
and less in low-income countries [3, 4]. CDMR has increased as A CDMR or a planned repeat CD without any other indica-
cesarean complications diminish, women have fewer children, tion should not be performed before 39 weeks.
Suspected macrosomia
4%
Nonreassuring
Malpresentation fetal status
18% 24%
Multiples Maternal request

7% 3%
Maternal-fetal
Preeclampsia 5%
3%
Arrest
36%
FIGURE 14.1 Primary cesarean delivery indications. (Adapted from Refs. 15, 347.)
Cesarean Delivery 159
Optimal CD rate guidelines with peer review [18], including precesarean consulta-
tion, mandatory second opinion, postcesarean surveillance, and
The optimal CD rate is unknown. Per the World Health audit, can lead to a 1–2% reduction in CD rates [19], predomi-
Organization (WHO), there were no reductions in maternal and nately in cases of intrapartum CD [20]. Conversely, guidelines
neonatal mortality with CD rates higher than 10% [12]. However, disseminated with endorsement and support from local opinion
it is important to note that this is based on an ecological anal- leaders resulted in a 13% decrease in CD rate (see Chap. 15) [19].
ysis at the population level and does not provide information Nurse-led relaxation classes and birth preparation classes
that can be used at an institutional or individual physician level may reduce CD rates in low-risk pregnancies [19]. Primary
[12]. Maternal and neonatal morbidity and mortality are the midwifery antenatal [21] and labor care in low-risk patients
important outcomes, not CD rate per se. A recent study on the may help decrease CD, but results are inconsistent [22–25].
relationship between CD rate and maternal and neonatal mor- Continuous labor support, such as a doula or nurse midwife, has
tality in 194 WHO member states revealed that about 19% was been associated with reduced rates of CD, lower rates of epidural
the CD rate associated with lower maternal and neonatal use, and more positive feelings about childbirth [25].
mortality [13]. CD rates of less than 15–19% have been associ- There is insufficient evidence that prenatal education and sup-
ated instead with higher neonatal mortality rates [14]. What is port programs, computer-based patient decision aids, decision-
most important is that a woman/fetus who needs a cesarean aid booklets, and intensive group therapy are effective. There is
can have one. insufficient evidence that training public health nurses, insur-
In centers with higher CD rates, strategies to decrease the ance reform, and legislative changes are effective.
rate should focus on the three main indications for CD: Arrest
(or dystocia, CPD), nonreassuring fetal heart rate tracings, and
malpresentation. These strategies include using 6 cm to define Timing of delivery
active labor, not performing CD for arrest before 6 cm or for pro-
In a study of 23,794 women, planned repeat CD at 37 or 38 weeks’
tracted disorders, reserving consideration of CD for arrest in the
gestation has a significantly increased risk of adverse neonatal out-
first stage of labor only for women ≥6 cm dilation with rupture
comes when compared with planned repeat CD at 39 or 40 weeks’
of membranes (ROM) who failed to progress despite ≥4 hours of
or expectant management [26]. A planned repeat CD should, in
adequate uterine activity, or ≥6 hours of inadequate uterine activ-
general, be performed at 390/7–396/7 weeks, unless there is a medi-
ity and no cervical change, calling a failed induction in the latent
cal indication for earlier delivery (Table 23.1, Chap. 23).
phase one which requires ≥18–24 hours of oxytocin after ROM,
using secondary means (e.g. scalp stimulation) to assure normal
fetal status in cases of nonreassuring fetal heart rate tracings, Preoperative considerations
routine use of external cephalic version for nonvertex presenta-
tions, use of operative vaginal delivery as appropriate, offering See Table 14.1 for summary of recommendations on how to per-
trial of labor after CD, and others [15, 16]. form a CD.
There are limited data of nonclinical interventions aimed Counseling should include a discussion of indications, ben-
at decreasing the unnecessary CD rate [17]. Implementation of efits, risks (including possible complications), and alternatives.
TABLE 14.1: Evidence-Based Recommendations for Cesarean Delivery (CDa)

CD Technical Aspect Comment
Prophylactic antibiotics
Yes or no Yes for all CDs
Antibiotic type First-generation cephalosporin or ampicillin preoperatively; add azithromycin if in labor or ROM >4–6 hours
Route of administration IV
Single dose Generally sufficient
Timing Administer 30–60 minutes before skin incision
Prophylaxis for VTE Mechanical prophylaxis with graduated compression stockings or pneumatic compression devices applied
preoperatively and continued until ambulation
In women with a history of VTE or inherited thrombophilia, pharmacologic prophylaxis should also be
initiated
Lateral tilt Manual displacers may be better than left lateral tilt, which is better than right lateral tilt
Indwelling bladder catheterization No complications with its avoidance; if placed, remove right after CD
Hair removal Pubic hair does not need to be removed; if the decision is made to remove hair, use hair clippers (not razors)
on the morning of the surgery
Skin cleansing Use chlorhexidine-alcohol (preferred) or povidone-iodine
Vaginal irrigation Use chlorhexidine-alcohol (preferred) or povidone-iodine
Active warming Consider performing
Adhesive drapes Avoid; use nonadhesive drapes
(Continued)
TABLE 14.1 (Continued): Evidence-Based Recommendations for Cesarean Delivery (CD)

CD Technical Aspect Comment
Skin incision
Type Transverse, Pfannenstiel, or Joel-Cohen
Changing to a second knife No need to change knife after skin incision
Subcutaneous dissection Blunt dissection is preferred
Fascial incision Transversely incise and extend bluntly or sharply
Rectus muscle cutting Avoid
Dissection of fascia off rectus Often unnecessary
Opening of peritoneum Bluntly
Bladder flap Avoid
Uterine incision
Type Low transverse uterine incision
Stapling device Not recommended
Expansion of uterine incision Bluntly in cephalocaudad direction with fingers
Fetal delivery Manual delivery of head preferred; reverse breech extraction recommended for delivery of impacted head
Skin-to-skin Recommended
Prevention of uterine atonya
Choice of agents Misoprostol plus oxytocin, or carbetocin
Oxytocin route IV
Oxytocin infusion rate Optimal rate unclear
Carbetocin Carbetocin superior or equivalent to oxytocin; should be used if available but associated with higher cost
Misoprostol Best if used in conjunction with oxytocin
Tranexamic acid Use prophylactically (especially in high-risk patients) to prevent postpartum hemorrhagea
Uterine massage No evidence of benefit
Placental removal
Spontaneous Spontaneous placental removal with gentle cord traction; avoid manual removal
Uterine exteriorization Either exteriorization or in situ repair is acceptable
Cleaning of uterus Can be performed, but may not be necessary
Cervical dilation Avoid
Closure of uterine incision
Two layers versus one layer Double layer generally, though single layer can be considered if bilateral tubal ligation performed
concurrently for closure of transverse incisions; double- or triple-layer closure for vertical incisions
Intraabdominal irrigation/drain Not recommended
Peritoneal closure Not recommended (for either parietal or visceral)
Reapproximation of rectus muscles Not recommended
Glove change Consider prior to closure of fascia
Fascial closure Recommended with continuous nonlocking delayed absorbable suture at 5- to 10-mm intervals
Subcutaneous irrigation Consider; if done, perform with 200 cc saline
Subcutaneous tissue closure Close subcutaneous space, especially if ≥2 cm
Subcutaneous tissue drain Not recommended
Closure of skin
Staples versus subcuticular suture Close transverse skin incision with suture, even in obese gravida
Negative pressure wound therapy Routine use not recommended
a See text for more details.
Abbreviations: CD, cesarean delivery; IV, intravenous; ROM, rupture of membranes; VTE, venous thromboembolism.
Informed consent should always be obtained after counseling. later have been directed at attempting to decrease SSI, blood loss,
A checklist, including pre-, intra-, and postoperative steps aimed and other CD morbidity [30].
at preventing complications, has been associated with benefits in
general surgery [27] and should probably be implemented prior Whom to give
to CD [28]. Prophylactic antibiotics should be administered before
every CD [31, 32]. They are associated with decreased inci-
Prophylactic antibiotics dence of endometritis by 62%, wound infection by 60%,
Surgical site infection (SSI) is a common complication after CD fever by 55%, and serious maternal infectious complications
(2–10%) and is associated with increased pain, morbidity, cost, by 69%. Urinary tract infections (UTIs) are also markedly
and more frequent office visits [29]. Many of the studies discussed decreased [33].
What to give compression stockings, and anticoagulants such as unfractionated

The efficacy of first-generation cephalosporins, such as cefazolin heparin (UH) or low-molecular-weight heparin (LMWH).
(Ancef) 1 gram, appears equivalent to that of ampicillin [34–37]; Pneumatic compression devices have been recommended
however, the former is preferred [38]. These are the recommended based on retrospective data [69–72] and appear to be safe and
agents to use unless the patient reports allergies. A seemingly equally effective [73]. While there are two RCTs on UH versus placebo, two
efficacious alternative is penicillin [39], though sample size may have RCTs of LMWH versus placebo, and four RCTs on LMWH ver-
been too small to show differences. A large meta-analysis reviewing sus UH given antenatally, the RCTs are, in general, small and the
multiple penicillin regimens was unable to show sufficient evidence data are insufficient to make any recommendation [70, 71]. A meta-
as to which regimen was most beneficial [40]. Later-generation (e.g. analysis that included seven RCTs showed no additional benefit
second or third) cephalosporins, or more expensive broad-spectrum with LMWH over UFH or control with respect to risk of VTE, but
agents, do not improve efficacy further [39]. A multiple-dose regimen was associated with a higher risk of bleeding and hematomas [74].
for prophylaxis appears to offer no added benefit over a single-dose It is not possible to assess the effects of any of these interventions
regimen [32, 36, 41–43]. If ampicillin or a first-generation cepha- on most outcomes, and especially on rare outcomes such as VTE,
losporin has been given in labor (e.g. for chorioamnionitis), there death, and osteoporosis, because of small sample sizes. There was
may be no need for additional prophylactic antibiotics at CD [38]. If some evidence of side effects associated with thromboprophylaxis.
preoperative antibiotics were not given, prophylaxis should include In summary, given the higher risk of VTE at CD compared with
an extended-spectrum regimen involving azithromycin or metroni- vaginal delivery, all women undergoing CD should receive at
dazole in the setting of chorioamnionitis [44]. Obese women may least mechanical VTE prophylaxis with either pneumatic com-
benefit from higher doses (e.g. Ancef 2–3 grams [38, 45–49]) and pression devices or compression stockings [71]. These should be
longer courses (i.e. 48-hour postoperative course of metronidazole applied preoperatively and continued until full ambulation.
and cephalexin PO [orally]) in addition to routine preoperative pro- In women with a history of VTE or inherited thrombophilia,
phylaxis to further reduce the risk of SSI within 30 days after CD pharmacologic prophylaxis with subcutaneous enoxaparin 40 mg
(see Chap. 3 in Maternal-Fetal Evidence Based Guidelines) [50]. For daily (preferred) or UH 5000 units every 8–12 hours should also be
unplanned (e.g. in labor) CD or patients with ROM >4–6 hours, initiated and continued for 6 weeks postpartum. In women with
there may be an additional reduction in infectious morbidity these risk factors and class III obesity, enoxaparin 40 mg every
with the addition of azithromycin [51–53]. 12 hours should be considered [71]. This pharmacologic prophylaxis
can start 12–24 hours (depending on enoxaparin dose) after block
When to give was performed, after concerns for hemorrhage have decreased [71].
Compared with after cord clamp, administration of antibi-
otics within 1 hour (optimally about 30 minutes) before
Summary
All women undergoing CD should receive mechanical VTE pro-
skin incision is associated with a lower incidence of endo-
phylaxis with either pneumatic compression devices or com-
metritis (by 46%) and wound infection (by 41%) [31, 54–62].
pression stockings. These should be applied preoperatively and
Pharmacokinetic studies demonstrate that adequate cefazolin
continued until full ambulation. In women with a history of VTE
tissue concentration is attained 30 minutes after administration
or inherited thrombophilia, pharmacologic prophylaxis with sub-
[31, 63, 64]. Systemic administration after cord clamping versus
cutaneous enoxaparin 40 mg daily (preferred) or UH 5000 units
lavage routes of antibiotic administration seem to have similar
every 8–12 hours should also be initiated and continued for 6 weeks
efficacy to each other [32, 41, 65], but are inferior to administra-
postpartum. In women with these risk factors and class III obesity,
tion prior to skin incision.
enoxaparin 40 mg every 12 hours should be considered.
Summary Fetal heart monitoring
Prophylactic antibiotics should be administered before every 1. If external monitoring has been employed, it should be con-
CD. The evidence suggests the use of a single dose of cefazolin tinued until the abdominal prep has begun. This includes the
(e.g. 1 gram) or ampicillin IV be given 30–60 minutes prior time when regional anesthesia is administered. If continuous
to skin incision. Higher doses (e.g. 2–4 grams) are appro- fetal monitoring is not possible, reapply the external monitor
priate for patients with greater body mass indexes (BMIs). for 2–3 minutes (if feasible) after completion of the regional
If performing CD in labor or after ROM >4–6 hours, add anesthesia to determine the postanesthesia fetal status.
azithromycin. 2. If internal monitoring has been employed, the scalp elec-
trode can be kept on until delivery of the fetal head, at which
Venous thromboembolism prophylaxis point the lead can be cut and the fetus delivered, or the fetus
There is insufficient evidence to give strong recommendations for delivered with the electrode attached. The operating room
thromboprophylactic methods or agents during pregnancy and team will be responsible for documenting on the count sheet
the early postpartum period [66]. A large meta-analysis (60 trials) the location of the scalp electrode after delivery.
showed an odds ratio (OR) of 3.7-fold increased risk of venous 3. If the CD is done for nonreassuring fetal status, all
thromboembolism (VTE) associated with CD versus vaginal attempts should be made to perform continuous fetal mon-
delivery [67]. European guidelines recommend the use of VTE itoring until the delivery occurs. This may not apply when
pharmacologic prophylaxis for at least 6 weeks post-CD for very the CD is done in an emergent manner.
high-risk patients, but can be limited to at least 7 days postcesarean
in medium-risk patients. The only group not significantly at risk There is no trial regarding optimal time from “decision to inci-
were healthy pregnant women with planned procedures who had sion” for CD. Thirty minutes for CD for nonreassuring fetal
early ambulation and the absence of infection [68]. The three most status and 60 minutes for CD for dystocia and most other indi-
commonly used interventions are pneumatic compression devices, cations have been proposed, but are not based on trials [75, 76].
Additionally, studies have shown that while many CDs are not of three trials showed that nonuse is associated with a lower
performed within this time frame, neonatal outcomes are not incidence of UTI (RR 0.08, 95% CI 0.01, 0.64), lower rate of dis-
adversely affected by longer intervals from decision to delivery comfort at first voiding (RR 0.06, 95% CI 0.03, 0.12), less time to
[77, 78], unless significant neonatal compromise is suspected first voiding (by 16 minutes), and less time until ambulation (by
(such as with fetal bradycardia). about 6 minutes) [92, 93]. No differences in intraoperative diffi-
culties, complications (including urinary retention), or operative
Steroids for fetal maturity time were seen [92]. Given that both studies were not powered to
If CD is necessary before 37 weeks, betamethasone 12 mg IM × assess differences in bladder or ureteral injury, were performed
2 doses, 24 hours apart (or dexamethasone 6 mg IM × 4 doses, in developing countries, and did not report important confound-
12 hours apart) should be given for fetal maturity, when indicated ers such as use of prophylactic antibiotics, there is insufficient
(see Chap. 19) [79, 80]. Betamethasone at 37 weeks or beyond before evidence to determine whether bladder catherization decreases
planned CD has also been shown to reduce the incidence of respira- complications such as injury. In summary, avoidance of bladder
tory distress syndrome (RDS), to 0.2% from 1.1% [81–83]. However, catherization does not seem to be associated with complica-
these data are insufficient for a definitive recommendation. tions. If bladder catheterization at CD is performed, the cath-
eter should be removed at the end of the CD (see later).
Music
Playing music preoperatively significantly increases positive emo- Hair removal
tions and decreases negative emotions [84–86]. Playing music Based on a meta-analysis of 1343 patients, shaving was associ-
during planned CD under regional anesthesia may improve pulse ated with twice the number of SSIs when compared to clipping.
rate and birth satisfaction score, as well as reduce maternal stress Hair removal is not necessary or beneficial at CD. In summary,
and anxiety [85, 86]. Preoperative exposure to Mozart decreased if opting to remove pubic hair, an electric clipper applied the
baseline anxiety (3.5 versus 4.6) and postoperative pain (0.6 ver- morning of the surgery is preferred to shaving [94, 95]. (See
sus 1.4) compared to no music; patient-selected music did not Chap. 7.)
result in benefit as compared to no music [87]. While the magni-
tude of these benefits is small and the methodological quality of Skin cleansing
trials is questionable [85, 86], this is a relatively simple interven- Skin is impossible to sterilize. Chlorhexidine-alcohol scrub
tion with possibility of benefit. In summary, the clinical impact results in less wound infections than povidone-iodine (p-i) scrub
of music seems promising [88, 89]. (9.5% versus 16.1%, RR 0.59; 95% CI 0.41, 0.85) in patients under-
going clean-contaminated surgeries [96]. A large RCT of 1356
Preparations on the operative table patients undergoing CD examined the use of chlorhexidine
cloths versus placebo and found no difference in rates of SSI at
Maternal position 6 weeks [97]. One small study showed that chlorhexidine scrub
There is insufficient evidence to support or clearly disprove is associated with less bacterial contamination of the cesarean
the value of tilting or flexing the table, the use of wedges and skin incision 18 hours later and lower rates of SSI as compared
cushions, or mechanical displacers at CD [90]. Most of the to p-i scrub [98]. Large RCTs have demonstrated superiority of
results presented here are from small RCTs. The incidence of air chlorhexidine-gluconate over p-i with respect to overall SSI (RR
embolism is not affected by head up versus horizontal positioning 0.55, 95% CI 0.34, 0.90; p = 0.02; n = 1147 [99]; RR 0.72, 95% CI
[90]. Left lateral tilt involves tilting the woman toward her left 0.52, 0.98; n = 3059 [100]), but this effect was lost when rates of
side 10–15 degrees to avoid inferior vena caval compression by superficial and deep SSI were analyzed separately (3.0% versus
the gravid uterus. There is no change in systolic blood pressure or 4.6%, p = 0.10, and 1.0% versus 2.7%, p = 0.07, respectively) [99].
incidence of hypotensive episodes when comparing various posi- Other large RCTs recruiting almost 1500 and 932 patients showed
tions, including left lateral tilt, right lateral tilt, head-down tilt, similar rates of SSI (ranging from 3.9% to 4.6%) with the use of
and right lumbar pelvic wedge with horizontal positions or when chlorhexidine-gluconate versus p-i or both [101, 102]. In a recent
comparing full lateral tilt with 15 degrees tilt [90]. Umbilical RCT, p-i with alcohol, chlorhexidine with alcohol, or both were
artery base excess was also not affected by 15 degrees lateral tilt associated with similar and low (3.9–4.6%) incidences of SSIs
versus supine position [91]. Hypotensive episodes are decreased [101]. While meta-analyses have shown no significant differences
with manual displacers (relative risk [RR] 0.11, 95% confidence between various antiseptic agents [103], a more recent Cochrane
interval [CI] 0.03, 0.45) and increased 1.64-fold with right lum- review showed a slightly decreased SSI rate (RR 0.72; 95% CI 0.58,
bar wedge compared to right pelvic wedge (95% CI 1.07, 2.53) and 0.91; 8 trials, 4323 women) with the use of chlorhexidine com-
increased 3.30-fold with right lateral tilt (95% CI 1.20, 9.08) ver- pared to p-i (however, the results were no longer significant when
sus left lateral tilt [90]. Manual displacers showed a decreased fall removing trials with high risk of bias [104]). In summary, the use
in mean systolic blood pressure compared with left lateral tilt. of chlorhexidine is slightly preferred compared to iodine solu-
The mean diastolic pressure is 7 mmHg lower in head-down tilt tion for skin cleansing before skin incision at CD.
when compared with horizontal positions. There are no statisti-
cally significant changes in maternal pulse rate, 5-minute Apgar, Vaginal irrigation
maternal blood pH, or cord blood pH when comparing different Compared with no scrub, vaginal irrigation with chlorhexidine
positions [90]. In summary, manual displacers may be better or p-i immediately before CD significantly reduces the incidence
than left lateral tilt; left lateral tilt is better than right lateral tilt. of endometritis [105–107]. Vaginal cleansing for patients in labor
and those who have ruptured membranes undergoing CD resulted
Indwelling bladder catheterization in lower rates of postoperative endometritis (8.1% versus 13.8%;
Compared with the use of indwelling urinary catheters inserted RR 0.52, 95% CI 0.28, 0.97; 4.3% versus 20.1%, RR 0.23, 95 CI 0.10,
pre-CD and removed at 12 hours after CD, a systematic review 0.52, respectively) and postoperative fever (9.4% versus 14.9%;
RR 0.65, 95% CI 0.50, 0.86) [106]. The effect remained significant during CD [120]. An RCT of 831 women showed no difference in
even for elective CD with reduction in postoperative infectious rate of SSI or endometritis when comparing 30% versus 80% sup-
morbidity (24.5% versus 8.8%) and endometritis (13.2% versus plemental oxygen after cord clamp and for 1 hour post-CD [121].
2.9%), though the rates in the control group were higher than In summary, there is no evidence that supplemental oxygen
expected [108]. A small trial showed a reduction in C-reactive improves outcomes at CD.
protein and postoperative pain in patients who received preop-
erative p-i vaginal cleansing [109]. A secondary analysis showed Anesthesia
no difference in SSI between vaginal prep versus control with For anesthesia, see Chap. 12.
use of standard prophylactic antibiotics and adjunct azithromy-
cin [110]. No adverse effects were reported with the p-i vaginal Surgical technique
cleansing [105, 111]. Most, but not all, of these studies used p-i
skin cleansing and prophylactic antibiotics, so it is difficult to Skin incision
determine if vaginal preparation is necessary in women who Skin incision techniques for CD have been evaluated separately
receive the current recommendations for preoperative anti- from other aspects of CD in limited studies [122, 123]. In general,
biotics and adequate skin cleansing; however, as a simple and a transverse skin incision is recommended, since this is associ-
generally inexpensive intervention, providers should consider ated with less postoperative pain and improved cosmesis com-
implementing preoperative vaginal cleansing. In 2019 an RCT pared with a vertical incision. The Pfannenstiel (slightly curved,
including 1114 patients showed that the use of 4% chlorhexidine- 2–3 cm or 2 fingerbreadths above the symphysis pubis, with the
gluconate reduced the risk of wound infection (0.6% versus 0.2%; midportion of the incision lying within the shaved area of the
RR 0.28, 95% CI 0.08, 0.98) compared to the use of p-i, but rates pubic hair) and Joel-Cohen (straight, 3 cm below the line joining
of endometritis and postoperative fever were similar [112]. A the anterior superior iliac spines, slightly more cephalad than the
meta-analysis of 23 trials showed that p-i is superior to cetrim- Pfannenstiel) are the preferred transverse incisions. Most RCTs
ide, metronidazole, and saline solution/no treatment in preven- do not only evaluate type of skin incision but also other technical
tion of endometritis [111]. A recent Cochrane review supports aspects of CD, making it often impossible to evaluate the effect
the use of chlorhexidine-gluconate or p-i for vaginal prep prior of only the type of skin incision [124]. The better designed, larger
to CD for laboring and nonlaboring patients [105]. In summary, trial revealed no differences in total operative time (32 versus
vaginal cleansing with chlorhexidine or p-i before CD is rec- 33 minutes), intra- and postoperative complications, and neona-
ommended compared to no vaginal cleansing, even in women tal outcomes, with the extraction time 50 seconds shorter for the
who have antibiotic prophylaxis prior to the skin incision. Joel-Cohen group [122]. In contrast, a smaller study [123] showed
significantly shorter operating times, reduced blood loss, and
Warming the patient postoperative discomfort associated with the Joel-Cohen incision
Maternal and neonatal hypothermia are decreased by active compared with the Pfannenstiel incision [125]. Considering the
warming at the time of CD under regional anesthesia [113]. absence of clinical benefits to the mother and fetus, there is no
However, studies were heterogeneous with respect to meth- clear indication for preferring either a Pfannenstiel or a Joel-
ods of warming (intravenous [IV] fluids, forced air, mattress Cohen incision for CD.
[114], increased ambient temperatures [115]), as well as assess- There are probably no absolute indications for performing a
ment of body temperatures [113]. In summary, active warming vertical skin incision. Compared with the transverse skin inci-
decreases maternal and neonatal hypothermia; however, the sion, the vertical skin incision is associated with slightly short-
optimal method of warming has not been established. ened incision-to-delivery intervals of about 1 minute for primary
and about 2 minutes for repeat CD [126, 127]. One underpow-
Cell salvage ered study showed no differences in outcomes when comparing
There were no clinically significant differences in rates of trans- Pfannenstiel versus vertical skin incisions in women with class
fusion when cell salvage techniques were routinely deployed; III obesity [128].
however, there was a higher rate of feto-maternal hemorrhage in Skin incision length has not been studied in a trial. Abdominal
Rh-negative mothers when cell salvage was used (adjusted odds surgical incision size should probably provide about 15 cm (size of
ratio [aOR] 5.63) [116]. In summary, cell salvage cannot be rec- a standard Allis clamp) of exposure to assure optimal outcome of
ommended at every CD. both mother and term fetus [1, 129].
Skin/subcutaneous tissue incision with diathermy as compared
Adhesive drapes to scalpel results in a shorter incision time and less postoperative
Adhesive drapes for CD are associated with a higher incidence pain; however, the study was underpowered to determine a dif-
of wound infection (13.8%) compared with the control group ference in wound complications between these techniques [130].
(10.4%) [117, 118]. In summary, adhesive drapes should be Changing to a second scalpel after skin incision versus no such
avoided at CD due to their association with higher incidence change has never been evaluated in a trial or in any obstetric liter-
of wound infection. ature. From general surgery data, one scalpel is probably adequate
to use throughout the whole surgical procedure.
Oxygen administration In summary, a transverse skin incision with either a Joel-
A Cochrane review of supplemental oxygen in adult surgical Cohen or a Pfannenstiel incision is recommended for CD skin
patients found no firm evidence that a high fraction of inspired incision.
oxygen (60–90%) reduces all-cause mortality or SSI as compared
to 30–40% inspired oxygen [119]. An RCT of 585 women showed Subcutaneous tissue opening
no difference in the rate of infectious morbidity when comparing There are limited data on whether the subcutaneous tissue should
2 L oxygen via nasal cannula versus 10 L oxygen by nonrebreather be opened with blunt or sharp technique. Blunt dissection has
been associated with shorter operating times. In one RCT, use of Retractors
diathermy (“Bovie”) for CD abdominal wall opening from subcu- A meta-analysis of 1669 women (six RCTs) noted that use of
taneous tissue to the peritoneum was associated with less blood O-ring retractors at CD reduced the need for uterine exteri-
loss, skin-to-peritoneum incision time, and post-CD pain com- orization (RR 0.48, 95% CI 0.33–0.69), but did not reduce the
pared with the use of no. 22 disposable scalpel blade [131]. In sum- risk of SSI, operating time, estimated blood loss, transfusion,
mary, blunt dissection of subcutaneous tissue is preferred. or postoperative analgesia [139]. In summary, there is insuf-
ficient evidence to recommend any particular type of retrac-
Fascial incision tor at CD.
Fascial incision has not been studied separately in a trial. A
transverse incision is usually performed with the scalpel and Bladder flap
then extended with scissors. Digital extension can alternatively Four RCTs of 581 women compared development of a bladder
be accomplished by inserting the forefingers into a small, mid- flap versus direct uterine incision above the bladder fold [140].
line transverse fascial incision and then separating the forefingers There were no differences in the rate of bladder injury, estimated
in a cephalad-caudad direction. In an RCT evaluating entry into blood loss, or length of hospitalization. However, one study was
the abdomen, blunt entry with rectus sheath incision extended unpublished, two were judged to be of poor methodological qual-
manually and parietal peritoneum entered and extended bluntly ity, populations were heterogeneous, emergency cesareans were
(manually) was associated with less blood loss, shorter opera- excluded from analysis, and the majority of fetuses were >32
tive time, and less post-CD fever and pain, compared to sharp weeks’ gestation [140]. Based on the trial that was of better
entry [132] and no difference in risk of abdominal hernias 3 years quality, there is some evidence that omission of the bladder flap
after delivery [133]. In summary, the fascia can be transversely shortened incision to delivery time in primary CD by 1 minute,
incised initially with the scalpel and this incision extended though there was no difference in total operating time [141].
bluntly or sharply with scissors. Creation of a bladder flap does result in an increase in dysuria
symptoms postpartum (42% versus 13%) [142]. As bladder injury
Rectus muscle cutting at CD is an uncommon event (1–3/1000), a sample size over
Rectus muscle cutting with the Maylard technique is not asso- 33,000 women would be required to show a difference in this
ciated with any difference in operative morbidity, difficulty outcome [143]. The use of a bladder blade to protect the bladder
with delivery, or postoperative complications compared with has not been studied separately in a trial. In summary, routine
the Pfannenstiel (no muscle cutting) technique [129, 134, 135], development of bladder flap is not necessary for CD. There is
but abdominal muscle strength at 3 months was better in the limited evidence to guide creation of a bladder flap in preterm
Pfannenstiel group [135]. Pain scores did not differ between the and emergency CD.
groups, but this may have been due to a sample size of only 97
women [135]. In summary, cutting the rectus muscle is prob- Uterine incision
ably not necessary [125]. Uterine incision type has not been studied separately in a trial.
The transverse incision of the lower uterine segment is usually
Dissection of fascia off the rectus muscles
recommended because there is less blood loss and it allows for
Nondissection of the fascia off the rectus muscles inferiorly may
TOLAC in subsequent pregnancies [1, 144]. Some experts advo-
result in less pain and similar blood loss as compared to dissec-
cate the classical vertical or at least low vertical incision if the
tion of the rectus sheath inferiorly during cesarean [136]. In sum-
lower uterine segment is not large enough to allow a transverse
mary, dissection of the fascia off the rectus muscles is often
incision, e.g. for the very preterm (<25 weeks) uterus, and leio-
unnecessary.
myoma, but this has been associated with increased blood loss
Extraperitoneal versus transperitoneal CD compared with low transverse incision [145].
Extraperitoneal cesarean was used in the first half of the 20th Women without a history of cesarean who underwent emer-
century to decrease infectious morbidity. However, with the gency CD in labor were randomized to hysterotomy performed
introduction of antibiotic prophylaxis, this benefit was elimi- 2 cm above versus 2 cm below the plica vesicouterina [146].
nated. When performed by one of two experienced surgeons, More women in the low-incision group (41%) had myometrial
one study demonstrated that extraperitoneal CD is associ- thickness over the uterine incision of ≤2.5 mm noted during
ated with decreased postoperative pain and analgesia and saline contrast sonohysterography 6–9 months after delivery
increased oral tolerability, without significant differences in as compared to those with high incisions (7%). Half the women
time to delivery [137, 138]. However, as the current standard is had a subsequent delivery, and there were no differences in
to perform CD transperitoneally, these findings are of limited complications.
clinical applicability. In summary, extraperitoneal CD is not Use of the uterine stapling (autosuture) device for opening and
recommended. closing of the uterus has been assessed in a meta-analysis of two
trials of 300 women: There was no difference in febrile morbidity
Opening of the peritoneum [147] and a nonsignificant increase in the duration of the proce-
Opening of the peritoneum has not been studied separately in a dure (by about 3 minutes) [148]. There is not enough evidence
trial. The peritoneum is usually carefully opened with blunt or to justify the routine use of stapling devices to extend the uter-
sharp dissection and blunt expansion, high above the bladder, ine incision of the lower segment, especially since there is a pos-
avoiding injury to organs below. As compared to sharp entry, sibility that stapling could cause harm by prolonging the time
blunt entry and extension of the rectus sheath incision and pari- to delivery. In summary, the uterus should be incised trans-
etal peritoneum was associated with less blood loss, shorter oper- versely with a scalpel. There is insufficient evidence to recom-
ative time, and less post-CD fever and pain [132]. In summary, mend the exact level of where this incision should be made
blunt peritoneal opening and extension is recommended. and whether it should be slightly curved or straight.
Expansion of uterine incision Professional supervision is warranted to ensure neonatal well-

Blunt expansion of the uterine incision with fingers is associated being. In summary, family-oriented CD, including transpar-
with significantly decreased unintended extension (8.8% versus ent drapes to allow the mother and support person to directly
4.8%), blood loss (by about 189 mL) [149], estimated blood loss visualize the baby’s delivery, as well as early skin-to-skin con-
(EBL) >1000 mL (11.4% versus 6.8%) [149], and need for transfu- tact after birth, is recommended.
sion (RR 0.24; 95% CI 0.09–0.62) [147]. As it is also quicker and
associated with less risk of inadvertently cutting the neonate or Collection and drainage of cord blood
cord, blunt should be preferred to sharp expansion of the uter- At CD, drainage of fetal blood from the umbilical cord is associ-
ine incision [150]. ated with less incidence of feto-maternal transfusion (measured
Compared with transverse expansion, cephalocaudal expan- by Kleihauer-Betke test) compared with no drainage [161]. The
sion of the low transverse uterine incision is associated with clinical significance of this finding is unknown.
significantly lower incidence of blood loss >1500 mL (0.2% ver- Delayed cord clamping (DCC) for 30–120 seconds increases
sus 2%) [151], fewer unintended uterine extensions (3.7% versus neonatal blood volume by approximately 30% and decreases mor-
7.4%) [151], and less blood loss overall [152]. A meta-analysis of these bidity, including intraventricular hemorrhage, in preterm infants
two RCTs showed that women who were randomized to the cepha- [162, 163]. In term infants, it is associated with higher hematocrit,
locaudal group had less postpartum blood loss (mean difference but also higher bilirubin levels [164]. In summary, DCC is rec-
[MD] –67.64 mL, 95% CI –102.85 to –32.43), hemoglobin drop (MD ommended routinely in preterm infants.
–0.26 g/dL, 95% CI –0.37 to –0.14) and hematocrit drop 24 hours
after CD (MD –1.20 g/dL, 95% CI –1.87 to –0.53), unintended Prevention of uterine atony and
extension (4.8% versus 8.9%; RR 0.51, 95% CI 0.30–0.88), injury of postpartum hemorrhage
uterine vessels (1.5% versus 2.8%; RR 0.52, 95% CI 0.20–1.37), blood Prevention of uterine atony and postpartum hemorrhage
loss >1500 mL (0.2% versus 1.7%; RR 0.12, 95% CI 0.02–0.99), and (PPH) has been comprehensively studied for both vaginal
need for additional stiches (20.3% versus 29.2%; RR 0.60, 95% CI delivery and CD (see Chap. 10). A Cochrane review from 2018
0.44–0.82). In summary, the uterine incision should be expanded examined this topic extensively by reviewing 140 RCTs with a
bluntly and in a cephalocaudal direction with the fingers [153]. total of 88,947 women predominantly at term and having vagi-
nal deliveries [175]. In this study 15 trials examined various
Instrumental delivery agents for PPH ≥500 mL in the setting of CD and found that
Instrumental delivery of the fetal head by either vacuum or for- either misoprostol plus oxytocin or carbetocin performed
ceps compared with manual means has been insufficiently evalu- the best. Oxytocin as a single agent ranked third; however,
ated for a firm recommendation in women with cephalic [154] ergotamines or ergotamines plus oxytocin were unable to
or breech presentation undergoing CD. As instrumentation has be studied, as no studies using those agents were able to be
been associated with maternal (especially for forceps) or fetal included in the subanalysis of CD [165].
(especially for vacuum) harm in vaginal deliveries, the principle
of “primum non nocere” (“first do no harm”) should be applied in Oxytocin
this setting, therefore favoring manual delivery of the fetal head In the setting of vaginal delivery, both IV and IM oxytocin effec-
whenever possible until further data are available. In summary, tively reduce postpartum hemorrhage and the need for thera-
manual delivery of the fetal head at CD is recommended. peutic uterotonics by at least 40% compared with placebo or no
routine prophylactic agent [166]. One study combined oxytocin
Tocolysis with methergine after CD and found a significantly lower rate of
Tocolysis for assisting in delivery of the fetal head at CD has been blood loss and higher postoperative hemoglobin as compared to
insufficiently studied [155]. oxytocin alone without increased risk of hypertension or cardiac
ischemia; but larger studies are needed to further evaluate this,
Delivery of the impacted/floating fetal head especially in patients who are at risk, such as smokers, diabetics,
Though a strong recommendation cannot be made based on the and hypertensives [167].
available evidence, in cases where the fetal vertex is wedged into The adequate rate of oxytocin is unclear; many different regi-
the maternal pelvis, vaginal displacement of the presenting part mens are used and appear to be provider and institution depen-
upward (“push) has been associated with longer operating time, dent. Rates of 1 IU [168], 3 IU [169], 15 IU [170], 20 IU, 30 IU
more extension of the uterine incision, increased postoperative [171], and 40 IU [172] administered after delivery of the infant
infections, and increased EBL (approximately 300 cc) as com- have similar outcomes with respect to uterine tone, blood loss,
pared to reverse breech extraction (“pull” method) in a meta- and use of other uterotonics. Higher doses of oxytocin tended
analysis of RCT and non-RCT data [156]. When the fetal head is to be administered as a one-time dose, while some of the lower
noted to be high/floating, internal podalic version results in fewer doses were used as an ongoing infusion. Patients required fewer
maternal and fetal complications as compared to the use of for- additional uterotonics (19% versus 36%) when treated with 80 IU
ceps or vacuum for delivery [157]. oxytocin/500 mL infused over 30 minutes as compared to those
who received 10 IU/500 mL infused over 30 minutes [173]. The
Family-oriented CD optimal infusion rate for oxytocin at CD is still unclear. One
One study showed that allowing the parents to directly visual- RCT of 200 women compared oxytocin administered prior to
ize delivery of the baby’s body (after the head is delivered), to uterine incision versus after umbilical cord clamping and showed
cut the umbilical cord, and to perform early skin-to-skin con- a similar rate in blood transfusion, but a significant reduction in
tact improves birth satisfaction without increased blood loss intraoperative blood loss (432.7 +/– 90.6 versus 588 +/– 96.3 mL,
[158]. Early skin-to-skin contact is beneficial for both mothers respectively, p = 0.001) and the need for additional uterotonics (7
and babies and can be performed at the time of CD [158–160]. women versus 19 women, p = 0.002) [174].
Carbetocin fewer blood transfusions (RR 0.29, 95% CI 0.18, 0.49; p <0.01),
In one RCT of 263 women, carbetocin and oxytocin were com- a lower drop in hemoglobin (MD –0.80 g/dL, 95% CI –1.07,
parable to each other and superior to misoprostol with respect –0.53; p <0.01) and hematocrit (MD –2.05, 95% CI –3.09, –1.01;
to prevention of uterine atony [175]. For CD, carbetocin (as a p <0.01), lower incidence of EBL >500 mL, (3.9% versus 41.9%;
single 100-microgram dose) is associated with more effective RR 0.06, 95% CI 0.04, 0.10), and EBL >1000 mL (RR 0.39, 95%
prevention of uterine atony, less need for additional uteroton- CI 0.30, 0.51; p <0.01) compared to controls [203]. There was no
ics, PPH, and transfusion [176] compared with oxytocin 8- or difference in the incidence of thromboembolic events between
16-hour infusions, but may be associated with a greater cost the two groups [204]. Therefore, prophylactic administration
[177–183]. A higher dose might be necessary for women with BMI of TA should be recommended to prevent PPH in women
≥40 kg/m2, but further studies are needed to establish the ideal undergoing CD who are suspected to have a high risk of PPH
dose [184]. Higher doses also appear to be associated with tachy- [202, 203, 205–208].
cardia, hypotension, and arrythmias and should be used with Postoperative bleeding and decrease in hemoglobin were simi-
caution [185]. With regard to improved uterine tone, a lower dose lar when comparing TA to prostaglandin analogue to manage
(20 micrograms) has been shown to be effective [186]. Carbetocin PPH caused by uterine atony; therefore, TA can potentially be
(where available) may be equivalent [187] or recommended over used (instead of prostaglandins) for patients with uterine atony
oxytocin [188] or oxytocin and ergotamine [189] for the preven- after vaginal delivery or CD [209].
tion of uterine atony. In summary, oxytocin (IV route preferred) and misopros-
tol (e.g. 400–600 mcg per rectum or oral) or carbetocin alone
Misoprostol are associated with less PPH compared to oxytocin alone.
There is insufficient evidence to compare misoprostol to oxyto- Carbetocin (not available in the United States), although more
cin for prevention of uterine atony and PPH at CD, as the seven expensive, appears superior to oxytocin alone for prevention
RCTs compared different regimens of misoprostol and oxytocin. of PPH if one agent is used. TA should be used prophylacti-
In single RCTs, either sublingual misoprostol or rectal miso- cally preoperatively, particularly in women at increased risk
prostol was associated with equivalent blood loss [190] and less for PPH.
need for additional uterotonics (10% versus 40%, RR 0.16, 95%
CI 0.06, 0.44) [191–195]. A large single-institution RCT found Magnesium sulfate
sublingual misoprostol superior to rectal misoprostol with respect A meta-analysis of five trials looking at 8909 patients showed a
to intraoperative blood loss (357.8 +/– 129.7 versus 457.5 +/– 140.7, similar incidence of PPH for patients treated with magnesium
p < 0.001) [196]. Given that misoprostol and oxytocin appear sulfate versus those that were not (17% versus 18%, RR 0.97, 95%
equally efficacious based on this limited evidence and that side CI 0.88–1.06) (210). The magnesium sulfate group had a signifi-
effects such as shivering and pyrexia [191, 194, 197] are more com- cantly lower rate of eclampsia (0.7% versus 1.9%, RR 0.4, 95% CI
mon with misoprostol, oxytocin remains preferred [198]. 0.3, 0.6), and therefore, women who require magnesium sulfate
Misoprostol combined with oxytocin (e.g. 200 μg, 400 μg, or for seizure prophylaxis should remain on this medication during
600 μg sublingual, or rectal, after cord clamping) was associated CD, as it decreases seizure risk, but does not affect overall blood
with less post-CD blood loss, fall in hematocrit, and need for loss or PPH [210]. In summary, magnesium sulfate, if indicated
additional uterotonic agents (7 versus 21 patients; P < 0.001) (for maternal or neonatal neuroprophylaxis), does not have to
when compared to oxytocin alone [197, 199–201]. In women at be stopped during CD.
high risk for post-CD hemorrhage, the combination of both miso-
prostol and oxytocin may be considered. Uterine massage
Uterine massage has not been studied by itself in an RCT for CD.
Tranexamic acid Uterine massage, associated with cord traction, is associated with
Tranexamic acid (TA) inhibits fibrinolysis that potentiates the less blood loss compared with no such interventions [211]. In
clotting system and can be used to prevent bleeding. Its half- summary, uterine massage in addition to cord traction should
life is 2–10 hours, and it typically works immediately after be performed at CD.
IV administration. Side effects include gastrointestinal upset,
but additional rare complications have been reported, including Placental removal
VTE, cerebral ischemia, and anaphylaxis. TA was administered A meta-analysis of 4694 women showed that manual removal
precesarean, though the time frame varied among trials (four out of the placenta is associated with greater morbidity than spon-
of nine studies administered TA 10 minutes prior to skin inci- taneous expulsion with gentle cord traction: Increased endo-
sion). There was significantly less PPH (OR 0.43), mean blood loss metritis (RR 1.64, 95% CI 1.42, 1.90) and PPH (RR 1.81, 95%
(–72 mL), need for blood transfusion (OR 0.23), and need for CI 1.44, 2.28), greater blood loss (by 94 mL), and decreased
uterotonics (OR 0.48) in those treated with TA compared to hematocrit after delivery (by 1.6%) [211]; these findings were
those that were not [202]. In the most recent meta-analysis of confirmed by a more recent RCT [212]. Therefore, gentle
21 RCTs (3852 patients), all women received standard oxytocin cord traction resulting in spontaneous expulsion should
prophylaxis; in addition, the TA group received TA 1 gram or be utilized for delivery of the placenta, given the signifi-
10 mg/kg IV 10–20 minutes before skin incision or spinal cant decrease in blood loss and endometritis as compared to
anesthesia [203]. Compared with controls, women who received manual placental removal. Less intraabdominal hemorrhagic
TA experienced less intraoperative blood loss (MD –155.23 mL, fluid was noted with extraabdominal placental removal as
95% CI –195.64, –111.81, p <0.01), postoperative blood loss (MD compared to intraabdominal removal, though intraoperative
–26.67 mL, 95% CI –32.98 to –20.36; p <0.01) and total blood loss blood loss, infectious morbidity, and pain did not differ [213].
(MD –184.88 mL, 95% CI –218.83, –150.94; p <0.01), less need In summary, gentle cord traction resulting in spontaneous
for additional uterotonics (RR 0.40, 95% CI 0.30–0.55, p <0.01), placental expulsion is recommended.
Change of gloves less decrease in hemoglobin compared with pulling the suture
Changing the operator’s gloves before manual removal of the pla- cephalad with the right hand [226].
centa does not alter the incidence of endometritis [214]. There are several RCTs comparing different sutures for uterine
closure. Polyglactin-910 was associated with generally similar out-
Uterine exteriorization comes compared to chromic catgut [132]. Knotless barbed sutures
Meta-analyses have showed there are no significant differences as compared to polyglactin-910 braided sutures resulted in shorter
in blood loss, intraoperative hypotension, nausea/vomiting, pain, uterine closure time (103–119 seconds), less need for hemostatic
blood transfusion, endometritis, or wound infection with uter- sutures, and less EBL during incision closure (47 mL) [227, 228].
ine exteriorization (extraabdominal uterine incision repair) ver- Monofilament suture resulted in higher residual myometrial thick-
sus repair in situ [215–217]; bowel function was noted to return ness (5.5 ± 2.24 versus 4.18 ± 1.76) than multifilament suture [229].
3 hours sooner with in situ repair [217]. There is no difference Compared with split-thickness repair (avoiding the endome-
in fertility or ectopic pregnancy 3 years post-CD [133]. The trium), full-thickness uterine incision repair is associated with
Cochrane review showed less febrile morbidity (RR 0.41; 95% CI a lower incidence of incomplete healing of the uterine incision
0.17–0.97) and 0.24-day longer hospital stay with extraabdominal after CD (documented by a split in uterine muscle seen on trans-
closure [215]; however, recent RCTs showed decreased operat- vaginal ultrasound about 40 days after the CD) [147, 230] and a
ing room time (by 10 minutes), postoperative pain and analge- lower incidence of niche prevalence (a triangular anechoic area
sia requirements [218], and nausea/vomiting and uterine atony noted at the uterine incision site) [231].
in those repaired intraabdominally [219]. So, the balance of the Continuous single-layer closure may save operating time and
benefits and harms is too close to justify a strong recommen- reduce blood loss compared with interrupted single-layer closure
dation, but many obstetricians subjectively prefer to exteriorize [232]. Locking of sutures in the first layer has been insufficiently
the uterus for easier uterine incision repair. In summary, either studied [233]. Compared with two (double) layers, one (single)
uterine exteriorization or repair in situ is acceptable. layer of suture for low transverse uterine incision repair is associ-
ated with no differences in febrile morbidity (13,980 women; RR
Uterine cooling 0.98). Although there was a reduction in mean blood loss for
Uterine cooling after uterine exteriorization and during uterine single-layer closure, there were no differences in blood transfu-
closure is associated with a decrease in blood loss and PPH in sion, and heterogeneity was high for included studies [132, 147].
one RCT [220]. In summary, there is insufficient evidence to Unfortunately, there were too few women who followed up to be
recommend uterine cooling. able to detect a significant difference in rare, but extremely impor-
tant, long-term outcomes, such as rates of rupture in the next
Cleaning the uterus pregnancy [133], with contradictory results noted in retrospective
Cleaning any placental remnants or blood clots from the uterus studies [232, 234–236]. Meta-analyses showed thinner residual
with a dry laparotomy sponge (versus no cleaning) after placental myometrial thickness and decreased healing ratio (residual thick-
removal was studied in one small RCT that showed no differences ness/adjacent myometrial thickness) with single-layer closure as
in rates of endometritis or other outcomes [221]. In summary, compared to double-layer closure, especially when locked sutures
cleaning the uterus after baby and placental delivery can be were used [231]; additionally, there was increased dysmenorrhea
performed, but may not be necessary. with single-layer closure (RR 1.23, 95% CI 1.01, 1.48) and no differ-
ences in uterine rupture [231]. Thinner residual myometrium was
Cervical dilation noted after single-layer closure as compared to double (MD –2.19
Routine cervical dilation at CD is not associated with decreased mm) [237], especially in those who underwent primary CD [238].
PPH, endometritis, or febrile morbidity, even in women with a Since there is, as of yet, no trial demonstrating consistent benefit
closed cervix [222, 223]. In summary, cervical dilation is not from two- versus one-layer uterine closure, it might be reason-
recommended at CD. able to omit the second layer if the woman is planning no more
pregnancies (e.g. receives tubal ligation). For women planning
Closure of the uterine incision future pregnancies, especially after primary CD, the uterus can
At least one-layer uterine closure is always done, as the uterus be closed in two layers [239]. Vertical uterine incisions require a
should not be left open. Closure of the uterine incision involves double- or triple-layer closure [231, 240].
several decisions, including use of blunt versus sharp needles, In summary, continuous, full-thickness, one-layer uterine
type of suture, full- versus split-thickness repair, continuous ver- closure is recommended if the woman is planning no more
sus interrupted sutures, locking versus nonlocking of sutures, pregnancies (e.g. receives tubal ligation). For women planning
and whether to imbricate the second layer, if it is even closed. future pregnancies, the uterus can be closed in two layers.
Blunt needles for closure of the uterus, peritoneum, and rec-
tus sheath are associated with similar outcomes compared with Intraabdominal irrigation
sharp needles in one RCT [224]. In another RCT, glove perfora- Intraabdominal irrigation with 500–1000 mL of normal saline
tion was significantly less with the use of blunt compared to sharp before abdominal wall closure should not be routinely per-
needles, especially for the assistant surgeon. However, physicians formed, since it provides no significant differences in infectious
reported decreased satisfaction performing CD with blunt nee- or other complications but does increase intraoperative nausea
dles [225]. In summary, there is still limited evidence to recom- and vomiting and postoperative nausea [241]. In summary, rou-
mend blunt versus sharp needles at CD. tine intraabdominal irrigation is not recommended.
In one RCT, the assistant surgeon pulled the suture caudally
with the left hand and used the right hand to hold the uterine Adhesion formation prevention
wall to prevent upward tissue tension; this was associated with There is insufficient evidence to assess if any intervention is
lower need for additional sutures, shorter operative times, and effective at adhesion prevention at CD. In one RCT, a hyaluronate
carboxymethylcellulose (Seprafilm) adhesion barrier applied Glove changing

at CD did not reduce adhesion formation at the subsequent CD Changing gloves prior to closure of the peritoneum/fascia
[242]. Evidence from non-CD abdominal surgery shows that decreases the rate of composite wound morbidity, especially skin
oxidized regenerated cellulose (Interceed) and hyaluronate car- separation (13.6% versus 6.4%, p = 0.008) [252]. In summary,
boxymethylcellulose (Seprafilm) safely reduce clinically relevant glove changing prior to fascial closure can be considered, but
consequences of adhesions [243]. In summary, routine use of the evidence is limited.
adhesion preventions barriers is not recommended.
Fascial closure
Intraoperative interventions to reduce Techniques of fascial closure have not been studied extensively
postoperative pain in CD RCTs. Most experts suggest continuous nonlocking clo-
One study of 370 patients who underwent primary CD showed sure with delayed absorbable suture at about 10-mm intervals.
that intraperitoneal instillation of 10 mL of 2% lidocaine signifi- Recent non-CD evidence has shown that small fascial tissue bites
cantly decreased persistent postoperative pain from 21% to 11%; of 5 mm every 5 mm are associated with prevention of incisional
the parietal peritoneum was closed [244]. In summary, there is hernia in midline incisions and are not associated with a higher
insufficient evidence to recommend routine use of lidocaine rate of adverse events compared to large fascial bites of 10 mm
for intraperitoneal instillation. every 10 mm [253]. In summary, continuous nonlocking fascial
closure with delayed absorbable suture at about 5- to 10-mm
Appendectomy intervals should be performed.
Performing a planned appendectomy without indication at CD
is not associated with inpatient morbidity in a small RCT [245]. Subcutaneous tissue
However, no clear benefits were shown. In summary, the evidence
Irrigation
is insufficient to recommend routine appendectomy at CD.
Irrigation of the subcutaneous tissue with 200 cc normal saline
Intraabdominal drain (NS) reduces hematoma and seroma but does not decrease SSI
There is insufficient evidence to evaluate the effect of plac- [254, 255]. No differences in SSI were noted with p-i irrigation. In
ing a drain in the abdominal cavity at CD. In one RCT, liberal summary, subcutaneous irrigation decreases hematoma and
use of a subrectus sheath drain was not associated with any seroma formation.
effect compared with the restricted use of such intervention
[246]. In summary, a routine intraabdominal drain is not Closure
recommended. Suture closure of subcutaneous fat in women with any subcuta-
neous thickness is overall associated with less wound disruption
Peritoneal nonclosure versus nonclosure, likely secondary to decreased seroma formation
Observational studies have shown that the peritoneum regen- (OR 0.53) [256], but inclusion of both women with <2-cm and ≥2-cm
erates in 5–6 days. Compared with closure, peritoneal non- thickness (which can have differing outcomes) and inability to blind
closure is associated with a reduction in operating time, represent possible sources of confounding and bias [257].
whether both or either visceral or parietal peritoneal layers Greater than or equal to 2-cm subcutaneous thickness:
were not sutured. While nonclosure of visceral peritoneum Suture closure of subcutaneous fat in women with ≥2-cm thick-
versus closure of both peritoneal surfaces showed an increased ness is associated with a significant decrease in wound dis-
risk of adhesion formation, one of the two included studies ruptions, defined as any wound complication that required
had a high risk of bias. Peritoneal nonclosure is also associated intervention, and seromas, compared with nonclosure [256, 258].
with significantly less postoperative pain and shorter opera- The evidence supports routine subcutaneous suture closure in
tive time (by 6 minutes) [247, 248] as compared to closure of women with a subcutaneous tissue depth ≥2 cm.
both layers. Nonclosure of the visceral peritoneum when the
parietal peritoneum is closed is associated with decreased Drainage
urinary symptoms of urgency, frequency, and stress incon- Some RCTs have evaluated drainage of subcutaneous tissue,
tinence [247]. compared with no drainage, or compared with tissue closure.
Long-term follow-up after 3 years showed no difference in In meta-analyses of all RCTs, there is no difference in the risk
fertility [133] and in 7 years [249] showed no differences in pain, of wound infection, other wound complications, febrile morbid-
fertility, urinary symptoms, and adhesions. A review of general ity, or endometritis in women who had wound drains compared
surgery and gynecologic data concluded that “we encourage with those who did not [259, 260]. Wound drainage of subcuta-
clinicians not to close both parietal and visceral peritoneum” neous tissue (in women who did not receive prophylactic anti-
[250]. The hypothetical benefits of closing these layers for ana- biotics) with a 2-cm corrugated rubber drain (typically a 7-mm
tomic barrier protection, reduction of wound dehiscence, and Jackson-Pratt drain) extruding from one end of the incision, left
minimization of adhesion have not been proven, and in fact have open to drain, and removed the following day is associated with
been invalidated by trials. In summary, there is no evidence to a trend toward increased wound infection [259]. Drainage is less
justify the time taken and the cost of peritoneal closure, so it effective than tissue closure for women with ≥2 cm of subcuta-
should be avoided. neous fat. Therefore, routine subcutaneous tissue drainage in
women undergoing CD cannot be recommended [246]. These
Reapproximation of the rectus muscles trials do not answer the question of whether wound drainage is of
Reapproximation of the rectus muscles results in increased benefit when hemostasis is not felt to be adequate.
postoperative pain and increased analgesic requirements [251]. In summary, the subcutaneous tissue should be irrigated
In summary, reapproximation of the rectus muscles is not and closed with sutures, especially if ≥2 cm in thickness.
recommended. Routine drainage should be avoided.
Closure of skin prophylactically with success to decrease SSI. A large meta-analysis

Closure of the skin incision at CD has been most commonly per- compared NPWT to standard care in obese women, and although
formed with either absorbable sutures or nonabsorbable metal the studies were heterogenous, there was a reduction in SSI (RR 0.45,
staples. In a meta-analysis of 3112 women, compared with sutures, 95% CI 0.31, 0.66) and overall wound complications (–6.0%, 95% CI
staple closure is associated with higher rates of wound compli- –10.0%, –3.0%, number needed to treat [NNT] 17) [279]. This risk
cations (13.0% versus 4.8%), separation (9.4% versus 2.5%), and a reduction was confirmed in a subsequent RCT that also demon-
shorter duration of surgery by 7 minutes [261–263]. This decrease strated cost-effectiveness (>30,000 Euros per quality-adjusted life
in wound complications persists even when only examining the years [QALY]), especially in those patients with pre-pregnancy BMI
1030 obese patients, as sutures were still associated with fewer >35 kg/m2 [280, 281]. However, other meta-analyses on obese women
complications (6.7% versus 12.8%) [262]; however, one small study found that NPWT did not reduce SSI [282–285]. It appears that
showed no difference in wound complications in class III obese evidence is mixed regarding the usefulness of NPWT to reduce
patients [264]. Though the incidences were small, there were no SSI in obese women. In summary, routine NPWT, even in obese
significant differences in hematoma, seroma, and readmission women, cannot be recommended at CD.
between groups [262]. Additionally, there were no significant dif-
ferences between groups with regard to pain perception, patient Incision treatment
satisfaction, and incision cosmesis [262, 265, 266]. One small A small RCT explored the placement of bupivacaine-soaked gelatin
study showed decreased wound complications with interrupted sponges subcutaneously and was able to demonstrate lower pain
instead of continuous subcuticular sutures [267]. Therefore, the scores, narcotic use, blood pressure, and heart rate postoperatively,
low transverse cesarean skin incision should be closed with as well as less anxiety and depression [286, 287]. Another small
sutures, regardless of obesity status. RCT explored the use of topical scar gel (Contratubex) applied
The suture most commonly used in the RCTs showing supe- twice daily and showed improvement in Patient Observer Scar
riority of sutures was poliglecaprone [262]. No differences in Assessment Scale (POSAS) scores with respect to color, stiffness,
wound complications were noted when comparing skin closure and irregularity of CD scars after 6 weeks of treatment [288]. One
with braided versus monofilament suture when analyzed by RCT compared the use of aloe vera gel to standard dressing and
actual suture received [268]. Polyglycolic acid sutures have been showed improved wound healing scores using the Redness, Edema,
associated with greater hypertrophic scarring compared to inter- Ecchymosis, Discharge, and Approximation (REEDA) scale
rupted nylon sutures [269]. Barbed sutures were associated with 24 hours postoperatively, but scores were equivalent 8 days post-
similar rates of wound dehiscence, infection, and other adverse operatively, and therefore, unnecessary, though not harmful [289].
outcomes compared to 3-0 polydioxanone suture [270]. There Silicone gel or sheets have been demonstrated to improve scar
were no differences in patient or physician assessments of scars healing when applied twice daily; when compared head-to-head,
at 8 weeks when comparing skin closure with suture versus with they appear to have similar Vancouver Scar Scale (VSS) scores, but
glue [271]. No differences were noted regarding wound complica- the silicone sheets had higher Visual Analogue Scores (VAS) with
tions when comparing tissue adhesive with sterile strips applied respect to itching [290]. Another method investigated for improved
after suture closure of the skin incision [272]. scar cosmesis is tranilast 8% liposomal gel. When applied twice
Absorbable staples were associated with similar outcomes as metal daily to the scar for 3 months, POSAS scores were lower (i.e. better)
staples, except for a longer skin closure time [273]. If staples are used, at 9 months compared to placebo [291]. Grapeseed extract oint-
they should be removed on or after day 7, as early (day 3) removal ment 5% has also been shown to improve REEDA scores at 6 and
is associated with a nonsignificant trend for higher rate of wound 14 days postoperatively [292]. There are no comparative trials to
dehiscence (15.2% versus 11.5%) compared to delayed removal on evaluate which of these treatments are associated with the best
days 7–10 [274]. There is insufficient evidence to evaluate the effec- cosmetic outcomes. In summary, no specific recommendations
tiveness of the Leukosan Skinlink wound closure device, though it can be made regarding CD incision treatment; the individual
may have similar cosmetic results as prolene suture closure [275]. treatments are safe options that can be considered.
In summary, the CD skin incision should be closed with
sutures. Postoperative care
Dressings Gum chewing
There is no RCT comparing placing or not placing a wound dress- Compared with no gum chewing, gum chewing after CD, typi-
ing at CD. One RCT compared dialkylcarbamoyl chloride (DACC, cally three times a day for at least 30 minutes each time, is
Cutimed Sobatec) to standard surgical dressing and found a lower associated with earlier return of bowel sounds (by 4.4 hours),
rate of SSIs (1.8% versus 5.2%, respectively, p = 0.04) [30]. This passage of flatus (10.4 hours, 95% CI –11.9, –8.9) [293] and stool
type of dressing also resulted in fewer outpatient visits, readmis- (12.7 hours, 95% CI –14.5, –10.9) [293], less ileus (OR 0.36) [294,
sions, and reduced health care costs [276]. Silver nylon dressing 295], and shorter hospital stay (0.7 days, 95% CI –0.8, –0.5) [293,
has also been investigated, but showed no risk reduction in SSIs 296]. Since this large review, many other RCTs and systematic
as compared to standard dressing [277]. With regard to optimal reviews have confirmed these findings [294, 295, 297–303]. In
timing of dressing removal, the evidence is limited. One RCT of summary, gum chewing starting immediately after CD three
320 patients compared 6-hour removal to 24-hour removal and times a day for at least 30 minutes each time is recommended.
found no detrimental effects with early removal [278]. In sum-
mary, the wound dressing at CD can be removed at 6 hours. Early oral fluids and feeding
A meta-analysis of 11 somewhat heterogeneous studies showed
Negative pressure wound therapy that compared with delayed (usually after 8 hours or upon pas-
Previously used in the treatment of postoperative wounds, more sage of flatus) oral fluids or food, early oral fluids or food is
recently, negative pressure wound therapy (NPWT) has been applied associated with reduced time to return of bowel sounds (by about
8.8 hours), flatus (7.3 hours), and bowel movement (6.3 hours) every 6–8 hours) and/or acetaminophen (325–650 mg every
[304]. It has also been associated with earlier ambulation, greater 4–6 hours) around the clock (rather than upon patient demand)
maternal satisfaction, shorter length of stay, and lower rates of should be recommended for post-CD pain relief. Narcotics such
narcotic use [305–309]. No significant differences were identi- as morphine and codeine should be used only if NSAIDs and
fied with respect to nausea, vomiting, abdominal distention, and acetaminophen, both at maximal safe dosing and around the
mild ileus [304, 308, 310]. Typically, feeding was initiated within clock, do not control the pain. There is limited evidence evaluat-
2–8 hours with water, clear liquids, or solid foods [311–313]. In ing oral narcotic use versus oral NSAIDs use after CD.
summary, early oral fluids and even food within 6–8 hours Wound infiltration with local analgesia and abdominal
after CD are recommended. nerve blocks as adjuncts to regional and general anesthesia seem
to be of benefit in reducing opioid consumption after CD in small
Ambulation RCTs. NSAIDs (even as a wound infiltration) as an adjuvant may
There is limited RCT evidence regarding walking after CD. A confer additional pain relief [324]. In women who had CD per-
small RCT showed that patients utilizing a pedometer had an formed under regional analgesia, wound infiltration is associated
increased number of steps in the first 48 hours postoperatively and with a decrease in morphine consumption at 24 hours compared
reported a significantly easier physical and mental recovery [314]. with placebo. In women with regional analgesia in addition to
Early ambulation starting 4 hours after CD is recommended. a local anesthetic, wound infiltration with an NSAID cocktail
is associated with less morphine use compared with local anes-
Other interventions to reduce postoperative ileus thetic infiltration. Women who have regional analgesia with
One RCT demonstrated decreased time to bowel sounds, first abdominal nerves blocked have decreased opioid consumption.
bowel movement, and time in bed with the use of acupuncture In women under general anesthesia, CD wound infiltration and
(20-minute sessions at 1 hour and 4 hours postoperatively) [315]. peritoneal spraying with local anesthetic reduce the need for opi-
Similar results were seen with the administration of 10 mg of oid rescue [324].
metoclopramide intraoperatively [316]. Another trial utilized gin- Post-CD, persistent opioid use is as high as 1 in 50 to 1 in 300 in
ger capsules, which helped decrease abdominal distension and previously opioid-naïve women [325, 326]; therefore, it is impor-
allowed patients to eat quicker but did not affect the time to flatus tant that obstetricians judiciously use narcotics for postpartum
or maternal satisfaction [317]. Another RCT showed that combin- pain control. One potential framework is the WHO analgesic
ing dexamethasone 8 mg and ondansetron 4 mg compared to just ladder endorsed by ACOG [327]. In summary, NSAIDs and
Zofran significantly decreased postoperative nausea and vomiting acetaminophen should be administered around the clock for
(9% versus 37%, p <0.01) [318]. In summary, these interventions post-CD pain relief. Wound infiltration with local analgesia
are options to decrease postoperative nausea and vomiting. and abdominal nerve blocks can also be utilized. Narcotics
should only be used if and when these interventions do not
Removal of Foley catheter
control the pain.
A small RCT randomized patients to removal of Foley catheter in
2 hours versus 12 hours and showed reduced urinary frequency
(p = 0.04), microscopic hematuria (p = 0.04), postoperative mobi- Discharge
lization time (p = 0.01), and length of hospital stay (p = 0.009) in
the group whose Foley was removed earlier [319]. Results were A study of almost 3000 women who were randomized to be
similar in another RCT with removal of the Foley immediately discharged with their newborn after 24 hours versus 72 hours
postoperatively [320]. In summary, the Foley catheter, if uti- postcesarean showed that those discharged after 24 hours
lized during CD, can be removed right after CD. were more likely to report mood swings and have less success
with breastfeeding. Additionally, although there was no differ-
Postoperative anxiety ence in maternal readmission, there were increased neonatal
CD can be associated with significant anxiety, especially for those admissions (typically due to jaundice) in those discharged
patients who underwent emergency surgery. Various interventions after 24 hours [328]. A recent smaller RCT showed that dis-
have been studied to reduce stress and anxiety postoperatively. One charge on the first as compared to the second day is not asso-
small RCT compared hand and foot massage to standard postop- ciated with any difference in maternal or perinatal outcomes,
erative management and observed reduced pain intensity, lower either immediately or at 6 weeks [329]. As part of an enhanced
blood pressure and respiratory rate, and increased rates of breast- recovery after surgery (ERAS) protocol with early feeding, cath-
feeding [321]. Another RCT evaluated the utilization of 30 minutes eter removal, and ambulation, patients with shorter hospital
of Reiki, a Japanese form of healing with energy (3 minutes for each stay (–1.95; 95% CI –3.80, –0.029) [330], had lower pain scores
area, 10 areas total) within the first 24–48 hours postoperatively and hospital expenses compared with those with a longer hospi-
and found significantly lower use of analgesics and less anxiety in tal stay without increased febrile or infectious morbidity [331].
the treatment group [322]. Auricular acupressure (applied twice For women who are discharged early, a home health nurse visit
a day) has also been tested and shown to reduce cortisol levels, is advised. In summary, discharge on day 2 or 3 after CD can
heart rate, anxiety, and fatigue when used postoperatively [323]. be considered.
Although there is insufficient evidence based on small sample
size, these nonpharmacologic interventions have no expected Management of complications
harmful side effects and can be recommended to those patients
who would like to utilize them. Disrupted (open) laparotomy wound
Compared with healing by secondary intention, reclosure of the
Pain relief after CD disrupted laparotomy wound is associated with success in
See also Chap 12. Nonsteroidal antiinflammatory drugs (NSAIDs, >80% of women, faster healing times (16–23 versus 61–72 days),
e.g. ketorolac intraoperatively followed by ibuprofen 600–800 mg and fewer office visits [332]. No serious morbidity or mortality
is associated with either method. There is insufficient evidence and takes into consideration category of pregnancy (singleton
to assess optimal timing (probably 4–6 days after disruption if cephalic/breech/other lie, multiples), prior obstetric record (nul-
noninfected) and technique (superficial vertical mattress or “en liparous, multiparous, with or without uterine scar), course of
bloc” reclosure of entire wound thickness with absorbable sutures labor (spontaneous, induced, CD before labor), and gestational
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15
TRIAL OF LABOR AFTER CESAREAN
Amen Ness
Key points pH <7.00 (1.5/1000 TOLAC), HIE (5–8/10,000 TOLAC),

and perinatal death (13/10,000 with TOLAC vs. 1/10,000
• A woman with a prior cesarean delivery (CD) has two for PRCD) (Table 15.3). The overall risk of adverse perinatal
options for mode of delivery in the subsequent preg- outcome is 1/2000 with TOLAC, slightly higher than with
nancy: A planned repeat cesarean delivery (PRCD) or a PRCD.
trial of labor after cesarean (TOLAC) to try to achieve a • When compared with women without a previous CD
vaginal birth after cesarean (VBAC). (instead of with those having a planned primary CD),
• There is insufficient evidence (no large randomized con- the perinatal mortality for TOLAC is higher than PRCD
trolled trial) to compare the safety, complications, and (10/10,000 vs. 0.4/10,000 births), but this rate is twice as
maternal and fetal/neonatal morbidity and mortality high as that of a non-VBAC multipara in labor and the
between these two options. same as that of a nullipara in labor.
• TOLAC is a reasonable option for most women with a • Appropriate counseling including risks as described
single prior low transverse CD with no other contrain- should be provided to the woman with a prior CD decid-
dications to a vaginal birth (Table 15.1). ing on subsequent mode of delivery. The ultimate decision
• Absolute contraindications to TOLAC are as follows: regarding TOLAC or PRCD is up to the patient.
• Medical or obstetric complications that preclude vagi- • To minimize risks, an experienced obstetrician in addi-
nal delivery tion to anesthesia, nursing, and operating room per-
• Inability to perform emergency CD sonnel in a facility equipped to perform emergency CD
• Vertical (classical) uterine scar or fundal or perifundal must be immediately available throughout the TOLAC.
complete (from endometrium to serosa) uterine scar
from other surgery (e.g. myomectomy) Historical perspective
• Prior uterine rupture
• Successful VBAC rates in the general population of Each year almost 1.5 million childbearing U.S. women have cesar-
women with previous low transverse uterine incisions ean deliveries (CDs). Most of these are primary CDs, but the larg-
vary from about 40% to 80%. est single indication for CD is prior CD, accounting for over half a
• Screening tools to estimate the likelihood of suc- million CDs each year [1]. In order to reduce this trend, there is a
cessful TOLAC can be used selectively and are best need to both prevent the first CD and increase the rate of trial of
used to confirm high rates of success but are less prelabor after cesarean (TOLAC) in appropriate candidates.
dictive at low rates. One available for clinical use is at
https://mfmunetwork.bsc.gwu.edu/web/mfmunetwork/
vaginal-birth-after-cesarean-calculator. TABLE 15.1: Candidates and Absolute and Relative Contrain
• Rates of maternal and perinatal complications are in gen- dications for Trial of Labor after Cesarean
eral similar and low with both TOLAC and PRCD, except • Singleton gestation
for the risk of uterine rupture (associated with TOLAC),
• Clinically adequate pelvis
which confers both maternal and perinatal risks.
• One (or two) prior low transverse cesarean delivery(ies)
• Uterine rupture is the main complication associated
• No other uterine scars or previous rupture
with TOLAC. Most maternal and perinatal morbidity
results from repeat CD after TOLAC (Table 15.2). Limited Evidence
• The overall risk of uterine rupture during a TOLAC at • A twin pregnancy who is a candidate for VBAC
term is 0.7% after one prior low transverse CD, versus • Unknown uterine scar (low clinical suspicion of prior classical
0.26% after PRCD. The risk is increased with >1 prior uterine incision)
CD, prior vertical scar, prior rupture, and induction of Absolute Contraindications
labor with no prior vaginal deliveries. • Medical or obstetrical complications that preclude vaginal delivery
• With term uterine rupture, the risks of fetal/neonatal • Inability to perform emergency CD
morbidity/mortality are about 33%, the risk of pH <7.00 • Vertical (classical) uterine scar
40%, admission to neonatal intensive care unit (NICU): • Fundal or perifundal complete (from endometrium to serosa)
6% risk of hypoxic-ischemic encephalopathy (HIE), and uterine scar from other surgery (e.g. myomectomy)
1.8% risk of neonatal death (rupture-related risk of neo- • Prior uterine rupture
natal death: 1/10,000 TOLAC) in equipped academic Relative Contraindications
centers.
• Multiple uterine scars (e.g. ≥3 prior CDs)
• Compared with PRCD, TOLAC is associated with
• Any other factor associated with a risk of rupture of >1% (see text)
slightly higher rates of adverse perinatal outcome: Cord
180 DOI: 10.1201/9781003102342-15

Trial of Labor after Cesarean 181
TABLE 15.2: Factors Associated with Success and Risk of Uterine Rupture Associated with TOLAC
Effect on Effect on Risk of Uterine
Factor Success Ratesa Rupture with TOLAC (% Risk) Comment (References)
Maternal Demographics
Older age ↓ ↑
Obesity ↓↓ NA
Obstetric History
Prior vaginal delivery ↑↑ ↓↓ (0.2%) Especially prior VBAC.
Recommend TOLAC [4, 17, 41]
No prior uterine scars NA NA (<0.01%)
Prior nonrecurring indication for CD ↑ For example, prior CD for
Malpresentation
Labor before primary CD ↓ [51]
More than 1 prior CDs ↓ ↑ (see later) 10%–15% lower success rate per CD
One prior LT CD (no prior VBAC) (0.7%, range 0.5–1.0)b [4, 5]
One prior LT CD (prior VBAC) ↓ (<0.5%) [15, 45, 46]
Two prior LT CDs (no prior VBAC) ↑ (1.8%, 1%–3.7%) [12, 45, 46]
Two prior LT CDs (prior VBAC) ↓ (0.5%) [45]
Prior vertical (classical) CD ↑↑ (4%–10%) Avoid TOLAC [5]
Prior low-vertical CD ↑ (1%–2%) [4, 8]
Prior “unknown uterine scar” CD (0.5%–2%) [4]
One-layer uterine closure ↑ (1%–2%) [8, 47, 48]c
Fever at prior CD ↑ If both intrapartum and postpartum fever
Prior preterm CD ↑ (1%)
Prior uterine rupture ↑↑ (6% if lower segment rupture; Avoid TOLAC [5]
32% if upper segment rupture)
Short interpregnancy interval ↑↑ (2%–5%) <18 months; avoid TOLAC [58, 59]
Current Labor Factors
PRCD NA (0%–0.15% in labor) (0.5 risk of [4, 67]
dehiscence)
Favorable cervical status ↑↑ ↓↓ Bishop score >8 or CL <15 mm
Postdates ↓ – Uterine rupture rate increased if induced/
augmented
Fetal macrosomia (e.g., BW >4000– ↓ ↑ Uterine rupture rate increased by relative
4500 g) risk 2.3 [20]
Induction/augmentation of labor ↓ ↑ (mostly 1%–2%) Avoid misoprostol; avoid PGE2 followed
by oxytocin; avoid oxytocin >20 mU/
minute; see later [4, 50–53]
Misoprostol induction ↑↑ (>5%) Avoid
PGE2-only induction ↑ (1%) Cannot predict if PGE2 will be sufficient
PGE2 then oxytocin induction ↑ (1%–3%) Probably avoid
Foley induction – Probably safe
Oxytocin-only induction ↑ (1.1%)
Oxytocin augmentation ↑ (0.9%)
a Chance of achieving vaginal birth after CD.
b Used as reference.
c See Chap. 13.
Abbreviations: CD, cesarean delivery; PRCD, planned repeat CD; TOLAC, trial of labor after CD; NA, not applicable; BW, birth weight.
Until the late 1970s, “Once a cesarean always a cesarean” was of studies in the 1970s, when the vaginal birth after cesarean
the general rule among most obstetricians. This phrase did not (VBAC) rate was very low, the National Institutes of Health
derive from formal studies and was clearly not evidence based. (NIH) in 1980 and then the American College of Obstetricians
A classical uterine incision was used until the1920s, when the and Gynecologists (ACOG) from 1988 to 2019 stated that a trial
low transverse incision was first introduced. The low transverse of labor (TOL) after a previous low transverse CD is a reason-
incision was associated with a tenfold decreased rate of uter- able option for most women with a prior low transverse CD
ine rupture in labor than the classical incision. On the basis [2, 3]. In response to these recommendations, the VBAC rate
TABLE 15.3: Maternal and Perinatal Risks of TOLAC versus VBAC rate: Number of vaginal births after previous CD per 100
PRCD live births to all women with a previous CD (same denominator
as the CD rate).
TOLAC
TOLAC rate: If the average success rate of a TOLAC is about
≥2 Prior 70%, then the TOLAC rate is the VBAC rate/0.7.
Favors PRCD 1 Prior CD CDs Adjusted VBAC rate: Number of women with prior CD and no
Maternal contraindications to TOL who had a VBAC per 100 live births to
Complications all women with a previous CD.
Successful VBAC rate: Percentage of women with prior CD who
Uterine rupture PRCD 1/200–250 1/111–140 1/55–140
attempted a TOLAC achieving VBAC.
Operative injury PRCD 1/166–200 1/250 1/250
Successful adjusted VBAC rate: Percentage of women with
Hysterectomy – 0–1/250 1/200–500 1/166
prior CD and no contraindications to TOLAC achieving a
Transfusion – 1/71–100 1/58–140 1/31 VBAC.
VTE – 1/1000 4/10,000 NA Failed TOLAC (failed VBAC): TOLAC that results in a repeat CD.
Endometritis – 1/47–66 1/34 1/32 Uterine dehiscence: Disruption of the uterine muscle with
Hospitalization TOLAC intact serosa [7]. It can include asymptomatic opening if the
Death – 1/2500–5000 1/5000 NA uterine scar is from a prior surgery, without protrusion of fetus/
Satisfaction – fetal organs outside the uterus.
Long-term risks a Uterine rupture: Disruption or tear of the uterine muscle and
Perinatal visceral peritoneum, or separation of the uterine muscle with
Complications extension to the bladder or broad ligament [7]. It includes
Stillbirth PRCD 1/1000 2–4/1000 NA symptomatic gross rupture of the uterine scar from a prior sur-
Low cord pH NA NA 1.5/1000 NA
gery, with or without protrusion of fetus/fetal parts outside the
uterus.
Neonatal death – 5/10,000 8/10,000 NA
Perinatal death PRCD 1/10,000 13/10,000 NA
Respiratory TOLAC 1–5/100 0.1–1.8/100 NA General considerations
Hyperbilirubinemia TOLAC 5.8/100 2.2/100 NA A woman with a prior CD has two options for mode of deliv-
HIE PRCD 1/10,000 5–8/10,000 NA ery in a subsequent pregnancy: A PRCD or a TOLAC to try to
Source: From Refs. [2, 9, 27, 41]. achieve a VBAC.
Note: Please notice that some numbers may contradict each other, as they are from There are two randomized controlled trials (RCTs) examining
different sources. outcomes for women who underwent PRCD vs. TOLAC [8, 9].
a See text.
Only one of these studies reported clinical outcomes and was
Abbreviations: CD, cesarean delivery; TOLAC, trial of labor after CD; PRCD, planned quite small, with a sample size of 22 [9]. The other, while larger,
repeat CD; NA, not available; HIE, hypoxic-ischemic encephalopathy. looked at maternal psychometric outcomes [8]. There is also a
small prospective cohort study to compare these two options,
in the United States increased from 3.5% in 1980 to a high of which also focuses on psychological outcomes, not maternal and
28.3% in 1996 (Figure 15.1). fetal safety and complications [10]. Virtually all studies on VBAC,
As more VBACs were attempted in the 1980s and 1990s, more with a few exceptions [11], are retrospective and often use dif-
ruptures were seen and litigation for complications of a TOL also fering criteria for patient selection and differ in their ability to
increased. In 1999, ACOG addressed these risks and added the correctly ascertain (make sure all cases are included) and define
requirements of a “readily available” physician “throughout labor” uterine rupture. Most studies also include women at various ges-
and “availability of anesthesia and personnel for emergency tational ages and may therefore not specifically apply to women
CD.” Since that time, after declining until about 1997, CDs have at term considering their options of delivery after a prior CD.
increased globally, 32% in the United States in 2018 and 28% in Studies with <1000 TOLACs cannot adequately assess maternal
England in 2018 [4–6]. and fetal/neonatal morbidity and mortality, as these complica-
At the same time, U.S. VBAC rates decreased to just 9% tions are rare, and meta-analyses [12, 13] might compound errors
in 2011 and rose from 2016 to 2018, reaching 13.3% in 2018 from different retrospective studies. Many studies do not differ-
(Figure 15.2) [4, 5], although they have remained relatively entiate between asymptomatic uterine dehiscence and true acute
high in the United Kingdom at 33% (range 6%–64%) [5]. The symptomatic uterine rupture.
ACOG requirement for “immediately available” personnel The main issues regarding TOLAC are the following:
for women undergoing a TOLAC, but not for other labor-
ing women, eliminated the option of TOLAC/VBAC in 1. Which women are candidates for TOLAC and which
many community hospitals. Since 1996, about one-third of should instead be recommended a PRCD?
hospitals and one-half of physicians have stopped offering 2. Among women who attempt a TOLAC, what is the VBAC
TOLAC/VBAC in the United States [7]. rate (successful TOLAC) and which factors influence it?
3. What are the short- and long-term maternal and peri-
Definitions natal benefits and harms of attempting TOLAC versus
PRCD, and what factors influence benefits and harms?
TOLAC: Trial of labor after cesarean.
VBAC: Vaginal birth after cesarean. Complications and safety are especially related to the risk of
PRCD: Planned repeat cesarean delivery (before labor). uterine rupture.
35%
30%
25%
20%
15%
10%
5%
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
VBAC rate CD rate Primary CD rate
FIGURE 15.1 Rates of vaginal birth after Cesarean (VBAC rate), total cesarean delivery (CD rate), primary Cesarean deliveries
(primary CD), and repeat cesarean delivery (RCD). (From Caughey et al., AJOG 2014, 210(3):179–193, with permission.)
These issues are important in order to properly counsel women Candidates for TOLAC
who are considering a TOLAC [7]. This information should be
shared with the woman in a way best suited to her understanding. The choice of candidates for TOLAC should be based on an
When a TOLAC and a PRCD are medically equivalent options, acceptable balance between the chance of achieving a VBAC and
the woman’s preference should be honored if possible [1]. fetal and maternal risks. The ACOG and the 2010 NIH consensus
35
30
25
20
15
10
0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Primary CS VBAC rate CS rate
FIGURE 15.2 Rate of VBAC and cesarean delivery since 2005.

statement acknowledged that TOLAC is a reasonable option for Prior indication for cesarean
most women with a single prior low transverse CD with no Breech presentation or other nonrecurring indication (e.g.
other contraindications to a vaginal birth [2, 3, 7]. Criteria to nonreassuring fetal monitoring) for the prior CD significantly
be a candidate and absolute and relative contraindications for increases the chances for a vaginal delivery (85%) compared with
TOLAC are shown in Table 15.1. CD done for a recurring indication such as dystocia or failure to
progress. These rates are similar to vaginal delivery rates in nul-
liparous women. Nevertheless, about 60%–70% of women under-
Factors affecting a successful TOLAC going a TOLAC for dystocia (failure to progress) deliver vaginally
Vaginal delivery rates for TOLAC in the general population of [1]. In addition, most studies show no reduction in the rates for a
women with previous low transverse uterine incisions vary from successful TOLAC after a prior CD done for failure to progress
60% to 80% [11, 13–15]. In tertiary care centers the rates may be in the second stage of labor (75%–80%), with no increased risk
higher, about 73%–76% [11, 16]. The rate is highly dependent on of operative vaginal delivery [1, 27–29].
demographic and obstetric factors (Table 15.2). Based on these This is confirmed in later retrospective studies showing the
factors, women with a probability for VBAC of at least 60%– success of TOLAC was 75.6% for women with prior arrest in the
70% have similar or less maternal and perinatal morbidity first stage of labor, 73.1% for women with a prior second-stage
with a TOLAC than a PRCD [17, 18]. Conversely, women with arrest, and 59.0% with prior failed induction [30]. For women
less than a 60% probability of VBAC have a greater likelihood of attempting TOLAC with prior cesarean for arrest of descent,
morbidity with TOLAC than if they had a PRCD. One study dem- the TOLAC success rate was 84% [31], and for those attempting
onstrated that composite neonatal morbidity is similar between TOLAC with prior cesarean for failed vacuum, the TOLAC suc-
TOLAC and PRCD for the women with the greatest probability cess rate was 67% [32].
of achieving VBAC [17]. Factors that influence the likelihood of
VBAC after TOLAC and their effect on success rates are shown Uterine scar type
in Table 15.2 and described later in this chapter. Vaginal delivery rates appear to be similar for low transverse, low
vertical, and unknown incision types [21, 33]. Most women with
Maternal demographics unknown scar types have had low transverse incisions.
Age
There is inconsistent evidence regarding the effect of age on Number of prior cesarean deliveries
VBAC after a TOLAC. Prospective studies did not show any Previous studies had reported that 75%–80% of women attempt-
relationship, although overall there appears to be a small inverse ing a VBAC with a single prior cesarean will deliver vaginally ver-
association between maternal age and the likelihood of vaginal sus about 60%–70% with more than one prior cesarean. Later
delivery [1]. studies have shown that the greater the number of prior CDs,
the lower the chances for a vaginal delivery (about 10%–15%
Race/Ethnicity lower per CD) [33]. But a large retrospective multicenter study
Race and ethnicity have been one of the strongest demographic found similar rates of vaginal delivery after TOL in women with
predictors of VBAC. Hispanic and African American women two versus one prior CD (75%) [34], while a meta-analysis of six
have lower rates of VBAC than non-Hispanic white women, but studies that compared outcomes between women having a TOL
there are concerns that these data are related to other factors in after one or two CDs found similar vaginal delivery rates of 77%
care rather than race itself. Other factors such as marital status and 72%, respectively [35]. Likewise, another study showed that
and insurance type were also identified as risk factors but not the vaginal birth rates were similar (65% vs. 69%) in women
included in the final predictive model [19]. undergoing induction with one or two prior CDs [36]. However,
a recent large retrospective study of over 42,000 women revealed
Obesity a much lower rate of successful VBAC in women with two prior
Obese women attempting a VBAC have lower vaginal delivery CDs—only 2.9% of these women attempted a TOL, and of these,
rates. This appears to be true whether measured at first prenatal only 39.4% had a successful VBAC [37].
visit (per body mass index [BMI] unit) or at delivery (BMI >30) ACOG considers it reasonable to offer TOLAC to those
(adjusted ORs [aORs] 0.94, 95% confidence interval [CI] 0.93–0.95 women with two prior low transverse CDs who also have a
and 0.55, 95% CI 0.51–0.60, respectively [20, 21]). Obese women, good probability of successful VBAC (ACOG). See “Prediction
weighing ≥300 lb, had rates of VBAC of only 15%, while women Tools for Vaginal Delivery” later.
weighing 200–300 lb had rates of 56% [19, 22]. Greater maternal
height and BMI <30 kg/m2 are associated with an increased Interdelivery interval
likelihood of VBAC. An interdelivery interval of <18 months may be associated with
similar success rates of TOL after CD compared to longer inter-
Obstetric history vals [33], but in one study, rates were lower with induction [38].
Prior vaginal delivery
A prior vaginal delivery, either before or after a prior CD, is the Current labor factors
strongest predictor of a VBAC after a TOLAC. A previous suc- Cervical status
cessful VBAC is the most predictive [23]. The VBAC rate is Labor factors associated with a higher VBAC rate include
>85% for women with a prior VBAC, compared with 65% for greater cervical dilation at admission or at rupture of mem-
women without a prior vaginal delivery [24, 25]. The rate of VBAC branes. The more favorable the cervix, the greater the odds for a
increases with each prior VBAC. Women with zero, one, two, vaginal delivery. Fetal head engagement and a lower station also
three, and four or more prior VBACs have likelihoods of VBAC of increase the likelihood of VBAC [1]. Prelabor rupture of mem-
63%, 88%, 91%, 91%, and 91% (p <0.001), respectively [26]. branes is associated with a decreased likelihood of VBAC (odds
ratio [OR] 4.47, 95% CI 2.07–9.63) [39]. Shorter cervical lengths Prediction tools for vaginal delivery
at mid-trimester ultrasound are associated with an increased Given the associations noted earlier, several different scoring
likelihood of VBAC but do not improve the VBAC prediction systems have been proposed to predict the likelihood of vaginal
model of Grobman [20, 36]. delivery or cesarean in women undergoing a TOLAC [1, 20, 24,
40, 48, 49]. The best studies used scoring systems that were vali-
Gestational age dated in separate data sets and in external studies [1]. These scor-
Preterm patients with a prior CD have a slightly higher VBAC ing systems performed as well in the validation testing as they did
success rate than term patients (82% vs. 74%) [40]. Gestational in the original data set. Unfortunately, although these models are
age greater than 40 weeks is associated with a decreased rate accurate at predicting which women will have a VBAC, they are
of VBAC. There are conflicting data regarding the chance of limited in their ability to predict who will have a repeat cesarean
VBAC after TOLAC in postterm pregnancy. Successful VBAC following a TOLAC [50, 51]. Half of women with unfavorable risk
rates of 65%–82% have been reported for women past 40 weeks, factors had a vaginal delivery.
with the higher rates in women with prior vaginal deliveries [1]. In One available tool developed by Grobman et al. for the MFMU
the Maternal-Fetal Medicine Unit (MFMU) cohort, women >41 Network can be found at http://www.bsc.gwu.edu/mfmu/vagbirth.
weeks had a lower chance for vaginal delivery than women <41 html, but this tool only includes factors known at the beginning of
weeks (aOR 0.61, 95% CI 0.55–0.68) [21]. If VBAC is still desired pregnancy [20]. Grobman also proposed a second nomogram with
after 40 weeks, awaiting the onset of spontaneous labor may improved performance that also utilized information obtained
be a better option than induction before 40 weeks for women at the time of admission (Figure 15.3) [52]. Metz et al. proposed
planning a VBAC, given the lower success rates with induc- another simple validated tool to be used at the time of admission
tion in this population, particularly for women with an unfa- (Figures 15.4 and 15.5) [50] and validated the original Grobman
vorable cervix [21, 41]. model in a population of women with two prior CDs [53].
One study compared the actual outcomes of 568 ethnically
Induction/Augmentation of labor diverse U.S. populations of women attempting VBAC to the
The overall estimated rate of vaginal birth with a TOLAC after success rate calculated by the MFMU Network calculator. For
any method of labor induction is 63% [1]. Women with a prior women with high predicted success rates, there was good correla-
CD who are induced have lower rates of successful TOLAC tion with actual outcomes, but for those with a low predicted rate
(about 10%) than those who labor spontaneously [12, 33, 42]. (29%), the actual VBAC success rate was 57% [54]. The authors
Studies demonstrate that the rate of VBAC ranges from 54% of the NIH-sponsored review of prediction tools recommend
for induction of labor with mechanical methods (transcervi- clinicians use a sequential approach to screening [51]. Initially,
cal balloon catheter) to 69% for induction with pharmacologic prenatal predictors such as previous vaginal delivery and previ-
methods. One RCT showed that for patients with a Bishop ous indication for CD, and possibly patient demographics and
score less than or equal to 4, beginning induction with a cer- fetal estimated weight, should be considered. This can then be
vical balloon was associated with a higher rate of successful modified by intrapartum predictors such as onset of spontaneous
VBAC (50%) compared to starting the induction with oxytocin labor or the need for induction, and cervical status can be used to
alone (37%) [43]. reevaluate the likelihood of vaginal delivery [20, 50].
It should be noted that the inclusion of race-based correction
Fetal macrosomia factors may not be valid and may perpetuate health care bias, as
The most consistent infant factor associated with an increased the data on which they are based may reflect social disadvantage
likelihood of VBAC is birth weight <4000 g. As expected, large similar to insurance type and marital status, which were not
for gestational age/macrosomia, especially birth weight >4000 g, included in the final algorithm. In addition, the models function
decreases the odds of a VBAC after TOLAC [44]. The success rates equally well without the inclusion of race [19].
for VBAC in women with a previous CD and no other births is A recent comparison of three of these models, including the
about 60% in the >4000 g group and 71% in the ≤4000 g group two by Grobman and the one by Metz [20, 50, 52], also showed
[45]. There is a progressive reduction in VBAC success rates as that two [20, 52] were very accurate when the probability of
birth weight increases. With a prior VBAC or a vaginal delivery, success was >60% but not accurate when <60%. Calculators
there is no success rate below 63% for any of the birth weight may be most useful in counseling women who are not plan-
strata. But with no previous vaginal delivery, VBAC success ning VBAC yet have a high probability of success. They are less
rates can drop below 50% as neonatal weight exceeds 4000 g helpful for discouraging women based on low probabilities
[24, 44]. This success rate can decrease further if the indication of success [55]. They are probably unnecessary for women with
for the previous CD is cephalopelvic disproportion or failure to >80% rate of success who are planning a VBAC.
progress. There are limited data regarding prenatal estimated
fetal birth weight and VBAC success. Even so, VBAC rates after Uterine rupture
TOL were noted to be 60%–70% in fetuses suspected to be macro-
somic [24]. This is likely due to the limitations of estimating birth Complications and safety of TOLAC are especially related to the
weight by ultrasound. Thus, suspected macrosomia alone should risk of uterine rupture. Uterine rupture is the most serious com-
not rule out a TOLAC [3]. plication associated with TOLAC. It is defined as a complete sep-
aration through the entire thickness of the uterine wall (including
Multiple gestations serosa). At all gestational ages, pooled data from one review indi-
Vaginal delivery rates of both twins after a prior CD generally cate that uterine rupture occurs in approximately 470/100,000
range from 65% to 84% [33, 46, 47]. In most series, rates do not (0.47%, 95% CI 0.28–0.47) of women undergoing TOLAC and in
seem to differ from success rates in singletons, without increased 26/100,000 (0.026%, 95% CI 0.009–0.082) of women undergoing a
risk for maternal morbidity or uterine rupture [46, 47]. PRCD (relative risk [RR] 20.74, 95% CI 9.77–44.02; p < 0.0010) [1].
Points
0 3 6 9 12 15 18 21 24 27
Maternal Age
50 45 40 35 30 25 20 15
BMI at Delivery
75 70 65 60 55 50 45 40 35 30 25 20 15
African American
Yes No
Hispanic
Yes No
Vaginal Delivery Since Last Cesarean

No Yes
Previous Vaginal Delivery

No Yes
Recurrent Indication
Yes No
Preeclampsia
Yes No
GA at Delivery
42 41 40 39 38 37
Cervical Dilation
0 1 2 3 4 5 6
Cervical Effacement
0 20 40 60 80 100
Fetal Station
B –5 –4 –3 –2 –1 0 +1 +2 +3
Induction of Labor
Yes No
Total Points
0 10 20 30 40 50 60 70 80 90 100
Probability (%)
0 5 10 15 20 25 30 40 50 60 70 75 80 85 90 95 99
FIGURE 15.3 Predictive graphical nomogram, incorporating information available up until the time of admission for delivery, for
probability of VBAC success resulting from a trial of labor. (From Grobman W, Lai Y, Landon M, et. al. Does information available at
admission for delivery improve prediction of vaginal birth after cesarean? Am J Perinatol. 2009;26(10):693–701. [II-2]. Ref. [52], with
permission.)
At term, the overall risk for rupture is 778/100,000 (0.78%, 95% Factors affecting the risk for uterine rupture
CI 0.62–0.96). This means that overall there are about 5 to 6 addi- The risk for rupture is modified by a number of important fac-
tional ruptures per 1000 in women undergoing a TOLAC [1]. No tors [57] listed in Figure 15.6 and described next. Prior vaginal
maternal deaths due to uterine rupture have been reported [1, delivery and prior VBAC reduce the risk of uterine rupture, while
56]. Perinatal death occurs in about 6% of women with uter- number of prior CDs, vertical scars, single-layer closure, induc-
ine rupture, which translates to an overall risk of intrapartum tion or augmentation, greater maternal age, fever, prior preterm
fetal death of about 20/100,000 and a risk of perinatal death at CD, and TOLAC at ≥40 weeks are associated with higher rupture
term of about 0%–2.8% in women undergoing a TOLAC [1]. rates.
Calculation of Integer Vaginal Birth after Cesarean Score Calculated Chance of

Calculate the Bishop score using the cervical examination at the VBAC No. of Study Successful Actual VBAC
time of admission Score Participants VBAC Success Rate
Add 4 points for history of vaginal delivery
Add 2 points if pre-pregnancy body mass index is less than 30 4 2 (0.17) 11.7 (6.4–20.5) 0.0
Add 3 points if primary cesarean delivery was not because of a 5 3 (0.26) 14.7 (8.5–24.3) 33.3
recurring indication 6 5 (0.43) 19.0 (11.8–29.1) 20.0
Add 2 points if maternal age at the time of delivery is younger 7 5 (0.43) 24.7 (16.7–35.0) 40.0
than 35 years 8 7 (0.60) 31.9 (23.3–41.9) 42.9
Sum total score in figure 15.5 9 16 (1.37) 40.2 (31.8–49.2) 25.0
10 23 (1.97) 49.1 (41.6–56.6) 60.9
FIGURE 15.4 Calculation of integer vaginal birth after 11 46 (3.93) 57.7 (51.6–63.6) 58.7
Cesarean score. (From Metz, T.D., et al., Simple, validated vaginal 12 58 (4.96) 65.6 (61.0–69.9) 65.5
birth after cesarean delivery prediction model for use at the time 13 95 (8.12) 72.2 (68.7–75.4) 73.7
of admission. Obstet Gynecol, 2013;122(3): p. 571–578. [II-2]. Ref. 14 102 (8.72) 77.5 (74.7–80.1) 71.3
[50], with permission.) 15 150 (12.82) 81.6 (79.1–83.8) 80.7
16 134 (11.45) 84.7 (82.3–86.8) 84.2
17 144 (12.31) 87.0 (84.6–89.0) 86.1
Increase risk
18 139 (11.88) 88.6 (86.3–90.6) 92.1
Maternal age 19 94 (8.03) 89.8 (87.6–91.8) 90.4
Maternal age (>30 years old) is associated with an increased risk
20 62 (5.30) 90.7 (88.5–92.6) 91.9
(1%–1.4%) of uterine rupture [58, 59]. 21 48 (4.10) 91.4 (89.1–93.2) 91.7
22 25 (2.14) 91.9 (89.6–93.7) 96.0
Number of prior cesareans
23 12 (1.03) 92.3 (90.1–94.0) 91.7
Women with two or more prior low transverse CDs may be at
increased risk of uterine rupture compared with women with
one prior CD, but the absolute risk is small (1.36%), while the FIGURE 15.5 Chance of successful vaginal birth after
success rate is high (71%) [35]. Current ACOG recommenda- Cesarean delivery based on calculated vaginal birth Cesarean
tions allow this option regardless of whether there is a prior delivery score. (From Metz, T.D., et al., Simple, validated vagi-
vaginal delivery [3]. Most ruptures occur in women undergo- nal birth after cesarean delivery prediction model for use at
ing induction or augmentation and in those without a prior the time of admission. Obstet Gynecol, 2013;122(3): p. 571–578.
vaginal delivery [34]. Earlier data had indicated an overall relative [II-2]. Ref. [50], with permission.) Abbreviations: VBAC, vaginal
increased risk of rupture (about twofold to threefold) in women birth after cesarean; CI, confidence interval. Data are n(%), %,
having a TOL after two low transverse CDs compared with one (95% CI) or %.
[56, 60–62]. A meta-analysis confirmed these findings (0.9% for
one prior CD vs. 1.8% for two prior CDs) [34]. A follow-up case-
for women with a single-layer uterine closure compared to those
control analysis of the study by Macones et al. showed no increased
with a double-layer uterine closure (OR 3.95; 95% CI 1.35–11.49)
risk (OR 1.46, 95% CI 0.87–2.44), and in the MFMU cohort [60],
[64]. However, a later study showed no difference in uterine rup-
there was no difference in the incidence of rupture after two CDs
ture by layers of closure (OR 1.17; 95% CI 0.78–1.76) [53].
compared with one (0.9% vs. 0.7%). Furthermore, the rupture rate
in women with a prior vaginal delivery and two prior CDs is only Fever
0.5%, no greater than a VBAC with only one prior CD [60]. The presence of both intrapartum and postpartum fever at CD,
but not either alone, may increase the risk of uterine rupture in a
Prior CD characteristics
subsequent pregnancy [67].
Direction of scar
Classical and low vertical uterine scars have higher rates of Previous preterm CD
rupture compared with low transverse uterine incisions (4%– The MFMU Network data showed a higher risk of rupture in
10%, and 1–2%, respectively) [3]. Records regarding the prior women with a prior preterm CD compared with those with a
CD(s) should be obtained, with special care in documentation prior term CD (1% vs. 0.68%; aOR 1.6, 95% CI 1.01–2.50) [68]. No
of direction of scar. If a woman has had a prior vertical (classi- difference in rupture rates were found in a secondary analysis of
cal) CD, PRCD at 36–37 weeks is recommended [3, 63]. the retrospective, multicenter cohort study comparing prior CD
before and after 34 weeks (aOR 1.5, 95% CI 0.7–3.5) [62].
Layers of closure
There is insufficient evidence to assess if the numbers of lay- Prior uterine rupture
ers performed at prior uterine closure affect the outcomes, As prior uterine rupture is associated with high rates (6%–32%)
specifically the rate of uterine rupture, for future pregnan- of recurrent rupture with TOLAC, these pregnancies should
cies. Randomized trials have insufficient follow-up numbers have a PRCD before labor, possibly around 36–37 weeks [63].
(see Chap. 13). Compared with women who had a double-layer
closure, women with a single-layer closure have been reported Interval between deliveries
to have anywhere from a similar to a fourfold increased risk of Interval between deliveries of <18 months are associated
uterine rupture compared with those with a double-layer closure with an increased risk of uterine rupture (2.3%–4.8%) com-
[64–66]. One large multicenter case-controlled study that exam- pared with longer intervals (1.1%–1.3%) in a number of stud-
ined operative reports found a fourfold increase in uterine rupture ies [58, 59, 69, 70].
Post dates evidence from RCTs regarding the method of induction (only
The risk of uterine rupture does not increase substantially after two small RCTs comparing two different types of prostaglan-
40 weeks, but is increased with induction of labor regardless of dins to oxytocin). One study was stopped due to two ruptures in
gestational age [71, 72]. the misoprostol group (2/17) [79]. ACOG therefore advises that
induction with sequential use of prostaglandins and oxyto-
Macrosomia >4000 g cin be avoided [3]. ACOG considers the use of a Foley bulb for
Macrosomia >4000 g is associated with a slightly increased risk cervical ripening an acceptable method of labor induction, as
of rupture. A multicenter case-control study showed that birth limited data appear to show no increased rates for rupture [3].
weight >3500 g had twice the risk for rupture (OR 2.03, 95% CI AN RCT showed significantly higher VBAC success rates if a
1.21–3.38) [44]. Foley bulb is used for ripening (compared to low-dose oxytocin)
in women with a low Bishop score [43]. There are no randomized
Induction/Augmentation trials comparing induction to elective repeat cesarean delivery
The rate of uterine rupture in women with one prior low trans- (ERCD).
verse CD undergoing TOLAC with spontaneous labor is about
0.4%. Almost all studies compare women undergoing induction Augmentation of labor
with those in spontaneous labor instead of expectant manage- Augmentation may be associated with an increased risk
ment. These studies (including the large prospective MFMU of rupture, up to about 1%, but the risk is mainly related to
observational trial) reported higher rates of uterine rupture higher doses of oxytocin [11, 80, 81]. A secondary analysis of a
(up to 1%–2%) with induction at any gestational age and of any large retrospective cohort and a follow-up nested case-control study
kind [11, 73, 74]. There are no RCTs comparing these two groups, reported a dose–response relationship between the maximum
but a meta-analysis of eight studies comparing women with prior oxytocin dose and increased risk for uterine rupture (fourfold
CD undergoing induction to those in spontaneous labor showed increased risk with 21–30 mU/minute vs. no oxytocin; attrib-
lower rates of vaginal delivery and higher rates of rupture among utable risk of 2.9%–3.6%) [81, 82]. Oxytocin should be used
women undergoing induction, but no differences in overall judiciously in women undergoing TOLAC, with a possible
maternal or neonatal morbidity [75]. maximum dose of 20 mU/minute.
At term, the risk of rupture is not statistically significantly
greater than women with spontaneous labor (OR 1.42, 95% CI Length of second stage
0.57–3.52). But women induced at >40 weeks have a higher risk The length of the second stage has been associated with an
of rupture than those induced between 37 and 40 weeks (3.2% vs. increasing risk for uterine rupture in a secondary analysis of the
1.5%) [1]. MFMU Cesarean Registry. The risk of uterine rupture or dehis-
In the MFMU cohort, induction increased the risk of rupture cence increased with second-stage length from less than 1 hour
only in women without a prior vaginal delivery (induced 1.5% (0.7%), 1 to less than 2 hours (1.4%), 2 to less than 3 hours (1.5%),
vs. spontaneous 0.8%). In women with a prior vaginal delivery, to 3 hours or greater (3.1%) (p <0.001) [83].
the incidence of rupture was similar (0.6% vs. 0.4%) [41]. A case-
control study including 111 cases of uterine rupture did not find Second-trimester induction of labor
an increase in rupture compared to spontaneous labor even after Induction of labor in the second trimester with misoprostol is
controlling for labor duration. But the risk was slightly higher associated with a 0.4% risk of uterine rupture (with 0% risk of
with an unfavorable cervix (<4 cm) [76]. hysterectomy and 0.2% risk of transfusion) after one prior low
Two studies compared induction to expectant manage- transverse CD and about 50% risk with a prior classical CD [81].
ment instead of spontaneous labor, a more clinically appropri- There is insufficient evidence to assess the safety of mifepristone
ate comparison. One was a secondary analysis of the MFMU induction in women with a prior CD.
data and showed that induction had higher rates of vaginal
delivery (73.8% vs. 61.3%) but also had higher rates of rupture No change or decreased risk
(1.4% vs. 0.5%) [77]. The other was a secondary analysis of the Prior vaginal delivery
Consortium on Safe Labor and found lower rates of vaginal Prior vaginal delivery significantly reduces the risk for rupture
delivery at 37–39 weeks but not at 40 weeks and no difference during TOLAC from 1.1%, in women with no prior vaginal
in uterine rupture [42]. deliveries, to 0.2%. After controlling for maternal demograph-
ics and labor characteristics, prior vaginal delivery reduced the
Type of induction risk for rupture fivefold (OR 0.2, 95% CI 0.04–0.08) [84]. This
The risks of uterine rupture with induction in women who had protective effect was also confirmed by large retrospective (OR
one prior CD may also depend on the type of induction. Risk 0.30, 95% CI 0.23–0.62) [85] and prospective (OR 0.66, 95% CI
of rupture may be as high as 1.4%–2.5% with induction with 0.45–0.95) studies [11].
prostaglandin (with or without oxytocin) [9, 67] and about 1.1%
with oxytocin alone [78]. In one large population-based study, Labor before primary CD
sequential use of prostaglandin and oxytocin was the stron- Labor before the primary CD has been associated with a lower
gest risk factor for rupture (OR 48, 95% CI 20.5–112.3) [58]. risk of uterine rupture in a future TOLAC compared with no
The MFMU data, which included all prostaglandins, and the labor before the primary CD [86].
Grobman et al. study, which excluded misoprostol, did not find an
increased risk for rupture when prostaglandins were used alone, Twins
but they did note a threefold increased risk with sequential The risk of rupture or maternal mortality is not increased with
use of prostaglandins and oxytocin versus spontaneous labor prior CD and subsequent TOL with twins, with uncommon peri-
[41]. The Cochrane review concluded that there is insufficient natal morbidity at ≥34 weeks [46, 87].
Prior CD for twins Venous thromboembolism

Compared with women with prior CD for singletons, women The risk is about 4/10,000 with TOLAC, similar to PRCD
with prior CD for twins have similar risk of uterine rupture and (1/1000) [11].
TOLAC success [88].
Endometritis
Preterm The risk is very similar for TOLAC or PRCD, with a 6% vs. 7–8%
In one study there was a trend toward a lower uterine rupture rate of fever [12], or 3% vs. 2% in academic centers [11]. The over-
rate in preterm patients who attempted a VBAC [40]. In the large all absolute risk for any fever with TOLAC is 6.5% [1]. Morbid
MFMU cohort, the rates of uterine rupture and dehiscence were obesity, cesarean after TOLAC, and increased number of CDs
lower in preterm TOL versus term; 0.34% vs. 0.74%, p = 0.03 and increase infection rates.
0.26% vs. 0.67%, p = 0.02, respectively [89]. On the other hand,
women with a very preterm delivery (<26 weeks) with a prior low Hospitalization
transverse CD may have an increased rate of rupture with subse- Overall, because most women deliver vaginally, a TOLAC results
quent TOL compared to women with a prior term low transverse in a shorter hospitalization compared with PRCD. This benefit
CD, 1.8% vs. 0.4%, respectively [73]. does not apply to morbidly obese women.
Maternal mortality
Benefits and harms associated with The risk of maternal mortality is lower overall for women
TOLAC (aside from rupture) having a TOLAC (3–4/100,000) compared with PRCD
(13.4/100,000). This compares to the overall U.S. maternal mor-
Most of the benefits and the least morbidity of a TOLAC are
tality rate of 11–15/100,000. At term, maternal mortality is lower:
dependent on having a VBAC, while the potential harms of a
1.9 for TOLAC versus 9.6 PRCD per 100,000 live births [1]. Based
TOLAC are associated with an unsuccessful TOLAC result-
on limited evidence, mortality is lower for TOLAC in high-volume
ing in CD. Studies comparing TOLAC to PRCD usually include
hospitals (more than 500 deliveries per year) [8].
both VBAC and TOLAC ending in CD. Thus, the outcomes for
women who have a TOLAC reflect both possibilities. These data
are therefore appropriate for women with a previous CD who are
Short-term satisfaction
Anxiety, depression, psychological well-being, and satisfac-
deciding on the mode of delivery for the current pregnancy. Most
tion scores are similar between women who choose TOLAC
studies show that rates of all maternal and perinatal complica-
versus those who elect for PRCD [10].
tions except rupture are infrequent and similar with both TOL
and PRCD, but these are small studies with few events [15, 16, 90].
One study of 2345 women with one prior CD compared out-
Long-term maternal risks
There is a clear association between the number of CDs and
comes among those with a planned ERCD and planned TOL
abnormal placentation, as well as other surgical complications
and noted lower rates of serious perinatal complications (0.9%
[92]. This complication is an important consideration for the 28%
vs. 2.4%) and major maternal hemorrhage (0.8% vs. 2.3%) in the
of women who have more than two births. For each CD, the risk
ERCD group. The vaginal delivery rate was 56.8% in the TOL
for placenta previa significantly increases, occurring in 900, 1700,
group, with similar rates of uterine rupture in both groups (0.1
and 3000 per 100,000 women who have one, two, and three or
vs. 0.2%) [9].
more prior CDs, respectively. The overall risk for placenta accreta
Maternal (Table 15.3) also increases (0.2% in the first CD to 0.3%, 0.6%, 2.1%, 2.3%, and
Surgical complications 6.7% for second, third, fourth, fifth, and sixth and up CD, respec-
Overall rates of surgical injury are low but may be slightly higher tively). In the presence of placenta previa, the risk for abnormal
with TOLAC compared with PRCD. This is primarily due to placentation is markedly increased for each additional CD (3.3%,
those women who have a TOLAC but deliver with a repeat CD 11%, 40%, and >60% for the first, second, third, and fourth or
in labor [9–11, 17, 91, 92]. There are no studies that specifically more CDs, respectively).
evaluated the risks of complications due to subsequent surgery Even without a placenta previa, the incidence of abnormal
after a TOLAC or PRCD. Nevertheless, an increasing number placentation, although much lower, increases with the number
of abdominal surgeries is commonly associated with increased of CDs (see Chap. 25). The major benefit of TOLAC is about a
risks of adhesions, injury to bowel and bladder, and other com- >70% chance of a VBAC and avoidance of multiple CDs.
plications at the time of subsequent CD or nonpregnancy-related In addition, as noted earlier, women who undergo multiple
hysterectomy. CDs are at increased risk for many complications unrelated to
placentation, including hysterectomy, adhesions, injury to bowel
Hysterectomy and bladder, transfusions >4 units of pRBCs, need for postopera-
The risk of hysterectomy is about 1–2/1000 TOLACs and similar tive ventilation, ICU admission, and increased operative time and
to PRCD [10, 11, 13, 16, 90, 93, 94] hospital stay [95]. There is insufficient evidence regarding long-
term pelvic floor function comparing TOLAC with PRCD. PRCD
Transfusion should not be used as a way to prevent pelvic floor disorders [1].
The risk of transfusion is very low, and in most studies not sig- A decision analysis evaluating both the immediate and subse-
nificantly different for TOLAC or PRCD (0.9% vs. 1.2%) [1, 11]. quent risks of the delivery decision for women with a prior CD
It has been estimated at about 2 units packed red blood cells suggested that for women planning only one additional preg-
(pRBC)/1000 TOLAC [13]. The risk is higher when labor is nancy, PRCD results in fewer hysterectomies than TOLAC,
induced with no prior vaginal deliveries, and it is related to the while for women planning two or more additional pregnan-
need for CD following a TOLAC [11]. cies, a TOL provides the lowest risk [96, 97]. Therefore, when
counseling women about risks and benefits of a TOLAC com- risk of adverse perinatal outcome is 1/2000 with TOLAC,
pared with PRCD, the discussion should address her plans for slightly higher than with PRCD [11]. In one study of women at
future pregnancies. term with vertex presentations, the risk of delivery-related peri-
natal mortality with a TOLAC was 11 times that of PRCD (OR
Fetal/Neonatal 11.6, 95% CI 1.6–86.7). When compared with women without a
The overall risk of serious perinatal complications is about 1 in previous CD (instead of to those having a PRCD), the perinatal
2000 TOLAC, which is slightly greater than that of PRCD [11]. mortality for TOLAC was the same as that of a nullipara in
Combining all poor perinatal outcomes, more than 600 PRCDs labor, but about twice as high as that of a non-TOLAC multipara
would need to be performed to prevent one poor perinatal in labor [16].
outcome. Although a woman with a TOLAC is at higher risk of
uterine rupture than any other group, the risk of perinatal death Respiratory complications
is similar to that of any nulliparous woman in labor [16]. The Rates of respiratory complications, transient tachypnea of
most serious fetal risk in women with prior CD is from uterine the newborn, and need for oxygen and ventilator support may
rupture during TOLAC. Risks of fetal/neonatal morbidity/mor- be slightly higher in infants delivered by PRCD versus those
tality with term uterine rupture are 33% risk of pH <7.00, 40% delivered by VBAC [1, 98]. It is unclear if there is a difference in
risk of admission to the NICU, 6% risk of hypoxic-ischemic respiratory outcomes in infants born by PRCD versus those born
encephalopathy (HIE), and 1.8% risk of neonatal death. The by repeat CD after a TOLAC.
rupture-related risk of neonatal death is 1/10,000 in equipped
academic centers [11]. In other centers, these risks are higher, Hypoxic-ischemic encephalopathy
including the risk of neonatal death from rupture up to 10%– Aside from perinatal death, HIE is the most serious adverse out-
25%. The large population-based Norway study showed that nor- come of uterine rupture and is one of the primary concerns regard-
mal prenatal outcomes occurred in about 44.7% with complete ing the decision to have a TOLAC. The incidence is 46/100,000
rupture (Figure 15.6) [76]. live births for TOLAC, versus none in the PRCD [11]. The overall
risk of rupture-related HIE is 1 in 2500 TOLAC. In term infants,
Stillbirth the overall incidence for HIE is 100/100,000 live births.
The rates of stillbirths are 2–6/1000 for TOLAC versus 1–2/1000
for PRCD. At 39 weeks or more, the rate of antepartum stillbirth
in the MFMU cohort was 1/1000 with TOLAC and 3/10,000 with Management
PRCD [9, 72]. This difference might be due to stillbirths occurring
Patients with contraindications (Table 15.1) to TOLAC should
at ≥39 weeks with TOLAC and/or to encouragement for TOLAC
receive a PRCD at 39 weeks, or earlier if labor starts, or in
with diagnosis of stillbirth [11].
certain cases (e.g. prior early uterine rupture). TOLAC can
Low cord pH be offered if the risk of uterine rupture is estimated to be
The risk of cord pH <7.00 is about 1.5/1000 TOLAC [13]. <2%, possibly <1% (Table 15.2), and if spontaneous labor
starts by 40 weeks. If the patient reaches her estimated due
Neonatal death date (EDC) with no labor and an unfavorable cervix, a PRCD
Neonatal death rates are similar between TOLAC versus PRCD may be appropriate, but induction with mechanical ripen-
(0.08% vs. 0.05%, respectively) in academic centers, with the neona- ing in women with at least a 60% chance of success is also a
tal death rate associated with a rupture at term of about 1.8% [11]. reasonable option. A VBAC calculator may be helpful in this
situation.
Perinatal death
Perinatal death rates at term (excluding malformations) are Counseling for TOLAC
1.3/1000 with TOLAC versus 0.5/1000 for PRCD [10]. Overall TOLAC can be offered to most women with a single or even two
prior low transverse CDs, but several safety and success factors
should be considered and discussed with the woman (Tables
50 15.1–15.3).
The composite of maternal complications is slightly higher
44.7 with TOLAC compared with the PRCD group primarily due to
40 Healthy (n=109) the risk of rupture and the increased risks of a CD in labor.
These estimates do not consider the long-term increased risks
30 Intrapartum/infancy
death (n=64)
of repetitive CD and the associated risks of placenta previa and
%
26.2 NICU for severe asphyxia accreta. Counseling should take into account how many future
20 23 only/others (n=56) pregnancies are planned.
Hypoxic ischemic The overall risk of serious perinatal complications is about 1
10 encephalopathy in 2000 TOLACs, which is slightly greater than that of PRCD
(no death) (n=15)
6.1 [11]. Combining all poor perinatal outcomes, more than 600
0 PRCDs would need to be performed to prevent one poor peri-
natal outcome. Although a woman with a TOLAC is at higher
FIGURE 15.6 Infant outcome after complete uterine rupture risk of uterine rupture than any other group, the risk of perinatal
(n = 244 births). (From Al-Zirqi I, Daltveit AK, Vangen S. Infant death is similar to that of any nulliparous woman in labor [16].
outcome after complete uterine rupture. Am J Obstet Gynecol. For the approximately 60%–80% of women having TOLAC
2018;219:109.e1. [II-2, population based with medical record who will deliver vaginally, the maternal and perinatal morbidity
review, n = 244 ruptures]. Ref. [109], with permission.) and mortality are lower than with PRCD.
For women in whom the chance of having a vaginal delivery clinical significance, best cutoffs, and appropriate management
with a TOLAC is over 60%, the maternal and perinatal morbidity of ultrasound findings. In one small study a cutoff of <2.3 mm
and mortality are lower than with PRCD. About 50% of women for the LUS thickness (from the bladder urine interface to the
with a prior CD have a 70% or higher chance of a successful decidua amniotic fluid or fetal scalp interface) was associated
VBAC, and they have no higher risk of maternal or perina- with rupture [78]. A subsequent meta-analysis of 21 studies look-
tal morbidity and mortality compared with those who have ing at data for 2776 women provided support for using ultrasound
PRCD [15]. measurement of the LUS in assessing for the presence of a uter-
Although the overall risks of TOLAC for all women are ine defect but recommended prospective validation before it can
higher than PRCD, the absolute risks are small and compara- be used in routine clinical practice [105]. In a multicenter study
ble to other potential complications of labor. Efforts to reduce of 1849 women where LUS thickness was used in counseling, of
the frequency of the first CD reduce the need for a TOLAC or 984 trials of labor, there were no symptomatic uterine ruptures.
repeat CD. Over 90% of women with a LUS thickness <2.0 mm had an ERCD
TOLAC should be approached with caution in those with [106]. A systematic review of 12 studies, including 1834 women
the lowest chance of vaginal delivery and highest risk of rup- and with a 6.6% rate of uterine scar defects, confirmed the strong
ture: For example, induction of labor in obese women over age 40 association between the degree of LUS thinning measured in the
with an unfavorable cervix and no prior vaginal deliveries. third trimester of pregnancy and the risk of uterine scar rupture/
The ultimate decision regarding whether to have a TOLAC dehiscence at delivery. The cutoff value proposed for predicting
or PRCD should be based on the patient choice, after appropri- these complications varied between 2.0 and 3.5 mm. Due to the
ate counseling and the availability of adequate resources and heterogeneity of the studies, no precise cutoff value could be rec-
personnel to respond to obstetric emergencies. Most women ommended [107].
should begin the decision process before term, and their decision
should be documented in the medical record. The decision can Requirements to minimize risks during a TOLAC [1]
then be modified at term in women to assess if spontaneous labor To minimize risks, the following must be immediately avail-
and/or favorable cervix make their chances of complications able throughout the TOLAC:
lower and of success higher. There is no evidence that examining
the adequacy of the pelvis benefits outcomes. • Experienced obstetrician
• Anesthesia
Prenatal education • Nursing and operating room personnel
Women who have had a prior CD need information and guid- • Ability to perform emergency CD
ance to help them decide whether to have a TOL or an ERCD.
Individualized prenatal education directed toward avoidance of a Labor and delivery units with >500/1000 births per year have
PRCD does not increase the rate of VBAC [99]. lower risks of uterine rupture and complications compared
The Cochrane review evaluated three RCTs of decision sup- with units with less volume [10, 101]. If centers cannot provide
port tools to help assist women in choosing ERCD or TOLAC the resources noted, this does not mean TOLAC should not be
and found no differences in the planned mode of birth or the offered. Referral should be made to adequate facilities early dur-
percentage of women who remained unsure about their final ing prenatal care so that TOLAC is safely available.
decision [100]. A subsequent RCT showed that interactive or
written evidence-based decision tools helped reduce conflict Detecting and managing rupture intrapartum
around the birth decision compared to baseline [101]. A sur- Fetal heart rate (FHR) disturbances are the most common
vey of a woman’s level of knowledge prior to TOLAC or ERCD (but not universal) sign of uterine rupture (55%–85%). The
showed most women had a poor understanding of the risks, most commonly reported FHR disturbance is repetitive, pro-
benefits, and likelihood of success of either option; they also gressively severe variable decelerations and prolonged brady-
were most likely to choose the mode of delivery favored by their cardia, although in most cases these are not caused by rupture
provider [102]. [108]. Nevertheless, in women with a prior CD, in the pres-
ence of such FHR disturbances, uterine rupture must be
Consent
considered. Immediate delivery is indicated, as one large
Specific consent for TOL after CD or PRCD should be signed by
population-based study from Norway showed a time to deliv-
the woman after appropriate counseling.
ery <20 minutes limited the incidence of intrapartum/infant
Nonvertex presentation deaths [109].
External cephalic version (ECV) can safely be performed in Abdominal pain over the area of the prior uterine scar is a poor
women with a prior CD. The success rate for ECV is similar or predictor of uterine rupture. Epidural usually does not mask rup-
higher in women with a prior CD compared to controls without ture. Epidural should not be withheld in women attempting TOL
a prior CD (82% vs. 61%) [103]. Women with a successful version after prior CD. Intrauterine pressure catheter (IUPC) monitoring
have successful VBAC rates of 65%–76% [103, 104]. has not been shown to be helpful [110]. Significant loss of fetal
station, especially in the second stage, may occur with rupture,
Ultrasound of the lower uterine segment but is of limited predictive value. There are insufficient data to
The data supporting the use of ultrasound to predict uterine rup- assess the utility of uterine exploration after a successful VBAC.
ture are limited, and so currently measurement of lower uter- Neonates delivered within 18 minutes after a suspected
ine segment (LUS) thickness is not routinely recommended uterine rupture have the best outcome, with all normal umbili-
for clinical management. Studies of the prior uterine scar have cal pH levels and 5-minute Apgar scores in one series, while
used varying terminology and methods and a wide range of those with a decision-to-delivery time >30 minutes have poor
results, yet there is still no consensus regarding the prevalence, outcomes [1, 111].
Cost-effectiveness 24. Flamm BL, Geiger AM. Vaginal birth after cesarean delivery: An admission
scoring system. Obstet Gynecol. 1997;90(6):907–910. [II-2]
Multiple cost-effectiveness analyses have been performed to exam-
25. Caughey AB, et al. Trial of labor after cesarean delivery: The effect of
ine the relative cost of TOLAC vs. PRCD. For women with at least a previous vaginal delivery. Am J Obstet Gynecol. 1998;179(4):938–941.
47% likelihood of successful vaginal delivery, TOLAC appears to be [II-2, n = 800]
more cost-effective than ERCD [112, 113]. In one analysis, TOLAC 26. Mercer BM, et al. Labor outcomes with increasing number of prior vaginal
has similar cost-effectiveness for the first TOL but becomes less births after cesarean delivery. Obstet Gynecol. 2008;111(2 Pt 1):285–291.
[II-2; prospective, n = 13,532]
costly and more effective with subsequent deliveries [114]. 27. Jongen VH, Halfwerk MG, Brouwer WK. Vaginal delivery after previous
caesarean section for failure of second stage of labour. Br J Obstet Gynaecol.
1998;105(10):1079–1081. [II-2]
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16
EARLY PREGNANCY LOSS
Lisa K. Perriera, Beatrice A. Chen, and Aileen M. Gariepy
Key points • Patients choosing medical management of EPL report an

average of 12 days of bleeding. Hemorrhage after medical
• The diagnosis of early (e.g. first trimester, <14 weeks) management of EPL is rare.
pregnancy loss may be suspected based on symptoms, but • Follow-up: Absence of a gestational sac using trans-
is usually made by transvaginal ultrasound and/or serial vaginal ultrasound after medical management of EPL
beta-human chorionic gonadotrophin (BHCG) levels. confirms successful expulsion of the gestational sac.
• Early pregnancy loss (EPL) is an inclusive term that com- Measurement of endometrial thickness is not predictive
prises the following: Incomplete, inevitable, or complete spon- of, and should not be used to determine, success.
taneous abortion (SAB); anembryonic pregnancy (“blighted • Advantages of medical management of EPL: Avoidance
ovum”); and embryonic/fetal demise (“missed abortion”). of surgery and anesthesia, perception of more natural
Early pregnancy failure (EPF) is a term that should be avoided, treatment, increased privacy, and increased control.
as it contributes to internalization of blame for patients.
• There are three options for the management of EPL: Surgical management
Expectant, medical, and surgical management. Choice
of management for EPL does not affect future fertility. • Surgical management has a high (>97%) success rate.
• Patient preference should guide treatment choice. • Endometritis or hemorrhage rates are less than 1%.
• Successful management of EPL consists of complete • Maternal safety is highest with vacuum aspiration under local
evacuation of the uterus. The success of each management anesthetic, avoiding regional or general anesthesia. Some
option depends on several factors, for example, whether or recommend continuous ultrasound guidance, if available.
not patients are experiencing symptoms.
• Threatened pregnancy loss can be defined as vaginal bleed-
ing in pregnancy before 20 weeks of gestation. Progesterone
Definitions
supplementation may reduce miscarriage rates in women • Pregnancy loss (PL): Spontaneous loss of pregnancy from
with threatened miscarriage. conception to <20 weeks.
• While progesterone supplementation cannot be recom- • Miscarriage: Lay term signifying PL.
mended for prevention of EPL in general, there may be • Threatened PL: Vaginal bleeding in pregnancy before 20
benefit in women with a history of recurrent miscarriage. weeks’ gestation.
Progesterone treatment for these women may be warranted • Early PL: Inclusive medical term describing inevitable abor-
(see Chap. 17) tion, incomplete abortion, anembryonic pregnancy, and
embryonic/fetal demise at <14 weeks [1]. It is also called “first-
Medical management trimester” PL. Early first-trimester PL is a loss of pregnancy
between conception and 96/7 weeks. Late first-trimester PL is a
• Medical management is a safe and effective alternative loss of pregnancy between 10 and 136/7 weeks. The terms early
to expectant management or surgical curettage for early pregnancy loss, miscarriage, and spontaneous abortion are
pregnancy loss (EPL). often used interchangeably in the first trimester [2].
• Medical management of EPL is more effective than expect- • Spontaneous abortion (aka loss): The term spontane-
ant management. ous abortion is often used as an equivalent term for EPL
• Due to its efficacy, mifepristone followed by misopro- but should be avoided, since women may associate nega-
stol is the preferred medical treatment for early preg- tive feelings with this term. This guideline does not dis-
nancy loss less than 13 weeks gestation. cuss voluntary (elective) termination (induced abortion).
• Mifepristone 200 mg orally followed by misoprostol 800 • Complete abortion: Clinical definition describing an
µg vaginally 24 hours later for the treatment of anembry- EPL that is characterized by a history of a positive preg-
onic pregnancy or embryonic demise less than 13 weeks’ nancy test and ultrasound showing intrauterine preg-
gestation has a success rate of 83% at initial follow-up nancy, vaginal bleeding with passage of tissue, and a
at 1–4 days and an overall success rate of 91% at 30 days closed cervical os at the time of diagnosis. Transvaginal
after treatment if a second dose of misoprostol is offered. ultrasound exam shows absence of a gestational sac.
• When mifepristone is unavailable, misoprostol 800 µg • Incomplete abortion: Clinical definition describing a
vaginally, with a repeat dose on day 3 if complete evacu- history of positive pregnancy test and ultrasound show-
ation is not confirmed by ultrasound, has a success rate ing intrauterine pregnancy, vaginal bleeding, and a cervi-
of 93% with incomplete or inevitable abortion, 88% with cal os that is open. Transvaginal ultrasound exam shows
embryonic or fetal death, and 81% with anembryonic heterogeneous tissue distorting the endometrial canal
pregnancy in patients at <13 weeks of gestation. with or without a gestational sac. There is no agreement
DOI: 10.1201/9781003102342-16 195

TABLE 16.1: Diagnostic Criteria for Early Pregnancy Loss Early First Trimester Diagnosis of Miscarriage and Exclusion of a
Viable Intrauterine Pregnancy [5].
Diagnosis Ultrasound Findings
It is important to recognize that not all patients may desire 100%
Anembryonic pregnancy • A gestational sac ≥25 mm MSD without certainty of pregnancy loss [2], and the wishes of the patient must be
(any of the three) an embryo considered when determining the level of diagnostic certainty that
• Absence of an embryo with cardiac will be used. Table 16.2 lists the sensitivity and specificity of dif-
activity ≥11 days after an ultrasound ferent diagnostic cutoffs that can be used to counsel patients [5, 6].
showed a gestational sac with a yolk sac
• Absence of an embryo with cardiac activity Beta-human chorionic gonadotropin
≥2 weeks after an ultrasound showing a In a clinically stable patient with a highly desired pregnancy, a
gestational sac without a yolk sac single beta-human chorionic gonadotropin (BHCG) level ≤3000
Embryonic/Fetal demise • Absence of cardiac motion in an embryo mIU/mL cannot differentiate between an ectopic pregnancy or EPL
measuring ≥7 mm if a gestational sac is not visualized in the uterus [5]. If the preg-
nancy is desired, ectopic precautions should be given and interven-
Abbreviation: MSD, mean sac diameter. tion should be avoided until additional testing is performed.
on a measurement of endometrial thickness that can dis- Symptoms

tinguish incomplete from complete abortion [3].
• Inevitable abortion: Clinical definition describing an Symptoms of EPL include vaginal bleeding, lower abdominal
EPL that is characterized by a history of a positive preg- cramping, and dilation of the cervix. Women with EPL may also
nancy test, vaginal bleeding without passage of tissue, be asymptomatic.
gestational sac in the uterus, and an open cervical os.
• Anembryonic pregnancy: Previously described as Epidemiology/Incidence
“blighted ovum.” This is a gestational sac without a
visible yolk sac and/or embryo (with no heart motion) Fifteen to twenty percent of clinically recognized pregnancies
in relationship to the mean sac diameter (MSD) size end in EPL [7]. It is estimated that up to 60% of conceptions
(Table 16.1). It occurs when the embryonic disk has become an EPL, and most are not clinically recognized (e.g.
failed to develop or has already been resorbed [4]. “late cycle”). Human reproduction is relatively inefficient. Only
• Embryonic/fetal demise: Previously described as 30% of fertilized eggs result in a viable pregnancy. Sporadic EPL is
“missed abortion.” It is defined by the failure of a previ- very common in humans. At least 15%–20% of clinically identified
ously identified embryo to grow and/or retain cardiac pregnancies (implanted) physiologically end with early PL, and only
activity over time (Table 16.1). 50%–60% of all conceptions advance to >20 weeks [8]. Most PLs
• Expectant management: No intervention. Awaiting natu- represent failure of implantation and are difficult to recognize clini-
ral passage of tissue. cally. Oocyte quality and normal karyotype are most important for
• Medical management: The use of medications to expel the normal implantation, more so than uterine factors. The prognosis
products of conception. after one uncomplicated EPL in a healthy young woman is for
• Surgical management: The mechanical removal of the >70%–80% chance of a viable pregnancy in the next pregnancy.
products of conception. Therefore, no workup or therapy is usually indicated after one
PL. For women with two or more EPLs, see Chap. 17.
Diagnosis
Etiology
Transvaginal ultrasound
To ensure 100% specificity to confirm early pregnancy loss, Chromosomal abnormalities are responsible for >50% of all
the diagnostic criteria shown in Table 16.1 were adopted by the spontaneous EPLs, most commonly aneuploidy. When tissue
Society of Radiologists in Ultrasound Multispecialty Panel on from EPLs <13 weeks (81% <9 weeks) obtained by chorionic villus
TABLE 16.2: Sensitivity, Specificity, and False-Positive Rates When Diagnosing Early
Pregnancy Loss
Sensitivity (95% CI) Specificity (95% CI) FPR (%)
CRL >5 mm without cardiac activity 0.50 (0.12–0.88) 1.00 (0.90–1.00) 0
CRL >6 mm without cardiac activity 0.50 (0.07–0.93) 1.00 (0.87–1.00) 0
CRL >7 mm without cardiac activity NA 1.00 (NA) NA
MSD >13 mm without yolk sac 0.96 (0.92–0.99) 1.00 (0.69–1.00) 0
MSD >16 mm without yolk sac 0.50 (NA) 1.00 (0.88–1.00) NA
MSD >20 mm without yolk sac 0.41 (0.30–0.52) 1.00 (0.96–1.00) 0
MSD >25 mm without yolk sac NA 1.00 (NA) NA
Source: Modified from Refs. [5, 6].
Abbreviations: CRL, crown–rump length; MSD, mean sac diameter; CI, confidence intervals; FPR, false-positive rate;
NA, not available.
Early Pregnancy Loss 197
sampling (CVS) and manual vacuum aspiration (MVA) is ana- in all women. A meta-analysis of all women, regard-
lyzed, about 72% of cases revealed aneuploidy, with trisomy less of gravidity and number of previous miscarriages,
being the most common [9]. Many spontaneous losses may be showed no statistically significant difference in the risk
secondary to other genetic defects that are impossible to discern of miscarriage between progesterone and placebo or
by simple karyotype. Many other factors are also associated with no treatment groups (OR 0.99; 95% CI 0.78–1.24) and
spontaneous losses (see Chap. 17). no statistically significant difference in the incidence
of adverse effects in either mother or baby [17].
Risk factors • However, in a subgroup analysis of four trials involv-
ing women who had recurrent miscarriages (3 +
The risk of EPL increases with maternal age, ranging from 9% at consecutive miscarriages; four trials, 225 women),
22 years old to 84% at 48 years old [10]. Other risk factors include progesterone treatment showed a statistically sig-
smoking, alcohol, excessive caffeine intake, African racial origin, nificant decrease in the miscarriage rate compared
previous EPL, previous stillbirth, medical complications such as to placebo or no treatment (OR 0.39; 95% CI 0.21–
diabetes, assisted reproductive technology, and vaginal bleeding 0.72), though these studies were of poorer quality.
[11]. A recent meta-analysis showed that caffeine and coffee con- • While progesterone supplementation cannot be
sumption, especially more than three servings per day, during recommended for prevention of EPL, there may be
pregnancy are significantly associated with pregnancy loss [12]. benefit in women with a history of recurrent mis-
carriage. Treatment for these women may be war-
ranted (see Chap. 17).
Threatened pregnancy loss
Threatened PL can be defined as vaginal bleeding in pregnancy Therapy
before 20 weeks of gestation. Several interventions have been • Bed rest
studied, but none has been confirmed to be beneficial. • There is insufficient evidence of high quality that
supports a policy of bed rest to prevent miscarriage
Complications in women with confirmed fetal viability and vaginal
• Vaginal bleeding in the first trimester has been associ- bleeding in the first half of pregnancy. There is no sta-
ated with several complications in pregnancy, including tistically significant difference in the risk of miscar-
antepartum hemorrhage (odds ratio [OR] 2.47), preterm riage in the bed rest group versus the no bed rest group
prelabor rupture of membranes (PPROM) (OR 1.78), pre- (placebo or other treatment) (RR 1.54, 95% CI 0.92–
term birth (PTB) (OR 2.05), fetal growth restriction (FGR) 2.58). Neither bed rest in a hospital nor bed rest at
(OR 1.54), low birth weight (LBW) (OR 1.83), and perinatal home shows a significant difference in the prevention
mortality (OR 2.15) [13]. of miscarriage. There is a higher risk of miscarriage in
• The presence of a subchorionic hematoma detected on those women in the bed rest group than in those in the
ultrasound (usually between 5 and 20 weeks) is associated HCG therapy group with no bed rest (RR 2.50, 95% CI
with increased risks of spontaneous abortion (SAB) (OR 1.22–5.11). The small number of participants included
2.18), abruption (OR 5.71), intrauterine fetal demise (IUFD) in these studies makes these analyses inconclusive [18].
(OR 2.09), PPROM (OR 1.64), and PTB (OR 1.40) [14]. • Bed rest cannot be recommended for prevention
of miscarriage. In fact, it might be harmful, given
Prevention the higher rates of venous thromboembolism (VTE),
• Lifestyle modifications muscle atrophy, and other detriments associated with
• Epidemiologic studies suggest that lifestyle modifica- bed rest.
tions can increase fertility potential, although these • Progesterone
have not been definitively tested in randomized con- • Progesterone supplementation may reduce miscar-
trolled trials. These modifications include eliminating riage rates in women with threatened miscarriage.
the use of tobacco products, alcohol, and caffeine and Treatment with oral progestogen compared to no
reduction in body mass index (BMI) [15]. treatment may reduce the miscarriage rate (RR 0.57,
• Multivitamins 95% CI 0.38–0.85), though there was no evidence of
• In non–high-risk women, vitamin C, vitamin A, and effectiveness with the use of vaginal progesterone
folic acid supplementation before 20 weeks are associ- compared with placebo in reducing the risk of miscar-
ated with similar total fetal loss (early/late miscarriage riage (RR 0.75, 95% CI 0.47–1.21) [19].
and stillbirth), early or late miscarriage or stillbirth, • Human chorionic gonadotropin
and most other outcomes compared with controls [16]. • The current evidence does not support the routine
Multivitamin supplementation with iron and folic acid use of HCG in the treatment of threatened miscar-
may be associated with a decreased risk of stillbirth riage. There is no statistically significant difference in
as compared to iron and folate only (relative risk [RR] the incidence of miscarriage between HCG and “no
0.92, 95% confidence interval [CI] 0.85–0.99) but is HCG” (placebo or no treatment) groups (RR 0.66, 95%
not associated with a difference in the risk of early or CI 0.42–1.05). There were no reported adverse effects
late miscarriage. Therefore, vitamin supplementation of HCG on the patient or fetus [20].
cannot be recommended for prevention of EPL. • Muscle relaxant
• Progesterone • There is insufficient evidence to support the use of
• There is no evidence to support the routine use of uterine muscle relaxant drugs for women with threat-
progesterone (synthetic or natural) to prevent EPL ened miscarriage, and therefore they should not be used.
In one poor-quality randomized controlled trial (RCT), • Methotrexate (IM or oral) antagonizes folic acid, a cofac-
compared with placebo, buphenine (a beta-agonist) was tor needed for the synthesis of nucleic acids. It is toxic to
associated with a lower risk of intrauterine death (RR the rapidly dividing cells of the trophoblast. There is no
0.25, 95% CI 0.12–0.51). PTB was the only other outcome role for methotrexate in the treatment of EPL [28].
reported (RR 1.67, 95% CI 0.63–4.38) [21]. • Success of medical management is determined by the
absence of significant symptoms, such as heavy vaginal
Management of EPL bleeding, and absence of the gestational sac on transvagi-
nal ultrasound. Studies that use an endometrial thickness
General principles of >15 mm to define failure of medical management may
• There are three main options for the woman with EPL underestimate success rates of expectant and medical
(unless the spontaneous loss is complete): Expectant, management [4]. Endometrial thickness should not be used
medical, and surgical management. to determine success of medical management.
• Successful management of EPL entails complete evacua- • Success of medical management is higher in patients
tion of the uterus, defined as expulsion of the gestational with symptoms, such as cramping and bleeding [29].
sac. The success of each management option depends on
several factors, for example, whether or not the patient has Contraindications: The contraindications listed in Table 16.3
symptoms. apply to medical management but some may also apply to expect-
• Failure of expectant or medical management results in the ant management [25, 30, 31].
need for surgical evacuation. Complications:
Principles of surgical management • Complications are rare. The incidence of gynecologic

• Procedure: Surgical management of EPL is best accom- infection after surgical, expectant, or medical manage-
plished with electric or manual vacuum aspiration comment of EPL is low (2%–3%). There is no evidence to show
pared to sharp curettage. a differential risk of infection by management choice [32].
• When comparing vacuum aspiration versus sharp curet- • In the largest RCT (n = 652) comparing medical with surgi-
tage, vacuum aspiration is preferred, as it is associated cal management, there was no difference in the following
with [22]: complications [25]:
• Less blood loss (mean difference [MD] –17.10 mL, 95% • Hemorrhage requiring hospitalization with or without
CI –24.05 to –10.15 mL). blood transfusion (1%)
• Less pain during the procedure (RR 0.74, 95% CI • Hospitalization for endometritis (<1%)
0.61–0.90). • Fever (3%–4%)
• Shorter duration of the procedure (MD –1.20 minutes, • Emergency visit to the hospital within 24 hours of
95% CI –1.53 to –0.87 minutes). treatment (2%–3%)
• The small sample sizes of the trials were too small to • Unscheduled hospital visits (17%–23%)
evaluate rare complications such as uterine perfora- • Decrease in hemoglobin ≥2 g/dL (4%–9%)
tion and other morbidity. • Decrease in hemoglobin ≥3 g/dL (1%–5%)
• Vacuum aspiration can be accomplished with electric vac-
uum aspiration (EVA) or MVA. Both EVA and MVA are Principles of expectant management
types of dilation and curettage (D&C). Expectant management of EPL is an option for women who would
• Location: Vacuum aspiration can be accomplished in the like to avoid surgical or medical treatment of EPL; however, time
operating room or in the office. until resolution of EPL is unpredictable and may take as long as
• MVA is a safe alternative for gestations 6–12 weeks with 6 weeks. Success of expectant management can range from 25%
EPL and can be performed in the office under local anes- to 83%, depending on length of time of follow-up, definition of
thesia [23]. This should be strongly preferred at these “failed” expectant management, and inclusion criteria [33–35].
gestational ages instead of an operating room procedure
necessitating general anesthesia [24]. Medical versus surgical management
• There is no significant difference in the success or com- • Cochrane review [36]:
plication rates for MVA versus EVA [25]. • Twenty-four RCTs were included in this Cochrane review
• Some experts recommend continuous ultrasound guid- of incomplete abortion before 13 weeks with n = 5577.
ance if available, but this should not be a barrier to access.
TABLE 16.3: Contraindications to Medical (or Expectant)
Principles of medical management Management
Medications used:
• Hemodynamically or medically unstable patients
• Signs of pelvic infection and/or sepsis
• Misoprostol is a prostaglandin E1 analogue. It is a utero-
• Suspected molar or ectopic pregnancy
tonic that results in cervical softening and contractions
that expel the products of conception. Routes of admin- • Caution should be used in women with hemoglobin <9.5 g/dL
istration include vaginal, oral, buccal, or sublingual. Side • History of coagulopathy or current use of anticoagulants
effects vary, based on route of administration [26]. • Contraindication to prostaglandinsa
• Mifepristone is an antiprogestin that results in weakening • Contraindication to mifepristone (if being used)a
of the uterine attachment of a pregnancy. This results in Source: Modified from Refs. [25, 31, 40].
capillary breakdown and synthesis of prostaglandins [27]. a Specific to medical management.
• Misoprostol routes varied, including seven studies via – At less than 24 hours after treatment (RR 4.73,
oral, six studies via vaginal, two studies via sublingual, 95% CI 2.70–8.28)
and one study via both vaginal and oral. – At less than 48 hours after treatment (RR 5.74,
• There was a slightly lower incidence of complete 95% CI 2.70–12.19)
miscarriage in the misoprostol group (RR 0.96, – Results in less need for uterine curettage
95% CI 0.94–0.98), but high success in both – Does not show a significant difference in need for
groups. blood transfusion (RR 0.2, 95% CI 0.01–4.0)
• Women using misoprostol had fewer surgical proce- – Does not have a significant increase in nausea (RR
dures (RR 0.05, 95% CI 0.02–0.11). 1.38, 95% CI 0.43–4.40) or diarrhea (RR 2.21, 95%
• Risk of unplanned procedure was higher with miso- CI 0.35–14.06)
prostol (RR 5.03, 95% CI 2.71–9.35). • Dosage of vaginal misoprostol: When comparing 400,
• Deaths and “serious complications” with either man- 600, and 800 µg dosages, higher-dose regimens were
agement are too rare to compare. not more effective at completing uterine emptying as
• Largest multicenter RCT [25]: compared to lower dosages (RR 0.82, 95% CI 0.58–
• n = 652; 491 participants treated with 800 µg vaginal 1.14). There was a similar incidence of nausea (RR 0.67,
misoprostol versus 161 participants treated with vac- 95% CI 0.31–1.41) between regimens.
uum aspiration • No advantage of “wet” versus “dry” preparation of vag-
• Participant characteristics: inal misoprostol or of adding methotrexate.
– 58% embryonic/fetal demise • There may be no difference between oral misoprostol
– 36% anembryonic pregnancy and vaginal misoprostol in emptying the uterus, but
– 6% incomplete/inevitable abortion one of the studies had serious risk of bias (RR 0.68, 95%
• Medical regimen: 800 µg vaginal misoprostol, CI 0.45–1.03).
repeated on day 3 if incomplete expulsion (diag- • Sublingual misoprostol is equivalent to vaginal miso-
nosed by persistence of gestational sac or endome- prostol in inducing complete uterine emptying (RR
trial lining greater than 30 mm on transvaginal 0.84, 95% CI 0.61–1.16) but was associated with more
ultrasound), vacuum aspiration on day 8 if still frequent diarrhea.
incomplete • Mifepristone:
• Success: • Efficacy of mifepristone followed by misoprostol for
– 97% success with vacuum aspiration treatment of miscarriage ranges from 65.5% to 91.2%
– 84% success with misoprostol overall [37–40].
– 71% success with one dose of misoprostol • In a Cochrane review published in 2019, three trials
– Success increases to 84% with a second dose of of mifepristone added to misoprostol did not show
800 µg vaginal misoprostol if the gestational sac increased efficacy with mifepristone [28]. However,
was still present on ultrasound on day 3 this Cochrane review did not include the Schreiber
• Success by type of EPL: et al. study that was published in 2018.
– 93% for incomplete/inevitable abortion • One small RCT (n = 115) found that mifepristone in
– 88% embryonic/fetal demise addition to misoprostol did not improve efficacy [39],
– 81% anembryonic pregnancy though one retrospective study did find increased
• Success did not vary by gestational age expulsion rates with mifepristone plus misoprostol
• Increased rates of nausea, vomiting, and diarrhea and versus misoprostol alone [41].
abdominal pain in the misoprostol group • A definitive multisite RCT (n = 300) published in 2018
• No difference in hemorrhage or endometritis between demonstrated that the success rate for the treatment of
groups (<1%) embryonic demise or anembryonic pregnancies with
• Success of medical management associated with one 800 µg dose of misoprostol 24 hours after mife-
cramping, vaginal bleeding, and nulliparity [29] pristone had an initial success rate of 83.8%, a 89.2%
success rate at day 8 when an additional dose of miso-
Conclusion: Medical management with misoprostol is an prostol was offered, and a success rate of 91.2% by day
acceptable alternative to surgical evacuation. Patient prefer- 30 [40]. Those subjects in the misoprostol-only arm
ence should guide decision-making [36]. had an initial success rate of 67.1% (p <0.001), success
at day 8 of 74.5%, and success at day 30 of 75.8%. The
Medical versus expectant management number needed to treat in order to achieve an addi-
Medical management commonly uses vaginal misoprostol [28]. tional outcome of treatment success by the first follow-
There are several additional studies looking at mifepristone fol- up was 6.
lowed by vaginal or oral misoprostol [37–39].
Conclusion: Medical management with mifepristone
• Cochrane review [28] 200 mg followed by 800 µg of vaginal misoprostol is signifi-
• Forty-three RCTs, n = 4966, of embryonic/fetal demise cantly more effective than management with misoprostol
or anembryonic pregnancy. alone or expectant management. There is now clear evidence
• Vaginal misoprostol compared with expectant that mifepristone combined with misoprostol appears to have
management: higher success rates compared to misoprostol alone. Based on
– Shortens the time to achieve complete uterine available evidence, adding mifepristone to misoprostol for medi-
evacuation: cal management is recommended, when available.
Expectant versus surgical management • There is insufficient evidence to recommend prophylac-

In a Cochrane review of seven RCTs, n = 1521 [42]: tic antibiotics for women undergoing surgical evacuation
of the uterus for embryonic/fetal demise or anembry-
• Expectant management has a higher incidence of the onic pregnancy, but the risk of infection is thought to be
following: similar to the risk of infection for induced termination of
• Incomplete miscarriage by 2 weeks (RR 3.98, 95% CI pregnancy.
2.94–5.38) or by 6–8 weeks (RR 2.56, 95% CI 1.15–5.69). • One large RCT (n = 3412) randomized patients undergo-
• Need for unplanned or additional surgical emptying of ing surgical treatment of pregnancy loss <22 weeks in low-
the uterus (RR 7.35, 95% CI 5.04–10.72). resource countries to antibiotic prophylaxis (400 mg of oral
• Surgical management is required in 28% in the expect- doxycycline and 400 mg of oral metronidazole) to placebo),
ant group, while only 4% in the surgical group require with a primary outcome of pelvic infection within 14 days
additional surgery. after surgery. The risk of pelvic infection for those in the
• More days of bleeding (weighted mean difference antibiotics and placebo arms were 4.1% and 5.3%, respec-
[WMD] 1.59, 95% CI 0.74–2.45)]. tively (RR 0.77, 95% CI 0.56–1.04). However, when using
• Need for blood transfusion (RR 6.45, 95% CI strict criteria for the definition of pelvic infection, the risk
1.21–34.42). of pelvic infection was statistically lower in the antibiotic
• There was no difference in infection risk. arm (1.5% versus 2.6%, RR 0.60, 95% CI 0.37–0.96).
• Cost was lower in the expectant management group. • The American College of Obstetricians and Gynecologists
(ACOG) recommends the use of a single preoperative dose
Conclusion: Expectant management is associated with of doxycycline in cases of EPL, but acknowledges the lack
more risk than surgical management; however, discussion of of data [2]. Administration of doxycycline 200 mg within
risks of all treatment options, shared decision-making, and 30 minutes of the procedure is a low-cost regimen, and
patient preference should guide decision-making. the benefits of administration outweigh the risks [47].
Mifepristone: Route, dose, and safety Rh negative

• Mifepristone 200 mg orally is the recommended dose Women who are Rh(D) negative and unsensitized should receive
and route [37–40]. Rh(D)-immune globulin within 72 hours of the EPL [2].
• All studies using mifepristone for medical management
have used it in combination with a prostaglandin, typi- Patient counseling
cally misoprostol [37–40].
Patients choosing medical management of EPL should have
Misoprostol: Route, dose, and safety appropriate counseling regarding expected symptoms.
There is published literature on a wide range of therapeutic regi-
mens [4, 31, 40, 43]. Optimal doses and routes of administration • Bleeding with medical management is heavier and longer
of misoprostol have not been determined by randomized trials. in duration than with surgical management and rarely
requires intervention [48].
• Misoprostol 800 µg per vagina is the most studied regi- • Women experienced approximately 12 days of bleeding
men for medical management of EPL. Success of medical after medical management of EPL [47]. Bleeding will most
management of EPL increases with multiple-dose regi- likely be heavy for about 3–4 days, followed by light bleed-
mens [25]. ing or spotting for several weeks [30].
• A single RCT showed that there is equivalent efficacy • Patients should be counseled to contact their physician if
between a multidose regimen of vaginal misoprostol 400 µg they experience heavy vaginal bleeding (soaking through
and 800 µg with a lower incidence of fever/rigors and more than two extra-large sanitary pads per hour for 2
higher satisfaction in the lower dose group [44]. consecutive hours) or signs of infection [30].
• An international panel of experts recommends a single • Some women experience fever and/or chills during the first
oral dose of 600 µg misoprostol for medical management of 24 hours after misoprostol use. Patients should call their
incomplete abortion [30] and a single vaginal dose of 800 µg doctor and be evaluated for infection if fever and/or chills
misoprostol for medical management of anembryonic persist beyond 24 hours after using misoprostol [30].
pregnancy and embryonic/fetal demise [44]. Misoprostol • Nausea and vomiting may occur with use of misoprostol
600 µg sublingual is an alternative regimen [45]. and will usually resolve 2–6 hours after taking it [30].
• Overall, misoprostol is safe and well tolerated. Side effects • Pain should be expected with medical or expectant
of prostaglandins include diarrhea, nausea, and vomit- management, and patients should be given prescrip-
ing. These side effects are increased when misoprostol is tions for pain medications [2].
given orally. Patients receiving misoprostol vaginally have
decreased gastrointestinal side effects and prolonged dura- Patient acceptability
tion of action when compared with oral administration [26].
• In one study, the majority of women would prefer medical
Antibiotics management of EPL with misoprostol to surgical manage-
• There is insufficient evidence to recommend or to abandon ment if its efficacy is >65% [49].
prophylactic antibiotics for surgical evacuation in women • In a large RCT comparing medical versus surgical manage-
with an incomplete abortion. Clinical judgment is recom- ment of EPL, women receiving medical management had
mended [31, 46]. significantly higher reports of treatment-related symptoms
(cramping and bleeding), but overall quality of life and expectant, medical, or surgical management of EPL, there was no
treatment acceptability were similar [50]. significant difference in the live birth rate 5 years after the index
• In a large RCT comparing medical versus surgical man- miscarriage [57].
agement of EPL, 83% of women with EPL randomized to
medical management with misoprostol would recommend • Expectant management: 177/224 (79%, 95% CI 73%–84%)
medical management to others, and 78% would probably/ • Medical management: 181/230 (79%, 95% CI 73%–84%)
absolutely use medical management again [25]. • Surgical management: 192/235 (82%, 95% CI 76%–86%)
Patient preference References

Most women have strong preferences regarding the management 1. National Institute for Health and Clinical Excellence: Guidance. Royal
of EPL [51]. Preferences are diverse, and different women place College of Obstetricians and Gynaecologists (RCOG). NICE Guideline 126.
different values on the advantages and disadvantages of avoid- Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management.
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17
RECURRENT PREGNANCY LOSS
Reshama S. Navathe and Shabani Ahluwalia
Key points on this definition (Table 17.1) [2–4]. The European Society of
Human Reproduction and Embryology (ESHRE) distinguishes
• The diagnosis of recurrent pregnancy loss (RPL) is ≥2 RPL from a similar entity, recurrent miscarriage, which is defined
failed clinical pregnancies. as a loss that has been confirmed as intrauterine [2].
• Workup includes karyotype of products of conception For diagnoses of pregnancy loss, miscarriage, spontaneous and
(if available), parental karyotypes, uterine study, and other kinds of abortions, anembryonic pregnancy, embryonic
antiphospholipid antibodies (APAs). demise, etc., please see Chap. 16.
• Prognosis with negative workup is for a 60%–70% subse-
quent successful pregnancy in women <35 years old and Classification
40%–50% in women ≥35 years old.
• Women with RPL who are diagnosed with antiphospho- Primary RPL: No intervening live births; secondary RPL:
lipid syndrome (APS) should be treated with low-dose Intervening live births. The prognosis is better with secondary
aspirin and heparin in subsequent pregnancies (see Chap. RPL [5].
28 in Maternal-Fetal Evidence Based Guidelines). Women
with unexplained RPL should not receive anticoagulant
therapy.
Incidence
• Women with RPL and uterine septum, synechiae, or Approximately 15% of pregnant women experience loss of a clini-
submucous myomata can consider hysteroscopic resec- cally recognized pregnancy. It is estimated that less than 5% of
tion of these abnormalities. women experience two consecutive pregnancy losses and only
• Couples with abnormal parental karyotype can be offered 1% experience three or more [6].
genetic counseling, in vitro fertilization (IVF) with pre-
implantation genetic screening (PGS), prenatal diagnosis,
and/or gamete donation.
Etiology
• Couples should be offered mental health support, as RPL Etiology of RPL is not established in at least 50% of cases
can be associated with significant anxiety and depression. after workup. General categories include genetic, anatomic,
• There is insufficient evidence for universal screening for endocrine, immunologic, thrombophilic, and environmental
diabetes mellitus (DM), thyroid disease, progesterone defi- (Table 17.2) [7].
ciency, infections, thrombophilia, etc., in women with RPL.
• Women with RPL should not be tested for alloimmuniza-
tion or receive any of the immune therapies, as they have Risk factors/Associations
thus far not shown benefit in RPL. Advancing maternal age is associated with a higher rate of RPL.
• There is increasing evidence that progesterone supple- The rate of clinically recognized miscarriage is 20% at age 35, 40%
mentation is beneficial, especially in women with ≥3 RPLs at age 40, and up to 80% at age 45 [8]. Other risk factors include
and early pregnancy bleeding. maternal medical diseases, especially poorly controlled, such as
• There is insufficient evidence to support estrogen, human hypertension and diabetes (see Chap. 16). A previous pregnancy
chorionic gonadotropin (hCG), aspirin alone, and vitamins loss is a risk factor for recurrence (Table 17.3) [6, 9]. Women
as interventions. with only an unsuccessful pregnancy history have a greater risk of
future miscarriage than primigravidas and women with a history
Diagnosis/Definitions of previous successful pregnancy [10].
The definition of recurrent pregnancy loss (RPL) varies in differ- Counseling

ent publications, which makes diagnosing and treating this entity
more challenging for physicians and couples. While the majority RPL can be emotionally devastating to couples, and its impact
of RPL comprises early pregnancy loss <14 weeks’ gestation, mid- on the mental health of both partners needs to be addressed
trimester losses have been included in some studies, which further (Table 17.3) [6, 10, 11]. Depression rates are almost fourfold higher
complicates accurate diagnosis. We choose to define RPL as two than women who do not suffer from RPL [12]. This emphasizes the
failed clinical pregnancies <14 weeks as the most inclusive and importance of mental health evaluation as part of the workup.
currently accepted definition. This includes biochemical preg- Patients could benefit from intensive supportive care early in
nancies and those diagnosed by ultrasound or histopathologic pregnancy, focusing on antenatal counseling and psychologi-
findings. This definition includes pregnancy of unknown loca- cal support. Stress has been associated with RPL, but couples
tion, but not confirmed ectopic or molar pregnancies [1]. There should be reassured that stress does not cause RPL [12]. Couples
are several guiding committees with slightly different variations should be provided reassurance after a first early pregnancy loss;
DOI: 10.1201/9781003102342-17 203

TABLE 17.1: Definitions of RPL

Committee Number of Pregnancies Consecutive? Specifics
RCOG 2011 3 Yes Not required to be intrauterine
ASRM 2013 2 No Clinical pregnancies confirmed by histology or ultrasonography
ESHRE 2018 2 No Biochemical or intrauterine, can include pregnancy of unknown location
Source: From Refs. [3, 4, and 7].
Abbreviations: RCOG, Royal College of Obstetricians and Gynecologists; ASRM, American Society of Reproductive Medicine; ESHRE, European Society
of Human Reproduction and Embryology.
TABLE 17.2: Etiology, Diagnostic Considerations, and Treatment in RPL

Etiology Percentage Diagnostic Evaluation Therapy
Genetic 3%–5% Karyotype: Parental Genetic counseling
Sporadic Karyotype: POC Genetic counseling, PGD
Anatomic 10%–20% 3D US Correction of anatomic defect
Hysterosalpingogram
SIS
Endocrinology 8%–12% TSH Levothyroxine
Prolactin Bromocriptine
Hgb A1c Diabetic optimization
Immunologic/thrombophilic 5%–15% APLAS Aspirin + heparin
Environmental Tobacco, EtOH Eliminate exposures
Exposure
Unknown 40%–50%
Abbreviations: RPL, recurrent pregnancy loss; POC, products of conception; PGD, preimplantation genetic diagnosis; 3D US, three-dimensional ultra-
sound; SIS, saline infusion sonogram; TSH, thyroid-stimulating hormone; Hgb A1c, hemoglobin A1c; APLAS, antiphospholipid antibody syndrome;
EtOH, alcohol.
after subsequent losses, couples should have detailed counseling exposures, and working conditions, as well as detailed obstetric
regarding prognosis (Table 17.3) [6, 9]. It should be made clear and gynecologic history) and physical exam (weight, blood pres-
that workup does not always lead to a definitive diagnosis, and sure, pelvic exam). Eliciting the gestational age of miscarriage
effective treatment may not be available for RPL. is important, as often RPL occurs at a similar gestational age in
subsequent pregnancies, and the most common cause of RPL
Candidates for evaluation varies by gestational age. Sometimes, though, obstetric history
is mixed, with early pregnancy loss (PL), second-trimester PL,
Workup should in general not be initiated after a first early preg- preterm birth (PTB), and/or fetal death. In these cases, workup
nancy loss, as the prognosis remains at baseline after an initial may include other tests (see specific chapters, including Chap. 57
loss. Workup should be in general be initiated after two failed in Maternal-Fetal Evidence Based Guidelines). Screening tests
clinical pregnancies [13]. (see later) can be recommended concomitantly, or they can be
performed based on clinical scenario and suspected etiology. The
latter approach allows for a more cost-effective practice and min-
Workup imizes unnecessary testing for couples. Appropriate diagnostic
Appropriate diagnostic workup of RPL is essential for choosing workup of RPL is essential for choosing the proper intervention.
the proper intervention (Table 17.4) [14]. The initial part of the
workup consists of a detailed history (medical comorbidities, Recommended screening tests
smoking, alcohol and caffeine use, illicit drug use, environmental
Genetic evaluation
POC karyotype/CGH
TABLE 17.3: Miscarriage Risk after Prior PL Management of women with ≥2 RPLs should begin with genetic
Prior PL (n) Risk of Miscarriage in Subsequent Pregnancy evaluation of products of conception (POCs) if possible
(Figure 17.1) [15]. About 75% of early pregnancy losses in the
0 10%–15%
first trimester result from random numeric chromosomal
1 13%–25%
errors [16]. More than 50% of aneuploidies are trisomies; the most
2 17%–35% common single aneuploidy is 45,XO. Additionally, as maternal
3 25%–45% age increases, miscarriage associated with aneuploidy increases,
4 60%–65% accounting for up to 80% in those over 35 years of age [17].
Source: Adapted from Refs. [6, 8]. Aneuploidy is typically considered sufficient explanation for
Abbreviation: PL, pregnancy loss. pregnancy loss; this provides the couple with an explanation
Recurrent Pregnancy Loss 205
TABLE 17.4: Evaluation of a Woman with Recurrent Miscarriages

Medical History Comment
Determine pattern and gestational age of preembryonic, Preembryonic and embryonic losses before 10 wk of gestation are the most
embryonic, or fetal death, if such information is available common type of miscarriage, although the onset of symptoms may be later
Evaluate for features suggestive of antiphospholipid syndrome Features include thrombosis, fetal death, autoimmune disease, and
thrombocytopenia
Assess whether patient has a history of uterine malformations Previous obstetric complication such as preterm labor or breech presentation
(e.g. seen on previous ultrasonographic examination or during suggests possibility of uterine malformation
intra-abdominal surgery)
Assess whether patient has had another fetus or infant with A congenital anomaly suggests the possibility of a parental karyotype abnormality,
congenital anomaly although these abnormalities may be present in the absence of such a history
Determine whether patient has history of symptoms suggestive of Can aid in direction of diagnostic workup
thyroid disease or diabetes
Physical Examination
Perform pelvic examination with particular focus on findings
compatible with uterine or cervical abnormalities
Examine patient for other physical findings suggestive of thyroid
disease or diabetes
Recommended Testsa
Lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2- Tests for lupus anticoagulant are reported as either positive or negative; levels of
glycoprotein 1 antibodies anticardiolipin and anti-beta-2-glycoprotein 1 antibodies are clinically
significant only in medium-to-high titers as defined by the laboratory;
antiphospholipid syndrome is diagnosed when tests are repeatedly positive at
least 12 wk apartb
Sonohysterography Sonohysterography and hysterosalpingography are noninvasive screening tests
used to evaluate uterine cavity and shape; MRI, hysteroscopy, or both may be
more informative but are more expensive and invasive, respectively; all are useful
in detecting a uterine abnormality
Chromosome analyses of father and mother Parental karyotyping is expensive and not always covered by third-party payers;
because treatment options are limited and do not surpass results of spontaneous
conception, some couples may choose to forgo this testing
Genetic analysis of products of conception Aneuploid conceptus indicates a more favorable outcome of a subsequent
pregnancy and may avert further unnecessary evaluation and treatment. Options
include chromosome analysis or (even better) direct array which increases
likelihood of results (see text)
Other laboratory tests (e.g. thyrotropin measurement or screening
for diabetes), if suggested by history or physical examination
a Routine testing for thyroid disease, diabetes, polycystic ovary syndrome, heritable thrombophilias, bacteria and viruses, and alloimmune abnormalities is not
recommended.
b See also Chap. 28 in Maternal-Fetal Evidence Based Guidelines.
Abbreviation: MRI, magnetic resonance imaging; wk, weeks.
and has been shown to decrease self-blame [18]. Karyotype reproductive loss rates, most will have successful pregnancies
can be obtained directly from POCs; however, this test requires without intervention [19]. Available intervention includes preim-
growing (dividing) cells to assess DNA in metaphase. Many times plantation genetic screening (PGS) and donor gametes.
cells of abortuses do not grow in culture, especially those with
aneuploidy. Potential pitfalls include culturing of maternal cell Anatomic evaluation
contaminants, falsely providing a “negative” test result (46,XX). Ten to twenty percent of women with RPL have uterine anom-
Array comparative genomic hybridization (aCGH) does not alies [7]. The most common congenital anomaly associated with
require dividing cells and therefore can be useful in settings of RPL is septate uterus (spontaneous abortion [SAB] rate is high,
culture failure. As such, aCGH has been suggested for use over about 65%) [20], followed by didelphys and bicornuate. Arcuate
karyotype. uterus has not been consistently associated with RPL. The rela-
tionship between RPL and acquired uterine abnormalities such
Parental karyotype as leiomyomata, adhesions, and endometrial polyps is not well
Three to five percent of couples with RPL have one parent with established. Uterine synechiae (Asherman syndrome) and dieth-
balanced translocation, mosaicism, or, less commonly, a chro- ylstilbestrol (DES) exposure are associated with RPL. Myomata
mosome inversion. Although these couples experience increased have been associated with decreased implantation rates in the
1st Miscarriage
standard to diagnose LPD [24]. Screening is not recom-
<14 weeks: mended in RPL.
Try another pregnancy; no • Immunologic workup.
action needed; provide
reassurance
Although autoantibodies have been reported in women with RPL
[25], there has been no consistent association and few interven-
tion studies. Currently, testing for antinuclear antibody (ANA),
2nd Miscarriage anti–double-stranded DNA, and anti-smooth muscle antibodies
<14 weeks: is not recommended. There does appear to be an association with
Cytogenetic analysis anti-thyroglobulin antibody based on a retrospective cohort.
Further studies are needed [26].
Thrombophilia workup
Inherited thrombophilias (factor V Leiden [FVL], prothrombin
Aneuploid Unbalanced Euploidy G20210A gene mutation [PTM], antithrombin III deficiency, protein
or polyploidy: translocation: or balanced S, and protein C deficiencies) have not been consistently associated
translocation:
Diagnostic evaluation with RPL in the best designed prospective studies. However, a higher
No further Cytogenetic analysis
evaluation needed of both partners (see text and tables) frequency of FVL carrier state has been shown in women with early
RPL [27]. Second-trimester PL has been associated with thrombo-
philic mutations. There is insufficient evidence regarding any
FIGURE 17.1 Evaluation of patients with early pregnancy interventions in women with RPL and inherited thrombophilias
loss based on cytogenetic analysis of products of conception. (see Chap. 29 in Maternal-Fetal Evidence Based Guidelines).
(Adapted from Ref. 7.)
Infectious workup
in vitro fertilization (IVF) literature [21]. A maternal uterine No infectious agent has been proven to cause RPL. Listeria,
study (sonohysterogram or hysterosalpingogram [HSG]) is rec- Toxoplasma gondii, and many viruses have been associated
ommended. Second-line tests (due to increased expense or inva- with sporadic early PL. Chlamydia, Mycoplasma/Ureaplasma
sive nature) such as MRI or hysteroscopy/laparoscopy may have (proposed diagnosis with endometrial biopsy, with treatment of
a role as well. Available intervention is hysteroscopic resection woman and partner with either doxycycline 100 mg PO bid or
of septum, synechiae, or submucous myomata. Surgical correc- ciprofloxacin 250 mg PO bid), and bacterial vaginosis are associ-
tion may not improve chances of a successful pregnancy (see ated with sporadic pregnancy loss, but not RPL [28].
“Abnormal Uterine Cavity,” later).
Male factor
Endocrine evaluation A meta-analysis of prospective studies showed an association
Endocrine factors may contribute to 8%–12% of RPL [22]. Basic between sperm DNA fragmentation and RPL (mean difference
evaluation should consist of screening for diabetes (hemoglobin 11.91, confidence interval [CI] 4.97–181.86) [29]. However, there
A1c [HgbA1c], fasting glucose, glucose tolerance testing) and is significant heterogeneity between the studies. Routine testing
screening for thyroid dysfunction (thyroid-stimulating hormone is not recommended.
[TSH] and free thyroxine [T4]); prolactin levels only if clinically
suspicious. Management
Immunologic evaluation Prevention
Five to fifteen percent of women with RPL have antiphos- Optimize preconception medical care of all maternal diseases.
pholipid syndrome (APS) [7]. Testing, which includes aPL
antibodies (lupus anticoagulant, anticardiolipin antibodies Preconception care
[ACAs], and beta-2 glycoprotein 1) should be positive twice, In patients with RPL, workup should be performed prior to con-
≥12 weeks apart. See Chap. 28 in Maternal-Fetal Evidence ception (Table 17.4). If workup is positive, patients should be coun-
Based Guidelines for details on diagnosis and other consider- seled regarding specific associations. If workup is negative (>50%
ations in pregnancy. of couples), counseling should include the fact that 60%–70% of
couples with unexplained RPL have successful pregnancies
Tests that cannot be routinely recommended in the next gestation (Table 17.3). This percentage, however,
decreases to 40%–50% in women ≥40 years old. All women with
• POC molecular genetic abnormalities (e.g. X-chromosome RPL should be offered a support group. UNITE offers services
inactivation) is associated with increasing maternal age, that provide emotional support through parent-to-parent shar-
but is not associated with RPL [23]. ing on issues related to grieving. UNITE can assist in referral if
• Endometrial biopsy or progesterone levels. additional professional support is needed [30].
• Luteal phase deficiency (LPD) has been suggested as a
cause of RPL. The corpus luteum fails to make enough Prenatal care
progesterone to sustain pregnancy implantation and early For recommend therapy specific for a positive workup, see next. In
growth. The diagnosis is hampered by inconsistent diag- cases of RPL, especially with current vaginal bleeding but even in the
nostic criteria. The American Society for Reproductive absence of it, progesterone has shown benefit (see “Therapy” section).
Medicine (ASRM) has determined that there is no Offer early and frequent ultrasounds as needed given patient anxiety.
Therapy (specific for workup) to Chap. 16 and to Chap. 29 in Maternal-Fetal Evidence Based
Abnormal parental chromosomes Guidelines.
Offer genetic counseling and prenatal diagnosis (termination is
an option for affected pregnancies). Preimplantation genetic Interventions for unexplained RPL
screening with IVF is not beneficial, including in women Progesterone
with RPL [31]. More data are needed; however, this intervention Women with recurrent miscarriage may benefit from the
appears to be commonly used for couples who are translocation use of vaginal micronized progesterone (e.g. 400 mg twice
carriers. Gamete donation is another option. daily) [38]. This was described in particular by two large RCTs:
PROMISE (vaginal progesterone in recurrent miscarriage,
Abnormal uterine cavity n = 836) and PRISM (vaginal progesterone in women with early
Septum, synechiae, and/or submucous myomata can be resected pregnancy bleeding, n = 4153) [39, 40]. While the primary out-
hysteroscopically, but there are no trials regarding this inter- comes for both trials were negative, preplanned subgroup anal-
vention. However, there have been prospective studies suggesting ysis in PROMISE showed a nonsignificant trend toward the
higher live birth rates in women with uterine septa and RPL who benefit of vaginal progesterone with an increasing number of
undergo septum resection [32]. Repair of the bicornuate or uni- miscarriages. In the PRISM RCT, prespecified subgroup analy-
cornuate uterus is not suggested in these women, as outcomes ses showed increasing benefit for vaginal progesterone with an
are usually good without repair, whereas surgical correction is increasing number of miscarriages. In women with one or more
associated with higher risk of complications. Consider referral miscarriage(s) and current pregnancy bleeding, the live birth rate
to a reproductive endocrinology specialist if necessary. There is was improved (n = 1515, RR 1.09, 95% CI, 1.03–1.15, p = 0.003).
a paucity of evidence to give a recommendation for women with The benefit was even greater for women with three or more prior
fibroids and RPL. The available data suggest resection of submu- miscarriages and current pregnancy bleeding (n = 285, RR 1.28,
cosal fibroids may confer benefit [33]. 95% CI 1.08–1.51, p = 0.004) [40].
Multiple meta-analyses have addressed progesterone in vari-
Medical condition ous routes and doses for women with RPL and generally show
If a medical condition is identified (e.g. diabetes mellitus benefit. In a 2018 meta-analysis of 10 trials, 1684 women showed
[DM], thyroid disease), treat as indicated (see specific chapters in reduced miscarriage rate (RR 0.73, 95% CI 0.54–1.00) [41]. A pre-
Maternal-Fetal Evidence Based Guidelines). Metformin has not vious 2016 meta-analysis of 10 trials, n = 1586, also showed ben-
been shown to reduce the risk of miscarriage in women with RPL efit (RR 0.72, 95% CI 0.53–0.97) [42].
and polycystic ovary syndrome [14, 34]. Thus, women with a history of miscarriage, and especially
those with early pregnancy bleeding, may benefit from pro-
Antiphospholipid syndrome gesterone. There should be shared decision-making between
Unfractionated heparin (UFH) combined with low-dose aspi- patients and their providers regarding timing, route of
rin is associated with improved live birth compared to aspirin administration, and dose.
alone (relative risk [RR] 1.74, 95%CI 1.28–2.35, 2 trials, n = 140).
There is no advantage in a higher dose of UFH over a prophy-
Human chorionic gonadotropin
There is not enough evidence to support the use of hCG for
lactic dose [35, 36]. Low-molecular-weight heparin (LMWH)
RPL. In a meta-analysis of five trials (596 women), when these
combined with low-dose aspirin also shows improved live birth
two studies were removed from analysis, there was no longer a
rates compared to low-dose aspirin (RR 1.20, 95% CI 1.04–1.38, 3
significant benefit of hCG (RR 0.74, 95% CI 0.44–1.23) [43].
trials, n = 1155) [35, 36]. Either UFH or LMWH has been shown
to reduce the risk of pregnancy loss (RR 0.48, 95% CI 0.32–0.71, Low-dose aspirin
5 trials, n = 1295) and to increase the live birth rate (RR 1.27, Compared with placebo, aspirin alone did not increase the chance
95% CI 1.09–1.49) (see Chap. 28 and Table 28.3) [36]. Therapy is of live birth (RR 0.94, 95% CI 0.80–1.11) in a pooled analysis of 256
usually begun once fetal viability is established. Low-dose aspi- women with unexplained recurrent miscarriage with or without
rin is usually about 75–100 mg daily. For prophylactic UFH, the thrombophilia [44]. Therefore, low-dose aspirin should not be
dose is 5000–7500 U in the first trimester, 7500–10,000 U in the recommended for women with recurrent unexplained early PLs.
second trimester, and 10,000 U in the third trimester SQ q12h.
Prophylactic LMWH, 40 mg SQ a day, is often recommended due Unfractionated heparin
to once-daily dosing and fewer side effects. Aspirin alone (three There is insufficient evidence to assess the effect of UFH alone in
trials), intravenous immunoglobulin (IVIG) plus UFH plus aspi- women with unexplained RPL [45].
rin (two trials), and prednisone plus aspirin (three trials) have not
shown significant benefit and should not be used [34]. Low-molecular-weight heparin
In summary, in women with RPL and APS, available guide- There are several RCTs that show no effect of LMWH alone in
lines recommend a combined therapy with low-dose aspirin the prevention of pregnancy loss in women with unexplained
and prophylactic doses of heparin, although the available ran- RPL [46–48].
domized controlled trials (RCTs) include heterogeneous groups Additionally, no reduction in pregnancy loss was observed when
of patients [36, 37]. LMWH and low-dose aspirin were used in combination [44, 46].
Inherited thrombophilia Vitamins

As stated earlier, a workup for inherited thrombophilia is not Vitamin D deficiency (VDD) has been associated with RPL,
indicated. If positive inherited thrombophilia is incidentally although the underlying mechanism is not clear. Immune dys-
or previously identified, no intervention has been consistently regulation has been theorized in RPL. A review of 11 studies
shown to improve outcomes in women with RPL. Please also refer of women with >2 RPLs showed a high prevalence of VDD in
women with RPL. Exposure to vitamin D promoted immune 2. Kolte AM, Bernardi LA, Christiansen OB, et al. Terminology for pregnancy
regulation and cytokine secretion. Vitamin D supplementation loss prior to viability: A consensus statement from the ESHRE early preg-
nancy special interest group. Hum Reprod. 2015;30(3):495–498. [III]
can be considered, but more studies are needed to investigate the 3. Practice Committee of the American Society for Reproductive Medicine.
association between VDD and RPL [47–49]. Definitions of infertility and recurrent pregnancy loss: A committee opin-
ion. Fertil Steril. 2013;99(1):63. [III]
Diethylstilbestrol 4. Regan L, Rai R, et al. Green-Top Guideline No. 17. Recurrent miscarriage,
DES should not be used in pregnancy for any indication. investigation and treatment of couples. RCOG. 2011. [III]
5. Ansari AH, Kirkpatrick B. Recurrent pregnancy loss. An update. J Reprod
DES use in pregnancy is significantly associated with several
Med. 1998;43(9):806–814. [Review]
harmful consequences for both mother and baby [50]. Exposed 6. Stirrat GM. Recurrent miscarriage I: Definition and epidemiology. Lancet.
female offspring have an increased incidence of cancer, infertility, 1990;336(8716):673–675. [III]
and genital tract abnormality. 7. Kaiser J, Branch DW. Recurrent pregnancy loss: Generally accepted causes
and their management. Clin Obstet Gynecol. 2016;59(3):464–473. [III]
Immunotherapy 8. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M.
Maternal age and fetal loss: Population based register linkage study. BMJ.
Various forms of immunotherapy have been studied in the treat- 2000;320(7251):1708–1712. [II-2]
ment of RPL. The theory is that the fetus is considered an allograft, 9. Clifford K, Rai R, Regan L. Future pregnancy outcome in unexplained recur-
and alteration of maternal immune response is needed for success- rent first trimester miscarriage. Hum Reprod. 1997;12(2):387–389.[II-2]
ful implantation. IVIG and donor leukocytes do not show signifi- 10. Regan L, Braude PR, Trembath PL. Influence of past reproductive perfor-
mance on risk of spontaneous abortion. BMJ. 1989;299(6698):541–545. [II-1]
cant differences between treatment and control groups in terms of
11. Voss P, Schick M, Langer L, et al. Recurrent pregnancy loss: A shared
subsequent live births [51, 52]. Currently, immunotherapy should stressor—couple-orientated psychological research findings. Fertil Steril.
be used in the context of research and should not be used in 2020;1288–1296. [II-3]
routine clinical practice to improve reproductive outcomes. 12. Kolte AM, Olsen LR, Mikkelsen EM, Christiansen OB, Nielsen HS.
Depression and emotional stress is highly prevalent among women with
recurrent pregnancy loss. Hum Reprod. 2015;30(4):777–782. [II-2]
Antepartum testing 13. van Dijk MM, Kolte AM, Limpens J, et al. Recurrent pregnancy loss:
Diagnostic workup after two or three pregnancy losses? A systematic review
No specific testing indicated. of the literature and meta-analysis. Hum Reprod Update. 2020;26(3):356–
367. [II-1]
14. Branch DW, Gibson M, Silver RM. Recurrent miscarriage. N Engl J Med.
Delivery 2010;363(18):1740–1747. [Review]
15. Stephenson MD. Recurrent early pregnancy loss: Is miscarriage evaluation
No specific precaution. the missing link? Contemp Ob/Gyn. 2008:53(10):m50–55. [Review]
16. Nicholas S, Orzechowski K, Potti S, Baxter J, Berghella V, Weiner S. Early
pregnancy failure as a training tool for chorionic villus sampling. Prenat
Anesthesia Diagn. 2013;33(11):1110–1112. [II-2]
17. Marquard K, Westphal LM, Milki AA, Lathi RB. Etiology of recurrent preg-
No specific precaution. nancy loss in women over the age of 35 years. Fertil Steril. 2010;94(4):1473–
1477. [II-2]
18. Nikcevic AV, Tinkel SA, Kuczmierczyk AR, Nicolaides KH. Investigation
Postpartum/Breastfeeding of the cause of miscarriage and its influence on women’s psychological dis-
tress. BJOG. 1999;106(8):808–813. [II-2]
No specific precaution. 19. Stephenson MD, Sierra S. Reproductive outcomes in recurrent pregnancy
loss associated with a parental carrier of a structural chromosome rear-
rangement. Hum Reprod. 2006;21(4):1076–1082. [II-2]
Future considerations 20. Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Mizutani E.
Uterine anomaly and recurrent pregnancy loss. Semin Reprod Med.
Effective treatment of an alleged alloimmune cause of recurrent mis- 2011;29(6):514–521. [Review]
carriage awaits more complete knowledge of the underlying patho- 21. Stovall DW, Parrish SB, Van Voorhis BJ, Hahn SJ, Sparks AE, Syrop CH.
physiology. A specific assay to diagnose immune-mediated early PL Uterine leiomyomas reduce the efficacy of assisted reproduction cycles:
Results of a matched follow-up study. Hum Reprod. 1998;13(1):192–197.
and a reliable method to determine which patients might benefit
[II-2]
from manipulation of the maternal immune system are needed. It 22. Kaur R, Gupta K. Endocrine dysfunction and recurrent spontaneous abor-
is not presently known how many RPLs are the result of anembry- tion: An overview. Int J Appl Basic Med Res. 2016;6(2):79. [II-2]
onic or chromosomally abnormal conceptuses or anatomic or struc- 23. Hogge WA, Prosen TL, Lanasa MC, Huber HA, Reeves MF. Recurrent spon-
tural abnormalities and how many are embryonic or fetal deaths. taneous abortion and skewed X-inactivation: Is there an association? Am J
Obstet Gynecol. 2007;196(4):384–e1. [II-1]
It is likely that some unexplained early losses are due to unde- 24. Practice Committee of the American Society for Reproductive Medicine.
fined subchromosomal genetic abnormalities impairing early Current clinical irrelevance of luteal phase deficiency: A committee opin-
development of the conceptus. The currently available molecular ion. Fertil Steril. 2015;103(4):e27–32. [III]
genetic techniques, including comparative genomic hybridization 25. Cervera R, Balasch J. Autoimmunity and recurrent pregnancy losses. Clin
Rev Allergy Immunol. 2010;39(3):148–152. [III]
and single nucleotide polymorphism microarray, may detect more of
26. Mumusoglu S, Beksac MS, Ekiz A, Ozdemir P, Hascelik G. Does the pres-
these abnormalities. New molecular techniques (e.g. whole-genome ence of autoantibodies without autoimmune diseases and hereditary
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27. Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with
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18
PRETERM BIRTH PREVENTION IN ASYMPTOMATIC WOMEN
Anju Suhag
Key points • Vaginal progesterone 200 mg every evening or 17

alpha-hydroxyprogesterone caproate 250 mg IM
• Gestational age (GA) determination is of the utmost weekly starting at 16–20 weeks until 36 weeks.
importance in preventing preterm birth (PTB) and the • Moderate fish intake, up to three meals per week,
management of presumed threatened PTB. before 22 weeks.
• PTB is defined as birth between 20 0/7 and 366/7 weeks. It • Cerclage if the TVU CL is <25 mm before 246/7
is the number-one cause of perinatal morbidity and weeks. Therefore, all singleton gestations with prior
mortality, and these complications are inversely propor- SPTB should have serial TVU CL screening in the
tional to GA at birth. Over 1 million babies die of the second trimester, usually at 16–23 weeks.
consequences of PTB every year in the world, 1 every 30 • In women with ≥3 prior early (usually <32 weeks)
seconds. SPTBs or second-trimester losses (STLs), history-
• An accurate history should be taken regarding risk factors indicated cerclage.
for PTB, especially obstetric-gynecologic (ob-gyn) history, • Avoid bed rest and/or routine maintenance tocolytics dur-
maternal lifestyle, and pre-pregnancy weight (Table 18.1). ing pregnancy for secondary prevention of PTB.
Consider preconception counseling for women with very • In women with cervical dilatation ≥1 cm before 24
early PTB or recurrent PTB or poor obstetric history. weeks, physical exam-indicated cerclage is associated
• Primary prevention strategies for PTB aimed at the gen- with a significant decrease in PTB; consider amniocentesis
eral population include family planning, avoidance of life- beforehand to detect intra-amniotic infection.
style risks, and proper nutrition. A reproductive-age woman • In women with asymptomatic bacteriuria of >100,000
should avoid (as feasible) extremes of age, extremes of bacteria/mL, appropriate antibiotics are associated with
interpregnancy interval (18–23 months is the optimal a significant decrease in PTB.
interval between last delivery and next conception), • In women with asymptomatic group B streptococcus
induced termination of pregnancy (TOP) without rip- (GBS) bacteriuria of any colony count, appropriate anti-
ening, multiple gestations, illegal drugs (e.g. cocaine), biotics (usually penicillin) are associated with a significant
physical abuse, sexually transmitted infections (STIs), decrease in PTB.
poverty, poor education, and a pre-pregnancy weight of • All other screening and treatment interventions for pre-
<50 kg (<120 lb). A normal BMI at the start of pregnancy, vention of PTB are not supported by strong evidence for
not dieting but instead a balanced diet during pregnancy, recommending their clinical use.
and achieving weight gain of >5 kg by 30 weeks for under-
weight and normal-weight women can certainly help avoid
PTB. Consider low-dose aspirin for PTB prevention (if no Background
contraindications).
• Screening with transvaginal ultrasound (TVU) cervi- Prevention of preterm birth (PTB) is the number-one issue in
cal length (CL) at 18–236/7 weeks should be offered to pregnancy, as being born preterm is the number-one cause of
all singleton gestations. In singleton gestations without neonatal mortality and the second leading cause of all under-5
a prior spontaneous PTB (SPTB), if CL ≤25 mm devel- childhood mortality in many developed countries, including the
ops, vaginal progesterone (e.g. 200 mg suppositories United States [1, 2]. This chapter reviews evidence-based guide-
daily until 36 weeks) should be recommended. If CL is lines for women without symptoms related to PTB. The follow-
less than 10 mm, consider physical (e.g. speculum and ing two chapters deal with women with symptoms of PTB: First
digital) cervical examination to evaluate for physical preterm labor (PTL) (Chap. 19), then preterm prelabor rupture of
examination–indicated cerclage. membranes (PPROM) (Chap. 20).
• Secondary prevention of PTB is based on identification
and treatment (or avoidance) of risk factors. A screening
test aimed at prediction of PTB is only beneficial if an Diagnoses/Definitions
intervention reduces the outcome once the screening test
is positive. Secondary prevention of PTB has been shown in Gestational age (GA) determination is of the utmost impor-
the following groups for the following interventions: tance in the prevention of PTB and management of presumed
• In women who smoke, smoking cessation threatened PTB (see Chap. 4 for the best GA determination
counseling/support programs. criteria).
• In women with ≥1 prior SPTBs now carrying a single- Definitions regarding prematurity vary in different publica-
ton gestation, all the following interventions are asso- tions, but the ones most commonly accepted and used in trials
ciated with a significant decrease in recurrent PTB: are the following:
210 DOI: 10.1201/9781003102342-18

Preterm Birth Prevention in Asymptomatic Women 211
TABLE 18.1: Selected Risk Factors for Spontaneous Preterm Second-trimester PL (aka second-trimester loss—STL): Birth
Birth between 14 0/7 and 196/7 weeks.
Cervical insufficiency (CI) (formerly called incompetence):
History:
Recurrent painless dilatation leading to STLs [4]. A better def-
• Obstetric-gynecological history: Prior SPTB; prior STL; prior D&Es;
inition is a cervical length (CL) <25 mm before 24 weeks in
prior LEEP; prior cone biopsy; uterine anomalies; DES exposure;
women with singleton gestations and prior SPTB <37 weeks.
myomata; short interpregnancy interval (<6 months); ART; prior
PTL: Uterine contractions (≥4 per 20 minutes or ≥8 per
stillbirth <24 weeks; prior early twin SPTB; prior full-term cesarean
hour) and documented cervical change with intact membranes
delivery for second-stage arrest
at 20–366/7 weeks. A better definition is uterine contractions
• Maternal lifestyle (smoking, drug abuse)
(≥4 per 20 minutes or ≥8 per hour) with TVU CL <20 mm,
• Maternal pre-pregnancy weight <120 lb (<50 kg) or low BMI or 20–29 mm with positive fetal fibronectin (fFN) at 20–366/7
(<19.8 kg/m2), short height (<53 inches or 3SD below any race/ weeks (see Chap. 19).
ethnicity); poor nutritional status Prelabor preterm rupture of membranes (PPROM):
• Maternal age (<19; >35 years old) Vaginal pooling, nitrazine, and/or ferning at 16–366/7 weeks (see
• Race (especially Afro-American) Chap. 20).
• Education (<12 grades)
• Certain medical conditions (e.g., DM, HTN, renal disease and • Early PPROM: PPROM between 24 and 336/7 weeks
intrahepatic cholestasis of pregnancy) • Very early PPROM: PPROM between 16 and 236/7 weeks
• Low socioeconomic status
• Limited prenatal care Epidemiology/Incidence
• Family history of SPTB
Incidence of PTB <37 weeks varies between about 5% and 18%
• Vaginal bleeding (especially during second trimester, subchorionic
in different countries [5]. The rate of PTB in the United States
hematoma)
steadily increased from 9.4% in 1981 and peaked in 2006 at 12.8%.
• Social or psychological stress (mostly related to earlier risks)
Since then, the rate of PTB in the United States dropped to 9.6%
• Infections (bacterial vaginosis, chlamydia, gonorrhea, asymptomatic
in 2014 (25% decline) [6, 7]. The incidence of PTB <32 weeks
bacteriuria, urinary tract infection, periodontal disease)
remains at about 2% in United States and ≤1% in most other
• Higher number of lifetime sexual partners
high-income countries. Over 1 million babies die of the conse-
Identifiable by screening: quences of PTB every year in the world, 1 every 30 seconds [1].
• Anemia The high incidence of PTB in many high-income countries may
• Infections (STIs, periodontal disease) be due to assisted reproductive technology (ART)–related multi-
• TVU CL <25 mm (especially <24 weeks) ple gestations, older and sicker mothers, earlier GA of registered
• fFN positive (≥50 ng/mL) (between 22 and 34 weeks) births and neonatal improvements, better and earlier timing of
Usually symptomatic: births (related to ultrasound), worsening socioeconomic fac-
• Uterine contractions tors, and other factors. In addition to the use of progesterone
Not spontaneous (indicated/iatrogenic): and cerclage in women at high risk for PTB, there are several
• Fetal demise/major fetal anomaly other demographic factors which lead to reducing the national
• Multiple gestation/polyhydramnios PTB rate. This decline in PTB in the United States appears to
• Nonreassuring fetal heart tracing be related also to a reduced teen birth rate, lower rate of higher-
• FGR order multiple births, smoking cessation counseling and bans,
and improved institutional/national policies of preventing non-
• Placenta previa
medically indicated PTB <39 weeks [8]. Early adoption of guide-
• Placental abruption
lines for the prevention of PTB has been shown to reduce the
• Major maternal disease (HTN complications, DM, etc.)
rate of PTB at a major academic center below the national aver-
Abbreviations: SPTB, spontaneous preterm birth; STL, second-trimester loss; LEEP, age [9]. This study emphasizes a call for uniform implementa-
loop electrosurgical excision procedure; DES, diethylstilbestrol; ART, assisted repro- tion of protocols suggested by national societies like the Society
ductive technology; STI, sexually transmitted infection; BMI, body mass index; DM, for Maternal-Fetal Medicine (SMFM) and the American College
diabetes mellitus; HTN, hypertension; TVU, transvaginal ultrasound; CL, cervical of Obstetricians and Gynecologists (ACOG) to further decrease
length; fFN, fetal fibronectin; FGR, fetal growth restriction.
the U.S. national rates of PTB.
Genetics
PTB: Birth between 20 0/7 and 366/7 weeks [3]
While a genetic predisposition in certain ethnic groups and fami-
• Very early PTB: Birth between 20 0/7 and 236/7 weeks lies has been reported, no clinical genetic studies are yet recom-
• Early PTB: Birth between 24 0/7 and 336/7 weeks mended for the prediction/prevention of PTB due to insufficient
• Late PTB: Birth between 34 0/7 and 366/7 weeks evidence [10].
Pregnancy loss (PL): Spontaneous loss of pregnancy from Etiology/Basic pathophysiology

conception to <20 weeks. The term spontaneous abortion is
equivalent, but should be avoided since women associate negative Just like cardiac disease, PTB is a final common manifestation
feeling with this term. Miscarriage is a lay term for PL (see also with a multifactorial, complex etiology. Several processes leading
Chaps. 16 and 17). to PTB are shown in Figure 18.1.
MULTIFACTORIAL, INTERACTIONS associated with GA at birth (Table 18.2) [12]. Morbidities

Social/Stress include respiratory distress syndrome (RDS), bronchopulmonary
Uterine Stretch
Hormonal Cervix Problem dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing
Progesterone Uterine contractions enterocolitis (NEC), sepsis, apnea, and retinopathy of prematu-
withdrawal Oxytocin initiation rity [13]. The long-term neonatal morbidities from PTB include
Immunologic/ chronic lung disease, grade III/IV IVH, NEC, vision and hearing
Inflammation Abruption impairment, cerebral palsy, reduced cognition, academic difficul-
Marker/Risk
ties, and attention deficit disorders [14, 15].
Genetic Abnormal implantation
Premature decidual
Infection SPONT.PTL/PPROM/CI
activation Prediction and prevention of PTB
Medically-indicated A screening test aimed at predicting PTB is only beneficial
if an intervention (prevention) reduces the outcome once the
PTB screening test is positive. Several predictive strategies have poor
sensitivity and specificity.
FIGURE 18.1 Preterm birth is the final common pathway of Prevention is preferable, rather than treatment, once symp-
many associated possible etiologies. Abbreviations: SPONT. PTL, toms have been identified. Prevention can be divided into
spontaneous preterm labor; PPROM, preterm prelabor rupture of three categories (Table 18.3). Primary and secondary prevention
membranes; CI, cervical insufficiency; PTB, preterm birth. are preferable, rather than tertiary prevention of symptomatic
women with PTL or PPROM. This chapter refers to prevention
of SPTB mostly in singleton gestations unless otherwise speci-
Classification fied. Prevention of PTB in multiple gestations is also discussed in
PTB can be spontaneous and follow PTL (50%; Chap. 19), PPROM Chap. 46 in Maternal-Fetal Evidence Based Guidelines.
(30%; Chap. 20), or, rarely, CI; or be iatrogenic (20%). CI may com- For women at risk for iatrogenic (indicated) PTB, one should
prise about 1% of spontaneous PTB (SPTB) and/or STLs (see Risk: aim to keep the pregnant woman as healthy as a nonpregnant
Cervical insufficiency (page 222, 2nd paragraph)). CI represents adult. Appropriate prevention and therapy of any maternal
one extreme of SPTB, as PTB is continuous. medical or fetal/congenital anomaly disorder are paramount,
as is appropriate prevention and therapy for preeclampsia and
fetal growth restriction (FGR) (please see specific chapters in
Risk factors/Associations Maternal-Fetal Evidence Based Guidelines) [1].
Most women who have a PTB have identifiable risk factors. Risk All pre-pregnancy evaluations of the cervix (e.g. hysterosal-
factors for SPTB (presenting as PTL, PPROM, or CI) are similar pingogram, no. 8 Hegar dilator passage, and catheter traction
(Table 18.1). All these risk factors should be reviewed in detail test) aimed at screening for CI have either been inadequately
with every pregnant woman at the first prenatal visit. The vast studied or been shown not to be sufficiently predictive and there-
majority of U.S. pregnant women (96% on in one study) has at fore useful in a prevention program (no trial ever reported).
least one risk factor for PTB [11]. For many of these risks, inter- An accurate history should be taken regarding risk factors
ventions are associated with the prevention of PTB. for PTB, especially ob-gyn history, maternal lifestyle, and
pre-pregnancy weight (Table 18.1). A detailed history should
include whether the prior PTB was spontaneous or indicated (iat-
Complications rogenic). Spontaneous PTB is defined as PTB prior to 37 weeks
due to PTL, PPROM, advanced cervical dilation (ACD), or cervi-
PTB is the number-one cause of perinatal mortality. Seventy-
cal insufficiency. It is also important to document the sequence of
five percent of perinatal mortality occurs in preterm babies; more
events (antepartum) leading to a PTB, as this could help counsel
than two-thirds of perinatal mortality (60% of total) occurs in
these women about their risk of recurrent PTB, and appropri-
infants aged <32 weeks. Mortality and morbidities are inversely
ate PTB prevention strategies could be utilized. For example,
TABLE 18.2: Preterm Neonatal Morbidity and Mortality

Delivery Gestational Age (Weeks)
Outcome All 23 24 25 26 27 28 29 30 31 32 33 34 35 36 p-value
Death 1.4 44.2 31.6 12.1 11.2 8.2 2.0 1.9 1.5 1.0 0.2 0.2 0.0 0.0 0.0 <0.001
Major morbiditya 7.9 44.2 52.6 54.8 52.1 40.3 21.9 22.5 13.7 7.1 8.7 4.2 4.4 2.8 1.8 <0.001
Minor morbidityb 37.6 9.3 15.8 31.5 34.9 48.4 73.5 69.0 78.6 81.7 76.3 63.5 51.0 27.2 15.9 <0.001
Survival without any of 53.1 2.3 0.0 1.6 1.8 3.1 2.6 6.6 6.1 10.3 14.9 32.1 44.6 69.9 82.4
earlier morbidities
Note: Data presented as %; n = 8334.
a Includes persistent pulmonary hypertension, intraventricular hemorrhage grade 3/4, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II/III,
bronchopulmonary dysplasia.
b Includes intraventricular hemorrhage grade 1/2, necrotizing enterocolitis stage 1, respiratory distress syndrome, hyperbilirubinemia requiring treatment, hypotension
requiring treatment.
TABLE 18.3: Definition of the Different Categories of Prevention of Preterm Birth

Definition Examples
Primary Prevention Prevention strategies aimed at all asymptomatic Encourage optimal (18–23 months) interpregnancy interval
pregnant women at risk for PTB (i.e. aimed at all Limit higher order multiple births (ART)
pregnant women)
Secondary Prevention Prevention strategies aimed at identifying Obtain comprehensive OB history and offer preventive interventions
asymptomatic women at high risk for PTB (progesterone, cerclage, CL screening) to appropriate candidates
through screening. Screen for predictive risk factor Smoking cessation
(prediction) in asymptomatic women and avoid/ Low-dose aspirin
treat (preventive intervention) Screen for infection, and treat if indicated
Tertiary Prevention Prevention strategies aimed at women with active Interventions for women with PTL (Chap. 19) or PPROM (Chap. 20)
symptoms of PTB
Abbreviations: ART, assisted reproductive technology; PTB, preterm birth; OB, obstetrical; CL, cervical length; PTL, preterm labor; PPROM, preterm prelabor rupture of
membranes.
women with a history of ACD are at an increased risk of having gestations (through ART improvements) seem self-evident for
cervical shortening (50% vs. 14.6% vs. 15.6%, p <0.01), recurrent efficacy in preventing PTB when feasible. Evidence suggests that
PTB (55.2% vs. 27.2% vs. 32.2%, p <0.01), and a lower GA at deliv- risks of PTB, low birth weight (LBW), and small-for-gestational-
ery (34.0 vs. 37.2 vs. 37.0 weeks, p <0.01) in a subsequent preg- age (SGA) infants are minimized when interpregnancy intervals
nancy compared with women with prior PTB-associated PPROM are between 18 and 23 months [20, 21]. For an appropriate inter-
or PTL, respectively [16]. pregnancy interval, physicians should pay close attention to plans
A Creasy score or other similar history-based systems to pre- for postpartum contraception. Improvements in postpartum
dict PTB have been associated with a low (10%–30%) positive pre- contraceptive use have been associated with decreased incidence
dictive value (PPV) for PTB and are not clinically useful, given in PTB. For every month of contraception coverage, the odds of
negative intervention trials. There are no trials on risk-scoring PTB <37 weeks decrease by 1.1% (odds ratio [OR] 0.98, 95% confi-
systems for predicting PTB [17]. There is a need for prospective dence interval [CI] 0.98–099) [22].
studies that evaluate the use of a risk-screening tool designed to
predict PTB (in combination with appropriate consequent inter-
ventions) to prevent PTB, including qualitative and/or quantita-
tive evaluation of their impact on women’s well-being. TABLE 18.4: Selected Effective Interventions for Prevention
There are four main risk factors for which there are effective of Preterm Birth
interventions for the prevention of PTB: Smoking, short TVU Avoid (as feasible) • Extremes of age
CL, prior SPTB, and asymptomatic bacteriuria (Table 18.4). A • Interpregnancy interval <6 months
TVU CL screening at 18–23 weeks is indicated in all women • Induced termination of pregnancy
with a singleton gestation (Figure 18.2). without ripening
Current evidence does not support the use of home uterine • Multiple gestation
activity monitoring (HUAM) [18] or bacterial vaginosis (BV) • Illegal drugs (e.g. cocaine)
screening [19] in asymptomatic, low-risk women. There are • Physical abuse
insufficient data to support the use of salivary estriol or fFN in • STIs
asymptomatic women (even if fFN is one of the best predictive • Poverty
screening tests). Cytokines, matrix metalloproteinases, cortico- • Poor education
tropin-releasing hormone (CRH), salivary estriol, relaxin, human • Pre-pregnancy weight of <50 kg
chorionic gonadotropin (HCG), prothrombin, fetal DNA, and (<120 lb)
many other tests remain research tools for the prediction of PTB Risk Intervention
and are not yet clinically beneficial, given the lack of intervention Smoking Smoking cessation programs
trials based on these screening tests. No prior spontaneous PTB Vaginal progesterone (e.g. 200 mg daily)
and CL ≤25 mm (screen
Primary prevention
every singleton and twin with
Primary prevention includes prevention strategies aimed at all
TVU CL at 18–236/7 wk)
asymptomatic pregnant women at risk for PTB (i.e. aimed at
Prior spontaneous PTB Progesterone
all pregnant women). Unfortunately, many primary prevention
(SPTB)a
interventions have been so far either insufficiently studied or
Prior SPTB and CL <25 mm Ultrasound-indicated cerclage
found not to be effective.
up to 236/7 wka
Preconception/Early pregnancy Prior ≥3 early PTB/STLa History-indicated cerclage
Family planning Asymptomatic bacteriuria Appropriate antibiotics
There are no trials to assess interventions. Avoiding extremes a For singleton gestations.
of age, avoiding short interpregnancy interval <6 months Abbreviations: TVU, transvaginal ultrasound; CL, cervical length; PTB, preterm
(18–23 months is the optimal interval between the last delivery birth; SPTB, spontaneous PTB; STL, second-trimester loss; STIs, sexually transmit-
and the next conception) [20], and reducing the rate of multiple ted infections; wk, weeks.
Induced TOP is associated with a higher risk of PTB, even epa.gov/fish-tech/epa-fda-advice-about-eating-fish-and-shellfish.

if just one early TOP is performed [23]. Recent meta-analyses There is limited evidence suggesting the potential benefit of
showed that dilation and curettage (D&C) compared with no maternal fish intake on reduction of PTB. A recent prospective
D&C increases the risk of PTB <37 weeks (OR 1.29, 95% CI 1.17– cohort study reported a significant reduction in the risk of PTB
1.42) [24, 25]. Women who had even just one uterine evacuation in women choosing a “prudent” or a “traditional” dietary pattern,
for either spontaneous or induced abortion have a higher risk of characterized by, for example, vegetables, cooking oil, fruit, berries,
PTB (OR 1.44, 95% CI 1.09–1.90) [25]. The risk of PTB <37 weeks olive oil, rice, water as a beverage, whole grain cereals, yoghurt,
is noted to be even higher in women with a history of multiple poultry, lean fish, and boiled potatoes, as well as a low intake of
D&Cs (OR 1.74, 95% CI 1.10–2.76) [24]. Avoiding TOPs as fea- processed meat products, white bread, and pizza/tacos [31].
sible with effective contraception seems to be an effective
preventive strategy to avoid PTB. If TOP is unavoidable, the Omega-3 fatty acids
dilation and evacuation (D&E) should be performed with preop- Low-risk women without a prior PTB have a similar incidence of
erative cervical ripening (e.g. misoprostol, mifepristone, or lami- PTB <37 weeks when given 12 eggs with either 133 mg DHA or
naria), as this is associated with no or very low risk for PTB [23]. 33 mg DHA per week starting at 24–28 weeks [32]. Supplementation
has been shown to prolong pregnancy by 3–8 days in different
Avoidance of lifestyle risks populations. When all RCTs are examined, women allocated to
There are no trials to assess interventions. Avoiding illegal a marine oil supplement had a mean gestation that was 2.6 days
drugs (e.g. cocaine and amphetamines), physical abuse, and longer than women allocated to placebo or no treatment. This
STIs (chlamydia, gonorrhea, syphilis, HIV, etc.) seem self- was not reflected in a clear difference between the two groups
evident for efficacy in preventing PTB [26]. Poverty, poor edu- in PTB <37 weeks, although women allocated to marine oil did
cation, lack of women’s empowerment, and several other social have a lower risk of PTB <34 weeks (RR 0.69, 95% CI 0.49–0.99).
stressors (Table 18.1) are all linked profoundly to an increased Birth weight was slightly greater (47 g) in infants born to women
risk of PTB and should be avoided as possible, especially in the marine oil group compared with controls. However, there
through political and social changes. Workplace conditions were no overall differences between the groups in the propor-
are only weakly related or are not related to adverse pregnancy tion of LBW or SGA babies. There was no clear difference in the
outcomes. In the third trimester, >42 hours of work per week, relative risk of preeclampsia between the two groups [33]. A large
>6 hours of standing per day, and pesticide exposure are asso- RCT found that DHA 800 mg supplementation before 21 weeks
ciated with PTB [27]. There are no trials on modifying other was associated with a decrease in PTB <34 weeks (RR 0.49, 95%
potential risks, such as a physically demanding job, prolonged CI 0.25–0.94) [34]. In contrast, in a recent meta-analysis of nine
standing, night work, or others. randomized trials including over 3800 asymptomatic women with
singleton pregnancies and no prior PTB, women who received
Proper nutrition and weight gain omega-3 had a similar rate of PTB <37 weeks as women who
A pre-pregnancy weight of <50 kg (<120 lb) should be avoided. received either a placebo or no supplementation (7.7% vs. 9.1%;
A recent meta-analysis of 17 randomized controlled trials (RCTs) RR 0.90, 95% CI 0.72–1.11) [35]. The evidence suggests minimal
showed the benefit of nutrition education to increase energy or no benefit of omega-3 supplementation in reduction in PTB
and protein intake in decreasing the risk of PTB (2 trials, 449 <37 weeks in asymptomatic, low-risk singleton pregnancies.
women) (relative risk [RR] 0.46, 95% CI 0.21–0.98, low-quality The PrimaCare vitamin supplement contains 150 mg of
evidence), and LBW (one trial, 300 women) (RR 0.04, 95% CI omega-3 fatty acids and has not been evaluated in a trial. The pos-
0.01–0.14) among undernourished women [28]. A normal BMI sible beneficial effects of omega-3 fatty acids to later fetal/neonatal/
at the start of pregnancy, not dieting but instead a balanced infant cognition remain not fully proven. For omega-3 supplemen-
diet during pregnancy, and achieving a weight gain of >5 kg tation in high-risk women, see the section “Risk: Prior PTB.”
by 30 weeks for underweight and normal-weight women can
certainly help to avoid PTB. Probiotics
The available evidence shows no benefit of balanced protein/ Women who report habitual intake of probiotic dairy foods (e.g.
energy supplementation in prevention of PTB [29]. A high- yogurt) have been associated with a lower incidence of PTB in
protein diet (>25% of total energy content) has no association with non-RCTs [36]. Currently, there are insufficient data from RCTs
PTB prevention and is not recommended in pregnancy because of to demonstrate any impact of probiotic food supplementation in
the increased risk of SGA (see also Chap. 2) [30]. low-risk women on PTB and its complications [37].
Early pregnancy Other nutritional changes

Fish intake There are no trials with the specific aim of preventing PTB to
Shark, swordfish, king mackerel, or tilefish contain high levels of evaluate other nutritional changes, such as vitamin supplemen-
mercury and should be avoided or eaten infrequently (≤1/week) tation (see Chap. 2), HCG, and anticytokine supplements. Pre-
in pregnancy. Canned light tuna, salmon, pollock, grouper, pregnancy weight <120 lb (<50 kg) is a significant risk factor
mussels, scallops, shrimp, and catfish are common fishes low for PTB and should be avoided if possible. Suggested pregnancy
in mercury, and two portions (6 oz = 1 portion) of these per weight gain in pregnancy is 25–35 lb for women with a normal
week can (and probably should) be safely eaten in pregnancy. BMI, but there are no trials on proper pre-pregnancy weight or
Albacore (“white”) tuna has more mercury and should be con- pregnancy weight gain.
sumed up to 6 oz/week. In general, for other fishes, smaller fishes
have less mercury than larger ones. More information on fish Vitamin C
and mercury intake in pregnancy is available at https://www.fda. Vitamin C supplementation alone is not associated with a reduced
gov/food/consumers/advice-about-eating-fish“-”https://www. risk of PTB [38].
Vitamin E Secondary prevention

Vitamin E supplementation alone or in combination with other Secondary prevention strategies involve screening for a predic-
supplements is not associated with the prevention of PTB [39]. tive risk factor (prediction) in asymptomatic women and avoiding
it or treating it (preventive intervention) (Table 18.3).
Vitamins C and E
Maternal supplementation with vitamin C 1000 mg and vitamin Risk: Smoking
E 400 mg daily from 9 to 16 weeks until delivery in nulliparous Intervention: Smoking cessation programs
low-risk women is not associated with a reduction in PTB [40]. It is estimated that 10%–15% of PTBs may be due to smoking.
In the United States, about 23% of women start pregnancy as a
Vitamin D smoker and 11% continue to smoke throughout pregnancy [46].
Level II evidence suggests a protective effect of vitamin D sup-
Psychosocial interventions (e.g. counseling, health educa-
plementation in women with low 25-hydroxyvitamin D concen-
tion, feedback, incentives, social support) to support women
trations (at or prior to 20 weeks) on the rate of PTB in low-risk
to stop smoking in pregnancy has been associated with an
women [41]. Routine vitamin D level assessment and/or vitamin
increase the proportion of women who stop smoking in late
D replacement or supplementation is not indicated in women at
pregnancy and a reduction in LBW (RR 0.82, 95% CI 0.71–0.94)
risk for PTB until a well-designed RCT confirms these findings.
and PTB (18% reduction, RR 0.82, 95% CI 0.70–0.96) [47]. The
Calcium supplementation ACOG has recommended use of the five A’s—ask, advice, assess,
Maternal supplementation of calcium versus placebo is not asso- assist, arrange—approach [48]. The most effective interven-
ciated with a reduction in PTB [42]. tion for smoking cessation in pregnancy is social support and
a reward component (23% decrease) [49, 50]. If this approach is
Magnesium supplementation not successful, consider nicotine replacement therapy (NRT) (see
There is insufficient high-quality evidence to show that dietary Chap. 22 in Maternal-Fetal Evidence Based Guidelines).
magnesium supplementation during pregnancy is beneficial.
In the analysis of all trials, oral magnesium treatment before Intervention: Nicotine replacement therapy
25 weeks showed no significant effect of magnesium on perinatal NRT is associated with a trend for a benefit in the reduction in the
mortality, SGA, preeclampsia, and PTB compared to placebo [43]. incidence of smoking (see Chap. 22 in Maternal-Fetal Evidence
Of the ten trials included in the review, only two were judged to Based Guidelines) [51–53]. There is limited evidence to assess
be of high quality and showed no association between magne- the effect of NRT, or nicotine gum, or bupropion, on the inci-
sium and pregnancy outcomes. dence of PTB (see Chap. 22 in Maternal-Fetal Evidence Based
Guidelines).
Progesterone
The mechanism of action of progesterone for the prevention of Other interventions
PTB is poorly understood but probably involves an antiinflamma- Interventions to increase smoking cessation among the partners
tory action. Safety for the fetus/neonate has not been yet proven of pregnant women, with the additional aim of facilitating ces-
with 100% certainty, but progesterone is known not to be a terato- sation by the women themselves, have been insufficiently stud-
gen, and long-term detrimental effects up to 18 years of age have ied (only one trial) [47]. Stages of change, or feedback, do not
not been shown. The effect of progesterone supplementation show benefit [47]. A recent RCT showed no benefit of combining
should be evaluated according to different patient populations supervised exercise and physical activity counseling to improve
and according to the type of progesterone. Here we review pro- the effectiveness of behavioral support for smoking cessation in
gesterone for low-risk women (see later for other risk groups). pregnancy [54]. There has been increased awareness and use of
In a small RCT including women in active military duty e-cigarettes, or electronic nicotine delivery system (ENDSs), in
with only a 3% rate of prior PTB and unknown CL, 17α- adolescents (especially in middle and high school students), the
hydroxyprogesterone (17P) 1000 mg IM weekly starting at 16–20 health impact of which is not clear [55, 56]. E-cigarettes are mar-
weeks was not associated with any effect on the incidence of PTB keted as smoking cessation devices and as better alternatives to
or perinatal outcomes compared with placebo [44]. No RCT has regular cigarettes. This perception of harm reduction in com-
evaluated the effect of vaginal progesterone in this population. parison to regular cigarettes may be prevalent due to the lack of
In summary, there is insufficient evidence to determine the FDA regulation on e-cigarette advertising, and this potentially
impact on PTB of progesterone in singleton gestations with can further increase use of e-cigarettes in adolescents/reproduc-
no prior PTB, with unknown or normal CL. tive-age women and in pregnant women as well (see Chap. 22 in
Maternal-Fetal Evidence Based Guidelines) [55, 57].
Low-dose aspirin
Low-dose aspirin for the prevention of preterm delivery in nullipa- Risk: Short cervix on ultrasound
rous women with a singleton pregnancy (ASPIRIN trial) was stud- Intervention: Activity restriction
ied in six low- and middle-income countries with 5780 women in Activity restriction is not associated with prevention of PTB in
the aspirin group and 5764 in the placebo group. This trial showed asymptomatic singleton gestations with a TVU CL <30 mm, and
a significant reduction in PTB <37 weeks in women who took aspi- in fact is associated with a 237% increase in PTB incidence [58].
rin compared to those who took placebo (11.6% vs. 13.1%, RR 0.89
[95% CI 0.81–0.98], p = 0.012). Women in the aspirin group showed Intervention: Progesterone
lower perinatal mortality, fetal loss, early PTB <34 weeks, and lower Regarding 17P, a multicenter RCT evaluating the effect of 17P
incidence of delivery before 34 weeks in women with hypertensive in women with singleton gestations, no prior PTB, and short CL
disorders of pregnancy [45]. In summary, low-dose aspirin seems <30 mm compared with placebo showed no difference in rate of
beneficial for the prevention of PTB. PTB <37 weeks (25.1% vs. 24.2%, RR 1.03, 95% CI 0.79–1.35) [59].
In another smaller RCT including women with singleton pregnan- but also cost, availability, and other factors, may influence the
cies (66% of which had no prior PTB) with CL<25 mm between 16 preferred dosing [64, 65].
and 24 weeks, 17P was associated with similar incidences of PTB These results also support universal screening with a sin-
and neonatal morbidity and mortality compared to cerclage [60]. gle TVU assessment of CL at around 20 weeks (18–23 weeks
Cerclage was significantly more effective than 17P at reducing range) in singleton gestations without prior SPTB (Figure 18.2).
the incidences of PTB <35 and <37 weeks in the subgroup with TVU CL screening of singleton gestations fulfills all criteria for
CL ≤15 mm [60]. In summary, 17P cannot be recommended for an effective screening program [66]. For example, multiple cost-
prevention of PTB in singleton gestations (no prior PTB) with effectiveness analyses evaluating universal CL screening in single-
a short TVU CL. ton gestations to identify those with a short CL eligible for vaginal
Regarding vaginal progesterone, several RCTs are avail- progesterone have been published [64, 65, 67]. All reported that
able. In 250 women with mostly (90%) singleton gestations and such a strategy would be cost-effective, and in fact cost-saving.
CL ≤15 mm at 20–25 weeks, of whom about 85% had no prior In one study, compared with other managements, including no
PTB, vaginal progesterone 200 mg nightly started at 24 weeks screening, “universal” sonographic screening of CL in singletons
until 34 weeks was associated with a 44% significant decrease in was associated with a reduction of 95,920 PTBs <37 weeks annu-
SPTB <34 weeks (19% vs. 34%, RR 0.56, 95% CI 0.36–0.86), but no ally in the United States, and was actually cost saving (almost $13
significant effects on neonatal morbidities (composite neonatal billion saved) [64]. Even when altering the variables (e.g. the cost
adverse outcomes: RR 0.57, 95% CI 0.23–1.31) [61]. A subgroup of vaginal progesterone or of TVU screening), universal screen-
analysis of only women without prior PTB confirmed a signifi- ing was the preferred strategy 99% of the time [64].
cant benefit of progesterone in preventing PTB <34 weeks (RR The other cost-effectiveness analysis, which looked at universal
0.54, 95% CI 0.34–0.88) [61]. The incidence of CL ≤15 mm was screening of singleton gestations without prior PTB with TVU
1.7%. Based on the frequency of short CL and effectiveness for the CL at 18–24 weeks, calculated over $12 million saved, 424 qual-
prevention of SPTB <34 weeks from the work of Fonseca et al., ity-adjusted life-years (QALY) gained, and 22 neonatal deaths or
the number of women needed to be screened with CL in order to long-term neurologic deficits prevented for every 100,000 women
prevent one SPTB <34 weeks is approximately 387 if all women screened, compared to no screening. Even when altering the vari-
with a CL ≤15 mm receive vaginal progesterone. Once the short ables (e.g. the cost of vaginal progesterone or of TVU screening),
CL ≤15 mm is identified, the number needed to treat to prevent universal screening was cost-effective over 99% of the time [65].
one PTB <34 weeks is 7. It should be noted that only 1.7%–2.3% of women were iden-
In 458 women with singleton gestations and CL 10–20 mm at tified to have a short CL in the two large trials published [61,
19–236/7 weeks, of whom about 84% had no prior PTB, vaginal 62] and that the incidence of CL ≤20 mm at 18–24 weeks is
progesterone 90 mg daily started at 20–236/7 weeks until 366/7 even lower (about 0.8%) in singletons without prior SPTB [66].
weeks was associated with a 45% significant decrease in PTB <33
weeks (9% vs. 16%, RR 0.55, 95% CI 0.33–0.92) and 43% signifi-
cant decrease in composite neonatal morbidity and mortality (8%
Singletons
vs. 14%, RR 0.57, 95% CI 0.33–0.99) [62]. The incidences of PTB without prior
<28 and <35 weeks and RDS were also significantly decreased. SPTB
Analysis of only women without prior PTB confirmed a signifi-
cant benefit of progesterone in preventing PTB <33 weeks (8%
vs. 15%, RR 0.50, 95% CI 0.27–0.90) [62]. The incidence of CL
10–20 mm was 2.3%. Based on the frequency of short CL and
Single TVU CL
effectiveness for prevention of PTB <33 weeks from this study at 18–23-6/7
[62], the number of women needed to be screened with CL in weeks
order to prevent one PTB <33 weeks is approximately 604 if all
women with a CL 10–20 mm receive vaginal progesterone. Once
the short CL 10–20 mm is identified, the number needed to treat
to prevent one PTB <33 weeks is 14.
A recent systematic review and meta-analysis of individual CL ≤ 25 mm CL > 25 mm
patient data of randomized trials, including OPPTIMUM, noted
a reduction of PTB and neonatal morbidity and mortality in
singleton gestations with CL ≤25 mm with vaginal progesterone
compared with placebo (STPB <33 weeks, RR 0.62, 95% CI 0.47–
0.81, p = 0.0006; composite neonatal morbidity and mortality, RR
0.59, 95% CI 0.38–0.91) [63]. Vaginal Routine
In summary, in women with singleton gestations, no prior Progesterone* Obstetric Care
SPTB, and short CL, vaginal progesterone is associated with a
reduction in PTB and composite perinatal morbidity and mortal-
ity. Based on these results, if a TVU CL ≤25 mm is identified FIGURE 18.2 Transvaginal ultrasound cervical length screen-
at ≤24 weeks, vaginal progesterone should be offered for the ing for the woman with a singleton gestation and no prior sponta-
prevention of PTB [61, 63]. There is insufficient evidence that neous preterm birth. (Adapted from Ref. 68.) *For example, daily
any of the vaginal preparations or doses are superior, as they have 200 mg suppository or 90 mg gel from time of diagnosis of short
not been compared. Vaginal progesterone 200 mg suppository CL to 36 weeks. Abbreviations: SPTB, spontaneous preterm birth
(which is cheaper) has been used in the trial for CL ≤15 mm [62], at 16–366/7 weeks; TVU, transvaginal ultrasound; CL, cervical
and 90 mg gel for the trial for CL 10–20 mm [62]. Therefore, CL, length.
There are more limited data to evaluate the effectiveness of vagi- far used the Arabin pessary. While the first RCT revealed a 82%
nal progesterone for CL 21–25 mm [63]. decrease in PTB <34 weeks associated with pessary use [77], sub-
Guidelines from SMFM and ACOG state that implementation sequent, other (some larger) RCTs have not shown any benefit
of universal TVU CL screening should be viewed as reasonable in PTB or neonatal outcomes [78, 79]. All these RCTs included
and can be considered by individual practitioners; third-party mostly (about 85%–90%) singletons without a prior SPTB. A sys-
payers should not deny reimbursements for this screening [68, temic review and meta-analysis of three RCTs (n = 1420), Arabin
69]. The International Federation of Gynecology and Obstetrics pessary placement did not reduce the risk of SPTB <37 weeks or
(FIGO) recommends TVU CL screening [70]. TVU CL exams improve neonatal outcomes in singleton gestations with short
should be done following strict quality criteria, in the United cervix 25 mm or less at 20–24 weeks [80]. A small RCT of single-
States via CLEAR and the Perinatal Quality Foundation (https:// ton gestation with short cervix 25 mm or less without a history
clear.perinatalquality.org) [71], and in Europe through the Fetal of prior PTB showed no difference in the rate of SPTB <37 weeks
Medicine Foundation [72]. Only TVU, and not transabdominal in pessary versus nonpessary groups (43% vs. 40%; relative risk
ultrasound, should be used for CL screening [68, 69]. 1.09; 95% CI 0.71–1.68) [81]. In summary, pessary cannot be rec-
Screening with TVU CL at about 20 weeks (18–23 weeks ommended for the prevention of PTB in singleton gestations
range) should be offered to all singleton gestations without (without prior PTB) with a short TVU CL.
prior SPTB. If CL ≤25 mm, vaginal progesterone (e.g. 200-mg
suppositories every evening until 36 weeks) should be recom- Intervention: Indomethacin
mended [61–63]. There is insufficient evidence to evaluate the effect of indometh-
acin on the incidence of PTB in women with a short CL on TVU
Intervention: Cerclage (ultrasound- [82], as no RCTs have been performed.
indicated cerclage)
An ultrasound-indicated cerclage (UIC) involves the first screen- Intervention: Antibiotics
ing of pregnancies with TVU of the cervix to determine during There is insufficient evidence to evaluate the effect of antibiotics
pregnancy the risk of PTB, since the majority of even women at on the incidence of PTB in women with a short CL on TVU, as no
high risk by obstetric risk factors for PTB do not develop a short RCTs have been performed.
CL and deliver at term even without intervention. A short CL
(<25 mm) on TVU in the second trimester (between 14 and 236/7 Risk: Pregnancy high-risk for PTB
weeks) significantly increases the risk of PTB in all populations Intervention: Activity restriction/bed rest
studied [73]. UIC is defined as a cerclage performed because a short Activity restriction and/or bed rest are probably the most com-
CL has been detected on TVU during pregnancy, usually in the sec- monly prescribed interventions for PTB prevention despite no
ond trimester. This cerclage has also been called therapeutic, sal- proven benefit and potential for increased maternal morbidity.
vage, or rescue cerclage, but these terms are confusing and should There is no evidence supporting bed rest or activity restriction to
be avoided. UIC has differing effects in different populations. prevent PTB [83, 84]. Per ACOG, bed rest should not be routinely
In women with singleton gestations, no prior PTB or other recommended for the prevention of PTB [85]. Bed rest (rest
risk factors for PTB, and CL <25 mm before 24 weeks, cerclage is 1 hour TID) in asymptomatic and symptomatic “high-risk”
associated with a nonsignificant reduction in PTB <35 weeks (RR singleton pregnancies is not associated with the prevention of
0.76, 95% CI 0.52–1.15; n = 275) [74]. A recent individual patient PTB over no bed rest [86]. Bed rest can be associated with an
data meta-analysis of five RCTs (with 419 women) showed no sig- increased incidence of complications; in-hospital extended strict
nificant association between cervical cerclage and the reduction bed rest for PTL or PPROM is associated with an up to 1%–2%
of SPTB <35 weeks or neonatal outcomes in asymptomatic sin- incidence of thromboembolic disease. Moreover, muscle wasting,
gleton women with a short cervix less than 25 mm and without cardiovascular deconditioning, bone demineralization, impaired
prior SPTB [75].The planned subgroup analysis noted a significant glucose tolerance, heartburn, constipation, failure of volume
decrease in SPTB <35 weeks in women with a cervical length expansion, headaches, dizziness, fatigue, depression, anxiety,
≤10 mm, with adjunct treatment with indomethacin and one and stress, as well as lost wages, lost domestic productivity, and
dose of antibiotics (39.5% vs. 58.0%; RR, 0.68; 95% CI 0.47–0.98, other costs may be other detrimental consequences of bed rest. A
0.98; I2 =0%). TVU CL ≤11 mm may identify a subgroup of secondary analysis of Maternal-Fetal Medicine Units’ (MFMUs)
patients at high risk for asymptomatic cervical dilation (30% preterm prediction study evaluated a cohort of 1086 singleton
risk of being ≥1 cm dilated) and poor perinatal outcome [76]. gestations at high risk of PTB, of which 9.7% (n = 105) of women
Physical examination for evaluation of cervical dilation should be were recommended activity restriction and 37.1% (n = 39) of these
performed in singletons with TVU CL ≤11 mm. If cervical dila- women had SPTB <37 weeks. In the group with no recommended
tion is noted, physical examination–indicated cerclage is recom- activity restriction (n = 981), 14.3% (n = 140) delivered SPTB <37
mended (see later, under “risk: cervical dilation intervention: weeks. The authors and national societies (including SMFM) dis-
cerclage (physical-exam indciated cerclage”). Therefore, cerclage courage the routine use of activity restriction in women at
can be considered for singleton gestations with prior SPTB and high risk for preterm birth [87, 88].
TVU CL ≤10 mm before 24 weeks, but more research is needed. It is true that rest decreases uterine activity and exercise
For singleton gestations with prior PTB and a short TVU CL, increases it, but these are small effects that do not change the
see later, under “Risk: Prior PTB and Short Cervix on Ultrasound.” rates of PTB. In nonrandomized studies, exercise in pregnancy
has been associated with a decrease in PTB [89], while physi-
Intervention: Pessary cally demanding work, prolonged standing, shift and night work,
There is contradictory evidence regarding the efficacy of a pes- and high cumulative work fatigue score have been associated
sary to prevent PTB in women with singleton gestations and a with PTB. Despite its use in about 20% of pregnancies, bed rest
short TVU CL ≤25 mm in the second trimester. All studies so or any activity restriction for the prevention of PTB cannot
be recommended. These interventions should be studied in tri-

als before clinical use. If prescribed bed rest, women should be Singleton with
allowed to ambulate to the bathroom a few times a day to limit prior SPTB
complications of strict bed rest. It is possible that women at high
risk of PTB from the previously noted or other risk factors have
not been studied adequately with this intervention of bed rest.
Intervention: Support Progesterone at

Programs of additional support during at-risk pregnancy (vary- 16weeks*
ing definitions), usually by a professional (social worker, mid-
wife, or nurse), do not reduce PTB or LBW [90]. “Additional
support” was defined as some form of emotional support (e.g.
counseling, reassurance, and sympathetic listening) with or
Serial** TVU CL
without additional information/advice, occurring during home at 16–23 6/7
visits, clinic appointments, and/or by telephone; most of the weeks
time, these were intensive programs started in the first or sec-
ond trimesters to the end of pregnancy. Other significant out-
comes are as follows: Antenatal hospital admission and cesarean
delivery are decreased [90].
CL ≤ 25 mm CL > 25 mm
Intervention: Weekly manual exams, education
A program of weekly manual cervical exams in addition to educa-
tion for women at high risk for PTB (≥10 on Creasy score) does
not reduce PTB [91–93].
Intervention: Antibiotics Cerclage;

See the section “Intervention: Antibiotics” under “Risk: Prior Continue
Continue
Progesterone
PTB.” Progesterone
Intervention: Cerclage
Different specific clinical scenarios have been studied for the pos- FIGURE 18.3 Transvaginal ultrasound cervical length screen-
sible benefit of cerclage. For efficacy of history-indicated cerclage, ing for the woman with a singleton gestation and prior spon-
transabdominal (TA) cerclage, UIC, physical exam–indicated taneous preterm birth(s). (Adapted from Ref. 69.) *Vaginal
cerclage, and in twins, see earlier and later. progesterone, usually 200 mg every night; or 250 mg IM
every week, from 16–20 weeks to 36 weeks. **Every 2 weeks; if
Risk: Prior PTB (Figures 18.3 and 18.4) [94]
26–29 mm, repeat in 1 week. Abbreviations: SPTB, spontaneous
Intervention: Low-dose aspirin preterm birth at 16–366/7 weeks; TVU, transvaginal ultrasound;
A recent secondary analysis of an RCT (underpowered) showed CL, cervical length.
no association between preconception low-dose aspirin in women
with one or more prior pregnancy loss and PTB on overall PTB
rates [95]. <37 weeks (38% vs. 41%; RR 0.91, 95% 0.77–1.07) and PTB <35
weeks (RR 0.95, 95% CI 0.72–1.25) [98]. Meta-analysis of these
Intervention: Fish intake two RCTs revealed that women who received omega-3 had simi-
Moderate fish intake, up to three meals per week, before 22 lar rates of PTB at <37 weeks (34.5% vs. 39.8%; RR, 0.81; 95% CI
weeks is associated with a reduction in repeat PTB, compared 0.59–1.12) and PTB at <34 weeks (12.0% vs. 15.4%; RR, 0.62; 95%
with women eating fish less than once per month (OR 0.60, CI CI 0.26–1.46) compared with controls. The omega-3 groups had
0.38–0.95) [96]. Moderate fish intake should be encouraged in a statistically significantly longer latency (mean difference, 2.10
women with prior PTB for the prevention of recurrent PTB days; 95% CI 1.98–2.22) and higher birth weight (mean differ-
(see also the text earlier for low-risk women). ence, 102 g; 95% CI 20–185) compared with control subjects [99].
In summary, in singleton gestations with prior SPTB on 17P,
Intervention: Omega-3 fatty acids omega-3 supplementation does not seem to be beneficial in
In one RCT, omega-3 fatty acids (fish oil, Pikasol: 32% eicosa- preventing recurrent PTB. The benefits in longer latency and
pentaenoic acid [EPA], 23% DHA, and 2 mg tocopherol/mL; 4 higher birth weight may deserve further study (see also earlier for
capsules/day: 1.3 g EPA and 0.9 g DHA, total 2.7 g/day; started low-risk women).
≥16 weeks at an average of 29–30 weeks) were associated with a
reduction in PTB <37 weeks by 46% and PTB <34 weeks by 68% Intervention: Antibiotics
in women with a prior PTB <37 weeks and a singleton gestation. Antibiotics to prevent PTB in women with prior PTB have been
The same omega-3 fatty acid regimen does not reduce PTB in evaluated either as preconception (one RCT) or as prenatal inter-
women with twins [97]. In another larger RCT, in singleton gesta- vention. In women with prior PTB <34 weeks, preconception
tions with prior SPTB and on 17P 250 mg IM, omega-3 supple- oral azithromycin 1 g twice (4 days apart) and metronidazole
mentation (1200 mg EPA and 800 mg DHA) from 16 to 22 weeks 750 mg daily for 7 days are not associated with an effect of subse-
until 36 weeks was associated with similar incidences of PTB quent PTB or miscarriage rates [100].
Offer Progesterone prophylaxis (16–36weeks) 100 mg nightly from 24 to 34 weeks was associated with a signifi-
cant reduction in the incidences of PTB <37 weeks (RR 0.48, 95%
CI 0.25–0.96) and <34 weeks, as well as contraction frequency,
compared with placebo [110]. In 659 women with singleton gesta-
≥3 Early SPTB and/or ≥2 STLs <3 SPTBs or <2 STLs
tion and prior SPTB 20–350/7 weeks, vaginal progesterone 90 mg
every morning starting at 18–226/7 weeks until 370/7 weeks was
not associated with significantly different rates of PTB <37, 36,
History-indicated cerclage Follow algorithm in 33, and 29 weeks and neonatal morbidity and mortality [111].
at 12–14weeks figure 18.3 Several women screened for this trial were excluded because of
short CL [106]; therefore, vaginal progesterone cannot be recom-
mended for the prevention of recurrent PTB when data against
SPTB <33weeks despite placebo is considered.
history-indicated cerclage For a comparison of 17P versus vaginal progesterone, there
are three RCTs. In 518 women with singleton gestation and prior
PTB between 20 and 34 weeks, 17P 250 mg IM weekly was asso-
ciated with similar incidences of PTB and neonatal morbidi-
Offer Transabdominal cerclage next pregnancy ties and mortality compared with vaginal progesterone 90 mg
(Crinone) daily, except for significant lower incidences of PTB
FIGURE 18.4 Clinical algorithm for care of asymptomatic 28–316/7 weeks, neonatal intensive care unit (NICU) admission,
women with multiple prior PTB or STLs (see text). (Adapted from and maternal side effects in the vaginal progesterone group [112].
Ref. 94.) Abbreviations: SPTB, spontaneous preterm birth; STL, Another RCT reported similar outcomes, including incidence of
second-trimester loss. PTB, with either vaginal progesterone or 17P in women with sin-
gleton gestations and prior PTB [113]. Another recent nonblinded
randomized trial of 78 singleton pregnancies from Iran compared
Clindamycin cream 2% for 7 days at 26–32 weeks does not effectiveness of vaginal progesterone with 17P in women with
reduce PTB <37 weeks in women with a prior PTB 24–36 weeks either prior PTB or short cervix TVU CL <25 mm. The authors
but may increase PTB <34 weeks, especially in women without BV, concluded that vaginal progesterone and intramuscular proges-
so that antibiotics in this setting may actually be detrimental [101]. terone have the same level of effectiveness and reported a similar
Cefetamet pivoxil (not available in the United States) 2 g × 1 at rate of PTB in the two groups [114]. In 145 women with singleton
28–32 weeks in women in Nairobi with prior PTB, fetal death, or gestations (16–20 weeks) and prior PTB, weekly intramuscular
LBW did not affect GA at delivery (PTB was not reported) [102]. administration of hydroxyprogesterone caproate (250 mg) and
Metronidazole 250 mg TID × 7 days and erythromycin base daily vaginal progesterone suppository (100 mg) exhibited similar
333 mg TID × 14 days in women with a prior PTB or pre-pregnancy efficacy in reducing the rate of recurrent PTB <37 weeks (43.9%
weight <50 kg do not prevent PTB <37 weeks but may increase vs. 37.9%, p=0.05) [115]. Overall these RCTs do not appear to be
PTB <34 weeks [103, 104]. high quality, and the study results should be used cautiously. A
In summary, antibiotics given just because of a prior PTB do systematic review and meta-analysis of three RCTs (680 women)
not prevent recurrent PTB. showed that daily vaginal progesterone (either suppository or gel)
started at about 16 weeks’ gestation is a reasonable, if not bet-
Intervention: Progesterone ter, alternative to weekly 17-OHPC injections for the prevention
The effect of progesterone supplementation should be evaluated of SPTB in women with singleton gestations and prior SPTB
according to different patient populations and according to the [116].The level of the summary estimates was low or very low as
type of progesterone. Here we review progesterone for prior PTB. assessed by GRADE; therefore, more data are necessary to eval-
For 17P, there are at least two RCTs available in women with uate how 17P and vaginal progesterone compare in efficacy in
prior PTB. In 43 women with mostly (>90%) singleton gesta- singletons with a prior PTB, but vaginal progesterone seems
tion and either prior PTB or prior >1 spontaneous abortion, 17P to be at least equivalent, if not possibly more efficacious, than
250 mg IM weekly started as soon as prenatal care began was 17P in preventing recurrent PTB in women with prior SPTB.
associated with a significant reduction in PTB <37 weeks and For oral progesterone, there are two small RCTs. In 150
perinatal mortality compared with placebo [105]. In 463 women women with singleton gestation and prior SPTB 20–366/7 weeks,
with a singleton gestation and prior SPTB at 20–366/7 weeks of a oral micronized progesterone 100 mg twice a day was associated
singleton gestation, compounded 17P 250 mg IM weekly started with significantly reduced incidences of PTB <37 weeks (39.2% in
at 16–20 6/7 weeks was associated with a reduction in the inci- the oral progesterone vs. 59.5% in the placebo group, p = 0.002)
dences of PTB <37 weeks (RR 0.66, 95% CI 0.54–0.81), PTB <35 and NICU admission compared with placebo [117]. In 33 women
weeks, and <32 weeks, as well as of supplemental oxygen, NEC, with singleton gestation and prior PTB 20–366/7 weeks, oral
and IVH, compared with placebo [106]. The number needed to progesterone 400 mg daily was associated with nonsignificant
treat to prevent one recurrent PTB was 5.4. Based mostly on this reductions in the incidence of PTB <37 weeks (26% vs. 57%) and
clinical trial, 17P 250 mg IM weekly started at 16–20 weeks is rec- ventilator use (0% vs. 21%) compared with placebo [118]. A meta-
ommended for all women with prior SPTB 20–366/7 weeks (Figure analysis and systematic review of the three trials on oral proges-
18.3) [107–109]. The estimated number of prevented PTBs <37 terone vs. placebo (involved 386 patients: 196 in oral progesterone
weeks in the United States by this policy is about 9870. and 190 in placebo) showed a significant decrease in the risk of
For vaginal progesterone, there are at least two RCTs avail- PTB <37 weeks’ gestation (42% vs. 63%; p = 0.0005; RR 0.68; 95%
able in women with prior PTB. In 142 women with singleton CI 0.55–0.84) and reduction in perinatal morbidity and mortal-
gestations and mostly (>90%) prior PTB, vaginal progesterone ity [119]. This study did not note any serious adverse effects and
reported a higher rate of maternal adverse effects with oral pro- of PTB in women with three or more STLs or early (e.g.
gesterone that included dizziness, somnolence, and vaginal dry- <32 weeks) PTBs [129]. Cerclage decreases the incidence of PTB
ness. In summary, there is insufficient but promising evidence <37 weeks from 53% (with no cerclage) to 32% and the incidence
to assess the efficacy of oral progesterone for the prevention of of PTB <32 weeks from 32% (with no cerclage) to 15% in women
PTB in women with prior PTB. with three or more prior PTBs or STLs (Figure 18.4) [129].
In summary, in women with prior SPTB and singleton The other clinical indication for history-indicated cerclage
gestation, progesterone administration is beneficial in pre- might include CI, defined by some as prior painless cervical dila-
venting recurrent PTB. Comparison RCTs seem to show vagi- tation leading to recurrent STLs. Unfortunately, no trial has been
nal progesterone is an effective alternative to 17P [112, 114]. So done to confirm the efficacy of history-indicated cerclage in
either vaginal progesterone 200 mg every night or 17P 250 mg reducing PTB in women with a diagnosis of CI. Other indica-
IM weekly, starting at 16–20 weeks until 36 weeks, should be tions such as prior cone biopsy, Mullerian anomaly, diethylstil-
recommended to women with singleton gestations and prior bestrol (DES) exposure, prior PTB not associated with CI, and
SPTB 20–366/7 weeks [106]. After the Meis publication, ACOG Ehlers-Danlos syndrome have occasionally been used clinically
and SMFM recommended progesterone supplementation (17P but have not been confirmed by any trial as indications that ben-
or vaginal progesterone) to reduce the risk of recurrent PTB in efit from history-indicated cerclage. History-indicated cerclage is
women with a prior SPTB [69, 120]. A recent meta-analysis of usually performed at 12–15 weeks’ gestation, and its techniques
17P vs. placebo or no treatment for prevention of recurrent PTB have been well described [73].
identified four RCTs, including the Meis trial. This meta-analysis TA cerclage has been associated with less recurrent PTB com-
showed a reduction in recurrent PTB at <37, <35, and <32 weeks pared with controls receiving transvaginal cerclage in women
by 29% (RR 0.71; 95% CI 0.53–0.96; p = 0.001), 26% (RR 0.74; 95% with a history of a failed (SPTB <33 weeks despite cerclage)
CI 0.58–0.96; p = 0.021), and 40% (RR 0.60; 95% CI 0.42–0.85; transvaginal history–indicated cerclage in a case-control study
p = 0.004), respectively, in the 17-OHPC group compared with [130]. It should be noted that in this study antibiotics and pro-
placebo or no treatment [121]. gesterone were uniformly given to the TA cerclage women. There
The Meis trial lead to FDA approval of Makena in 2011 [122]. is no RCT on TA cerclage. The efficacy of TA cerclage for other
The requirement of FDA approval led to a confirmatory second clinical scenarios such as a cervix with no intravaginal portion
trial called PROLONG (Progestin’s Role in Optimizing Neonatal has not been adequately studied. TA cerclage can be performed
Gestation), which was a multicenter, international, double-blind, prophylactically at around 10–12 weeks, and its technique has
randomized, placebo-controlled trial of 1700 women from 93 been well described [73, 130]. TA cerclage has been successfully
sites in nine countries (with approximately 25% of women from performed also laparoscopically and robotically, in particular
the United States) with a history of spontaneous PTB that was pre-pregnancy, but also in the early first trimester [131].
conducted from 2009 through 2018 with co-primary outcomes In summary, the vast majority of women with prior PTB
of PTB <35 weeks and neonatal composite index. The PROLONG (e.g. those with only one or two prior SPTBs) does not ben-
study showed the incidence of PTB at less than 35 weeks of gesta- efit from universal history-indicated cerclage and can instead
tion (17a-hydroxyprogesterone caproate–treated group 11.0% vs. be followed with serial TVU CL screening starting usually at
placebo 11.5%, p = 0.72) and the percentage of neonates with the 16 weeks. A policy of TVU CL screening with cerclage for short
morbidity and mortality composite index (5.6% vs. 5.0%, p = 0.73) CL is associated with similar incidences of PTB <37 weeks (31%
[123]. The discordant results of the Meis and PROLONG trials vs. 32%; RR 0.97, 95% CI 0.73–1.29), PTB <34 weeks (17% vs. 23%;
have been extensively reviewed by ACOG and SMFM and other RR 0.76, 95% CI 0.48–1.20), and perinatal mortality (5% vs. 3%;
experts in the field [124–126]. The differences in these two trials RR 1.77, 95% CI 0.58–5.35) compared with universal history-
include different study populations, especially with respect to the indicated cerclage and omits an obviously unnecessary cerclage
baseline risk of PTB, characteristics of prior PTBs, and additional in about 58% of these women [132]. Therefore, all singleton ges-
demographic and reproductive characteristics (such as ethnicity, tations with a prior spontaneous PTB should be screened with
marital status, and smoking) [125]. The SMFM statement con- serial TVU CL starting at 16 weeks, every 2 weeks, until 236/7
cluded, “On the basis of the evidence of effectiveness in the Meis weeks. If the CL is 26–29 mm, repeat TVU CL can be done in
study, with the largest number of US patients, and given the lack 1 week instead of 2 weeks. If the CL <25 mm is detected before
of demonstrated safety concerns, SMFM believes that it is rea- 24 weeks, singleton gestations with prior PTB should undergo
sonable for providers to use 17-OHPC in women with a profile ultrasound-indicated cerclage (Figure 18.3) (see also the section
more representative of the very-high-risk population reported in “Risk: Short Cervix on Ultrasound”) [133].
the Meis trial. For all women at risk of recurrent SPTB, the risk/ If cerclage is performed, it should be performed according
benefit discussion should incorporate a shared decision-making to the best technique. McDonald cerclage, with suture (usu-
approach, taking into account the lack of short-term safety con- ally Mersilene tape) placed as close to the internal os as possible
cerns but uncertainty regarding benefit. It is important to con- (as high as possible), under spinal anesthesia, is recommended.
sider that 17-OHPC use is associated with substantial health care There is usually no need for preoperative antibiotics or tocolytics
costs, injection-site pain, and extra patient visits and that long- [134]. A double suture might improve outcomes compared to one
term potential maternal and neonatal effects are unknown” [125]. suture, but the evidence is still insufficient for a recommendation
[135]. Cervical occlusion has no significant additional effect on
Intervention: Cerclage cerclage [136].
A history-indicated cerclage is placed based solely on prior ob-
gyn history (previously called a prophylactic or elective cerclage). Intervention: Oral tocolytics
Trials on women with only one or two prior PTBs have not shown There is insufficient evidence (only one small old RCT) to support
benefit from history-indicated cerclage [127, 128]. A history- the use of prophylactic oral betamimetics for preventing PTB in
indicated cerclage has been associated with the prevention women with prior PTB with a singleton pregnancy [137].
For a summary of care of pregnant women with prior PTB, see TVU CL screening with UIC for a short cervix is acceptable
also Ref. [89]. and possibly more effective than a routine HIC in women with
UIC in prior pregnancy. A consideration can be given to HIC in
Risk: Prior PTB and short cervix on ultrasound the small subset of women who delivered prior to 32 weeks in
Intervention: Progesterone their prior pregnancy despite UIC [143].
In a secondary analysis of an RCT evaluating just 46 singleton There is insufficient evidence to suggest an upper limit of GA
gestations with prior SPTB <35 weeks and short CL <28 mm at UIC placement [145]. A retrospective study of 426 singleton
at 18–226/7 weeks, vaginal progesterone 90 mg daily started at gestations who underwent UIC in previable (16 to <22 weeks)
18–236/7 weeks until 37 weeks was associated with significant and periviable (22 to <24 weeks) GA showed similar obstetric
decreases in the incidences of both PTB <32 weeks and NICU outcomes. The authors showed a lower risk of recurrent PTB
admission compared with placebo [138]. <36 weeks in women who had a periviable cerclage compared
In a small RCT which did not recruit the planned sample size, to those with previable cerclage placement (26.6% vs. 38.3%,
17P in singleton gestations at high risk for PTB (56% with prior respectively, p <0.04) [146]. The authors support continued use
PTB) with TVU CL <25 mm 20–316/7 weeks was noted to have no of UIC up until 24 weeks. Further well-designed randomized
benefit in prolonging pregnancy compared to no 17P. The sample studies on the safety and efficacy of cerclage at or beyond 24
size was too small, and the intervention probably too late, to show weeks are suggested.
significance [139]. If the TVU CL shortens again later after the UIC has been
In a randomized trial that did not recruit the planned sample placed, a second “reinforcing” cerclage has not been associated
size, 17P and cerclage had a similar effect in women for CL <25 with the prevention of PTB [147, 148].
mm for the prevention of PTB, but cerclage was more effective in For singleton gestations without a prior PTB and with a
women with CL <15 mm [60]. So, while cerclage seems to be more short TVU CL, see the earlier sections “Risk: Short Cervix on
efficacious (lower RRs) as the CL is shorter [140, 141], progester- Ultrasound” and “Intervention: Cerclage.”
one seems to be most efficacious in cases of “moderate” short CL
[61, 62]. Intervention: Adjunctive treatment at cerclage
Until further evidence is available, we suggest continuation There is insufficient evidence to evaluate the effect of combining a
of 17P in women with prior PTB and short cervix in the index tocolytic (indomethacin) and antibiotics (cefazolin/clindamycin)
pregnancy. Some instead have suggested switching from 17P to with cervical cerclage compared with cervical cerclage alone for
vaginal progesterone, but not based on RCT data [142]. There is preventing spontaneous PTB in women with singleton pregnan-
no good evidence suggesting the benefit of the addition of vaginal cies undergoing HIC. Further well-designed randomized trials
progesterone in women with a prior PTB on 17P who are noted are warranted [149].
to have a short cervix [142]. In summary, women with prior PTB
should be screened with TVU CL from 16 to 23 weeks. Vaginal Intervention: Vaginal progesterone vs. cerclage
progesterone or 17P should be recommended to women with There is no RCT comparing directly vaginal progesterone to cer-
prior SPTB starting at 16 weeks, as described earlier. If the cerclage in this population, and therefore there is insufficient evi-
vix shortens, there is insufficient evidence to assess efficacy of a dence for a recommendation. While an indirect meta-analysis
different progesterone therapy, and therefore it is reasonable to reported that either vaginal progesterone or cerclage is equally
continue 17P until 36 weeks. efficacious in the prevention of PTB in women with a sonographic
short cervix in the mid-trimester, singleton gestation, and previ-
Intervention: Cerclage ous PTB, the populations compared were not similar, introducing
In women with a singleton gestation, prior SPTB, and CL <25 significant bias [150]. We offer progesterone based on the prior
mm before 24 weeks, cerclage is associated with a significant PTB, and cerclage for the short CL, based on data reviewed earlier.
30% reduction in PTB <35 weeks (28.4% vs. 41.3%; RR 0.70, 95%
CI 0.55–0.89); significant reductions in PTB <37, <32, <28, Intervention: 17P vs. cerclage
and <24 weeks; and a significant 36% decrease in composite Progesterone in addition to cerclage
perinatal mortality and morbidity (15.6% vs. 24.8%; RR 0.64, There is insufficient evidence to assess the size of any cumula-
95% CI 0.45–0.91), compared to no cerclage [133]. Therefore, cer- tive effect of 17P for prior PTB in singletons already with cerclage
clage is recommended in women with a singleton gestation, for short CL. 17P was associated with a reduction in PTB <35eeks
prior SPTB, and CL <25 mm before 24 weeks [68, 69]. in women with UIC in the current pregnancy for TVU CL<25
There are no randomized trials on the management of subse- mm, but the sample size was too small to show significance [151,
quent pregnancy in women who required UIC in their prior 152]. Another retrospective study showed a 69% reduction in PTB
pregnancy. Level II evidence suggests similar outcomes with <24 weeks in women with cerclage plus 17P compared to cerclage
TVU CL screening with UIC for short cervix of 25 mm or less alone [153]. The secondary analysis of ultrasound indicated– and
or planned history-indicated cerclage (HIC) in the subsequent physical exam–indicated cerclage showed a 91% and 89% reduc-
pregnancy, in singleton gestations with prior UIC. The authors tion in delivery at less than 24 and less than 28 weeks of gesta-
reported less than 50% of the TVU CL screening group required tion, respectively (CI 0.004–0.6 and CI 0.02–0.46; p <0.05) in
a repeat UIC in the subsequent pregnancy [143]. Another retro- women with cerclage plus 17P compared to cerclage alone [153].
spective study of women with a prior UIC also reported that the A recent systematic review and meta-analysis of adjuvant 17P in
majority of women who underwent CL surveillance in the next UIC showed no benefit [154]. The results should be interpreted
pregnancy did not require intervention for a short cervix. The with caution due to insufficient evidence and lack of randomized
authors reported a higher rate of PTB in women who received trials confirming or refuting the benefit. Expert opinions recom-
HIC in the subsequent pregnancy, which was not justified based mend continuation of progesterone supplementation after cer-
on their risk status [144]. Based on the available level II evidence, clage placement [155].
Cerclage in addition to progesterone more unscheduled antenatal visits and prophylactic tocolytic use
There is insufficient evidence to assess the size of any cumulative in the HUAM group compared to controls. Therefore, HUAM
effect of cerclage for short CL in singletons already on 17P for should not be routinely provided for prevention of PTB.
prior PTB. UIC was associated with a reduction in PTB <35 weeks
in women already on 17P for prior PTB in the current pregnancy, Risk: Cervical dilatation
but the sample size was too small to show significance [156]. Intervention: Cerclage (physical
exam–indicated cerclage)
Risk: Cervical insufficiency Physical exam–indicated cerclage (PEIC; aka emergency, urgent,
Intervention: Cerclage or heroic) is the cerclage placed because of changes in the cervix
No intervention has been specifically studied in this popula- (dilatation, effacement, etc.) detected by physical (manual) exam-
tion (see earlier under prior PTB). There are no randomized trials ination. Since about 50% of women with asymptomatic cervical
evaluating the role of HIC in women with prior PTB or pregnancy dilatation ≥2 cm in the second trimester have microbial invasion
loss due to cervical insufficiency. There is insufficient evidence of the amniotic cavity, an amniocentesis should be considered
to recommend an HIC in women with fewer than three prior before offering PEIC.
PTBs or STLs. A policy of TVU CL screening with UIC if the There are limited data to assess the efficacy of PEIC in women
CL shortens to <25 mm at <24 weeks has been shown to be with cervical dilatation in the second trimester, as only one small
equivalent to a policy of universal HIC in women with one or trial has been reported. In women with membranes at or beyond
more than one prior SPTB [73, 132, 157]. the external os at around 20–24 weeks, PEIC (and indometh-
acin) is associated with a delay in delivery of about 4 weeks
Intervention: 17P in addition to cerclage compared with controls (30 vs. 26 weeks) [171]. The major limita-
There is insufficient evidence to assess the possible cumulative tions of this study are the small sample size and the inclusion of
effect of 17P on PTB <35 weeks in women with an HIC [158]. twins. Over 25 retrospective observational series, mostly with no
controls, have claimed benefit of PEIC. The largest cohort study
Risk: IVF ART reported a significant decrease of 92% in the prevention of PTB
Intervention: Progesterone or HCG <28 weeks with PEIC, compared with no cerclage, in singletons
17∝-hydroxyprogesterone caproate or HCG supplementation in with ≥1 cm of cervical dilatation before 26 weeks [172]. A recent
the first trimester is associated with an increase in the inci- meta-analysis reported that PEIC is associated with a significant
dence of fetal heart activity on ultrasound by 238% and of increase in neonatal survival and prolongation of pregnancy of
pregnancy ≥24 weeks’ rate by 380% compared with placebo approximately 1 month when compared with no cerclage. The
[159]. strength of this conclusion is limited by the potential for bias in
the included studies [173]. For PEIC, perioperative indomethacin
Risk: Amniocentesis and antibiotics have been associated with a significant 28-day
Intervention: Progesterone prolongation of pregnancy [174]. In summary, PEIC in singleton
Natural progesterone 200 mg IM daily for 3 days post-amniocen- gestations with a cervix dilated to ≥1 cm in the second trimes-
tesis followed by 17∝-hydroxyprogesterone caproate 340 mg IM ter is associated with a prevention in PTB and neonatal ben-
twice a week until the second week after the amniocentesis did efits. Clearly a large, well-designed randomized trial is needed to
not reduce PTB <25 weeks in women undergoing amniocentesis confirm these benefits.
[160].
Intervention: Indomethacin
Risk: Uterine contractions detected by There is insufficient evidence to evaluate the effect of indo-
home uterine activity monitoring methacin on the incidence of PTB in women with a short CL on
Intervention: Varied, per obstetrician TVU [175], as no RCT has been performed. An RCT of periop-
Uterine contractions have been associated with PTB, but their erative indomethacin and antibiotics in women receiving a PEIC
predictive value is poor. HUAM usually consists of 1 hour of between 16 and 23 weeks showed a significant prolongation of
tocomonitoring twice daily at 24–36 weeks. HUAM with or gestation by 28 days compared to control [174].
without nursing contact and education is not associated with
prevention of PTB. Some studies show earlier (at lower cervical Intervention: Perioperative considerations
dilatation) detection of PTL. The lack of benefit in prevention of and surgical technique of PEIC
PTB might have been secondary to a lack of effective interven- Observation for 12–24 hours for evaluation of PTL, PROM,
tion (usually tocolysis) once PTL was diagnosed. Three different chorioamnionitis and placental abruption, and appropriate
populations of women at high risk for PTB have been studied: cervical and vaginal sample collection to evaluate for cervi-
Singleton gestations with risk factors for PTB (e.g. prior PTB), citis and vaginitis may be warranted by clinical evaluation.
twin gestations, and women status-post an episode of PTL. Amniocentesis can be considered especially in women with
Unfortunately, there is no published meta-analysis of all trials, 2 cm or more cervical dilation and/or prolapsed membrane to
and most trials do not report results for each population specifi- rule out intraamniotic infection. Perioperative antibiotics
cally and also report differing outcomes. A meta-analysis of pub- (one dose just before cerclage, e.g. cephalexin) and tocolyt-
lished data shows no decrease in PTB <37 weeks in any of these ics (i.e. indomethacin 100 mg then 50 mg per rectum every
three subgroups: Mostly singletons at high risk (9 trials; n = 3613) 6 hours for 48 hours peri-cerclage) should be given (details
[161–170]: RR 1.01, 95% CI 0.91–1.11; twins (5 trials; n = 998) [64, provided earlier). Cerclage technique and suture selection is
67, 69–71]: RR 0.91, 95% CI 0.80–1.04; or women status-post PTL per the surgeon’s preference. If the cervix is flushed, consider-
episode (4 trials; n = 218) [67, 72–74]: RR 1.21, 95% CI 0.92–1.60. ation can be given to a modified Shirodkar technique. Various
The largest study [170] and a recent meta-analysis [18] showed techniques have been described to avoid iatrogenic rupture of
membranes, including but not limited to lithotomy position or prior FGR (see Chaps. 1 and 47 in Maternal-Fetal Evidence
with deep Trendelenburg position, tocolytics, and retrograde Based Guidelines) [181]. A large systematic review showed an 8%
refill of bladder to assist with repositioning the membrane in reduction in the rate of PTB <37 weeks in women (many with
the uterus. Other options include placement of ring forceps on prior preeclampsia or fetal growth restriction [FGR]) treated with
the external os followed by gentle easing of the membranes into antiplatelet agents (RR 0.92, 95% CI 0.88–0.97) [182]. This reduc-
the uterus [176]. tion in the rate of PTB was higher if low-dose aspirin therapy is
initiated at or prior to 16 weeks compared to after 16 weeks (RR
Intervention: Progesterone 0.35, 95% CI 0.22–0.57, compared with RR 0.90, 95% CI 0.83–
There is no randomized trial to evaluate the effect of adjuvant 0.97, respectively) [183]. Low-dose aspirin started earlier than
progesterone supplementation after PEIC. A small retrospective 16 weeks is recommended for women at high risk of recur-
study of 53 singleton gestations with PEIC at 17–24 weeks showed rent preeclampsia due to prior history of preeclampsia or FGR
an association with reduction of SPTB <36 weeks (17% vs. 51%, leading to early (<34 weeks) PTB.
p <0.05), low birth weight, and NICU admission with adjuvant
vaginal progesterone therapy. The authors noted this association Risk: Periodontal disease
of reduction in SPTB<36 weeks after adjusting for confounding Intervention: Periodontal therapy
variables such as a visible membrane size of ≥4 cm, GA, prior Periodontal disease has been associated with an increased risk of
SPTB, and use of amnioreduction (adjusted odds ratio [aOR] 0.12, PTB in several observational studies. Periodontal treatment such
95% CI 0.02–0.69, p <0.05) [177]. Further well-designed trials are as scaling, root planning, plaque control, and daily rinsing have
suggested. been evaluated as an intervention to decrease PTB in women with
Prior PEIC and subsequent pregnancy outcomes are not very periodontal disease [184, 185].
well studied. Limited data from a retrospective study of a rare Periodontal treatment has not been associated with a
cohort of women with prior PEIC showed similar outcomes if decrease in PTB in women with periodontal disease (RR 0.63,
they received either TVU CL screening with UIC for CL ≤25 mm 95% CI 0.32–1.22), even when controlling for probing depth and
or planned HIC in the subsequent pregnancy. The authors noted attachment loss for periodontitis criteria, multiparity, prior PTB,
87.5% of the women in TVU CL screening require a repeat UIC in or genitourinary infections [186].
the subsequent pregnancy [178].
Infections
Risk: Asymptomatic bacteriuria
Risk: Positive fFN Intervention: Antibiotics
Intervention: Antibiotics Asymptomatic bacteriuria occurs in 2%–10% of pregnancies, can
fFN is a basement membrane protein present between the lead to pyelonephritis, and is associated with an increased risk
decidua/uterus and fetal membranes/placenta and produced by of PTB. Screening for asymptomatic bacteriuria and treat-
the trophoblast. Its presence (>50 ng/mL) at ≥22 weeks in the ing for urine colony count of >100,000 bacteria/mL reduce
cervicovaginal canal has been associated with an increased risk the incidence of PTB by 73% (RR 0.27, 95% CI 0.11–0.62, 2
for PTB. In fact, fFN is one of the best predictors of PTB in all studies, n = 242) [187]. The optimal time to perform the urine
populations, including asymptomatic low- and high-risk women, culture is unknown; it seems reasonable to perform the urine
twins, and women in PTL. Even at 13–22 weeks, higher (using culture and treat, as done in most studies, at the first prenatal
the 90th percentile) fFN levels are associated with a twofold to visit. Quantitative urine culture of a midstream or clean-catch
threefold increased risk in subsequent SPTB. In women found to urine is the gold standard for detecting asymptomatic bacteri-
be fFN positive at 21–25 weeks, treatment with metronidazole uria in pregnancy. The choices of a sulfonamide or sulfonamide-
250 mg TID and erythromycin 250 mg QID × 10 days is associ- containing combination, a penicillin, or nitrofurantoin, based
ated with similar incidences of PTB <37 weeks to placebo. Among on the results of susceptibility testing, are appropriate regimens
women with a prior SPTB, this antibiotic regimen is associated for the management of asymptomatic bacteriuria. A short (3–7
with a significantly higher incidence of PTB <37 weeks than the days) course of therapy for asymptomatic bacteriuria has become
placebo group [179]. In women with at least one other risk factor accepted practice and is as effective as longer therapy. A single-
for PTB (e.g. prior PTB), and positive fFN at 24–27 weeks, met- dose regimen of antibiotics may be less effective than a short
ronidazole 400 mg orally TID for 7 days was associated with no (4–7 days) regimen [188]. Women with asymptomatic bacteri-
effect on the reduction of PTB and maternal and perinatal out- uria in pregnancy should be treated by the standard regimen of
comes compared with placebo; rather, the authors reported that antibiotics until more data become available on the cure rate of a
metronidazole use can be detrimental due to a trend of higher shorter course (3–5 days) compared with the standard regimen.
PTB rate, antenatal admission, and LBW in the metronidazole Although it is recommended that a urine culture be done fol-
group compared with placebo [180]. In summary, screening low- lowing treatment, with retreatment as necessary, the evidence is
risk or high-risk asymptomatic pregnant women for fFN is not insufficient to specifically evaluate the effectiveness of this strat-
effective, as no intervention (the one tried used antibiotics) has egy. Treatment of asymptomatic pregnant women with lower
been shown to alter outcomes. colony counts is not currently recommended, but further study
of appropriate strategies to manage these women is warranted.
Risk: Prior FGR or preeclampsia Asymptomatic women with even low (100+) colony-forming
Intervention: Low-dose aspirin units (CFUs) of group B streptococcus (GBS) in the urine cul-
Compared to no aspirin or placebo, low-dose aspirin (usually ture at 27–31 weeks have decreased PTB <37 weeks (5.4% in
50–150 mg) is associated with a decreased incidence of PTB the penicillin group vs. 38% in the placebo group, p <0.002)
(RR 0.22, 95% CI 0.10–0.49) in women at high risk for preg- when treated with penicillin 1 million IU three times per day
nancy complications, such as those with prior preeclampsia for 6 days compared with placebo [189].
Antibiotic treatment compared with placebo or no treat- positive for TV. Symptomatic women with TV should still be
ment is effective in clearing asymptomatic bacteriuria. adequately treated with metronidazole as a single 2-g oral dose,
Antibiotic treatment of asymptomatic bacteriuria is then clini- or 500 mg twice a day for 7 days (see Chap. 38 in Maternal-Fetal
cally indicated to reduce the risk of pyelonephritis in pregnancy. Evidence Based Guidelines).
If untreated, the overall incidence of pyelonephritis is about 21%.
Overall, the number of women needed to treat to prevent one epi- Risk: BV, Candida, and Trichomonas
sode of pyelonephritis is seven, and treatment of asymptomatic Intervention: Antibiotics
bacteriuria will lead to approximately a 75% reduction in the inci- In one large RCT, screening for BV (treatment: Clindamycin 2%
dence of pyelonephritis (RR 0.23, 95% CI 0.13–0.41; 11 studies, vaginal cream for 6 days), Candida (treatment: Local clotrima-
n = 1932) [187]. The apparent reduction in PTB is consistent with zole 100 mg for 6 days), and Trichomonas (treatment: Local met-
current theories about the role of infection as a cause of PTB. ronidazole 500 mg for 7 days) was associated with lower risks
Prevention of pyelonephritis, which in early studies prior to the of PTB <37 weeks (3% vs. 5%; RR 0.55, 95% CI 0.41–0.75). The
availability of effective antimicrobial therapy was associated with incidence of PTB for BW <2500 g and <1500 g were significantly
PTB, may be a factor, but treatment of bacteriuria with antibiotics lower in the intervention group (RR 0.48, 95% CI 0.34–0.66 and
may also eradicate organisms colonizing the cervix and vagina RR 0.34; 95% CI 0.15–0.75, respectively) compared to screening,
that are associated with adverse pregnancy outcomes. The use of with results unavailable to the managing physician [196]. Very
tetracycline is contraindicated in pregnancy. Insufficient data are few women were positive for Trichomonas, while about 21% of
available to determine the effectiveness of treatment to prevent women had either BV or Candida, or both.
recurrent bacteriuria during pregnancy. There is a need to define
the appropriate frequency of follow-up cultures and retreatment Risk: GBS vaginal-cervical colonization
strategies [187]. See Chap. 18 in Maternal-Fetal Evidence Based Intervention: Antibiotics
Guidelines. GBS colonization of the cervicovaginal tract is common in preg-
nancy (10%–20%), and has been associated with a slight (OR
Risk: Bacterial vaginosis 1.5–3, usually) increased risk of PTB. Antibiotic therapy with
Intervention: Antibiotics erythromycin does not prevent PTB in women with GBS coloni-
BV is a massive overgrowth of organisms such as anaerobes, zation or affect stillbirths. Subanalysis by heavy colonization did
Gardnerella, Mycoplasma, and others in the vagina. Most of not change the results [197].
these organisms are normally present in the vagina, but are at
higher concentrations in BV, while predominant normal flora Risk: Ureaplasma vaginal-cervical colonization
such as lactobacilli is decreased. Intervention: Antibiotics
The diagnosis of BV is usually made clinically with at least three Ureaplasma urealyticum and/or Mycoplasma hominis coloniza-
out of four of these (Amsel) criteria: pH >4.5 (most important), clue tion of the cervicovaginal tract is common in pregnancy and has
cells, thin homogenous discharge, and “amine” test, while in many been associated with a possible increased risk of PTB. There is
studies Nugent criteria (≥7 on Gram stain) are used for diagnosis. insufficient evidence to show whether giving antibiotics to
All these screening tests are not very accurate in predicting PTB women with Ureaplasma in the vagina prevents PTB. The
(PPV 6%–49% depending on PTB prevalence and patient popula- only trial did not report data on PTB [198]. Compared to placebo,
tion) in both asymptomatic and symptomatic women. erythromycin is associated with a nonsignificant 30% decrease
Antibiotic therapy is effective at decreasing the presence in the incidence of LBW <2500 g (RR 0.70, 95% CI 0.46–1.07).
of BV during pregnancy. In nonselected women, antibiotic Although some studies appeared to meet the inclusion criteria
treatment is not effective in reducing the incidence of PTB for this review, in most studies Ureaplasma was not an essen-
<37 weeks, PTB <34 weeks, PTB <32 weeks, or PPROM [190]. tial entry criterion or studies reported just a post hoc subgroup
However, treatment before 20 weeks may reduce the risk of PTB analysis of Ureaplasma.
<37 weeks (OR 0.72, 95% CI 0.55–0.95). There is insufficient information at this time to evaluate
In women with a previous PTB, treatment did not affect the other interventions such as pessary. These therefore cannot
risk of subsequent PTB <37 weeks, with a 17%–25% nonsignifi- be recommended for clinical use, unless in a research trial.
cant trend for benefit [166, 167]. It may decrease the risk of PPROM Multiple gestations
and LBW. Subgroup analysis of treatment with metronidazole or See Chap. 46 in Maternal-Fetal Evidence Based Guidelines.
clindamycin does not alter the incidence of PTB <37 weeks [191].
Bed rest
Risk: Trichomonas vaginalis In uncomplicated twin pregnancies, prophylactic bed rest in the
Intervention: Antibiotics hospital does not reduce PTB, perinatal mortality, LBW, and
Antibiotics (metronidazole was the only one tested) do not pre- other complications of pregnancy [199]. In fact, the incidence of
vent PTB in women with asymptomatic T. vaginalis (TV) infec- PTB <34 weeks is significantly increased by 84% [200–204].
tion [191–195]. In fact, metronidazole as studied (two 2-g doses In twin pregnancies with cervical dilatation, bed rest in the
48 hours apart—possibly an excessive dose) is associated with a hospital does not decrease PTB in women in Zimbabwe [205].
78% higher incidence of PTB <37 weeks [194] and similar inci- In the trial in which it was recorded, only 6% of women appre-
dences of PTB <32 weeks and perinatal mortality [105]. Even in ciated in-hospital bed rest. For complications, see the section
women with a prior PTB, metronidazole is associated with an “Intervention: Bed Rest” (for singleton pregnancies).
84% higher risk of PTB [191]. Metronidazole does eradicate TV
in >90% of pregnant women. Therefore, at least for the purpose Reduction
of decreasing PTB, asymptomatic women should not be screened There is no trial to assess the effect of multifetal reduction to pre-
for TV and treated with metronidazole at doses studied so far if vent PTB. Compared to triplets/higher-order multiples, triplets/
higher-order multiples reduced to twins have a higher incidence meta-analysis found that vaginal progesterone was not beneficial in
of loss <24 weeks, but lower incidences of PTB <32 weeks and preventing PTB at <34 weeks in 58 twin pregnancies (with >95% of
better neonatal outcome of the remaining twins after reduction mothers with no prior spontaneous PTB) with a TVU CL ≤25 mm
in case-control studies. See Chap. 44 in Maternal-Fetal Evidence before 24 weeks, but was associated with a significant 43% decrease
Based Guidelines. in adverse perinatal outcome [213]. A Cochrane review on antena-
tal progesterone treatment in multiple gestations concluded that
Cervical length screening administration of progesterone (IM or vaginal) does not appear to
Routine second-trimester TVU assessment of CL in twin gesta- be associated with a reduction in the risk of PTB or improved neo-
tion is not associated with improved outcomes when incorporated natal outcomes. Further well designed meta-analyses and random-
into the standard management of otherwise low-risk twin preg- ized trials are needed [223]. In summary, vaginal progesterone in
nancies in an RCT [206]. See later for information on progester- multiple gestations with a short cervix ≤25 mm is associated
one, cerclage, and pessary as interventions for short CL in twins. with prevention of PTB and neonatal benefits.
Women with twins with prior SPTB can be offered progester-
17P one, e.g. vaginal progesterone 200mg daily starting at 16 weeks,
17P is not associated with prevention of PTB or neonatal until 36 weeks, but the evidence for this intervention is limited.
adverse outcomes in more than six RCTs including twins [207– There is insufficient evidence to assess the effect of vaginal pro-
212]. A meta-analysis revealed no benefit of 17P in unselected gesterone on unselected triplet gestations [218].
twin pregnancies [213]. In summary, the evidence is insufficient to recommend the
In twins with short CL, there was no effect of 17P on PTB use of any type of progesterone for the prevention of PTB
rates, but numbers are limited [210, 214]. A meta-analysis showed in unselected multiple gestations. Vaginal progesterone in
that 17-alpha-hydroxy progesterone caproate is not beneficial in women with both multiple gestations and short CL is associ-
reducing PTB or adverse perinatal outcomes in 175 twin preg- ated with PTB prevention and neonatal benefits. Therefore,
nancies (with >90% of mothers with no prior spontaneous PTB) TVU CL at around 20 weeks can be reconsidered as routine in
with a TVU CL ≤25 mm before 24 weeks. multiple gestations.
In women with twins and prior PTB, 17P did not affect inci-
dence of PTB [211]. Cerclage
In triplet gestations, 17P is not associated with an effect on the HIC does not prevent PTB in unselected twin gestations in one
incidence of PTB [215, 216]. small RCT [224].
There is insufficient evidence to assess the efficacy of UIC in
Vaginal progesterone twin pregnancies with a short TVU CL. UIC does not prevent
Vaginal progesterone 90 mg daily starting at 24 weeks for PTB in a meta-analysis of the 49 twin gestations and TVU CL <25
10 weeks, in 500 women with unselected twin gestation, was mm included in the three RCTs published so far [74]. An individual
not associated with significant effects in incidences of PTB or patient-level data meta-analysis of three RCTs showed no benefit
perinatal morbidity and mortality [217]. Other RCTs also showed of cerclage compared to no cerclage in preventing PTB <34 weeks
no effect of vaginal progesterone in unselected twins [218, 219]. [225]. For multiple gestations, there is no evidence that cerclage is an
A recent double-blinded, placebo-controlled RCT on nonselected effective intervention for preventing PTBs and reducing perinatal
twin pregnancies with no prior PTB investigated the use of daily deaths or neonatal morbidity [226]. A recent retrospective cohort
vaginal progesterone or placebo from 18–21 weeks to 34 weeks study of asymptomatic twin gestation with short cervix (TVU CL
for prevention of PTB <34 weeks [220]. There was no difference ≤25 mm) between 16 and 24 weeks showed UIC was not associ-
in mean GA at delivery, the rate of SPTB <34 weeks (18.5% in ated with perinatal outcomes compared to controls. However, in a
the progesterone group and 14.6% in the placebo group, OR 1.32, planned subgroup analysis of asymptomatic twin pregnancies
95% CI 0.24–2.37), and no reduction of neonatal morbidity and with TVU CL ≤15 mm before 24 weeks, UIC was associated
mortality. Another RCT evaluated two different doses of vaginal with a significant prolongation of pregnancy by almost 4 more
progesterone (200 mg vs. 400 mg daily) to placebo in dichorionic weeks, significantly decreased SPTB <34 weeks by 49%, and
multiple gestations and showed no difference in the rate of PTB admission to NICU by 58% compared with controls [227]. Given
<37 weeks in the three groups [221]. A meta-analysis revealed the available evidence, with lack of large RCT data, UIC cannot
no benefit from vaginal progesterone in unselected twins [213]. yet be recommended for twin gestations with a short TVU CL,
In summary, vaginal progesterone should not be given to and further research is warranted.
unselected twin pregnancies for prevention of PTB. Regarding the effectiveness of PEIC in twins, a recent multi-
A systematic review and metanalysis including twins with short center, open-label RCT of diamniotic twins with asymptomatic
mid-trimester CL ≤25 mm showed that vaginal progesterone, cervical dilation before 24 weeks of gestation showed a signifi-
compared with placebo or no treatment, was associated with a sta- cant decrease in PTB <34 weeks (RR 0.71; 95% CI 0.52–0.96)
tistically significant reduction in the risk of preterm birth <33 with a combination of PEIC, indomethacin, and antibiotics [228].
weeks’ gestation (31.4% vs. 43.1%; RR, 0.69 95% CI, 0.51–0.93; The mean GA at delivery of cerclage vs. the “no cerclage” group
moderate-quality evidence). Vaginal progesterone administration was 29.05 ± 1.7 vs. 22.5 ± 3.9 weeks (p <0.01), respectively; the
was associated with a significant decrease in the risk of PTB <35, mean interval from diagnosis of cervical dilation to delivery was
<34, <32, and <30 weeks’ gestation (RRs ranging from 0.47 to 8.3 ± 5.8 vs. 2.9 ± 3.0 weeks (p = 0.02), respectively. PEIC in twins
0.83), neonatal death (RR 0.53 95% CI 0.35–0.81), RDS (RR 0.70 with a dilated cervix before 24 weeks should be recommended.
95% CI 0.56–0.89), composite neonatal morbidity and mortal-
ity (RR, 0.61 95% CI 0.34–0.98), use of mechanical ventilation Pessary
(RR 0.54 95% CI 0.36–0.81), and birth weight <1500 g (RR, 0.53 In unselected twin gestations, the largest RCT found no benefit
95% CI 0.35–0.80; all moderate-quality evidence) [222]. Another of pessary use [229]. In summary, there is sufficient evidence
to recommend against pessary use for prevention of PTB in 2016. pii: S0002-9378(16)00006-5. doi: 10.1016/j.ajog.2016.01.004. [Epub
unselected twins. ahead of print] [II-2].
13. Simhan HN, Berghella V, Iams JD. Preterm labor and birth. In Creasy and
There is contradictory evidence regarding the efficacy of a Resnik’s Maternal-Fetal Medicine: Principles. 8th ed (2019). ch 41. Elsevier,
pessary to prevent PTB in women with twin gestations and a Philadelphia, PA. [Review]
short TVU CL in the second trimester. All studies so far used 14. Simhan HN, Iams JD, Romero R. Preterm birth. In Obstetrics: Normal and
the Arabin pessary. One RCT on twins with TVU CL ≤25 mm Problem Pregnancies. Chapter 28, 627–658.e12. Elsevier, Philadelphia, PA.
[Review]
revealed that SPTB <34 weeks was significantly less frequent
15. Platt MJ. Outcomes in preterm birth. Public Health. 2014;128:399–403.
in the pessary group than in the expectant management group [Review]
(11/68 [16.2%] vs. 26/66 [39.4%]; RR 0.41; 95% CI 0.22–0.76) [230]. 16. Drassinower D, Obican SG, Siddiq Z, et al. Does the clinical presentation of
A secondary analysis of an RCT suggests pessary use is associated a prior preterm birth predict risk in a subsequent pregnancy? Am J Obstet
with a decreased rate of PTB <28 weeks and <32 weeks (but not Gynecol. 2015;213:686.e1–7. [II-2]
17. Davey MA, Watson L, Rayner JA, et al. Risk-scoring systems for predict-
<37 weeks) in twin pregnancies with TVU CL <38 mm before 23
ing preterm birth with the aim of reducing associated adverse outcomes.
weeks GA [231]. In the largest RCT so far, pessary use on twins Cochrane Database Syst Rev. 2015;(10): CD004902. [Review]
with TVU CL ≤25 mm was not associated with prevention of PTB 18. Urquhart C, Currell R, Harlow F, et al. Home uterine monitoring for detect-
≤34 weeks (33/106 [31%] vs. 28/108 [26%]; RR 1.20; 95% CI 0.78– ing preterm labour. Cochrane Database Syst Rev. 2015;(1): CD006172. (15
1.83) or other PTB or neonatal outcomes [229]. A multicenter randomized trials, n = 6008)
19. Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm
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222. Romero R, Conde-Agudelo A, El-Refaie W, et al. Vaginal progesterone twins (PoPPT): A randomized controlled trial. Ultrasound Obstet Gynecol.
decreases preterm birth and neonatal morbidity and mortality in women 2017;49(5):567–572. [RCT, n = 46]
with a twin gestation and a short cervix: An updated meta-analysis of
19
PRETERM LABOR
Rebecca Horgan
Key points with a significant decrease in the incidence of cerebral

palsy.
• See Chap. 18 for primary and secondary prevention of pre- • Other interventions studied to prevent PTB in women with
term birth (PTB) in asymptomatic women and for risk fac- PTL and intact membranes, including bed rest, hydration,
tors and complications. sedation, and antibiotics, have not been shown to be benefi-
• The diagnosis of preterm labor (PTL) is based on the cial in the management of PTL.
clinical criteria of regular uterine contractions (≥4 per • No tocolytic agent has been shown to improve perinatal
20 minutes or ≥8 per hour) at 20–366/7 weeks with either: mortality.
• Manually detected cervical dilatation of ≥ 3 cm • Tocolytics should not be used without concomitant use of
• Transvaginal ultrasound (TVU) cervical length corticosteroids for fetal maturity.
(CL) <20 mm • No tocolytic agent has been shown to be superior in terms
• Positive fetal fibronectin (FFN) and TVU CL of safety and effectiveness. Cyclooxygenase (COX) inhibi-
20–29 mm tors are the only class of primary tocolytics shown to
• Threatened PTL (regular uterine contractions (≥4 per decrease PTB <37 weeks compared with placebo. COX
20 minutes or ≥8 per hour) at 20–366/7 weeks) should be inhibitors and oxytocin receptor antagonists (ORAs)
assessed and managed with knowledge of TVU CL; and of have been shown to significantly prolong pregnancy by
FFN results if TVU CL 20–29 mm (Figure 19.1). 48 hours and by 7 days compared with placebo. COX
• Women with threatened PTL but TVU CL ≥30 mm have a inhibitors, calcium channel blockers (CCBs), and ORAs
≤2% chance of delivering within 1 week and a >95% chance have significantly fewer side effects than betamimetics.
of delivering ≥35 weeks without therapy and should there- CCBs and COX inhibitors are the tocolytic agents best
fore not receive any treatment. supported by evidence for safety and effectiveness.
• Corticosteroids (e.g. betamethasone 12 mg IM every • In general, maintenance tocolysis has not been proven to
24 hours × 2 doses) given to pregnant women at high risk prevent PTB or reduce perinatal morbidity/mortality,
for PTB (either spontaneous or indicated) between 23 and and therefore maintenance tocolysis should not be used.
336/7 weeks are effective in preventing respiratory dis- • There is insufficient evidence to evaluate multiple tocolytic
tress syndrome (RDS), intraventricular hemorrhage agents for primary tocolysis, refractory (primary agent is
(IVH), necrotizing enterocolitis (NEC), and neonatal failing, so another is started) tocolysis, or repeated (after
mortality and should therefore be recommended. They successful primary tocolysis) tocolysis.
can also be considered for pregnant women at high risk for • In preterm neonates, delayed cord clamping for 30–60
PTB between 220/7 and 226/7 weeks. (maximum 120) seconds is associated with fewer transfu-
• Corticosteroids (e.g. betamethasone 12 mg IM every sions for anemia, better circulatory stability, less intra-
24 hours × 2 doses) given to pregnant women at high risk ventricular hemorrhage, and lower risk of necrotizing
for birth (either spontaneous or indicated) between 340/7 and enterocolitis compared to early clamping at <30 seconds.
366/7 weeks decrease neonatal respiratory morbidity and can
be considered. However, delivery should not be delayed. Diagnosis
• A single rescue course of antenatal corticosteroids should
only be considered if more than 2 weeks have elapsed since Preterm labor (PTL) was often defined in the past as regular
the initial course of corticosteroids and a new episode of PTL uterine contractions (≥4 per 20 minutes or ≥8 per hour) with
or preterm prelabor rupture of membranes (PPROM) or either manually detected cervical change, or cervical effacement
impending risk of PTB presents again at <34 weeks. A single ≥80%, or cervical dilatation ≥3 cm at 20–366/7 weeks [1]. A more
rescue course of betamethasone, two 12-mg doses 24 hours evidence-based definition using current diagnostic technology
apart, received before 33 weeks at least 14 or more days after is regular uterine contractions (≥4 per 20 minutes or ≥8 per
the first course, which was administered before 30 weeks, is hour) with transvaginal ultrasound (TVU) cervical length
associated with decreased RDS, ventilatory support, surfac- (CL) <20 mm, or positive fetal fibronectin (FFN) and TVU CL
tant use, and composite neonatal morbidity. A repeat course 20–29 mm at 20–366/7 weeks. Threatened PTL can be defined as
of antenatal corticosteroids given prior to 34 weeks to women regular uterine contractions (≥4 per 20 minutes or ≥8 per hour)
at risk of PTB is associated with reduced likelihood of the neo- between 20 and 366/7 weeks, before cervical dilatation and TVU
nate requiring respiratory support. More than two courses of CL have been assessed.
corticosteroids for fetal maturity should be avoided.
• Intravenous magnesium sulfate (loading dose of Symptoms
4–6 g infused for 20–30 minutes, followed by a mainte-
nance infusion of 1–2 g/hour) given at 24–316/7 weeks Symptoms of PTL are often nonspecific and include menstrual-
immediately (within 12 hours) before PTB is associated like cramps, abdominal “tightenings,” mild irregular contractions,
232 DOI: 10.1201/9781003102342-19

Preterm Labor 233
Pregnant patient with SIUP between o SSE to r/o SROM if +, then Rx per PPROM protocol,
23 0/7 and 33 6/7 weeks c/o PTL including latency Abx
(contractions >6/hr, abdominal o Consider obtaining FFN, GBS, GC/Chl & Urine Cxs
pain/pressure, vaginal bleeding) o Continuous EFM/Tocometer
≥ 3 cm dilated or cervical change < 3 cm dilated or no cervical change
o Hospital admission
o Corticosteroids for fetal maturity Perform TVU CL & obtain FFN
o GBS prophylaxis
o Consult NICU and MFM
o Establish fetal presentation, EFW, AFI, placental location CL < 20 mm CL 20–29 mm CL ≥ 30 mm
o Order labs as appropriate
o Consider amniocentesis to rule out infection
FFN pos FFN neg

Tocolysis
If ctx persist,
consider prolonged
GA 23–31 6/7 weeks GA 32–33 6/7 weeks observation &
possibly repeat
or TVU CL
o Indocin 50–100 mg load, then o Nifedipine 20 mg po. Can

25–50 mg q 6 hrs to achieve repeat q 20 mins for 2
48 hours of steroids. additional doses if ctx persist. Persistent ctx Discharge
o Consider magnesium sulfate Continue with 10–20 mg po q w/o cervical home with
for fetal neuroprotection if 4–6 hrs to achieve 48 hours of Persistent change dx:
ctx w/ manage at preterm ctx
delivery is considered steroids. Hold for BP < 90/50.
cervical physician's
imminent (see protocol).
change discretion
FIGURE 19.1 Suggested algorithm for the management of PTL. Abbreviations. PTL, preterm labor; SLIUP, single live intrauterine
pregnancy; R/O, rule out; CTX, contractions; SSE, sterile speculum exam; SROM, spontaneous rupture of membranes; Rx, treat;
PPROM, preterm prelabor rupture of membranes; FFN, fetal fibronectin; Amnio, amniocentesis; GBS, group B streptococcus; GC,
gonorrhea; Chl, chlamydia; EFM, external fetal monitoring; TVU CL, transvaginal ultrasound cervical length; dx, diagnosis; NICU,
neonatal intensive care unit; MFM, maternal-fetal medicine specialist; EFW, estimated fetal weight; GA, gestational age; AFV, amni-
otic fluid volume; IVF, intravenous fluids; BP, blood pressure.
low backache, pelvic pressure, increased vaginal discharge, spot-

ting, or bleeding.
For epidemiology/incidence, genetics, etiology/basic patho-
physiology, classification, risk factors/associations, and com-
plications, see Chap. 18. TABLE 19.1: Estimated Incidences of Intraamniotic Infection
in Women in Different Clinical Scenarios
Condition Percent
Workup (Figure 19.1)
GA <37 weeks
• History: Ensure correctness of gestational age (GA) esti- Asymptomatic second trimester 0.5
mation; evaluate signs and symptoms of PTL, and all risk PTL (intact membranes) 13
factors for preterm birth (PTB) (Table 19.1). PPROM, no labor 25
• Physical exam: Maternal vital signs; frequency, intensity,
PPROM, labor 39
and duration of uterine contractions; fetal heart rate pat-
Cervix ≥2 cm/80% in second trimester 50
tern; assess uterine tenderness, firmness, fetal position.
GA ≥37 weeks
Perform speculum exam:
• Estimate cervical dilatation [2] Labor 19
• Assess presence/amount of uterine bleeding PROM 34
• Assess for preterm prelabor rupture of membranes Abbreviations: GA, gestational age; PPROM, preterm prelabor rupture of mem-
(PPROM) (nitrazine, pooling, ferning) branes; PTL, preterm labor.
• Obtain swab for FFN testing in which TVU CL was the main screening test, with FFN used
• If no PPROM, perform digital cervical exam only for “indeterminate” results (Figure 19.1) [10]. Recent evi-
• If cervix <3 cm dilated, send FFN swab and perform dence suggests that placental alpha-microglobulin-1 (PAMG-1)
TVU CL may be more effective at predicting PTB in symptomatic women
• If cervix ≥3 cm dilated, discard FFN swab and manage with a short CL than FFN, but further evidence is necessary
PTL before guidance can be provided [11].
• Laboratory tests: Rectovaginal group B streptococcus (GBS)
culture; gonorrhea and chlamydia; urinalysis and urine cul- Management
ture (Figure 19.1); FFN in women <34 weeks gestation with
cervical dilation <3 cm and TVU CL 20–29 mm. Principles of management
Before treatment is considered, the diagnosis and risk of PTB
TVU CL must be established. Women with preterm uterine contractions
but negative FFN and TVU CL ≥30 mm have a <2% chance of
Symptomatic women with CL ≥30 mm have a low risk (<5%) of delivering within 1 week and a >95% chance of delivering ≥35
delivering preterm, regardless of FFN result. For women with weeks without therapy, and should therefore not receive any
CL 20–29 mm, the PTB rate is somewhat increased but still <5% treatment (Figure 19.1) [4].
within 7 days if the FFN test is negative. A CL <20 mm is asso- Women with preterm uterine contractions and cervical dil-
ciated with a high risk (>25%) of PTB within 7 days. With this atation ≥3 cm, TVU CL <20 mm, or TVU CL 20–29 mm and
degree of cervical shortening, FFN testing does not improve the positive FFN, have a moderate to high risk of PTB within 7
predictive accuracy of CL measurement alone [3, 4]. days and are those with true PTL and should be managed with
Compared to no knowledge, knowledge of TVU CL results strong consideration for admission, steroids, magnesium for neu-
is associated with a statistically significant decrease in PTB roprophylaxis, and possibly tocolysis, depending on GA.
<37 weeks (22.1% versus 34.5%; relative risk [RR], 0.64, 95% If PTL is diagnosed without using TVU CL, about 70%–80%
confidence interval [CI], 0.44–0.94). Delivery occurred at a later of women diagnosed with the condition deliver at term. Women
GA (by about 4–5 days) in the knowledge versus no-knowledge without cervical change do not have PTL and should not receive
groups [5, 6]. Given the clinical and cost-effectiveness of TVU tocolysis. Women with multiple gestations should not be treated
CL in the assessment of suspected PTL, TVU CL should be differently than those with singletons, except that their risk of
used in the management of women with threatened PTL pulmonary edema is greater when exposed to betamimetics or
(Figure 19.1). magnesium sulfate [12].
Referral to a tertiary care center should be considered if the
Fetal fibronectin neonatal ICU is not adequate for the GA of the potential neo-
FFN testing has been shown to predict PTB with moderate accu- nate. There is insufficient evidence to justify the use of steroids for
racy in symptomatic women resulting in health care cost benefits fetal maturity and tocolysis before 23 weeks. Amniocentesis may
by identifying women who do not require intervention [7]. In a be considered to assess intraamniotic infection (IAI) (incidence
meta-analysis of six randomized controlled trials (RCTs), com- about 5%–15%) and fetal lung maturity (especially between 33
pared to no knowledge, knowledge of FFN results in women and 35 weeks). IAI (documented by amniotic fluid culture) rates
with threatened PTL is not associated with effects on the inci- can be estimated by pregnancy status (Table 19.1). IAI rates can
dence of PTB <37 weeks or any other outcome, maternal or also be estimated by TVU CL [13].
neonatal, including time in triage; PTB <34, 32, or 28 weeks; GA Counseling regarding morbidity and mortality for preterm
at delivery; birth weight less than 2500 g; perinatal death; mater- infant, using recent and ideally national or institutional data,
nal hospitalization; tocolysis; or steroids for fetal lung maturity should be provided (Table 19.2) [14]. Neonatal consult at 22–34
[8, 9]. The benefit in knowledge of FFN was seen only in one RCT, weeks is indicated for counseling regarding prognosis and
TABLE 19.2: General Guidance Regarding Obstetric Interventions for Periviable Birtha
20 0 –216 weeks 220 –226 weeks 230 –236 weeks 240 –246 weeks
Neonatal assessment for resuscitation Not recommended Consider Consider Recommended
Antenatal steroids Not recommended Consider Consider Recommended
Tocolytics to allow steroids Not recommended Not recommendedb Consider Recommended
Magnesium sulfate for neuroprotection Not recommended Not recommendedb Recommended Recommended
Antibiotics for PPROM to prolong latency Consider Consider Consider Recommended
Antibiotics for GBS prophylaxis Not recommended Not recommendedb Consider Recommended
Continuous intrapartum electronic fetal monitoring Not recommended Not recommendedb Consider Recommended
a Survival of infants born in the periviable period is dependent on resuscitation and support. Several factors (e.g. intrauterine growth restriction, small fetal size, the presence
of fetal malformations or aneuploidy, and pulmonary hypoplasia due to prolonged membrane rupture) can impact the potential for survival and the determination of viabil-
ity. Personal and family values should be extensively discussed, allowing individual decisions. See text.
b Limited data for efficacy at this early gestation, but gestational age when interventions start to be offered continues to be moved earlier in pregnancy, with 22 weeks becom-
ing currently the lower limit when interventions are beginning to possibly be considered.
# For example, persistently abnormal fetal heart rate patterns or biophysical testing (category II–III), malpresentation.
Abbreviation: GBS, group B streptococcus; PPROM, preterm prelabor rupture of membranes.
Preterm Labor 235
neonatal management. Current neonatal survival in the United Recent evidence has demonstrated that steroids are associ-
States is 0% at 21 weeks, 5%–15% at 22 weeks, 15%–40% at 23 ated with neonatal benefits also at ≥34 weeks, as three RCTs
weeks, 60%–75% at 24–25 weeks, 75%–95% at 26–28 weeks, have been done on steroids 34–366/7 weeks in women at risk of
and >95% at 29–30 weeks, whereas intact survival at 18 months PTB and two RCTs in women at ≥37 weeks [22]. Women who
is about 50% after 25 weeks [15]. Disabilities in mental and psy- received antenatal corticosteroids ≥34 weeks had a significantly
chomotor development, neuromotor function (including cerebral lower incidence of RDS (RR 0.76, 95% CI 0.62–0.93), mild RDS
palsy), or sensory and communication function are present in at (RR 0.40, 95% CI 0.23–0.69), moderate RDS (RR 0.39, 95% CI
least 50% of fetuses born ≤25 weeks’ gestation [16]. 0.18–0.89), transient tachypnea of the newborn (RR 0.62, 95%
Pregnancies at risk for periviable PTB are particularly chal- CI 0.50–0.77), severe RDS (RR 0.66, 95% CI 0.53–0.82), use of
lenging to counsel and manage. The periviability period varies surfactant (RR 0.61, 95% CI 0.38–0.99), mechanical ventilation
according to several factors, including by level of care provided (RR 0.62, 95% CI 0.41–0.94), significantly lower time on oxygen
in the hospital and the country where the care is being provided. (mean difference [MD] –2.06 hours, 95% CI –2.17 to –1.95), lower
In many developed countries, this period, in 2015, was between maximum inspired oxygen concentration (MD –0.66%, 95% CI
22 and 24 weeks. Table 19.2 provides some guidance for care, but –0.69 to –0.63), lower length of stay in the NICU (MD –7.64 days,
should be adjusted according to local capabilities [16]. Patients 95% CI –7.65 to –7.64), and higher Apgar score at 1 and 5 minutes
with an intrauterine demise or undergoing pregnancy termina- (MD 0.06, 95% CI 0.05–0.07) compared to those who did not.
tion are not to be included in this group. For patients in whom the Administration of steroids to women >34 weeks at risk of PTB
GA has not been clearly established, plans for intervention and who have not previously received antenatal corticosteroids is
information provided to the patient should be based on the best now recommended to decrease respiratory morbidity, except
estimate of GA. Several algorithms have been developed to pro- in the presence of clinical chorioamnionitis [23]. However,
vide patient-specific mortality and morbidity information [17], as tocolysis should not be attempted in the late preterm period to
well as an online calculator [18]. Status can be reevaluated with delay delivery in order to administer steroids [23]. Limited evi-
each additional gestational week. dence also suggests late preterm steroids are cost-effective [24].
Type of steroid: There is no clear evidence of superior-
Prophylaxis to prevent neonatal morbidity/ ity between betamethasone and dexamethasone. Based on a
Mortality from PTB (fetal maturation) recent Cochrane review, dexamethasone was associated with a
Corticosteroids reduced risk of IVH compared to betamethasone (RR 0.44, 95%
Betamethasone, dexamethasone (only two corticosteroids that CI 0.21–0.92) [25]. There were no statistically significant differ-
cross the placenta reliably). ences in other perinatal outcomes, including perinatal death,
Dose: One course: Betamethasone 12 mg SQ q24h × 2 doses or RDS, and NICU admissions, however. In one study, infants
dexamethasone 6 mg SQ q12h × 4 doses. exposed to dexamethasone had a significantly shorter stay in the
Mechanism of action: Enhanced maturational changes in NICU. Results for biophysical parameters were inconsistent, but
lung architecture and induction of lung enzymes resulting in bio- no important differences were seen for these or other secondary
chemical maturation. outcomes. Indirect comparisons of betamethasone and dexa-
Evidence for effectiveness: Corticosteroids given prior to methasone suggested that betamethasone is more effective in
PTB (either spontaneous or indicated) are effective in prevent- reducing RDS risk than dexamethasone, while chorioamnionitis
ing respiratory distress syndrome (RDS), intraventricular hem- and puerperal sepsis were more likely with dexamethasone [25].
orrhage (IVH), necrotizing enterocolitis (NEC) and neonatal Oral dexamethasone significantly increased the incidence of
mortality [19]. Antenatal administration of 24 mg of betametha- neonatal sepsis (RR 8.48, 95% CI 1.11–64.93) compared to intra-
sone (12 mg intramuscularly q24h), or of 24 mg of dexametha- muscular dexamethasone in one trial of 183 newborns [25].
sone (6 mg intramuscularly q12h), to women expected to give Betamethasone administered at 12-hourly compared to
birth preterm is associated with a significant 28% reduction in 24-hourly intervals has been associated with reduced maternal
neonatal mortality, 34% reduction in RDS and respiratory length of stay, but no other differences in maternal or neonatal
support, 45% reduction in IVH, 50% reduction in NEC, 32% outcomes [25].
reduction in requirement for mechanical ventilation, and 40% In an international cluster-randomized trial designed to
reduction in systemic infections in the first 48 hours of life in increase the use of antenatal corticosteroid therapy in low-
preterm infants. There are also decreased needs for surfactant, oxy- resource settings involving almost 100,000 pregnant women,
gen, and mechanical ventilation in the neonatal period. Treatment identification of women at risk for PTB and increased use of
with antenatal corticosteroids does not increase risk to the mother antenatal corticosteroids increased overall newborn mortality by
of death, chorioamnionitis, or puerperal sepsis [19]. 12% (RR 1.2, 95% CI 1.01–1.22), perinatal mortality by 11% (RR
These benefits apply to gestational ages of at least 23–336/7 1.11, 95% CI 1.04–1.19), and suspected maternal infection rate
weeks and are not limited by gender or race. There are insuffi- by 45% (odds ration [OR] 1.45, 95% CI 1.33–1.58) [26]. Possible
cient data to assess effectiveness before these GAs. However, if explanations for these unexpected findings in low-resource set-
neonatal resuscitation is to be attempted, corticosteroids can tings include unreliable dating criteria to establish GA, the reli-
be considered from 22 weeks’ gestation [20]. At 22–25 weeks, ance on birth weight rather than estimated GA to define PTB
cohort studies have shown benefit in decreasing neonatal death and evaluate other important outcomes, and the coding of sus-
[21]. The effects are optimal at 48 hours to 7 days from the first pected maternal infection by treatment rather than by diagnosis.
dose [21], but treatment should not be withheld even if delivery Inconsistent access and limited resources to provide optimal neo-
appears imminent. Antenatal corticosteroids should be admin- natal intensive care and potential targeting of term, low-birth-
istered when PTB is considered imminent within 7 days, the GA weight infants for antepartum corticosteroid treatment may have
estimate is accurate, adequate neonatal care is available, and also contributed to these results. As reaffirmed by the World
there is no clinical evidence of maternal infection. Health Organization, the study’s findings should not alter current
recommendations regarding the use of antenatal corticosteroids Phenobarbital

to improve newborn outcomes [27]. The use of prophylactic maternal phenobarbital administra-
Weekly repeat courses of antenatal corticosteroids: tion prior to preterm delivery does not prevent periventricu-
Evidence for repeating antenatal corticosteroids weekly is pro- lar hemorrhage (PVH) or protect from neurologic disability in
vided by a recent Cochrane systematic review of 10 trials (4738 preterm infants [33]. Prenatal maternal phenobarbital is associ-
women/5700 babies) [28]. Administration of repeat dose(s) to ated with a significant 35% reduction in the rates of all grades of
women who remained at risk for PTB 7 or more days after the PVH and a 59% reduction in severe grades PVH (3 and 4) in the
initial dose was associated with a reduction in the risk of RDS (RR infants. The results were influenced by poor-quality trials that
0.83, 95% CI 0.75–0.91) and the risk of serious neonatal adverse excessively influenced the analysis due to their higher rates of
outcome (RR 0.84, 95% CI 0.75–0.94). In the largest international severe PVH. When only higher-quality trials were included, phe-
multicenter RCT, multiple repeat doses were associated with nobarbital was not associated with any beneficial effects, includ-
decreased birth weight, length, and head circumference at birth ing similar incidences of all grades of PVH and severe grades of
[29]. At early childhood follow-up, no statistically significant dif- PVH to placebo. No difference in the incidence of neurodevelop-
ferences were seen for infants exposed to repeat prenatal corti- mental abnormalities at childhood follow-up assessed between 18
costeroids compared with unexposed infants for the primary and 36 months of age was observed. Maternal sedation is a com-
outcomes (total deaths, survival free of any disability or major mon side effect in women receiving phenobarbital [33].
disability, disability, or serious outcome) or in the secondary out-
come growth assessments [28]. Vitamin K
Single repeat (rescue) course of antenatal corticosteroids: Vitamin K administered to women prior to very PTB has not
Given the potential short- and long-term adverse effects of mul- been shown to significantly prevent PVHs or other neurode-
tiple doses of corticosteroids combined with the optimal ben- velopmental abnormalities in preterm infants. Antenatal vita-
efit 7 days following administration, timing the first course is min K is associated with a nonsignificant reduction in all grades
extremely important. A single rescue course should only be con- of PVH (RR 0.76, 95% CI 0.54–1.06) and a significant reduction
sidered if PTB has not occurred within 14 days of the initial dose, in severe PVH (grades 3 and 4) (RR 0.58, 95% CI 0.3–0.91) [34].
current GA is <34 weeks, and subsequent clinical assessment When the two quasi-randomized trials are excluded, antenatal
demonstrates a new episode of PTL or PPROM and PTB appears vitamin K is not associated with a reduction in all grades of PVH
highly likely within 7 days [12, 30]. A repeat course of antenatal (RR 0.87, 95% CI 0.60–1.26) or severe PVH (RR 0.82, 95% CI 0.49–
corticosteroids given prior to 34 weeks to women at risk of PTB 1.36). Treatment with vitamin K results in a significant reduction
who had received their first course of antenatal corticosteroids in the Bayley Mental Development Index at 2 years of age, but
>7 days previously was associated with a reduced likelihood of these results are derived from one trial with a high lost to follow-
requiring respiratory support, with a number needed to treat of up rate. No difference is found in the incidence of other neuro-
21 patients (RR 0.91, 95% CI 0.85–0.97, n = 5791 infants) [23, 31]. developmental abnormalities at childhood follow-up at 18–24
Given the concerns regarding multiple courses of corticosteroids, months or 7 years of age between children exposed to vitamin K
more than two courses should be avoided [23]. and children not exposed [34].
Contraindications: None.
Side effects: When used for only one course, no significant side Ambroxol
effects are seen, except for transient maternal hyperglycemia Giving ambroxol to women at risk of PTB to prevent neo-
from 12 hours to about 5–7 days after the dose. This effect results natal RDS is not supported by available evidence. Prenatal
in false-positive glucose screening tests or difficulty in manag- administration of ambroxol to reduce the risk of RDS in preterm
ing diabetes. There is no significant increase in maternal or fetal/ infants has not been shown to reduce the incidence of RDS or
neonatal infection. If ≥4 courses are used, there is an associa- perinatal mortality when compared to betamethasone or pla-
tion with birth weight <10th percentile and probably with small cebo. Maternal adverse effects were similar in ambroxol- and
(<10th percentile) neonatal head circumference, with evidence of betamethasone-treated women. Since the trials included in the
later “catch-up” [28, 29]. No adverse consequences of prophylac- Cochrane systematic review were of very low to moderate quality,
tic corticosteroids for PTB in either mothers or infants, even at there is insufficient evidence to support or refute this interven-
10+ years follow-up, have been identified, but long-term follow-up tion [35].
data are limited.
Magnesium sulfate for neuroprotection
Thyrotropin-releasing hormone Antenatal magnesium sulfate therapy given to women at
Prenatal thyrotropin-releasing hormone (TRH), in addition risk of PTB significantly reduces the risk of cerebral palsy in
to corticosteroids, given to women at risk of very PTB does not their child (RR 0.68, 95% CI 0.54–0.85) [36–38]. There was also
improve infant outcomes and can cause maternal side effects a significant reduction in the rate of substantial gross motor
[32]. Overall, prenatal TRH, in addition to corticosteroids, does dysfunction (RR 0.61, 95% CI 0.44–0.85). No statistically signifi-
not reduce the risk of neonatal respiratory disease or chronic cant effect of antenatal magnesium sulfate therapy is detected
oxygen dependence and does not improve any of the fetal, neo- on pediatric mortality (RR 1.04, 95% CI 0.92–1.17) or on other
natal, or childhood outcomes. Prenatal TRH may actually have neurologic impairments or disabilities in the first few years of
adverse effects for women and their infants. Side effects (nausea, life. There are higher rates of minor maternal side effects in the
vomiting, lightheadedness, urgency, flushing) are more likely to magnesium groups, but no significant effects on major maternal
occur in women receiving TRH. Among infants, prenatal TRH complications [36].
increases by 16% the risk of needing ventilation, by 48% at having Magnesium sulfate should be administered to women with
a low Apgar score at 5 minutes, and was associated with poorer singleton or twin pregnancies 230/7–316/7 weeks for neuroprotec-
childhood outcomes at follow-up [29]. tion when PTB is imminent. Imminent PTB is defined as a high
Preterm Labor 237
likelihood of birth due to active labor with ≥4 cm cervical dil- in maternal infection with the use of prophylactic antibiotics.
atation, with or without PPROM or planned PTB for maternal Use of antibiotics in women with PTL and intact membranes is
or fetal indications. Women with an indicated PTB anticipated associated with an increased risk of functional impairment and
within 2–24 hours (e.g. for severe preeclampsia) are candidates cerebral palsy [12, 36, 45]. Given these data, antibiotics should
for magnesium sulfate. The optimal timing of magnesium sul- not be used for prevention of PTB in women with PTL and
fate to reduce the risk of cerebral palsy in preterm neonates is intact membranes. However, among preterm patients at immi-
within 12 hours of delivery [39]. nent risk of delivery with an unknown GBS status, antibiotics for
Intravenous magnesium sulfate is administered with a GBS prophylaxis is recommended, with optimal timing of antibi-
loading dose of 4–6 g infused for 20–30 minutes, followed otics 4 hours prior to delivery [46].
by a maintenance infusion of 1–2 g/hour [27]. If delivery has
not occurred after 12 hours and is no longer considered immi- Cervical pessary
nent (e.g. if the patient is not having regular uterine contrac- There are conflicting data regarding the effectiveness of a cervical
tions), the infusion should be discontinued and resumed when pessary following an episode of arrested PTL to decrease the risk of
delivery is deemed imminent again (e.g. when contractions PTB in singleton pregnancies. One RCT (n = 130) found that use of
develop). If at least 6 hours have passed since the discontinuation a cervical pessary did not reduce the risk of delivery <37 weeks or
of the magnesium sulfate, another loading dose should be given. improve perinatal outcome. However, another RCT (n = 357) found
Administration of magnesium sulfate for prevention of cerebral no decrease in PTB <34 weeks with pessary use (RR 0.78; 95% CI
palsy should not delay the delivery. 0.45–1.38) but did report a decrease in the rate of spontaneous PTB
<37 weeks (RR 0.58; 95% CI 0.3–0.90; p = 0.01), threatened PTL
Nontocolytic interventions for PTL recurrence (RR 0.23; 95% CI 0.11–0.47; p < 0.0001), and PPROM
Bed rest (RR 0.28; 95% CI 0.09–0.84; p = 0.01) [47].
Bed rest in hospital or at home in singleton gestations compli- There is one RCT (n = 132) examining the use of cervical pes-
cated by PTL or PPROM has been evaluated in one multi- sary following an episode of arrested PTL to decrease the risk of
intervention RCT [40]. Bed rest offered no benefit over no PTB in women with twin gestations. The trial found a decreased
treatment or placebo in preventing PTB. In multiple pregnan- risk of spontaneous PTB <34 weeks (RR 0.51; CI 0.27–0.97; p =
cies, bed rest in the hospital did not reduce the risk of PTB or 0.03) [48]. However, due to limited evidence, further studies are
perinatal mortality, whether uncomplicated twin pregnancy or required before recommendations regarding the effectiveness of
twin or triplet pregnancy with cervical dilatation [41]. cervical pessaries in both singleton and twin pregnancies after an
episode of arrested PTL can be made.
Hydration
There is no benefit of intravenous hydration in preventing PTB. Tocolysis
Intravenous hydration does not seem to be beneficial, even dur- Principles
ing the period of evaluation soon after admission, in women with Tocolytic therapy may provide short-term prolongation of preg-
PTL. Women with evidence of dehydration may, however, benefit nancy, allowing antenatal corticosteroid administration, magne-
from the intervention. Compared with bed rest alone, hydration sium sulfate for neuroprotection, and/or maternal transport to a
is associated with similar incidences of PTB <37 weeks, <34 tertiary care facility. However, there is no evidence that treatment
weeks, or <32 weeks and of admission to the NICU [34]. Cost of of PTL with tocolytic agents improves perinatal outcomes [27].
treatment was slightly higher (US$39) in the hydration group for Calcium channel blockers (CCBs) and cyclooxygenase (COX)
hospital costs during a visit of less than 24 hours. Women studied inhibitors are the agents best supported by evidence of safety and
were at low risk, as only 30% of women required tocolysis and effectiveness (see Table 19.3).
<30% had PTB. No studies evaluated oral hydration [42]. With regard to the use of a combination of tocolytic agents, a
recent Cochrane review concluded that the effectiveness of com-
Screen for infections bination regimens in terms of maternal and neonatal outcomes is
Several infections are associated with a higher risk of PTL and unclear due to a lack of data. The review noted that there are no
PTB. These include chlamydia, gonorrhea, syphilis, trichomo- RCTs examining combinations of commonly used tocolytics [49].
niasis, and others, as well as bacterial vaginosis (see Chap. 18).
There is insufficient evidence to assess the effect of screening Contraindications
and treating for genitourinary infections in women with PTL, as See Table 19.4.
no RCTs have been performed. However, a recent meta-analy-
sis demonstrated a 9% prevalence of chlamydia in women with Primary tocolysis: Single agent
threatened PTL, which was significantly increased in comparison Betamimetics
to controls, and further studies are necessary to assess the effec- Types: Ritodrine, terbutaline.
tiveness of screening and treating vaginal infections in PTL [43]. Dose: Ritodrine: 50–100 mg/minute IV initial dose, increase
50 mg/minute q10min (max 350 mg/min) [PO: 1–20 mg q2–4h].
Antibiotics Terbutaline: 0.25 mg SQ q20min at first, then 2–3 hours; or
There is no evidence of benefit with the use of prophylactic anti- 5–10 mg/min IV, max 80 mg/min; or 2.5–5 mg PO q2–4h (hold
biotic treatment for PTL with intact membranes on important for maternal HR >120/minute).
neonatal outcomes [44]. PTB <36 or 37 weeks was similar in anti- Mechanism of action: Stimulate B2 receptors through cyclic
biotics and placebo groups. There is a trend for a 52% increase in adenosine monophosphate (AMP), so no free calcium for myo-
neonatal mortality for those who received antibiotics (RR 1.52, metrial contraction.
95% CI 0.99–2.34), with similar overall perinatal mortality (RR Evidence for effectiveness (Table 19.5): Compared with
1.22, 95% CI 0.88–1.70) [35]. The only benefit is a 26% reduction placebo, betamimetics are associated with a decrease in the
TABLE 19.3: Principles of Tocolytic Therapy

• At 23–336/7 weeks, steroids for fetal maturation should be given if tocolysis is initiated. Tocolytics should not be used without concomitant
use of steroids for fetal maturation.
• Tocolysis is typically used for 48 hours to allow steroid effect. Given side effects, consider stopping tocolytic therapy at 48 hours after steroids
given if PTL under control.
• No tocolytic agent has been shown to improve perinatal mortality.
• There is no tocolytic agent that is more safe and efficacious. COX inhibitors are the only class of primary tocolytics shown to decrease PTB <37
weeks compared with placebo. COX inhibitors and ORAs have been shown to significantly prolong pregnancy at 48 hours and 7 days compared
with placebo. COX inhibitors, CCBs, and ORAs, properly used, have significantly fewer side effects than betamimetics. Currently, CCB and COX
inhibitors are the tocolytic agents best supported by evidence for safety and effectiveness.
• There is no maintenance tocolytic that prevents PTB or perinatal morbidity/mortality, and therefore maintenance tocolysis should in general
not be used. There is insufficient evidence to evaluate multiple tocolytic agents for primary tocolysis, refractory (primary agent is failing, so
another is started) tocolysis, or repeated (after successful primary tocolysis) tocolysis.
Abbreviations: COX, cyclooxygenase; ORA, oxytocin receptor antagonists; CCB, calcium channel blockers; PTB, preterm birth; PTL, preterm labor.
number of women in PTL giving birth within 48 hours (RR sodium excretion—sodium and therefore fluid retention).
0.68, 95% CI 0.53–0.88) and a decrease in the number of births Ritodrine: Altered thyroid function, antidiuresis.
within 7 days (RR 0.80, 95% CI 0.65–0.98) but there was no Fetal/neonatal: Ritodrine: Neonatal tachycardia, hypogly-
reduction in PTB <37 weeks [50]. No benefit is demonstrated cemia, hypocalcemia, hyperbilirubinemia, hypotension, IVH.
for betamimetics on perinatal or neonatal death or on RDS. A Terbutaline: Tachycardia, hyperinsulinemia, hyperglycemia,
few trials reported the following outcomes, with no difference myocardial and septal hypertrophy, myocardial ischemia.
detected: Cerebral palsy, infant death, and NEC. Betamimetics
are significantly associated with the following side effects (see Calcium channel blockers
later): Withdrawal from treatment due to adverse effects, chest Types: Nifedipine, nicardipine.
pain, dyspnea, tachycardia, palpitation, tremor, headaches, Dose: Nifedipine 20–30 mg × 1, then 10–20 mg q4–8h (max
hypokalemia, hyperglycemia, nausea/vomiting, nasal stuffi- 90 mg/day) (similar dosing for nicardipine).
ness, and fetal tachycardia [42]. There is insufficient evidence to Mechanism of action: Impairs calcium channels, so inhibits
assess which of the studied betamimetics is most effective and/ influx of calcium into cell and therefore myometrial contraction.
or associated with fewer side effects, with most data reported for Evidence for effectiveness (Table 19.5): Two small RCTs com-
ritodrine. For comparison with other tocolytics, RCTS are too paring CCB with placebo showed a reduction in PTB <48 hours
small and varied to make meaningful comparisons [50]. (RR 0.30, 95% CI 0.21–0.43) and an increase in maternal
Specific contraindications: Cardiac arrhythmia or other adverse effects, with insufficient evidence to assess effect on PTB
significant cardiac disease, diabetes mellitus (DM), poorly con- within 7 days and <37 weeks [44].
trolled thyroid disease (for ritodrine). When compared with other tocolytic agents (betamimetics,
Side effects: nonsteroidal antiinflammatory drugs [NSAIDs], glyceryl trini-
Maternal: Hyperglycemia (glucose 140–200 mg/dL in 20%– trate [GTN], magnesium sulfate and oxytocin receptor antago-
50%; mechanism: Decreased peripheral insulin sensitivity and nists [ORAs]), CCBs increased the interval from initiation of
increased endogenous glucose production; hyperinsulinemia; treatment to delivery, increased GA at birth, and decreased
hypokalemia (K <3 mEq/L in 50%); tremors, nervousness, short- preterm and very preterm birth. RDS, NEC, IVH, hyperbiliru-
ness of breath (10%), chest pain (5%–10%), tachycardia/palpi- binemia, and admission to the NICU were also decreased [44].
tations, arrhythmia (3%); ECG changes (2%–3%); hypotension CCB also reduced the requirement for women to have treat-
(2%–3%); pulmonary edema (<1%–5%); mechanism: Reduced ment ceased for adverse drug reaction. There are insufficient
data regarding the effects of different dosage regimens and for-
mulations of CCBs on maternal and neonatal outcomes; the most
TABLE 19.4: Contraindications to Tocolytic Therapy studied is nifedipine, at the dosage shown earlier. CCBs should
be preferred to betamimetics for tocolysis.
Maternal: Specific contraindications: Cardiac disease; hypotension
Chorioamnionitis (<90/50); concomitant use of magnesium; caution in renal disease.
Severe vaginal bleeding/abruption Side effects:
Preeclampsia Maternal: Flushing, headache, dizziness, nausea, transient
Medical contraindications to specific tocolytic agenta hypotension. Caution in women with hypotension and renal dis-
Other maternal medical condition that makes continuing the ease, as well as women on magnesium (cardiovascular collapse).
pregnancy inadvisable Fetal/Neonatal: None.
Fetal:
Death
Cyclooxygenase inhibitors
Types: Nonselective COX inhibitors: Indomethacin (Indocin).
Major (especially if lethal) fetal anomaly or chromosome abnormality
Selective COX inhibitors (preferential COX-2 inhibitor): sulin-
Other fetal conditions in which prolongation of pregnancy is inadvisable
dac, rofecoxib (Vioxx), celecoxib, nimesulide.
Documented fetal maturity
Dose: Indomethacin: 50–100 mg loading dose (rectal or vaginal
a See text. route preferred, oral otherwise), then 25–50 mg q6h for 48 hours
Preterm Labor 239
TABLE 19.5: Summary of the Evidence for Tocolytic Therapy

Tocolytics <48 Hours <7 Days <34 Weeks <37 Weeks Perinatal mortality
Primary—Single Agent versus Placebo
Betamimetics 0.68 (0.53–0.88) 0.84 (0.46–1.55) NC 0.95 (0.88–1.03) 0.90 (0.27–3.00)
[n = 1209] [n = 1332] [n = 1212] [n = 1174]
CCB 0.30 (0.21–0.43) NC NC NC NC
[n =173]
COX 0.20 (0.03–1.28) 0.41 (0.10–1.66) NC 0.21 (0.07–0.62) 0.80 (0.25–2.58)
[n = 70] [n = 70] [n = 36] [n = 106] (NND)
Mg 0.56 (0.27–1.14) NC NC 0.62 (0.46–0.83) 4.56 (1.00–20.86)
[n = 182] [n = 265] [n = 257]
ORA 1.05 (1.15–7.43) 0.74 (0.61–0.91) 1.33 (0.84–2.14) 1.17 (0.99–1.37) 2.25 (0.79–6.30)
[n = 152] [n = 302]a [n = 287]a [n = 501] [n = 566]
NOD 1.19 (0.74–1.90) NC 0.93 (0.61–1.41) NC 0.43 (0.06–2.89)
[n = 186] [n = 153] [n = 186] (NND)
Progesterone NC NC 0.62 (0.30–1.27) 0.62 (0.39–0.98) 0.31 (0.01–7.41)
[n = 62] [n = 293] [n = 83]
Comparisons
CCB vs. Betamimetics 0.86 (0.67–1.10) 0.76 (0.59–0.99) 0.78 (0.66–0.93) 0.89 (0.76–1.05) 0.80 (0.53–1.22)
[n = 1505] [n = 242] [n = 1505] [n = 389] [n = 630]
COX vs. Betamimetics 0.27 (0.08–0.96) 0.88 (0.52–1.46) NC 0.53 (0.28–0.99) 0.99 (0.27–3.57)
[n = 100] [n = 146] [n = 80] [n = 237] (NND)
COX vs. CCB 1.08 (0.59–2.01) 0.26 (0.52–1.46) 0.92 (0.70–1.21) 1.08 (0.94–1.25) 2.81 (0.82–9.62)
[n = 230] [n = 146] [n = 148] [n = 148] [n = 249] (NND)
COX vs. Mg 0.87 (0.59–1.29) NC 0.84 (0.64–1.11) 0.88 (0.52–1.47) 1.59 (0.59–4.29)
[n = 547] [n = 128] [n = 216] [n = 570]
Mg vs. Betamimetics 1.09 (0.72–1.65) NC NC 1.03 (0.77–1.39) 0.49 (0.05–5.12)
[n = 503] [n = 473] [n = 263]
Mg vs. CCB 1.19 (0.86–1.65) NC 0.89 (0.55–1.45) 1.06 (0.87–1.29) 0.27 (0.03–2.29)
[n = 588] [n = 88] [n = 362] [n = 292]
Mg vs. COX 1.08 (0.91–1.27) NC NC NC 0.98 (0.06–15.35)
[n = 318] [n = 117]
ORA vs. Betamimetics 0.89 (0.66–1.22) 0.91 (0.69–1.20) NC NC 0.55 (0.21–1.48)
[n = 1389] [n = 731] [n = 816]
ORA vs. CCB 1.06 (0.92–1.22) 1.04 (CI 0.89–1.21) NC NC NC
[n = 790] [n = 890]
NOD vs. Betamimetics 0.96 (0.87–1.05) 1.03 (0.92–1.15) 0.71(0.36–1.42) 0.73 (0.50–1.05) 2.06 (0.19–22.38)
[n = 420] [n = 679] [n = 365] [n = 679] [n = 191]
NOD vs. CCB 0.97 (0.77–1.21) NC NC NC NC
[n = 50]
Maintenance Therapy after Treatment of PTL (versus Placebo or No Treatment)
Betamimetics NC NC 2.41 (0.86–6.74) 1.11 (0.91–1.35) 2.96 (0.72–12.14)
[n = 681] [n = 644] [n = 467]
CCB 0.46 (0.07–3.00) NC 1.07 (0.88–1.30) 0.97 (0.87–1.09) 1.36 (0.35–5.33),
[n = 128] [n = 540] [n = 681] [n = 787]
COX NC NC NC NC NC
Mg NC NC NC 1.05 (0.80–1.40) 5.00 (0.25–99.16)
[n = 99] [n = 50]
ORA NC NC 0.85 (0.47–1.55) 0.89 (0.71–1.12) 0.77 (0.21–2.83)
[n = 285] [n = 510] [n = 512]
Progesterone NC NC OR 0.80 (0.60, OR 0.77 (0.62–0.96) NC
1.08) [n = 1307] [n = 1411]
Note: Data are shown as relative risk (95% confidence intervals) unless otherwise stated. Significant results are shown in bold.
a Data courtesy of Vincenzo Berghella.
Abbreviations: PTB, preterm birth; NC, not calculable from the available reports; CCB, calcium channel blocker; COX, cyclooxygenase; ORA, oxytocin receptor antagonists;
NOD, nitric oxide donors; NND, neonatal death; Mg, magnesium sulfate; Rx, therapy; excl. cong. anom, excluding congenital anomalies.
max, and always <32 weeks. Sulindac 200 mg PO q12h × been shown to be beneficial in perinatal outcomes compared with
48 hours. Ketorolac: 60 mg IM, then 30 mg IM q6h × 48 hours. a dose of 2 g/hour and is associated with significant side effects
Mechanism of action: Inhibits prostaglandin synthesis, there- [54]. Weaning MgSO4 tocolysis has no benefits and a few harmful
fore inhibits myometrial contraction. side effects compared with stopping MgSO4 abruptly [55].
Evidence for effectiveness (Table 19.5): (The nonselective COX Mechanism of action: Intracellular calcium antagonist.
inhibitor indomethacin was used in most trials.) When compared Evidence for effectiveness (Table 19.5): Compared with placebo,
with placebo, COX inhibition (indomethacin only) results in a there is insufficient evidence to show if MgSO4 reduces the inci-
79% reduction in PTB <37 weeks in a small trial, an increase dence of PTB or perinatal morbidity and mortality [56].
in GA of 3.5 weeks, and a >700 g increase in birth weight [51]. Compared with all controls (including other tocolytics),
No difference was shown in birth within 48 hours of initiation MgSO 4 did not prevent PTB at 48 hours, PTB <37 weeks, or
of treatment (RR 0.20, 95% CI 0.03–1.28). No differences were PTB <32 weeks. Perinatal death was higher (only two perina-
detected in neonatal morbidity or mortality. tal deaths), while perinatal morbidities were similar. Dose of
Compared with other betamimetics, COX inhibition resulted magnesium did not affect efficacy. Given these results, there is
in a 47% reduction in PTB <37 weeks’ gestation and a 73% no convincing evidence for recommending magnesium for
reduction in PTB within 48 hours [51]. No differences were tocolysis [57].
detected in the fetal or neonatal outcomes such as perinatal Management: Aim for 4–7 MgSO4 level. Monitor urinary out-
mortality, RDS, IVH, NEC, premature closure of the ductus, or put. Follow deep tendon reflexes: ↓ at level ≥8, absent ≥10. At ≥10,
persistent pulmonary hypertension of the newborn (PPHN). No respiratory depression; at ≥15, risk of cardiac arrest.
differences were found when COX inhibitors were compared to Specific contraindications: Myasthenia gravis.
magnesium sulfate or CCBs [51]. Side effects:
A comparison of nonselective COX inhibitors versus selective Maternal: Flushing, lethargy, headache, muscle weakness, dip-
COX-2 inhibitors did not demonstrate any differences in maternal lopia, dry mouth, pulmonary edema (1%; mechanism: Intravenous
or neonatal outcomes [51]. Due to small numbers, all estimates of overhydration), cardiac arrest.
effect are imprecise and need to be interpreted with caution. Fetal/neonatal: Lethargy, hypotonia, hypocalcemia, respira-
Specific contraindications: Renal or hepatic disease, active tory depression. Prolonged use: Demineralization.
peptic ulcer disease, poorly controlled hypertension, NSAID-
sensitive asthma, coagulation disorders/thrombocytopenia. Oxytocin receptor antagonists
Side effects: When used for only 48 hours, no serious mater- Types: Atosiban (Tractocile); barusiban.
nal and fetal/neonatal side effects occur, and fetal surveillance Dose: Atosiban 6.75 mg bolus, then 300 mg/minute IV × 3 hours,
is not indicated. Usually COX inhibitors are better tolerated then 100 mg/minute (max 45 hours).
by the mother than other tocolytics such as magnesium and Mechanism of action: Competitive inhibitor of oxytocin via
betamimetics. blockade of oxytocin receptor.
Maternal: As with any NSAIDs, mild gastrointestinal (GI) Evidence for effectiveness (Table 19.5): Compared with pla-
upset—nausea, heartburn (take with some food/milk) (COX-1). cebo, atosiban does not reduce the incidence of PTB or
GI bleeding (COX-1), coagulation, and platelet abnormalities improve neonatal outcome [58]. In one trial, atosiban was asso-
(COX-1), asthma if aminosalicylic acid (ASA)-sensitive. May ciated with an increase in extreme PTB <28 weeks and infant
obscure elevation in temperature. Long-term rofecoxib (Vioxx) deaths at 12 months of age compared with placebo [58]. However,
use in adults has been associated with stroke, so this drug is now this trial randomized significantly more women to atosiban
not available in many countries. before 26 weeks’ gestation. Compared with betamimetics, ato-
Fetal/neonatal: In trials, 403 women received short-term tocol- siban is associated with similar incidences of PTB and perina-
ysis (up to 48 hours) with COX inhibitors (mainly indomethacin), tal morbidity/mortality and with fewer maternal drug reactions
and there was only one case of antenatal closure of the ductus requiring treatment cessation [58]. Recent data comparing ato-
arteriosus. There was no increase in the incidence of patent duc- siban and nifedipine for tocolysis found no difference in preg-
tus arteriosus (PDA) postnatally (eight treated with COX inhibi- nancy prolongation or perinatal outcome but fewer maternal side
tors versus eight treated with placebo or other tocolytics) [52]. effects associated with atosiban [59, 60]. However, nifedipine was
No difference in incidences of IVH, bronchopulmonary dysplasia more cost-effective than atosiban [61]. There is insufficient evi-
(BPD), PDA, NEC, or perinatal mortality was noted in a review dence to assess the effectiveness of a different ORA, barusiban,
of trials aimed at evaluating safety [53]. Use for >48 hours, espe- as only one RCT has tested it against placebo at 34–35 weeks,
cially ≥32 weeks, is associated with significant fetal effects such as with no changes in recorded outcomes [62]. Therefore, as per
constriction of the ductus arteriosus, which can lead to hydrops, magnesium, the only evidence supporting the use of ORAs for
pulmonary hypertension and death, and renal insufficiency, primary tocolysis is that they have fewer side effects than the
manifested in utero by oligohydramnios. Other effects with pro- (effective) betamimetics.
longed use, such as hyperbilirubinemia, NEC, and IVH, have Side effects: Minimal to none.
not been shown with <72 hours use. Selective COX-2 inhibitors
have not been shown consistently to be any safer for the fetus/ Nitric oxide donors
neonate than nonselective COX inhibitors such as indomethacin. Type: Nitroglycerine.
Therefore, continuous use of COX inhibitors for >48 hours Dose: Nitroglycerine transdermal patch 0.4 mg/hour.
and ≥32 weeks is contraindicated. Mechanism of action: Direct relaxation of uterine muscle.
Evidence for effectiveness (Table 19.5): There is currently insuf-
Magnesium sulfate (MgSO4) ficient evidence to support the routine administration of nitric
Dose: 40 g MgSO4 in 1 L half normal saline (NS). Initial: oxide donors (NODs) for prevention of PTB in women with
4–6 g/30 minutes, then 2–4 g/hour. A dose of 5 g/hour has not PTL [63]. Compared with placebo, there was no evidence that
Preterm Labor 241
NOD prolonged pregnancy beyond 48 hours or improved neonatal Maintenance tocolysis: After successful
outcomes. When compared with other tocolytic agents (betami- primary tocolysis
metics, magnesium sulfate, CCBS, or a combination of tocolytics), Betamimetics (oral)
there was no evidence that NODs perform better than other toco- Dose: Ritodrine: 1–20 mg PO q2–4h. Terbutaline: 2.5–5 mg PO
lytics. Nitroglycerine has been the only NOD used in trials. q2–4h.
Specific contraindications: NODs should not be used in women Evidence for effectiveness: Compared with placebo, oral beta-
with hypotension or with preload-dependent cardiac lesions, mimetic therapy for maintenance tocolysis does not prevent
such as aortic insufficiency. PTB, recurrent PTL, recurrent hospitalizations, or perina-
Side effects: tal morbidity and mortality [69]. Some adverse effects such as
Maternal: NODs cause dilatation of arterial smooth muscle tachycardia are more frequent in the betamimetics group. Given
and commonly cause headache and may result in hypotension. this ample evidence from 13 trials, there is absolutely no evi-
Other side effects include dizziness, flushing, and palpitations. dence to support the use of oral betamimetics after PTL has
Fetal/neonatal: Although maternal hypotension could com- resolved.
promise utero-placental blood flow, no adverse fetal or neonatal
effects have been reported. Terbutaline pump
Dose: 0.05 mg/hour.
Progesterone Evidence for effectiveness: Compared with placebo, terbutaline
There are insufficient data to assess the efficacy for progesterone pump does not prevent PTB or improve perinatal morbidity and
as a primary tocolysis. There are some data suggesting that pro- mortality. Side effects and costs associated with this therapy fur-
gesterone may reduce PTB and increase birth weight and that pro- ther advise against its use [70].
gesterone may reduce uterine contractility, prolong pregnancy, and
attenuate cervical shortening. However, current evidence does not Calcium channel blockers
support a role for progesterone as a tocolytic agent [64]. A meta-analysis examining the use of oral nifedipine for main-
tenance tocolysis found no difference in the incidence of perina-
Primary tocolysis: Multiple agents simultaneously tal death (RR 1.36; 95%, 95% CI 0.35–5.33), IVH ≥grade II (RR
Indomethacin, ampicillin-sulbactam, and 0.65; 95% CI 0.16–2.67), NEC (RR 1.15; 95% CI 0.50–2.65), infant
magnesium versus magnesium alone respiratory distress syndrome (IRDS) (RR 0.98;95% CI 0.51–1.85),
Compared with placebos, indomethacin and ampicillin-sulbactam and prolongation of pregnancy (hazard ratio 0.74; 95% CI 0.55–
did not prevent PTB in women in PTL already receiving magne- 1.01) [71]. Therefore, maintenance tocolysis with nifedipine is not
sium sulfate tocolysis [65]. recommended.
Nifedipine and sildenafil citrate COX inhibitors

versus nifedipine alone Compared with placebo, after successful tocolysis, oral sulindac
One RCT with 239 women found the combination of nifedipine either 200 mg q12h × 7 days or 100 mg q12h until 34 weeks does
and vaginal sildenafil citrate in comparison to nifedipine alone not reduce PTB compared with placebo [63, 64]. Given the asso-
for acute tocolysis was associated with a decreased likelihood of ciation with fetal/neonatal complications with COX inhibitor use
delivery within 7 days (9.1% versus 20.3%; p = 0.014), prolonged for >48 hours, COX inhibitors should not be used for mainte-
latency (29 versus 7 days; p = 0.002), fewer admissions to neonatal nance tocolysis [72].
intensive care units (31.4% versus 44.1%; p = 0.043), fewer preterm Compared with oral terbutaline, oral indomethacin is asso-
deliveries from 28 to 32 weeks (20.7% versus 38.1%; p = 0.043), and ciated with a similar incidence of PTB when used for mainte-
increased neonatal birth weight (1900 versus 1500 g; p = 0.018). nance tocolysis after successful IV tocolysis, but indomethacin is
Although these data are promising, further studies are necessary associated with significant constriction of ductus arteriosus and
before recommendations can be made [66]. oligohydramnios when used for >48 hours [73]. Therefore, indo-
methacin should not be used for maintenance tocolysis, espe-
Primary tocolysis: Additional agents versus cially after 26 weeks.
one agent only
Progesterone vs. placebo in addition to ritodrine Magnesium sulfate
Compared with placebo, in women receiving ritodrine tocolysis, Compared with placebo or no treatment, magnesium mainte-
the addition of progesterone was not associated with a significant nance therapy does not prevent PTB (RR 1.05, 95% CI 0.80–1.40)
reduction in PTB <37 weeks (16% versus 33% in placebo) in a very or affect perinatal morbidity and mortality (mortality, RR 5.00,
small trial [67]. In detail, in this RCT, in 44 women with mostly 95% CI 0.25–99.16) [74]. It has a similar effect on PTB as alterna-
(>90%) singleton gestations and threatened PTL at less than 35 tive tocolytic drugs (RR 0.99, 95% CI 0.57–1.72) (i.e. it is equally
weeks treated with ritodrine, natural progesterone 400 mg orally ineffective). Therefore, magnesium sulfate should not be used as a
q6h × 24 hours (then 400 mg q8h for next 24 hours, and then maintenance tocolytic.
300 mg q8h onward) was associated with a similar incidence of
PTB, with less quantity of ritodrine administered and shorter Oxytocin receptor antagonists
maternal hospital stay compared with placebo [67]. Compared with placebo, ORA (atosiban) maintenance therapy
(30 μg/minute) via pump up to 36 weeks does not prevent PTB or
Refractory tocolysis: Primary agent is failing affect perinatal morbidity and mortality, with a 5-day (32.6 versus
Indomethacin was similar to sulindac in the prevention of PTB 27.6, p = 0.02) longer interval to delivery in one trial [75]. There
in women failing primary magnesium sulfate tocolysis in a small are no side effects compared with placebo except for injection-site
trial [68]. reactions. ORAs are not available in oral form for maintenance.
Progesterone Prenatal care

There is conflicting evidence regarding the effectiveness of pro-
gesterone for maintenance tocolysis. Women with a singleton Preconception counseling as noted earlier, if not already done.
gestation who received 17P maintenance tocolysis for arrested Management should follow recommendations as discussed
PTL had a similar rate of PTB <37 weeks (42% versus 51%; RR (Table 19.3). See also Chap. 2.
0.78; 95% CI 0.50–1.22) and PTB <34 weeks (25% versus 34%; RR
0.60; 95% CI 0.28–1.12) compared to controls [76, 77]. Women Antepartum testing
who received 17P had significantly later GA at delivery (MD 2.28
weeks; 95% CI 1.46–13.51), longer latency (MD 8.36 days; 95% CI No specific fetal testing is indicated. Home uterine activity moni-
3.20–13.51), and higher birth weight (MD 224 g; 95% CI 71–378) toring (HUAM), discussed in Chap. 18, is not effective in prevent-
as compared to controls. As 17P for maintenance tocolysis is asso- ing any complication.
ciated with a significant prolongation of pregnancy and signifi-
cantly higher birth weight [76, 77], further research is suggested.
One study examining maintenance tocolysis with vaginal pro- Delivery
gesterone for arrested PTL found its use was associated with a
Mode
significantly lower rate of PTB <37 weeks (42% versus 58%; RR
There is insufficient evidence to evaluate the use of a policy for
0.71; 95% CI 0.57–0.90), significantly longer latency (mean dif-
uniform planned cesarean delivery (CD) compared with expect-
ference 14 days), later GA at delivery (MD 1.3 weeks), lower rate
ant management and selective CD for preterm (24–36 weeks)
of recurrent PTL (24% versus 46%; RR 0.51; 95% CI 0.31–0.84),
infants [65, 84]. Mothers in the planned CD group had more
and lower rate of neonatal sepsis (2% versus 7%; RR 0.34; 95% CI
morbidity. There was no significant difference between planned
0.12–0.98) compared to placebo or no treatment [78]. However,
CD and expectant management in perinatal morbidity or mortal-
due to the poor quality of the trials, maintenance therapy with
ity or in abnormal childhood follow-up. Differentiation of data
vaginal progesterone should be studied further before a strong
between breech and vertex presentations is difficult, with num-
recommendation can be made.
bers too small for definite conclusions.
A recent RCT examining the effectiveness of vaginal progester-
one and 17-OHP for maintenance tocolysis among women with
Delayed cord clamping
threatened PTL and a CL <25 mm but without a history of a prior
In preterm neonates, delayed cord clamping by about 30–60
PTB found no difference in the rate of PTB in either group com-
seconds (120 maximum) is associated with fewer transfusions
pared to the control group [79]. A 2017 meta-analysis, which again
for anemia, less hypotension, and less IVH than early clamping
included both the use of vaginal and 17-OHP progesterone for
at less than 30 seconds [83]. In addition, delayed cord clamping
maintenance tocolysis, found the overall pooled analysis favored
likely decreases the risk of neonatal death [83].
treatment effect regarding delivery <37 weeks (OR 0.77, 95% CI
Milking of the cord has been evaluated only in small RCTs
0.62–0.96). However, this was not sustained when only high-qual-
in preterm neonates, so there is insufficient evidence for recom-
ity RCTs were considered (OR 1.23, 95% CI 0.91, 1.67) [80].
mendation. Compared with 30-second delayed cord clamping,
In summary, there is insufficient evidence to recommend
milking of the cord four times achieved a similar amount of plac-
progesterone for prevention of PTB in women who remain
ento-fetal blood transfusion [85]. However, compared with no
pregnant after an episode of PTL, but recent evidence
milking, milking of the cord has been associated with a similar
about vaginal progesterone for maintenance tocolysis is
need for fetal blood transfusions and increased risk of the neo-
encouraging.
nate requiring phototherapy [86].
PTL resolved: Home versus in-hospital care Analgesia/Anesthesia

After PTL has resolved (and cervical dilatation has not pro- No specific changes from term intrapartum management (see
gressed ≥4 cm), home management is associated with similar Chap. 12).
incidences of reaching ≥36 weeks compared with hospital
management [81, 82]. Hospitalization may increase maternal
stress, vaginal examinations, time in recumbent position (and Postpartum/Breastfeeding/Counseling
its consequences), and decreased plasma volume. For the many As in other pregnancies, breastfeeding is encouraged as toler-
women with arrested PTL, continued hospitalization after ated for the preterm infant. Milk expression using a breast pump
steroid administration is unnecessary. Women sent home with is also encouraged. Extensive counseling should be provided
a diagnosis of false PTL are not at increased risk for early (<34 regarding the rate of recurrence of PTB and future management
weeks) PTB or neonatal mortality, but they are at risk for later in pregnancy. Treatment with antibiotics before pregnancy does
(≥34 weeks) PTB [1]. not prevent recurrent PTB. In women with a prior spontaneous
PTB <34 weeks, oral azithromycin and metronidazole every
Preconception counseling 4 months after the PTB and before the next conception does
not significantly reduce subsequent PTB [87]. Vaginal and IM
Given its major impact of perinatal morbidity and mortality, it progesterone has been shown to reduce the risk of recurrent PTB
is important to review risk factors for PTB in every pregnant and adverse perinatal outcomes in women with a history of spon-
woman. In the woman with a risk factor (e.g. prior PTB), it is taneous singleton PTB. Following spontaneous singleton PTB,
important to review the prognosis, possible complications, and women should be counseled about the benefits of progesterone
management of a future pregnancy (see earlier). prophylaxis in subsequent pregnancies [88]. (See also Chap. 18.)
Preterm Labor 243
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20
PRETERM PRELABOR RUPTURE OF MEMBRANES
Anna Locatelli, Sara Consonni, and Annalisa Inversetti
Key points Definition

• Definite diagnosis is by direct visualization of fluid (“pool- Preterm prelabor rupture of membranes (PPROM) refers to cho-
ing”), with pH test or ferning as usual confirmatory rioamniotic membrane rupture before the onset of labor in preg-
tests. In equivocal cases, biochemical tests may aid in the nancies at <37 weeks of gestation.
diagnosis, but these additional tests should not be used
without other clinical assessments because of concerns Diagnosis
about inaccurate interpretation.
• Complications of preterm prelabor rupture of membranes Diagnosis is made in the majority of cases by history and direct
(PPROM) include premature labor/delivery with related visualization of fluid (pooling) in the posterior vaginal fornix at
complications of prematurity such as respiratory distress sterile speculum examination. History of persistent leakage of
syndrome (RDS), intraventricular hemorrhage (IVH) and fluid and ultrasonographic diagnosis of oligohydramnios are two
periventricular leukomalacia (PVL), infection, and necro- other confirmatory, but not diagnostic, findings.
tizing enterocolitis (NEC); maternal or neonatal infections Traditional confirmatory tests:
(chorioamnionitis, endometritis, and sepsis); abruptio pla-
centae; cord prolapse; and, especially for PPROM <24 weeks, • Ferning test: The presence of arborization on a slide of
perinatal death, pulmonary hypoplasia (PH), compression amniotic fluid collected in a sterile way from the posterior
deformities, long-term infant morbidities, increased need vaginal fornix. Arborization represents the crystalliza-
for cesarean delivery (CD), and retained placenta. tion of amniotic fluid due to its high contents of salts and
• Corticosteroids should be administered in women with proteins. False-positive results for contamination by cer-
PPROM at 230/7–336/7 weeks, as this intervention is associ- vical-vaginal mucus, seminal fluid, fingerprints, and urine
ated with lower incidences of RDS, IVH, NEC, and peri- crystals. False-negative results for blood or meconium con-
natal death rate. Corticosteroid administration should tamination or inadequacy in slide preparation.
probably be avoided after 35 weeks in most cases. • pH test (nitrazine test): The normal pH of vaginal secre-
• Antibiotics are associated with less chorioamnionitis, tions is generally 3.8–4.5, whereas amniotic fluid usually
preterm birth (PTB) within 48 hours, PTB within 7 has a pH of 7.1–7.3. False-positive test results may occur
days, neonatal infection, surfactant use, oxygen ther- in the presence of blood or semen, alkaline antiseptics,
apy, and abnormal cerebral ultrasound scan (including certain lubricants, Trichomonas, or bacterial vaginosis.
IVH). RDS and NEC are also decreased with ampicillin Alternatively, false-negative test results may occur with
and erythromycin treatment. A combination of ampicillin prolonged membrane rupture and minimal residual fluid.
and macrolides is suggested.
• Tocolytic therapy in women with PPROM is not associ- In equivocal cases, additional tests could be used. Statistical mea-
ated with maternal or perinatal benefits and should, in sures (sensitivity, specificity, positive predictive value, negative pre-
general, be avoided. dictive value) of the main prelabor rupture of membranes (PROM)
• Cervical cerclage should, in general, be removed when diagnostic tests are reported in Table 20.1 [1–4]. The American
the diagnosis of PPROM is made. Cerclage might be left in College of Obstetricians and Gynecologists (ACOG) published
place to allow corticosteroid therapy, especially at < 28 weeks. 2020 guidelines [5] reminding health care providers that these tests
• Delivery is indicated for nonreassuring fetal heart rate should not be used without other clinical assessments because of
tracing (NRFHT), preterm labor (PTL), chorioamnion- concerns about “misuse, overreliance, and inaccurate interpretation”
itis, or >37 weeks (Figure 20.1). Before 34 weeks, conser- of lab test results used to detect rupture of membranes. These can
vative management is recommended, if possible. Between lead to serious adverse events, including fetal death, infection, and
34 and 366/7 weeks, in the absence of overt signs of infection other health complications in pregnant women.
or fetal compromise, either delivery or a policy of expectant Main biochemical tests:
management with delivery at 370/7 weeks is suggested.
• There are limited data to assess the benefit of interventions for • Placental alpha microglobulin test (AmniSure): Placental
PPROM <23 weeks. Deciding upon a threshold of viability alpha microglobulin-1 (PAMG-1) is a placental glycoprotein
is challenging. High variability in live birth rates is reported. of amniotic fluid (2000–25000 ng/mL); it can be detected
Perinatal outcomes are related to whether or not families and also in lower concentrations in maternal blood (5–25 ng/mL)
clinicians agree on aggressive neonatal intervention after and in cervical-vaginal secretions (0.05–0.2 ng/mL) if
counseling. From 23 weeks, active management (cortico- fetal membranes are intact [6]. PAMG-1 is a good marker
steroids and [re]admission) should be considered. for PROM diagnosis due to this different concentration
• In general, the management of PPROM in twin pregnan- between amniotic fluid and cervical-vaginal secretions.
cies should not differ from that of singletons. PAMG-1 is dosed by an immune-chromatographic test able
DOI: 10.1201/9781003102342-20 245

Diagnosis confirmed
(Fluid per cervical os
or vaginal pool with
positive pH or Ferning test)*
Ultrasound for gestational age,

Growth, anomalies as appropriate
Cervical cultures: Chlamydia, Gonorrhea

Ano-vaginal culture: Group B streptococcus
Urine culture
Initial continuous monitoring for labor, fetal status
Chorioamnionitis, abruptio
placentae, fetal death, Yes
nonreassuring fetal testing, cord Deliver
prolapse or advanced labor
No
Previable PPROM PPROM at

PPROM late preterm
<23 weeks 23–33 6/7 weeks
34–36 6/7 weeks
counseling
Initial monitoring
for infection, labor,
abruption placentae,
GBS culture and
broad spectrum
Conservative management Consider delivery,
antibiotics
Serial evaluation for or expectant management (at
chorioamnionitis, least upto 36 0/7 week) with
labor, abruption, fetal well-being, delivery at 37 0/7 weeks
growth Serial evaluation for
Evaluate for
persistent chorioamnionitis,
Re-counsel
oligohydramnios Administer corticosteroids and labor, abruption, fetal wellbeing,
and pulmonary antibiotics growth
hypoplasia with
serial ultrasound Deliver for chorioamnionitis, Administer antibiotics
non-reassuring fetal testing, abruption,
Re-counsel cord prolapse, advanced labor Deliver for chorioamnionitis,
non-reassuring fetal testing,
Deliver at 34 0/7 weeks, or within abruption, cord prolapse,
If discharged before
Induction with 37 weeks if stable until then advanced labor
viability and remains
misoprostol; or pregnant, readmit at
dilatation & fetal viability for When delivery appears imminent
evacuation conservative at <34 weeks, administer
management magnesium sulfate for fetal
neuroprotection
Intrapartum group B streptococcus prophylaxis if no recent

negative ano-vaginal culture
Broad spectrum antibiotics if chorioamnionitis
FIGURE 20.1 Management of PPROM. (Adapted from Refs. 1–5, 11–56.) *See also text and Table 20.1.
Preterm Prelabor Rupture of Membranes 247
TABLE 20.1: Predictive Accuracy of PROM Diagnostic Tests

Positive Predictive Negative Predictive
Brief Description Sensitivity (%) Specificity (%) Value (%) Value (%)
Nitrazine test Vaginal pH by a cervical-vaginal swab 85 39.7 49.3 79.3
Ferning test Arborization on a slide of amniotic fluid 84 78.7 79.7 83.1
Placental alpha Immune-chromatographic test on 92.7 100 100 95.2
microglobulin test cervical-vaginal secretion detecting
(PAMG-1) PAMG-1
Insulin-like growth factor Immune-chromatographic test on 87.5 94.4 92.1 91.1
binding protein (IGFBP)-1 cervical-vaginal secretion detecting
IGFBP-1
Diagnostic panty liner Pad with a reactive strip to detect 95.4 80 82.4 94.7
amniotic fluid
Fetal fibronectin (FFN) Immune-chromatographic test on 94.5 89.1 89.7 94.2
cervical-vaginal swab detecting FFN
Source: Adapted from Refs. [1–5].
to detect small concentrations of this glycoprotein in cervi- collagen degradation, decreased membrane collagen content,
cal-vaginal secretions (AmniSure PROM test). It is an easy, localized membrane defects, bleeding, uterine overdistention,
rapid (5–10 minutes), noninvasive test (speculum examina- and programmed amniotic cell death [6]. Evidence that sup-
tion is not necessary). This test can be performed from 11 to ports a causal association between PPROM and infection is
42 weeks of pregnancy. The result is not influenced by the vast and includes the fact that microorganisms in the amni-
presence of seminal fluid, urine, blood, or vaginal infections. otic fluid are more frequently present and the rate of histologic
• Insulin-like growth factor binding protein (IGFBP)-1 chorioamnionitis is higher in PPROM than in intact mem-
(PROM test): Immune-chromatographic test that detects branes preterm delivery, and the frequency of PPROM is sig-
amniotic fluid in the vaginal secretions. Monoclonal anti- nificantly higher in women with lower genital tract infections
bodies identify IGFBP-1, whose concentration is elevated (e.g. group B streptococcus [GBS] and bacterial vaginosis).
in amniotic fluid (IGFBP-1 ≥10 μg/L: Positive test). The Microorganisms that colonize the lower genital tract pro-
Actim PROM test is easy and rapid. The result is not influ- duce phospholipases, which can stimulate the production of
enced by the presence of urine or seminal fluid, although it prostaglandins and lead to uterine contractions; the immune
can be altered by contamination with blood [2, 4]. response in endocervix and/or fetal membranes leads to the
• Diagnostic panty-liner with polymer-embedded strip: A production of multiple inflammatory mediators (particularly
pad with a reactive strip put in contact with external geni- matrix metalloproteinases) that can weaken membranes and
talia detects the presence of amniotic fluid. result in PPROM [8]. Invasive uterine procedures performed
• Fetal fibronectin: This test is sensitive but not specific for during pregnancy (such as amniocentesis, chorionic villus
PROM—a negative result suggests the absence of PROM sampling, fetoscopy, and cervical cerclage) can damage the
with high accuracy, while a positive result is not diagnostic membranes, causing them to leak.
for PROM. Fetal fibronectin test is not recommended in
the case of PROM [1].
Classification
Transabdominal amnioinfusion of dye (indigo carmine,
Evans blue, fluorescein) can be used as a confirmatory test in PPROM can be classified into PPROM <23 weeks (usually
doubtful cases at low gestational ages. Methylene blue must be 16–22 6/7 weeks, also called previable or mid-trimester or very
avoided, as it can cause fetal meta-hemoglobinemia [7]. early PPROM—see also end of this chapter) and PPROM at
23 0/7–36 6/7 weeks. PPROM at 23–36 weeks can be further
subdivided into PPROM at 23–33 6/7 weeks (early PPROM)
Symptoms and PPROM at 34–36 6/7 weeks (late-preterm PPROM—for
management, see also Chap. 21). In 50% of PPROM, labor
Over 90% of women with PPROM report a history of a “gush of fluid.”
occurs within 24 hours, and in 80%–90% within 7 days.
Median latency to delivery after PPROM is similar from 24 to
Incidence 28 weeks’ gestation (about 9 days) and shortens with PPROM
≥29 weeks [9]. The latency with PPROM >30 weeks is usually
PPROM occurs in <1% at <24 weeks, about 1%–3% at 24–33
only 2–4 days.
weeks, and 3%–5% at 34–36 weeks compared with about 8%–10%
for PROM at term. PPROM is associated with about 25%–30% of
all premature births (PTBs). Risk factors
Etiology/Basic pathophysiology The main risk factors for spontaneous PPROM are listed in
Table 20.2 [10]. However, most cases of preterm PROM occur in
Etiology is complex and multifactorial (see Chap. 18). Possible otherwise healthy women without identifiable risk factors. See
mechanisms leading to PPROM are choriodecidual infection, also Chap. 18.
TABLE 20.2: Selected Risk Factors for Spontaneous Preterm TABLE 20.3: PPROM Complications
Prelabor Rupture of Membranes
Fetal/Neonatal and Maternal
Maternal Factors PPROM Complications Complications
• Preterm prelabor rupture of membranes (PPROM) in a prior Preterm birth Neonatal RDS, IVH, PVL, NEC, ROP,
pregnancy (recurrence risk is 16%–32% as compared with 4% in perinatal death, long-term infant
women with a prior uncomplicated term delivery) morbidities
• Antepartum vaginal bleeding Intrauterine infection/ Neonatal or maternal sepsis
• Chronic steroid therapy inflammation Childhood neurodevelopmental problems
• Collagen vascular disorders (such as Ehlers–Danlos syndrome, Chorioamnionitis, endometritis
systemic lupus erythematosus) Umbilical cord Fetal asphyxia
• Direct abdominal trauma compression or prolapse CD
• Preterm labor Abruptio placentae
• Exposure to infections Oligohydramnios Pulmonary hypoplasia and limb deformities
• Cigarette smoking (more frequent in the setting of severe
• Illicit drugs (cocaine) oligohydramnios in the early-to-mid
• Anemia second trimester)
• Low body mass index (BMI 19.8 kg/m2) Umbilical cord compression
• Inadequate maternal weight gain Fetal malpresentation Umbilical cord prolapse
• Nutritional deficiencies of copper and ascorbic acid CD
• Low socioeconomic status
• Unmarried status Source: Adapted from Ref. [11].
• Young or advanced maternal age

• Occupational factors (strenuous working conditions, long weekly
work hours) Counseling should also review all risk factors for PTB (Table 20.2).
• Psychological factors Several risk factors, such as smoking; low body mass index (BMI
Uteroplacental Factors 19.8 kg/m2); inadequate maternal weight gain; exposure to infec-
• Uterine anomalies (such as uterine septum)
tions; illicit drug use; nutritional deficiencies of copper, ascorbic
• Placental abruption (may account for 10%–15% of PPROM)
acid, and vitamin D; young or advanced maternal age; anemia;
• Advanced cervical dilatation (cervical insufficiency)
occupational factors such as prolonged walking or standing;
• Prior cervical conization
strenuous working conditions; and long weekly work hours, in
• Cervical shortening in the second trimester (<2.5 cm)
addition to psychological factors such as depression, anxiety, and
• Uterine overdistension (polyhydramnios, multiple pregnancy)
chronic stress, can be modified and best addressed preconcep-
• Intra-amniotic infection (chorioamnionitis)
tion (Table 20.2; see also Chap. 18). The woman with a history of
• Multiple bimanual vaginal examinations (but not sterile speculum
PPROM should also be made aware that interventions in preg-
or transvaginal ultrasound examinations)
nancy, such as progesterone and cerclage, can further decrease
her chance of recurrence (see later).
Fetal Factors
• Multiple pregnancy (PPROM complicates 7%–10% of twin Prenatal counseling
pregnancies) Counseling regarding prognosis, possible complications, man-
• Fetal anomalies (malformations, aneuploidies) agement, and expectations for neonatal outcome should be pro-
Source: Adapted from Ref. [10]. vided, preferably with reference to local/national data. Prognosis
depends mostly on GA at PPROM and GA at delivery. Latency
is inversely related with GA at PPROM (Table 20.4) [12] and can
Complications be prolonged by some interventions (see Antibiotics). Fetal matu-
rity depends on GA and is probably not enhanced or delayed by
Complications are inversely correlated with gestational age (GA)
PPROM.
at PPROM and at delivery. Fetal/neonatal and maternal PPROM-
related morbidity are shown in Table 20.3 [11]. Workup (Figure 20.1)
The current gold standard for the diagnosis of PROM is based
Management (Figure. 20.1) on three traditional tests: Visual pooling of clear fluid in the
Prevention
See Chap. 18. TABLE 20.4: Approximate Latency Depending on Gestational
Age at PPROM
Preconception counseling
See Chaps. 1 and 18. Women with prior PPROM have a 20%–30% GA at Delivery
chance of PTB, including a 15%–20% chance of recurrent PPROM PPROM (weeks) Mean Latency <48 Hours <7 Days <14 Days
in the next pregnancy. Recurrence is higher in black women.
<24 7 days 20% 40%–50% 70%
These incidences are inversely related with GA at PPROM (the
24–336/7 3–6 days 50% 70%–80% 90%
earlier the GA at PPROM, the higher the recurrence rate) and
interpregnancy interval (shorter than 6 months is particularly 34–366/7 24 hours 70%–80% 90% >95%
associated with higher recurrence). Source: Adapted from Ref. [12].
posterior fornix of the vagina or leakage of fluid from the cervi- antiretroviral therapy, and viral load. The patient should be
cal os at speculum examination, ferning test, and pH test. Such adequately counseled and involved in the clinical choices. See
tests become progressively less accurate when more than 1 hour Chap. 34 in Maternal-Fetal Evidence Based Guidelines.
has elapsed after the membranes have ruptured. We still perform
these tests initially, with no need for additional tests in diagnosis Amniocentesis
in about 99% of women with possible PPROM. Alternative tests Amniocentesis is seldom, if ever, used clinically in the manage-
can be used in equivocal cases, but caution is needed due to ment of PROM. It can be of use in rare cases for evaluation of the
the possible misleading results if used without a clinical assess- following:
ment (see earlier). See Table 20.1 for the accuracy of diagnosis of
PPROM with different tests [5]. • Diagnosis: If the diagnosis is in doubt, 1 mL of indigo car-
Tests for gonorrhea and chlamydia infection are indicated mine (not currently available in the United States; alterna-
in high-risk groups beyond the usual serologic third-trimester tives are Evans blue, or fluorescein) in 9 mL of normal saline
screening. GBS culture should be sent from anorectal and vaginal can be injected into the amniotic cavity under continuous
areas. Consider that the proposed antibiotic prophylactic ther- ultrasound guidance. Presence of blue on a pad worn on the
apy (see later) covers GBS and Mycoplasma. Avoid manual/ perineum for 2–4 hours confirms the diagnosis.
digital examination of the cervix in any woman with suspected • Eventual intraamniotic infection: Send amniotic fluid
PPROM and also after PPROM is diagnosed by speculum exami- glucose (<15 mg/dL associated with positive culture), Gram
nation. Digital examination is associated with shorter latency and stain, and culture. Leukocyte esterase, white blood cell
higher incidences of infection [13]. count, and interleukin-6 (IL-6), where available, can also be
used. The role of amniocentesis to rule out intraamniotic
Ultrasound infection is controversial, and it is not routinely performed.
Periodic ultrasound evaluation for presentation, growth, and • Fetal lung maturity (FLM): Assessment of fetal maturity
amniotic fluid is suggested. Oligohydramnios per se is not an can be obtained from amniotic fluid by amniocentesis or
indication for delivery at the lowest GA. Fifty to seventy percent of from the vaginal pool [21]. The predictive value of lung matu-
PPROM cases have low amniotic fluid volume on initial sonogra- rity tests is not modified by PPROM. Phosphatidylglycerol
phy, and low amniotic fluid volume is associated with an increased (PG) and lamellar body counts (LBC) are accurate when
risk of shorter latency (the lower the amniotic fluid index, the tested in the vaginal pool. PG is not accurate in the pres-
shorter the latency between PROM and delivery) and umbilical ence of meconium or blood, LBC is not accurate in the
cord compression [14, 15]. Patients with nonvertex presentations presence of meconium, while the TDx/FLM is accurate
have a higher risk for prolapsed umbilical cord and of an unin- with blood and/or meconium in the vaginal pool, yielding
tended vaginal delivery when compared with vertex presentations. results similar to those observed with samples obtained
PPROM may also interfere with fetal growth; thus Doppler sur- with amniocentesis. Demonstration of a mature fetal lung
veillance is recommended in the case of fetal growth restriction index by antenatal testing does not improve neonatal out-
[FGR], with the consequent management (see Chap. 47 in Maternal comes [19]. FLM testing is not clinically useful, and it is
Fetal Evidence Based Guidelines). In a recent meta-analysis evalu- no longer recommended [20].
ating the impact of oligohydramnios following PPROM, the risk of
delivery within the first 2 days and the rate of neonatal death and Meconium
respiratory distress syndrome were increased, whereas the risk of Meconium-stained amniotic fluid is associated with higher fre-
placental abruption was not significant [16]. In a recent prospec- quencies of clinical chorioamnionitis and positive amniotic fluid
tive study, the presence of hyperechoic membranes at ultrasound cultures when compared to clear amniotic fluid. In the absence of
assessment was associated with a higher incidence of spontaneous chorioamnionitis, meconium alone is not an indication for inter-
onset of labor within 72 hours independently from the gestational vention; however, its presence is an exclusion criterion from most
age at PPROM [17]. See also Chap. 18. randomized studies regarding expectancy. See Chap. 25.
Infection precautions Hospitalization

In women with PROM with recurrent active herpes simplex There is insufficient evidence to compare hospital versus home
virus (HSV) or human immunodeficiency virus (HIV) infection, management for PPROM.
expectant management is usually recommended before 340/7 A Cochrane review [21] including only two small trials shows
weeks of gestation. Antiviral therapy is indicated during expect- no significant differences between home management and hos-
ant management. If active HSV disease is present at the time of pitalization in PPROM. Outpatient management can be offered
delivery, cesarean birth is recommended. In the case of primary only to reliable patients in these conditions: Absence of infec-
HSV infection, the risk of vertical transmission is increased and tion, an easy way to the hospital, evaluation in hospital before
the management of PPROM is less clear. Antiviral therapy is indi- discharge, vertex presentation, vertical pocket of amniotic fluid
cated, and if there is active HSV infection at the time of delivery, >2 cm, recording of temperature and pulse every 6 hours, fetal
cesarean birth is recommended [5]. See Chap. 52 in Maternal- movement count, twice-weekly nonstress tests (NSTs), and
Fetal Evidence Based Guidelines. weekly ultrasound. Only 18% of patients with PPROM meet
Some data on the management of women with PPROM and these criteria; thus most of them are managed in the hospi-
HIV suggest that the latency-to-delivery interval is not corre- tal. A randomized controlled trial (RCT) reported 11% of women
lated with risk of vertical transmission in patients who receive with PPROM managed at home delivered unexpectedly at other
antiretroviral therapy, have a low (e.g. undetectable) viral load, hospitals [22]. Women were monitored for 48–72 hours before
and receive antepartum and intrapartum zidovudine [18]. The randomization to hospitalization versus no hospitalization in the
management should be individualized, taking into account GA, two RCTs on this subject [21]. Compared to hospitalization,
outpatient management was associated with similar inci- likelihood to deliver within 7 days of membrane rupture (RR
dences of perinatal mortality (relative risk [RR] 1.93, 95% con- 0.18) [33]. These results are encouraging but limited by the sparse
fidence interval [CI] 0.19–20.05), serious neonatal morbidity, data and low methodological robustness [33]. Transcervical
chorioamnionitis, GA at delivery, birth weight, and admission amnioinfusion to prevent NRFHT is discussed later, under the
to neonatal intensive care unit, as well as cesarean delivery (CD) section “Delivery.”
(RR 0.28, 95% CI 0.07–1.15). There was no information on serious
maternal morbidity or mortality. Mothers randomized to care at Corticosteroids for fetal/Neonatal
home spent approximately 10 fewer days as inpatients and were maturation and benefit
more satisfied with their care. Furthermore, home care was asso- A single course of corticosteroids is recommended for preg-
ciated with reduced costs [21]. Evidence on the role of bed rest nant women between 240/7 weeks and 340/7 weeks of gestation
or activity restriction on latency and perinatal outcomes is who are at risk of PTB [34]. Antenatal corticosteroid therapy in
poor; these interventions are not recommended [23, 24]. cases of intact or ruptured membranes or PPROM is associated
with lower combined fetal and neonatal death (RR 0.72, 95% CI
Maternal surveillance 0.58–0.89), respiratory distress syndrome (RDS) (RR 0.66, 95%
All women with PPROM should be monitored for infection CI 0.56–0.77), fewer intracranial hemorrhages (RR 0.55, 95%
by assessment of clinical parameters (e.g. fever, maternal/fetal CI 0.40–0.76), and necrotizing enterocolitis (NEC) (RR 0.50,
tachycardia, uterine tenderness, and purulent vaginal discharge). 95% CI 0.32–0.78). There is no evidence that membrane status
A diagnosis of chorioamnionitis is usually made by the presence leads to differences in maternal death, chorioamnionitis, puer-
of two or more of these criteria. The value of the novel definition peral sepsis, or perinatal death [35]. A course of antenatal steroid
of “Triple I” is not well defined in the context of PPROM [25]. The therapy (24 mg of betamethasone—12 mg IM every 24 hours—
presence of fever of unknown origin in the presence of PPROM is or 24 mg of dexamethasone—6 mg IM every 12 hours) should
highly suspicious for chorioamnionitis. The higher the incidence not be repeated in patients with PPROM, since weekly courses do
of chorioamnionitis, the shorter the latency period. See Chap. 24. improve severe RDS, resulting in less composite neonatal mor-
There is no clear evidence to support the use of C-reactive bidity among neonates delivered at 24–27 weeks, but are associ-
protein (CRP) or procalcitonin (PCT) for the early diagnosis of ated with shorter latency, higher risks of chorioamnionitis and
chorioamnionitis. CRP shows better sensitivity (0.71; 95% CI neonatal sepsis, and no improvement in overall composite neona-
0.53–0.84) and better specificity (0.75; 95% CI 0.55–0.88) com- tal morbidity [34, 35].
pared with PCT (sensitivity 0.50; 95% CI 0.28–0.73 and speci- A single rescue course of antenatal corticosteroids may be
ficity 0.72; 95% CI 0.51–0.87) in diagnosing clinical or histologic considered if the antecedent treatment was given more than
chorioamnionitis. Maternal leukocytosis at admission is associ- 2 weeks prior, the GA is less than 326/7 weeks, and the woman
ated with higher adverse infant neurodevelopmental outcomes at is judged to be likely to give birth within the next week [36,
2 years of age in a study [26, 27]. 37]. If the initial course was given at less than 26 weeks of gesta-
tion, a single repeated course may be considered if the delivery is
Fetal surveillance (antepartum testing) expected within 1 week. A single rescue corticosteroid course in
Fetal surveillance is based mainly on NST and biophysical profile PPROM is not associated with an increased rate of neonatal sep-
score (BPS). Abnormalities of these tests can be somewhat pre- sis [38], maternal chorioamnionitis, or neonatal morbidity (see
dictive of fetal infection or umbilical cord compression related also Chap. 18) [39].
to oligohydramnios. There is insufficient evidence to assess the Prior to 23 weeks’ gestation there is a paucity of data on the
optimal test or frequency of testing. NST or BPS performed efficacy of corticosteroids in women with PPROM; moreover, at
daily has poor sensitivity (39% and 25%, respectively) and simi- low GAs there are only a few primitive alveoli on which the drug
lar predictive values for predicting infection [28]. No improve- can exert an effect to improve lung tissue, but the beneficial
ment in perinatal outcome has been reported in one trial effect could be related to the maturation of other organ func-
[29]. Given the lower cost, NST is usually suggested for daily tion. A large study from the United States observed a reduction
(e.g. continuously for the first 24 hours, then three times per day of death, intraventricular hemorrhage (IVH), periventricular
for about 30–60 minutes) to twice-a-week fetal surveillance. leukomalacia (PVL), and NEC in neonates exposed to steroids
Monitoring may be more frequent with oligohydramnios, because at 23–25 weeks [40].
it is associated with an increased risk of umbilical cord compres- At 23 weeks it is reasonable to administer corticosteroids if
sion and shorter latency, with a preference for BPS as a backup if delivery in the next 7 days and active intensive care are antici-
the NST is nonreassuring. One non-RCT study supports continu- pated [21, 22, 41]. The decision should be always discussed.
ous fetal monitoring (CFM) in the management of PPROM [30], A recent randomized study of steroids for fetal maturity includ-
but there is insufficient evidence for a recommendation, and most ing 620 cases of late PPROM at 34 and 36 + 6 weeks showed a
practitioners and patients adopt intermittent (e.g. 1 hour every reduction of respiratory complications (RR 0.67, % CI 0.53–0.84)
8–12 hours) fetal monitoring for inpatient management of and an increase of hypoglycemia (RR 1.6, 95% CI 1.37–1.87).
PPROM. Moreover, continuous prolonged fetal monitoring may PPROM data were not analyzed separately (See Chap. 21) [42].
not be practically feasible [31] and is associated with higher rates of
intervention and CD compared with periodic NST, with no effect Antibiotics for prolongation of latency
on perinatal mortality [32]. See previous paragraph on Ultrasound. and fetal/Neonatal benefit
Administration of broad-spectrum antibiotics is indicated, as it
Amnioinfusion for prolonging latency after viability prolongs pregnancy and reduces maternal and neonatal infections
Transabdominal amnioinfusion is associated with a reduction and GA-dependent morbidity. A systematic review of placebo-
in neonatal death (RR 0.30), neonatal sepsis (RR 0.26), pulmo- controlled randomized trials involving over 6800 women evalu-
nary hypoplasia (RR 0.22), puerperal sepsis (RR 0.20), and less ated the use of antibiotics following PPROM before 37 weeks of
gestation. Compared with placebo, antibiotics for women with Azithromycin can be used instead of erythromycin [5, 53].
PPROM are associated with short-term benefits for both women A retrospective comparison between azithromycin and erythro-
and neonates [43, 44], in particular: mycin in addition to ampicillin in PPROM showed no differences
in latency or maternal/fetal outcomes [54]. Another retrospective
• Maternal: 34% less chorioamnionitis cohort study comparing erythromycin and azithromycin similarly
• Fetal/Neonatal: found no difference in latency to delivery [55]. A cost-effectiveness
• 29% reduction in PTB within 48 hours analysis demonstrated cost benefits for azithromycin [56]. A pro-
• 21% reduction in PTB within 7 days spective cohort study demonstrated that azithromycin instead of
• 33% reduction in neonatal infection erythromycin was associated with lower rates and decreased risk of
• 21% reduction in positive neonatal blood culture clinical chorioamnionitis, neonatal sepsis, and postpartum endo-
• 17% reduction in use of surfactant metritis with no difference in pregnancy latency [57].
• 12% reduction in use of oxygen therapy Azithromycin can be administrated as a single oral dose of 1 g
• 19% reduction in abnormal cerebral ultrasound [55, 57], even if there are several commonly used doses and there is
scans (including IVH) prior to discharge from hospital no standard dosing regimen. A retrospective cohort study compar-
• 5 fewer days in neonatal intensive care unit (5.05 ing different dosing regimens of azithromycin versus erythromycin
[–9.77, –0.33]) in PPROM reported no difference in latency to delivery, incidence
• 10% prolongation of pregnancy of chorioamnionitis, or neonatal outcomes. An extended course
• Decreasing trend in perinatal mortality (RR 0.93, 95% of azithromycin beyond the single-day dosing suggested by some
CI 0.76–1.14) authors [53] is considered insufficient by others to maintain an
• Decreased rates of RDS and NEC with ampicillin and inhibitory concentration in the amniotic fluid [58, 59].
erythromycin treatment (see later) [45] The mechanism of action of single antibiotic drugs should also
be considered. Macrolides diffuse slowly in the tissues and act
A meta-analysis limited to PPROM before 34 weeks showed mainly on gram-positive microorganisms and Chlamydia; more-
similar results [46]. The ORACLE study evaluated children’s health over, the microorganism disruption in the phagocyte prevents
at 7 years and found no difference in any functional impairment prostaglandin release and the consequent inflammatory cascade
after prescription of erythromycin, with or without co-amoxiclav, activation. Compared with erythromycin, azithromycin has an
compared with those born to mothers who received no erythromy- increased pharmacokinetic distribution, a longer half-life, and a
cin or after prescription of co-amoxiclav, with or without eryth- slower elimination rate.
romycin, compared with those born to mothers who received no Azithromycin is easy to administer, has decreased dosing fre-
co-amoxiclav. Long-term adverse effects of antepartum prophy- quency, fewer side effects, and decreased cost [60, 61].
lactic antibiotics for PPROM have not been observed in children Cephalosporins have few side effects and a broad-spectrum anti-
followed to age 7 years [47]. This finding is in contrast to the obser- bacterial effect [62]. A randomized trial comparing cefazolin plus
vation from the same authors that in patients with spontaneous macrolide (erythromycin or clarithromycin) versus cefazolin alone
preterm labor (PTL) and intact membranes, the rate of cerebral in PPROM showed no difference among the three antibiotic regi-
palsy was increased in children with in utero exposure to antibiot- mens in terms of newborn outcome [49]. In a large trial, amoxicil-
ics [48]. These results suggest that further caution should be used lin/clavulanate was associated with an increased risk of neonatal
when considering the routine treatment of women with antibiotics NEC, although there is no consistent trend toward a positive or
if there is uncertainty about the diagnosis of PROM. negative effect of broad-spectrum antibiotics for NEC in the lit-
Benefits in short-term outcomes (prolongation of pregnancy, erature [45, 47]. According to a Cochrane review, co-amoxiclav
infection, need for respiratory therapy, less abnormal cerebral should be avoided in women at risk of PTB due to an increased
ultrasound before discharge from hospital, etc.) should be bal- risk of neonatal NEC (RR 4.72, 95% CI 1.57–14.23). Possible antibi-
anced against a lack of evidence of benefit for other outcomes, otic regimens are listed in Table 20.5. Our preference is ampicillin
especially long-term outcomes, such as the effect of in utero
exposure to antibiotics on the child’s gut microbiota and on mat- TABLE 20.5: Possible Antibiotic Regimens
uration from the infant to the adult microbiome.
Ref. Antibiotic Dose
Antibiotic type [55, 57] Ampicillin 2 g IV, then 1 g IV every 6 hours and
Multiple regimens have demonstrated benefit, but there is insuf- Azithromycin 1000 mg PO single dose; or 500 mg PO
ficient evidence on the optimal antibiotic type (and regimen) in single dose every 24 hours for 3 days
women with PPROM. Frequently used antibiotics are penicil- followed by
lins or macrolides. Antibiotic regimens may consist of an initial Amoxicillin 500 mg PO every 8 hours for 4 days
parenteral phase, followed by an oral phase. A 7-day course of [54] Ampicillin 2 g IV every 6 hours and
therapy of latency antibiotics with a combination of intravenous Erythromycin 250 mg IV every 6 hours for 48 hours
ampicillin and erythromycin followed by oral amoxicillin and followed by
erythromycin is recommended during expectant management
Amoxicillin 250 mg PO every 8 hours and
of women with PPROM [5, 45, 47–50]. In patients allergic to beta-
Erythromycin 333 mg PO every 8 hours for 5 days
lactam antibiotics, macrolide antibiotics should be used alone
[52] Erythromycin 250 mg PO every 6 hours for a maximum of
[43, 45, 46, 51, 52] or another agent effective against GBS can be
10 days
considered. Since there are no evidence-based alternatives, the
choice of antibiotic type should be based on the severity of the [49] Cefazolin 1 g IV every 6 hours and
reported allergic reaction and antibiotic susceptibility results of Erythromycin 250 mg PO every 6 hours for 7 days
the GBS culture, if available [5]. Source: Adapted from Refs. [47–62].
2 g IV, then 1 g every 6 hours and azithromycin 1000 mg PO single demonstrated by randomized trials (cumulative absolute risk
dose, or 500 mg PO single dose every 24 hours for 3 days, followed reduction of 1.7) [68–72]. Results in PPROM cases were not
by amoxicillin 500 mg PO every 8 hours for 4 days. reported separately in any study, but constituted almost the 90%
Women with PPROM should be screened for GBS [5]. Patients of the population in the largest study [72]. In the absence of evi-
with PPROM in whom intrapartum GBS prophylaxis is indicated dence for an optimal dose of magnesium sulfate, scientific societ-
should receive intrapartum antibiotic prophylaxis regardless of ies suggested adopting the minimum dosage used in the published
previous antibiotic treatments [63]. See Chap. 39 of Maternal- trials and when delivery appears imminent at <34 weeks [73, 74].
Fetal Evidence Based Guidelines. Further, a recent guideline by the Society of Obstetricians and
Detection of specific cervicovaginal pathogens should be Gynecologists of Canada (SOGC) stated that maintenance infu-
appropriately treated (see Chaps. 34–38 of Maternal-Fetal sion is not necessarily required and that administration of mag-
Evidence Based Guidelines) even if routine cervicovaginal swab nesium sulfate should not influence decisions about neonatal
analysis, except for GBS, is not indicated. Women with PPROM resuscitation [75]. We administer magnesium sulfate 2–4 g load
screened for urinary tract infections should be treated with over 20 minutes, followed by 1 g/hour predelivery (see Chap. 19).
appropriate antibiotics if positive.
Clinical chorioamnionitis requires therapeutic antibiotics Progesterone
(see Chap. 24). For example, ampicillin (2 g IV every 6 hours) Progesterone (17P) or rectal progesterone is not associated with
or cefazolin (1 g IV every 6 hours), plus gentamicin (3–5 mg/kg increased latency, and administration should not be commenced
single dose IV every 24 hours). In case of CD, an additional sin- once a patient has experienced PPROM [76]. Vaginal progesterone
gle dose of antibiotic therapy is suggested (or more doses based administration could increase the risk of ascending infection and
on the clinical course), and further prophylactic antibiotics for should be discontinued in the absence of evidence of benefit [77].
anaerobe coverage is indicated (clindamycin 900 mg IV or met-
ronidazole 500 mg IV) (see also Chap. 14). Intrapartum GBS pro- Vitamin supplementation
phylaxis should be given until culture results are available and There is insufficient evidence to assess the effect of vitamin sup-
to carriers. There are insufficient data to assess the need for this plementation in women with PPROM [78]. Vitamin D and vitamin
intervention in women with PPROM in whom GBS is sensitive to C may have potential benefits, but it has not been proved yet [79].
antibiotics—like ampicillin—already given for PPROM. The sug- In one small trial, compared with placebo, vitamin C 500 mg and
gested regimen is penicillin (5 million units IV and then 2.5 mil- vitamin E 400 IU daily in women with PPROM at 26–34 weeks
lion units every 4 hours) or (if unavailable) ampicillin (2 g IV, then were associated with 7-day prolongation in latency, but no other
1 g every 4 hours). effects on maternal or neonatal morbidity and mortality [80]. In
a recent RCT, the use of vitamins C 1000 mg and E 400 IU in
Tocolysis for prolongation of latency women with PPROM was associated with a longer latency period
and fetal/Neonatal benefit before delivery. Adverse neonatal and maternal outcomes, which
In a Cochrane review, tocolysis was associated with longer latency are often associated with prolonged latency periods, were similar
(mean difference [MD] 73.12 hours; 95% CI 20.21–126.03) and between groups [81]. Deficiency in vitamin D has been associated
fewer births within 48 hours (average RR 0.55; 95% CI 0.32–0.95). with several adverse pregnancy outcomes, including PTB [82, 83].
However, tocolysis was associated with increased incidence of In a study of asymptomatic women who developed PPROM later
5-minute Apgar of less than 7 (RR 6.05; 95% CI 1.65–22.23) and in pregnancy, Vitamin D-binding protein (VDBP) was signifi-
increased need for ventilation of the neonate (RR 2.46; 95% CI cantly elevated. VDBP concentrations increase in pregnancy and
1.14–5.34), while it was not associated with a significant effect on thus influence the biologically active form of vitamin D, free vita-
perinatal mortality. For women with PPROM before 34 weeks, min D. In this research VDBP and other proteins are responsible
there was a significantly increased risk of chorioamnionitis; for some processes underlying membrane rupture [84].
neonatal outcomes were not significantly different. Therefore,
there is insufficient evidence to support tocolytic therapy for Cerclage removal
women with PPROM, and in fact there is evidence to recom- PPROM occurs in about 38% of women with cerclage in place
mend against this intervention, as there was an increase in [85]. The benefit of a retained cerclage to prolong latency and
maternal chorioamnionitis without significant benefits to the decrease complications related to prematurity has to be weighed
infant. However, the included studies did not consistently admin- against the risk of adverse maternal and neonatal outcomes [86,
ister antibiotics and corticosteroids, both of which are now consid- 87]. Leaving the cerclage in place >24 hours is associated with
ered standard of care [64]. A recent large retrospective study with a longer latency >48 hours (94% vs. 51%; odds ratio [OR] 16.1,
90% use of antibiotic and corticosteroids shows no differences in 95% CI 3.7–71.3), but also significantly increased maternal and
the prolongation of pregnancy and histologic chorioamnionitis, fetal/neonatal infection risks, such as chorioamnionitis (43%
confirming no neonatal benefits of this practice [65]. vs. 20%; OR 2.9, 95% CI 1.7–5.0) and neonatal mortality from
Long-term tocolysis >48 hours is associated with a nonsig- sepsis (12% vs. 1%; OR 13.2, 95% CI 1.6–108.3) and a trend for
nificant prolongation of pregnancy and no differences in neo- more neonatal sepsis (13% vs. 6%; OR 2.4, 95% CI 0.9-6.0) and
natal complications, but increased rate of chorioamnionitis and neonatal mortality (17% vs. 10%; OR 2.0, 95% CI 0.9–4.3) [37, 38,
postpartum endometritis. It should therefore be avoided [66]. 85]. A recent small, randomized trial, stopped after an interim
In agreement, a recent trial that was stopped before ending the analysis, showed no differences between the two managements
recruitment did not show a beneficial effect [67]. in terms of latency, infection, and composite neonatal outcomes.
However, there was a numerical trend in the direction of less
Magnesium sulfate for fetal neuroprotection infectious morbidity in case of immediate cerclage removal
A protective role of magnesium sulfate against the risk of cere- [88]. In a recent meta-analysis, cerclage retention after PPROM
bral palsy in preterm infants born before 34 weeks has been did not significantly prolong the gestational latency period, but
it increased the rates of delivery after the first 48 hours. It did risk of neonatal sepsis in the subgroup of patients with a positive
not significantly increase the rates of neonatal sepsis or neona- vaginal culture at the time of randomization [96, 97].
tal death. Maternal chorioamnionitis was more prevalent among At 340/7–366/7 weeks either delivery or a cautious expectant
women with cerclage retention (OR 1.78) [89]. Therefore, in most management policy should be offered. Parent opinion, even-
cases, cerclage should be removed in women upon diagnosis tual vaginal colonization status, and GA at presentation after 34
of PPROM, especially if corticosteroids have been previously weeks should be considered to balance the risk and benefit of con-
administered and if GA is >32 weeks. servative management (see Chap. 21).
Delivery Amnioinfusion for preventing NRFHT

Timing There is insufficient evidence to assess the effect of routine
Once PPROM occurs, the options for management include amnioinfusion in all women with PPROM for prophylaxis either
delivery versus expectant management until later in pregnancy. before labor or during labor. Compared with no amnioinfusion,
In the absence of clear indications for expeditious delivery, transcervical amnioinfusion (warmed saline at 10 mL/min for
such as nonreassuring fetal status, clinical chorioamnionitis, 1 hour, then 3 mL/min—total volume infused mean 1160 mL) at
abruptio placentae, or cord prolapse, the optimal GA for deliv- the time of labor for women with PPROM at 26–35 weeks is asso-
ery is less clear. A longer latency is associated with a higher ciated with statistically similar but more favorable incidences of
rate of chorioamnionitis, and a shorter latency with higher CD, low Apgar scores, and neonatal death in one small trial. In
risks related to prematurity. the amnioinfusion group, the number of severe fetal heart rate
A recent meta-analysis of 12 RCTs (3617 women) concluded decelerations per hour during the first stage of labor was reduced
that before 37 weeks’ gestation, an expectant management with by just about one in this small trial. Fetal umbilical artery pH at
careful monitoring was associated with better outcomes for the delivery was higher. These outcomes are consistent with the bene-
mother and baby. GAs at birth were lower in those randomized fits found for amnioinfusion for cord compression. Transcervical
to early birth than those randomized to expectant management amnioinfusion also reduced persistent variable decelerations
(MD –0.48 weeks, 95% CI –0.57 to –0.39). In particular, no dif- during labor (RR 0.52) in a trial with 86 participants [98].
ferences were observed between early birth and expectant man- In conclusion, to date, routine intrapartum amnioinfusion
agement in neonatal sepsis (RR 0.93, 95% CI 0.66–1.30, 12 trials), cannot be recommended for all women with PPROM given the
proven neonatal infection with positive blood culture (RR 1.24, limited data (see Chap. 11).
95% CI 0.70–2.21), overall perinatal mortality (RR 1.76, 95% CI
0.89–3.50), or intrauterine deaths (RR 0.45, 95% CI 0.13–1.57).
Mode and site of delivery
Mode of delivery should not be chosen only on the basis of PPROM
However, early birth was associated with a higher incidence of
occurrence. Malpresentation is more common with PTB, being
RDS (RR 1.26, 95% CI 1.05–1.53), a higher rate of neonatal death
indirectly related to weeks of GA (see Chap. 26). Early preterm
(RR 2.55, 95% CI 1.17–5.56), need for ventilation (RR 1.27, 95%
delivery should occur in a well-equipped facility, managed by
CI 1.02–1.58), and admission to neonatal intensive care (RR 1.16,
skilled clinicians, providing all the necessary support to the mother
95% CI 1.08–1.24, 4 trials). In assessing maternal outcomes, early
and fetus/neonate born preterm. Transferring women at risk of
birth was associated with a decreased rate of chorioamnionitis
very PTB to perinatal referral centers for delivery decreases the
(RR 0.50, 95% CI 0.26–0.95), an increased rate of caesarean sec-
neonatal mortality and morbidity rate considerably [99, 100].
tion (RR 1.26, 95% CI 1.11–1.44), endometritis (RR 1.61, 95% CI
Predicting the time of delivery in PPROM is often impossible.
1.00–2.59), and decreased total length of hospitalization (MD
–1.75 days, 95% CI –2.45 to –1.05). Prophylactic antibiotics were Anesthesia
shown to be effective in reducing maternal infections in women No specific precautions.
randomized to expectant management [90].
Delivery before 34 weeks is associated with severe neonatal Postpartum
complications, including death, and it is traditionally consid- See Chaps. 18 and 31. Women with PPROM are at high risk of
ered the cutoff age for expectancy. It is highly improbable that recurrence in subsequent pregnancies, with an association
future RCTs will include these patients, although evidence is not between GA at the time of PPROM, latency period, and inter-
strong, and, unfortunately, many old trials did not use steroids val between pregnancies. Patients with a history of cervical
for fetal maturity or antibiotics [91–94]. A recent RCT was pre- insufficiency and fetal loss/miscarriage should be considered at
maturely stopped for difficulty at recruitment [95]. Women with increased risk of mid-trimester PPROM in the following preg-
PPROM before 340/7 weeks should be managed expectantly if nancy. See “Prevention” earlier.
no maternal or fetal contraindications exist [5].
Evidence on late PPROM (34–36 + 6 weeks) is based on more Special considerations must be given when PPROM occurs
recent studies. An individual participant data meta-analysis of before fetal viability, after invasive procedures, and in twin
trials of PPROM from 34 + 0 to 36 + 6 weeks [96] showed that gestation.
the two approaches resulted in similar rates of composite adverse
neonatal outcome (neonatal sepsis, NEC, RDS, stillbirth, or neo- PPROM <23 weeks
natal death; RR 1.20, 95% CI 0.94–1.55). Concerning maternal
morbidity, immediate delivery reduced the risk of antepartum Definition
hemorrhage (RR 0.57, 95% CI 0.34–0.95) and chorioamnionitis PROM <23 weeks, or “previable PPROM” (an arbitrary definition
(RR 0.21, 95% CI 0.13–0.35), but slightly increased the risk of CD that varies among investigators and from year to year because
(RR 1.26, 95% CI 1.08–1.47). The rate of endometritis and the of advances in neonatal intensive care) is a relevant and unique
length of hospitalization (3.45 versus 3.39 days) were not statisti- nosological entity because of its significant association with fetal
cally different between groups. Immediate delivery did reduce the and neonatal morbidity and mortality.
Incidence 0.8% of the general obstetric population [101]. The risk is highest
The incidence is about 0.6% of pregnancies. with lower GA at PPROM and with vaginal bleeding occurring
prior to or after membrane rupture [110].
Etiology/Basic pathophysiology
There are two different categories: Spontaneous and iatrogenic. Cord prolapse
Risk factors for spontaneous PPROM <23 weeks are simi- The incidence of prolapse is about 2%. The risk is higher (11% in
lar to those for PTL and for PPROM later in pregnancy (see one study) in the setting of nonvertex fetal presentations [111].
Table 20.2 and Table 18.1 in Chap. 18). The major risk factors are
a prior history of PPROM or PTB and intraamniotic infection. Fetal death
Fluid leakage or PPROM occurs in about 1% of second-trimester Fetal demise is primarily related to abruption, cord prolapse and
amniocenteses [88], 3%–5% of diagnostic fetoscopies, and 30%– compression, or infection. The average risk of fetal death after
40% of fetal surgery procedures [101]. mid-trimester PPROM is about 10%, and it is difficult to deter-
mine which pregnancies will reach viability [112].
Complications
Incidences of most complications are inversely proportional to Pulmonary hypoplasia
GA at PPROM, latency, residual amniotic fluid volume, and Pulmonary hypoplasia (PH) is characterized by a decrease in
GA at delivery. the number of lung cells, airways, and alveoli, mainly due in the
context of PPROM to alterations of normal amniotic fluid pres-
Fetal/Neonatal sure and egress of lung fluid during the canalicular stage of lung
Neonatal death development (ending at nearly 24 weeks) (Figure 20.2). The gold
Published data on neonatal survival after early PPROM varies standard for the diagnosis of PH is lung weight by autopsy. The
widely (20%–68%) [102–106]. The mortality rates may be under- incidence of PH resulting from mid-trimester PPROM varies
estimated by selection bias due to the high rate of elective ter- from 13% to 28% [113, 114]. The mortality rate in neonates with
mination prior to viability and consequent inclusion of patients this condition is 50%–95% [115]. The main independent reported
who chose to continue pregnancy or who have experienced initial risk factors for development of PH are as follows: (1) early GA at
latency. In 2012 an interesting study compared perinatal out- membrane rupture [114, 116]—a risk of 50%–60% was reported
comes of two settings with different rates of elective termination when PPROM occurs at 20 weeks or less—and (2) low residual
of pregnancy (TOP) (assuming that patients with a poorer prog- amniotic fluid volume [117]. PH is more common among pregnan-
nosis opted more frequently for TOP). Perinatal outcomes (mean cies with oligohydramnios (defined by maximum vertical pocket
GA at delivery, latency, birth weight, and survival) were better in <2 or amniotic fetal index [AFI] <5), after controlling for GA at
the centers with a lower TOP rate; in particular, survival among rupture. Incidences of PH with severe, moderate, and absent-to-
live births was 95.8% in the center with lower TOP and 65% in the mild oligohydramnios are 43%, 21%, and 7%, respectively [118].
center with higher TOP [105]. A retrospective study on 58 women Candidate tests to diagnose PH prenatally are the following:
with prolonged PPROM at less than 24 weeks reported a survival Ultrasound measurement of amniotic fluid, fetal breathing move-
rate in newborns of 90%, although pulmonary morbidities were ments, fetal chest circumference, lung length, lung volume, fetal
common [98, 106]. Recent reports on perinatal survival in PROM lung area to head circumference ratio (LHR), Doppler studies of
<24 weeks involved patients routinely managed with antibiotics, pulmonary vessels, and O2 tests. In general, the predictive accuracy
antenatal steroids, postnatal surfactant, and high-frequency ven- is poor and may be improved by combining tests [116, 119, 120].
tilation. A comparison between PPROM less than 25.0 weeks and
25.0–31.9 weeks showed a higher rate of severe composite neona- Fetal compression syndrome
tal morbidity and composite severe childhood morbidity in case In early PPROM, asymmetric intrauterine pressure and restric-
of early PPROM. Neonatal death occurred in nearly 17% of early tion in fetal movement can lead to limb position deformities
PPROM. Neonatal mortality is comparable to that in preterm and craniofacial defects of variable severity, originally described
deliveries matched for GA without PPROM. in the context of renal agenesis. The mean frequency of skeletal
deformities is 7%. Prolonged latency and severity of oligohydram-
Chorioamnionitis nios independently increase the risk of skeletal abnormalities and
Antenatal infection is the major complication limiting the act synergistically [121]. The GA at PPROM is not a significant
latency interval. If clinical infection occurs at any time dur- determinant due to the progressive and continuous development
ing the latency period, delivery is indicated. Chorioamnionitis of the axial skeleton.
complicates about 40% of cases of mid-trimester PPROM [107]. Increased likelihood of skeletal deformities observed among
The occurrence of chorioamnionitis is higher early in the latency infants diagnosed with PH suggests that the two disorders share
period; more than 50% of cases occur within the first 7 days common risk factors. Surgical correction is not generally required,
after rupture, with the maximum clinical occurrence on 2–5 as they resolve with postnatal growth and physiotherapy.
days [108]. After the first week of latency, the incidence falls,
suggesting that subclinical uterine or chorioamniotic infections Other morbidities
that weaken membranes and cause rupture were probably pres- Other neonatal morbidities are similar to that in PTB and are
ent before, whereas bacteria migration is a less important com- related to GA at PPROM. These include RDS, bronchopulmo-
ponent. The risk of chorioamnionitis is inversely proportional to nary dysplasia (BPD), IVH, NEC, sepsis, and retinopathy of
residual amniotic fluid volume [109]. prematurity. The incidence of neonatal IVH and cystic PVL
increases in cases complicated by clinical chorioamnionitis [122].
Placental abruption Since mid-trimester PPROM is associated with early delivery and
Abruptio placentae is more frequent in pregnancies with mid- infections, it constitutes a potential risk factor for long-term neu-
trimester PPROM, occurring in up to 44% of cases compared with rologic morbidities. There may be a higher risk of PVL in infants
Gestational Age (weeks) Stage of lung development Description
4 to 6 EMBRIONIC Lung bud arises
7 to 16 PSEUDOGLANDULAR Non respiratory bronchi and

bronchioles develop
17 to 24 CANALICULAR First gas exchanging acini

and pulmonary capillaries
are forming
25 to 37 TERMINAL SAC Subsaccules and alveoli

develop with extensive capillary
invasion and expansion of the
alveolar blood barrier surface area
38 to age 3 years ALVEOLAR Subsaccules become alveoli
FIGURE 20.2 Phases of lung development.
born after prolonged PPROM compared with other types of pre- opportunity for survival and reduce morbidities among survivors
maturity. Prolonged latency in mid-trimester PROM patients is (See Chap. 18) [41].
not associated with an increasing frequency of abnormal neona-
tal cranial ultrasound examination [108]. Retained placenta
The risk of undergoing either uterine exploration or curettage is
Long-term morbidities 9%–18% and more likely if rupture occurs prior to 20 weeks of
About 63%–84% of survivors after mid-trimester PPROM will be gestation.
neurologically intact [113]. Cerebral palsy rate in a group of 275
pregnancies complicated by early PPROM was 9.8% [106]. Postpartum endometritis
This condition occurs in about 13% of cases. Postpartum mater-
Maternal nal sepsis (about 0.8%) and death (about 1/1000) are uncommon.
Cesarean delivery The risk of maternal infection is inversely proportional to the
Higher CD rates are mainly due to common fetal heart rate abnor- latency period.
malities (related to oligohydramnios and chorioamnionitis), mal-
presentation, and abruptio. A traditional uterine incision may be Management
required to reduce fetal trauma at early GA (oligohydramnios, Counseling
fetal malpresentation, and lower uterine segment characteristics Parents should be counseled regarding the prognosis, complications,
constitute risk factors). In general, CD should be avoided before and management of PPROM <23 weeks. The options are expectant
22 weeks, if possible, and neonates should receive palliative care. management or delivery. The impact of immediate delivery on neo-
Because most newborns at 24–25 weeks of gestation will survive natal outcome and the potential benefits and risks of conservative
if resuscitated, efforts to prolong pregnancy, intrapartum inter- management should be reviewed. PPROM related to genetic amnio-
ventions for fetal benefit, and neonatal resuscitation should gen- centesis is associated with favorable outcomes even with expectant
erally be offered, if appropriate. Special consideration is needed management (91%–99% perinatal survival), which is very different
if the newborn is at 22–23 weeks of gestation: Management deci- than the prognosis with spontaneous PPROM <23 weeks.
sions will need to be made based on whether the fetus is con- Incidences of most complications are inversely proportional to
sidered potentially viable on individual clinical circumstances GA at PPROM, latency, residual amniotic fluid volume, and
and whether the family desires aggressive measures to improve GA at delivery.
the potential for newborn survival after birth. In general, those The latency period between membrane rupture and delivery is
born at 23 weeks of gestation should be considered potentially critical in determining perinatal outcome.
viable, as survival with resuscitation is 26%–28% or more. Those Latency is indirectly correlated with GA at PPROM (Table 20.4)
considered nonviable at 22–23 weeks of gestation can be treated [12]. While the mean latency is about 7 days, the median latency
similarly to pregnancies at 20–21 weeks of gestation, while those may be up to about 10–21 days. Up to 14% of women with mid-
considered potentially viable should be treated consistent with trimester PPROM stop amniotic fluid loss, presumably due to
similar pregnancies at 24–25 weeks of gestation. If feasible, deliv- resealing of membranes. This subgroup of cases has similar out-
ery of potentially viable infants should be undertaken in settings comes to uncomplicated pregnancies. In 10%–20% of patients,
in which resources are available to care for extremely small and amniotic fluid loss continues, but a partial reaccumulation during
immature infants. This approach has the potential to increase the expectant management is observed [114].
Oligohydramnios (AFI <5 or mean vertical pocket [MVP] GBS culture and prophylaxis
<2 cm) on admission, during the latency period, or at the last In a previable PROM, a rectovaginal GBS culture should be
ultrasonographic examination is associated with shorter obtained. Antibiotics for GBS carrier or unknown carrier status
latency and higher occurrences of PH, chorioamnionitis, should be started from 23 weeks.
and perinatal mortality [123]. Conversely, adequate residual
amniotic fluid volume identifies cases with elevated odds of Antibiotics
perinatal survival (85%–93%) and better long-term neurologic In 2016, ACOG [126] stated that most studies on antibiotic pro-
outcomes [123]. phylaxis with preterm PROM enrolled patients only after 24 0/7
In a retrospective cohort of 92 cases of PPROM under 24 weeks, weeks of gestation; thus there are no adequate data to assess the
the overall neonatal survival rate at discharge was 85%; the sur- risks and benefits of such treatment at earlier GAs. However, it is
vival rate was lower and the developmental delay more frequent reasonable to offer a course of antibiotics for pregnancy pro-
in patients with persistent oligohydramnios compared to those longation to patients with previable PROM (usually ≥20 weeks)
with normal amniotic fluid volume [124]. who choose expectant management [41].
Workup Transabdominal amnioinfusion before viability

See earlier. Serial amnioinfusion in the second trimester is a procedure used
in an attempt to increase amniotic fluid, reduce PH, prolong preg-
Therapy nancy and improve neonatal outcomes. Data are mostly derived
See Figure 20.1. from prospective nonrandomized or retrospective studies. Three
Delivery in previable PPROM is indicated in the presence of: meta-analyses have been published, two of which report an
improvement in mortality after amnioinfusion [127, 128], while a
• Intrauterine death Cochrane review on the argument [129] did not identify any ran-
• Spontaneous onset of labor domized studies focused on PROM management before 26 weeks.
• Evidence of maternal and/or or fetal infections Regarding the use of this clinical practice in nonviability con-
• Any other obstetric or medical condition necessitat- texts, a multicenter randomized controlled study (PPROMEXIL
ing delivery (e.g. abruptio placentae, cord prolapse, and III) concluded that this procedure does not lead to a reduc-
preeclampsia) tion in perinatal mortality [130]. Long-term follow-up of these
• Pregnancy termination request small cohorts at 5 years of age revealed that amnioinfusion
did not improve neurodevelopmental outcomes; of note, 71%
Delivery (termination) can be carried out usually by induction of survivors did not report neurodevelopmental delay [131]. A
or by dilatation and extraction (D&X) by experienced operators, European randomized multicenter study (AMIPROM) is ongo-
with no trials comparing these two modalities. ing. Transabdominal amnioinfusion can be considered in a
For management of women who elect expectant manage- research context.
ment, recent data [125, 126] give a direction, taking into account
that deciding upon a threshold of viability is challenging. Outpatient-inpatient management and
timing of hospitalization (see Figure. 20.1)
Tocolysis In women desiring expectant management with PPROM <23
Tocolytic therapy in previable PROM is not recommended weeks, avoid vaginal examination until labor or delivery.
[125, 126]. In summary, prophylactic tocolysis may be associ- During expectant management, monitor on an outpatient basis
ated with a longer latency but an increased risk of chorioam- for the onset of infectious complications, observing temperature,
nionitis, without significant maternal or neonatal improved maternal or fetal tachycardia, uterine contractions or tenderness,
outcomes. or purulent vaginal discharge. As an outpatient, instruct to avoid
intercourse, check temperature, and refer to hospital for vaginal
Antenatal corticosteroids bleeding and contractions. At 23–24 weeks, consider (re)admis-
Antenatal corticosteroids are not recommended before 22
sion to the hospital, taking into account whether or not families
weeks. The latest joint workshop on periviable management by
and clinicians agree on aggressive neonatal intervention after
the American Academy of Pediatrics and ACOG stated that a
counseling.
single course offered in the mid-22nd week is reasonable if deliv-
ery at 23 weeks is anticipated and the family agrees on aggres-
sive neonatal intervention after counseling [41]. NICE Guidelines PPROM following invasive procedures
2019 [125] stated that it may be considered from 230/7 weeks (iatrogenic PPROM) and strategies to repair
after discussion of the potential benefits and risks. If the preg-
nancy is not delivered within 7 days, it is not recommended to Iatrogenic PPROM (iPPROM) and spontaneous PPROM have dif-
offer routine repeat courses, but GA should be taken into account, ferent characteristics. In iPPROM, the hole, which subsequently
along with the interval since the end of the last course and the fails to close, is created by the instrument (needle or fetoscope,
likelihood of delivery within 48 hours. as an example).
Although the introduction of increasingly sophisticated
Magnesium sulfate neuroprotection screening techniques for chromosomal abnormalities led to less
Magnesium sulfate for neuroprotection is not recommended invasive testing based on maternal age, advancing skills in ultra-
before 23 weeks [41, 125, 126]. Between 23+0 and 23+6 sound screening have meant that there is an increased need for
weeks, neuroprotection should be discussed with the invasive prenatal testing via chorionic villus sampling in the first
woman and her family in the context of her individual cir- trimester or amniocentesis in the second trimester [132]. A risk
cumstances [125]. of approximately 1%–3% for subsequent amniotic fluid leakage
is reported [132]. Subclinical leakage after amniocentesis may between the mechanical sealing group and the standard care
occur more frequently than initially thought [133]. In these cases, control in relation to the incidence of neonatal sepsis (RR 1.19,
outcomes are better than after spontaneous PPROM, and reaccu- 95% CI 0.28–5.09 [very low-quality evidence]) or chorioamnio-
mulation of normal amniotic fluid volume is more probable [134]. nitis (RR 1.19, 95% CI 0.28–5.09 [very low-quality evidence]).
Parameters that have been suggested to affect iPPROM rates Concerning oral immunologic membrane sealant versus stan-
are the diameter of the surgical instrument and the number of dard care (one study, data from 94 participants), no data were
entries to the uterine cavity [135]. Other possible risk factors available for perinatal mortality (this review’s primary outcome)
are duration and difficulty of the procedure, operator experi- or for the majority of this review’s infant and maternal secondary
ence, membrane friction due to instrument manipulation, type outcomes. Compared to standard care, the immunologic mem-
of anesthesia, GA at intervention, number of interventions, and brane sealant was associated with a reduction in PTB less than
placental location. In one review the maximum diameter of the 37 weeks (RR 0.48, 95% CI 0.34–0.68 [very low-quality evidence])
instrument predicted iPPROM rate, GA at birth, and fetal sur- and a reduction in neonatal death (RR 0.38, 95% CI 0.19–0.75
vival [136]. [very low-quality evidence]). However, there was no clear differ-
In a retrospective study of 1092 cases of Twin-to-twin transfu- ence between groups in terms of neonatal sepsis (RR 0.64, 95%
sion syndrome (TTTS) operated by fetal laser coagulation between CI 0.28–1.46 [very low-quality evidence]) or respiratory distress
2000 and 2016 [137], both survival and PPROM rates rose; in par- syndrome (RR 0.64, 95% CI 0.28–1.46 [very low-quality evi-
ticular, PPROM <32 weeks increased from 15% to 40% along with dence]). In conclusion there is insufficient evidence to recom-
an overall improvement of perinatal outcomes: Dual survival rose mend sealing procedures for PPROM.
from 42% to 66%, whereas dual losses dropped twofold, from 19% There was limited evidence to suggest that an immunologic
to 9%. GA at surgery at <17 weeks was a significant risk factor for membrane sealant was associated with a reduction in PTB at less
PPROM, with an additional risk of 10% within the first week of than 37 weeks and neonatal death, but these results should be
surgery. Although early PPROM at <20 weeks carried a 56% risk interpreted with caution, as this is based on one small study, with
of miscarriage, the occurrence of PPROM at >20 weeks did not a high risk of bias, and the intervention has not been tested in
affect survival, despite an increase in PTB at <32 weeks. Surgical other studies.
technique is probably the most prominent factor. Substantial Even if such practices have not yet been incorporated into
changes were introduced throughout the study period: First, a clinical practice, current experience suggests that in cases of fluid
gradual improvement in the selectivity of the procedure between leakage following an invasive fetal procedure, the use of seal-
2000 and 2008 and secondly, the introduction of the “Solomon” ing techniques is a therapeutic option that should be researched
technique, which consists of a continuous chorionic coagulation further.
along the vascular equator. Recent reports [138] stated that the
Solomon technique could improve perinatal survival, but there PPROM in twin gestations
are concerns that the amount of coagulation required to com
plete the procedure could lead to significant placental damage, Overall, PPROM complicates 7%–8% of twin pregnancies at
increasing the occurrence of PPROM and preterm birth. a mean GA of 30–32 weeks (see also Chap. 46, in Maternal-
Several techniques have been developed in an attempt to arti- Fetal Evidence Based Guidelines). PPROM occurs at an earlier
ficially reseal the fetal membranes and prevent leakage of amni- GA among multiple gestations, with 36% of twin PPROM cases
otic fluid. These include intraamniotic injection of platelets and occurring at less than 28 weeks. PPROM in singleton pregnan-
cryoprecipitate (amniopatch), sealing the cervical canal [139]. cies is related mainly to infection/inflammation, while PPROM in
Compared to spontaneous PPROM, iPPROM is not only a dif- twin gestation may probably be more related to uterine overdis-
ferent entity etiologically but also has a better response to thera- tension. The latency period seems to be shorter in twins com-
peutic measures. One report demonstrated successful membrane pared with singleton pregnancies [144].
sealing for persistent oligohydramnios after amniocentesis and Most studies report a median latency of less than 24 hours
fetoscopy in seven women, using intraamniotic injection of plate- with only 16%–50% of twin pregnancies remaining undelivered
lets and cryoprecipitate through a 22-gauge needle [140]. at 48 hours, decreasing to 7%–22% at 7 days. Latency tends to be
According to a review of cases of iPPROM, amniopatch effec- longer when PPROM occurs before 30 weeks of gestation [145].
tively seals the fetal membranes in over two-thirds of cases [141]. The membrane rupture usually occurs in the lower sac (90% of
A retrospective analysis of 24 amniopatch procedures performed cases) [146].
for PPROM after a needle-based procedure or after fetoscopic Most studies comparing obstetric outcome between single-
intervention reported a success rate of 58% [142]. ton and twin pregnancies with PPROM reported no differ-
A Cochrane review of 2016 [143] included two studies (involv- ence in neonatal outcome [147]. A retrospective cohort of 23
ing 141 women, with data from 124 women), both considered multifetal pregnancies complicated by PPROM before 260/7 weeks
being at high risk of bias. Meta-analysis was not possible because showed a median latency of 11 days with expectant management.
the included studies examined different interventions (both in Of the 46 newborns, 20 (43%) survived to hospital discharge. Of
comparison with standard care) and reported on few, but differ- these, 12 (60%) experienced severe neonatal morbidity. The mul-
ent, outcomes. One study compared cervical adapter (mechani- tiple pregnancy cases with ruptured membranes were more likely
cal sealing), and the other study examined an immunologic to experience intrauterine fetal demise, but all other outcomes
membrane sealant. Neither of the included studies reported on did not differ by membrane status [148]. In 48 multiple pregnan-
this review’s primary outcome of interest—perinatal mortality. cies complicated by PPROM and delivering at a median GA of
Similarly, data were not reported for the majority of this review’s 31 weeks, neonatal morbidity and mortality were not different
secondary infant and maternal outcomes. Concerning cervi- between the presenting and nonpresenting twin, and no difference
cal adapter (mechanical sealing) versus standard care (one was found between fetuses with or without a ruptured sac. The out-
study, data from 35 participants), there was no clear difference comes were not affected by duration of the latency period [149].
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21
PRELABOR RUPTURE OF MEMBRANES AT OR NEAR TERM
Teodora Kolarova and Kimberly Ma
Key points clothes or a constant trickle of fluid that does not stop. Physical
exam for PROM starts with a sterile speculum examination [1–3].
• The diagnosis of prelabor rupture of membranes (PROM) Visualization of amniotic fluid passing from the cervical
at term is based on pooling, ferning, and nitrazine tests canal is diagnostic of this condition [1–3].
on speculum exam. Rapid bedside immunoassays such as Another helpful test is the nitrazine test. The pH of the vagina
placental alpha-microglobulin-1 or others may be helpful in is usually 4.5–6.0, whereas amniotic fluid has a pH 7.0–7.7; nitra-
cases in which the diagnosis of rupture of membranes (ROM) zine paper turns blue with pH >6.5 [1, 2]. A false-positive nitra-
is suspected but cannot be confirmed with pooling, ferning, zine test can be caused from blood, semen, alkaline antiseptic, or
and/or nitrazine tests. Initial digital examinations should be bacterial vaginosis. A false-negative nitrazine test can be caused
avoided and subsequent such exams kept to an absolute mini- by prolonged leaking of amniotic fluid or minimal residual fluid.
mum, as they are associated with a higher risk of infection. The sensitivity of nitrazine is 90.2% (81.3%–100%), and the speci-
• The main complication of PROM is intrauterine infection; ficity is 79.3% (16%–100%) [2].
this incidence increases with the duration of PROM, and with A third helpful test is called “ferning.” A swab of vaginal fluid
longer latency, the risk of neonatal infection also increases. from the posterior fornix is placed on a slide and allowed to air
• Women with PROM at term should be hospitalized and dry. Arborization (ferning) under microscopic visualization sug-
induced with oxytocin within 6–12 hours of PROM, or gests rupture of membranes. Cervical mucus can cause a false-
earlier as feasible. Most women with PROM at term, if positive result. Ferning has a sensitivity of 90.8% (62.0%–98.5%)
given a choice, prefer induction. Oxytocin induction and a specificity of 95.3% (88.2%–100%) [2].
is safe, effective, and cost-effective, and is therefore The combination of vaginal pool of fluid, nitrazine, and
the preferred first-line agent for induction after PROM. ferning has a sensitivity of 90.8% and a specificity of 95.6% [2].
Misoprostol induction is an alternative, with limited data These tests are more accurate when patients present in labor and
suggesting safety and noninferiority to oxytocin. Foley less accurate when nonlaboring [3]. If these tests are equivocal,
catheter ripening is not superior to other methods of an ultrasound can be performed to evaluate for amniotic fluid,
induction and has been associated with increased risk for but oligohydramnios is not diagnostic of PROM, since it can be
intrauterine infection. associated with other etiologies, such as placental insufficiency.
• Antibiotics are recommended if the patient is group B Placental alpha-microglobulin-1 is a 34-kDa glycoprotein
streptococcus (GBS) positive or complications (chorioam- abundant in amniotic fluid (2000–25,000 ng/mL); there is a negli-
nionitis) develop during labor. In women expected to have gible amount of this glycoprotein in vaginal fluid with intact fetal
a latency from PROM to delivery of over 12 hours, antibiot- membranes (0.05–2.0 ng/mL) [2, 4, 5]. AmniSure is a bedside
ics are associated with significantly decreased chorioam- immunoassay that uses the delta in concentration of placental
nionitis and endometritis. alpha-microglobulin-1 for diagnostic accuracy. AmniSure has a
• PROM at 340/7 and 366/7 can be managed expectantly if infec- sensitivity of 98.7%–98.9% and a specificity of 87.5%–100% [4, 5].
tion is not present, or delivered immediately. Decision should Insulin-like growth factor binding protein 1 (IGFBP-1) has a
be made after sufficient counseling and through shared deci- high concentration in amniotic fluid compared to other body
sion-making. Corticosteroid administration for fetal maturity fluids such as vaginal secretions, urine, or semen [6]. An immu-
should be offered if not received previously. If expectant man- nochromatography dipstick method (Actim PROM) is available
agement is chosen, latency antibiotics should be administered to diagnose rupture of membranes. The test is more popular in
per institutional protocol for PROM <34 weeks. Europe compared to the United States and is most accurate when
the timing of the test is close to the timing of rupture of mem-
Definition branes. The sensitivity of the test is 95%–100% with a specificity
of 93%–98% [7–10].
Prelabor rupture of membranes is rupture of fetal membranes A negative fetal fibronectin can be helpful in ruling out rupture
prior to the onset of labor [1]. Preterm prelabor rupture of mem- of membranes; however, a positive test cannot distinguish between
branes (PPROM) is prelabor rupture of fetal membranes ≤37 intact and ruptured membranes [11]. Alpha-fetoprotein levels are
weeks [1]. This chapter includes guidance for late-preterm (340/7– higher in amniotic fluid compared to urine, semen, or normal vagi-
366/7 weeks), as well as term (≥37 weeks) prerupture of membranes nal discharge. A recent study showed a 96.2% sensitivity and 100%
(PROM). For PPROM <34 weeks, see Chap. 20. specificity; however, it may be falsely positive if a vaginal infection
is present and requires further study in a larger cohort [12]. Further
Diagnosis studies are needed to assess reliability, with special attention paid
to time of presumed membrane rupture [2, 3]. Placental alpha-
The diagnosis of PROM and PPROM is based on history and microglobulin-1, IGFBP-1, and these other tests have limited
physical examination findings (see also Chap. 20). A maternal clinical applicability currently, given the high accuracy of pool-
history suggestive of PROM includes a gush of fluid soaking ing, ferning, and nitrazine tests. Nonetheless, they can be helpful
262 DOI: 10.1201/9781003102342-21

Prelabor Rupture of Membranes at or Near Term 263
in cases in which the diagnosis of ROM is suspected but cannot TABLE 21.1: Management of PROM at ≥37 Weeks
be confirmed with pooling, ferning, and/or nitrazine tests.
• Deliver (e.g. start induction <6–12 hours after PROM)
• Manage in hospital
Incidence • Oxytocin is the induction agent with the best safety and
effectiveness
PROM occurs in approximately 8% of all term deliveries [1].
• Antibiotics are recommended if the patient is GBS positive or
complications (chorioamnionitis) develop during labor. In women
Etiology expected to have a latency from PROM to delivery of over 12 hours,
antibiotics are associated with significantly decreased
The etiology of PROM without signs of infection or bleeding is chorioamnionitis and endometritis
often unknown, and this should be considered a physiologic, not
Abbreviations: PROM, prelabor rupture of membranes; GBS, group B streptococcus.
pathologic, event.
Risk factors
in the need for maternal antibiotics for nulliparas and 97% more
The risk factors associated with rupture of fetal membranes
neonatal infections [16]. PROM at term should be managed in
include low socioeconomic status, low body mass index (BMI)
hospital.
<19.8 kg/m2, nutritional deficiencies of ascorbic acid and cop-
per, connective tissue disorders, smoking, cold knife cone biopsy, Delivery versus expectant management
cervical cerclage, pulmonary disease, uterine overdistension, and Women with PROM ≥37 weeks should be delivered. Induction
amniocentesis [1]. In addition, pregnant women with a previous of labor with oxytocin has been shown to decrease the rate of
preterm birth, midtrimester short cervix, and preterm labor are maternal chorioamnionitis and postpartum fevers without
at increased risk for PROM; however, the majority of cases have significantly affecting the rate of cesarean delivery, compared
no identifiable cause [1]. with expectant management, and is the preferred method of
induction with PROM [14]. In most randomized controlled trials
Complications (RCTs), induction was with oxytocin or prostaglandins, with one
trial using homeopathic Caulophyllum and another acupuncture.
The most common complications of PROM are chorioam- Overall, no differences were detected for mode of birth between
nionitis, endometritis, and postpartum hemorrhage. With induced and expectant groups: Cesarean (relative risk [RR]
increasing time interval from ROM, there is a significant 0.84, 95% confidence interval [CI] 0.69–1.04) or operative vagi-
increase in these complications: About 12 hours for chorio- nal birth (RR 1.03, 95% CI 0.67–1.59). Significantly fewer women
amnionitis, 16 hours for endometritis, and 8 hours for post- in the induced compared with expectant management groups
partum hemorrhage [13]. As the latency from ROM to delivery developed chorioamnionitis and/or endometritis (RR 0.49 95% CI
increases, so does the risk for neonatal infection. Maternal 0.33–0.72). Infants of those who were induced experienced less
group B streptococcus (GBS) colonization also increases the probable or definitive early-onset sepsis (RR 0.73, 95% CI 0.58–
risk for neonatal infection. Incidence of cesarean delivery is 0.92). Further, fewer infants under induced management went to
not affected by management with either induction or expect- the neonatal intensive unit or special care nursery compared with
ant management, but depends on other risk factors (e.g. nul- expectant management (RR 0.75 95% CI 0.66–0.85) [17]. In sub-
liparity) [14]. group analysis, parity did not have an effect on cesarean delivery
rates or maternal or neonatal infections [17].
Compared with expectant management, induction of labor by
Management oxytocin is associated with a 42% decrease in the risk of mater-
Initial evaluation nal infection and 36% in definitive or probable neonatal infec-
Initial evaluation of PROM involves confirmation of the diag- tion [17]. Based on one trial, women were more likely to view their
nosis. Digital examination can increase the risk of infection care positively if labor was induced with oxytocin [14]. Cesarean
and as a result should be avoided [14]. The cervix can be visu- delivery rates are similar between groups if induced with oxy-
ally assessed for dilation and effacement [15]. Fetal presentation tocin. Perinatal mortality rates are low and not significantly
should be confirmed by ultrasound. Fetal well-being and the different between groups, although the trend is toward fewer
presence of uterine contractions should be assessed by external perinatal deaths with induction of labor by oxytocin [17].
monitoring. Studies utilizing prostaglandins as the initial mode of induc-
tion of labor are varied in the type, formulation, dosage, and
Counseling duration of use [17]. No clear differences were observed in neo-
Risk factors, complications, and management of PROM should natal infections using prostaglandins compared to placebo or
be reviewed with the patient. About 50% of women with PROM no treatment. Subgroup analysis suggests a differential treat-
at term deliver within 6–12 hours, and 95% of women will deliver ment effect for maternal infectious morbidity (RR 0.21, 95% CI
within 28 hours of membrane rupture [1, 14]. Principles of man- 0.12–0.36) and cesarean section (RR 0.54, 95% CI 0.45–0.66)
agement can be reviewed (Table 21.1). when sublingual misoprostol (prostaglandin E1) is used com-
pared to expectant management, but this was based on a single
Hospitalization clinical trial [17]. There is insufficient data to make meaning-
Compared with management in the hospital, expectant manage- ful comparisons of the different prostaglandin formulations in
ment of PROM at term at home is associated with a 52% increase clinical use.
Medications for induction presents with PROM at term, antibiotics can be administered
Immediate induction of labor with intravenous oxytocin has and induction of labor can begin concurrently. In addition, if a
been shown to decrease the rate of maternal and neonatal infec- woman is scheduled for a repeat cesarean section and presents
tion without increasing the rate of cesarean section [14, 17]. with PROM, GBS antibiotic prophylaxis should be administered
Misoprostol (PGE1) and dinoprostone (PGE2) have not been while arranging for the repeat cesarean section [32].
shown to be superior to intravenous oxytocin even in women GBS negative: Although ACOG guidelines recommend
with an unfavorable cervix [17, 18]. However, when misopros- against routine antibiotic prophylaxis in patients with docu-
tol is compared to PGE2, length of labor is shorter but there is mented GBS-negative status, there is evidence that women with
increased uterine tachysystole [18]. Cost is less with oxytocin PROM and latency >12 hours have a reduced risk of infectious
induction. Vaginal or oral misoprostol appears to be an effective morbidity with administration of antibiotics. A meta-analysis
means of labor induction comparable to oxytocin, but the studies and Cochrane review evaluated the efficacy of antibiotic pro-
reviewed were not large enough to exclude the possibility of seri- phylaxis in women with term or late-preterm prelabor rupture
ous adverse events with misoprostol [19–23]. There is insufficient of membranes and concluded that routine antibiotic prophy-
evidence to assess if the combination of PGE2 together with oxy- laxis was not associated with maternal or neonatal benefits,
tocin is superior to oxytocin alone [24]. although for women with latency greater than 12 hours, pro-
The efficacy of Foley bulb or other mechanical means of phylactic antibiotics were associated with significantly
induction in women with PROM has been evaluated, and Foley lower rates of chorioamnionitis (2.9% versus 6.1%, RR, 0.49,
does not shorten time to delivery when compared to oxyto- 95% CI, 0.27–0.91) and endometritis (0% versus 2.2%; RR, 0.12,
cin alone in PROM [25, 26]. Foley is also not superior to pros- 95% CI, 0.02–0.62) in the meta-analysis, and a similar trend was
taglandins for induction of labor in women with term PROM observed in the Cochrane review [34, 35]. Thus, in women with
[27]. Regarding its safety, induction with Foley bulb has been latency over 12 hours, prophylactic antibiotics can reduce the
associated with increased risk for clinical chorioamnionitis risk of maternal infectious morbidity.
in one RCT where women received antibiotic prophylaxis per GBS status unknown: Per ACOG and CDC guidelines, if the
American College of Obstetricians and Gynecologists (ACOG) patient has no risk factors (previous infant with GBS sepsis, <37
guidelines [25]. weeks, rupture of membranes >18 hours, chorioamnionitis, GBS
In summary, in patients with PROM at term, once the diag- presence in previous pregnancy), routine antibiotic use should
nosis has been confirmed, induction of labor is recommended. be avoided [32, 33, 35]. As referenced earlier, however, there is
Induction should probably occur at least within 6–12 hours of evidence of benefit when antibiotics are administered with rup-
PROM, or earlier if feasible. If expectant management is per- ture of membranes >12 hours and can be considered sooner
formed, there is a significant increase in chorioamnionitis and than 18 hours as suggested by ACOG [34, 35]. Alternatively, in
neonatal infection as duration increases [28–30]. Oxytocin is PPROM 340/7–366/7 weeks, if the patient has no GBS culture
the recommended induction medication, as it is safe, effec- from the previous 5 weeks, antibiotics should be administered
tive, and cost-effective. Foley bulb (or other balloon) is not per protocol, or a rapid GBS test can be performed. If the rapid
superior to oxytocin or prostaglandins and confers an increased GBS result is negative, antibiotics can be withheld unless other
risk for chorioamnionitis [25–27, 31]. Vaginal and oral misopro- risk factors develop (chorioamnionitis or rupture of fetal mem-
stol are also safe and effective but have not been proven to be branes greater than 12–18 hours) [32].
superior to oxytocin when appropriate doses (e.g., 25 mcg for In summary, for PROM at ≥37 weeks, antibiotics should
vaginal misoprostol) are used [18]. With increasing latency from be given if the woman is GBS positive or clinical chorioam-
PROM to delivery, there is an increased risk for chorioamnio- nionitis develops during labor and should be considered for
nitis, endometritis, and postpartum hemorrhage [13]. Women all women with expected latency from PROM to delivery
should be counseled to initiate induction of labor as soon as >12 hours [33–35]. In PPROM between 340/7 and 366/7 weeks,
amenable after PROM in order to decrease the risk of these antibiotics should be administered if GBS status is positive or
complications. unknown [33, 34].
Antibiotics Special considerations for PPROM

GBS positive: In women with a positive GBS culture, antibiot- at 34–36 weeks’ gestation
ics should be administered according to the Centers for Disease Delivery versus expectant management
Control and Prevention (CDC) and ACOG guidelines [32, 33] (see Based on newer evidence reviewed next, the ACOG Practice
Chap. 39 in Maternal-Fetal Evidence Based Guidelines). Women Bulletin suggests that in patients with PROM between 340/7
who are GBS positive with PROM at ≥34 weeks are treated and 366/7 weeks of gestation, either expectant management
with penicillin in labor. Ampicillin is a reasonable alternative. or immediate delivery is a reasonable option; the balance
If the patient is penicillin-allergic but not at high risk for ana- between benefit and risk from both a maternal and neona-
phylaxis, cefazolin is the agent of choice. For women at high risk tal perspective should be carefully considered (Table 21.3). If
for anaphylaxis, GBS isolate should be tested for susceptibility to expectant management is continued beyond 34 0/7 weeks of gesta-
clindamycin and erythromycin. Vancomycin is recommended tion, it should not extend beyond 370/7 weeks of gestation [1].
if the isolate is resistant to either clindamycin or erythromycin. The original research determining the best antenatal approach
Intrapartum treatment for chorioamnionitis is recommended to PPROM, including the late preterm period, studied patients
regardless of GBS maternal status. with documented fetal maturity [36, 37]. Overall, these studies
In these revised recommendations, 4 hours of intravenous anti- found that expectant management in late preterm PPROM pro-
biotics are considered adequate treatment for a neonate; however, duced longer latencies; however, there was a significant increase
no medically necessary obstetric procedure should be delayed to in maternal infection without demonstrated neonatal benefit
achieve 4 hours of intravenous antibiotic therapy [32]. If a patient [36–40].
Recent studies have called attention to the neonatal complica- TABLE 21.3: Risks and Benefits of Expectant Management
tions of late preterm birth, which include respiratory complications, versus Immediate Delivery in Late-Preterm (between
sepsis evaluations, hyperbilirubinemia requiring phototherapy, 340/7 and 366/7 weeks) PROM
and death. This combination of potential complications has led
Benefits of Expectant Management Benefits of Immediate
to an increase in neonatal intensive care unit (NICU) admissions,
Delivery
increasing length of stay, urgent hospital visits, and hospital read-
missions [41–48]. The effort to decrease late-preterm birth in the Less neonatal respiratory distress Less antepartum hemorrhage
United States has been successful, with a decrease from 9.15% in syndrome
2006 to 7.99% in 2013 (a 13% decrease) [49]. Less hyperbilirubinemia Less chorioamnionitis
More contemporary research addressing the management Less NICU or SCN admission In women with positive
of late preterm PROM has included two international RCTs vaginal culture, decreased
(PPROMEXIL and PPROMEXIL-2) and a third multicenter neonatal sepsisa
RCT (PPROMT study) [50–52]. An individual participant Shorter NICU stays
meta-analysis of these three trials showed no difference Shorter neonatal hospital stays
in their primary outcome, a composite of neonatal adverse Decreased risk of cesarean delivery
events, in the immediate delivery versus the expectant man-
a See Table 21.2 for details.
agement group (RR 1.20, 95% CI 0.94–1.55) [53]. Specifically,
Abbreviations: PROM, premature rupture of membranes; NICU, neonatal intensive
there was no difference in neonatal sepsis between the
care unit; SCN, special care nursery.
groups (RR 0.74, 95% CI 0.47–1.15). However, neonates in the
immediate group were more likely to be diagnosed with
respiratory distress syndrome (RR 1.47, 95% CI 1.10–1.97) or immediate delivery is a reasonable option for rupture of
and hyperbilirubinemia and to be admitted to the NICU or membranes between 340/7 and 366/7 weeks after sufficient
special care nursery (RR 1.17, 95% CI 1.11–1.23), leading to counseling [1]. Care should be individualized through shared
longer hospital stays [53]. In a subgroup analysis of patients decision-making. Women with vaginal infections should be
with a positive vaginal culture (included 14 different patho- induced at 340/7 weeks (see Tables 21.2 and 21.3).
gens), immediate delivery did reduce the risk of neonatal
sepsis (see Table 21.2). In regard to maternal outcomes, those Steroids for fetal maturity
who were delivered immediately experienced less antepar- Regarding corticosteroid administration for fetal maturity, evi-
tum hemorrhage (RR 0.57, 95% CI 0.34–0.95) and less cho- dence suggests that steroids are associated with neonatal benefit
rioamnionitis (RR 0.21, 95% CI 0.13–0.35), but were more in the late preterm period. The largest of these trials (the ALPS
likely to require cesarean delivery (RR 1.26, 95% CI 1.09–1.47) trial) demonstrated a decrease in multiple neonatal respiratory
[53]. Most women received antibiotics (76% in the immediate morbidities with steroid administration, but also an increased
delivery group and 78% in the expectant management group, risk of neonatal hypoglycemia [54]. A meta-analysis of six RCTs
but the rates varied in each trial) [53]. In the subgroup analysis with three of these trials including women at 34 0/7–366/7 weeks at
for positive GBS, antepartum tocolysis, corticosteroid admin- risk for imminent premature delivery confirmed these findings
istration, and administration of latency antibiotics showed no [55]. Neonates who received antenatal corticosteroids ≥34 weeks
difference in treatment effect for the composite adverse neo- had a significantly lower incidence tachypnea of the newborn (RR
natal outcome or any of its components [53]. 0.72, 95% CI 0.56–0.92), severe respiratory distress syndrome
With the additional information from this meta-analysis, (RDS) (RR 0.60, 95% CI 0.33–0.94), and any RDS (RR 0.74, 95%
ACOG now recommends that either expectant management CI 0.61–0.91) [55]. Steroids should be considered for decreas-
ing respiratory morbidities and other neonatal outcomes in
women 340/7–366/7 weeks [55]. It should be noted that although
evidence supports short-term benefit, long-term benefits of ante-
TABLE 21.2: Management of PPROM at 340/7–366/7 Weeks natal corticosteroids in the late preterm period are unknown.
See Chap. 20 for other details on management for women with
• Deliver if infection presenta PPROM <34 weeks [48].
• If no infection present, deliver OR expectantly manage until 37 weeks
0 days. Shared decision-making weighing risks and benefits (see Antibiotics
Table 21.3) ACOG currently does not recommend the administration of
• Manage in hospital latency antibiotics in those patients who elect for expectant man-
• Single course of corticosteroids for fetal maturity, if steroids not agement in late-preterm PPROM [1]. However, most patients in
previously given (if no contraindications exist and delivery not the individual participant meta-analysis on late-preterm PPROM
expected in less than 24 hours or greater than 7 days) received antibiotics [53]. A Cochrane review on antibiotic use for
• Antibiotics are recommended if the patient is GBS positive, GBS patients with PPROM <37 weeks also demonstrates that antibiot-
unknown, or expectant management is chosen ics decrease the risk for chorioamnionitis and neonatal infection
and prolong latency [56]. It is unclear what antibiotics are best,
a Infections include clinical chorioamnionitis or any of the following on vaginal cul-
because different regimens were used in the late-preterm PPROM
ture: Bacterial vaginosis, Candida albicans, Candida glabrata, Candida tropicalis,
Chlamydia, coagulase-negative Staphylococcus, Enterococcus, Escherichia coli,
trials. If PROM occurs at 340/7–366/7 weeks and expectant
group B streptococcus, Hemophilus influenza, Staphylococcus aureus, Staphylococ management is elected, it is recommended that the patient
cus agalactiae, Trichomoniasis, and Ureaplasma urealyticum. receive the same institutional latency antibiotic regimen uti-
Abbreviations: PPROM, preterm prelabor rupture of membranes; GBS, group B lized in patients who experience PPROM <34 weeks [56] (see
streptococcus. Chap. 20).
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22
MANAGEMENT OF THE UNCOMPLICATED TERM PREGNANCY
Rebecca Jackson
Key points can be defined as a pregnancy that has lasted until ≥41 weeks,
or ≥287 days, or ≥7 days after the due date (EDC) [1]. The term
• Postterm pregnancy is defined as a pregnancy that has “postdates” can signify a pregnancy that lasted until ≥40 weeks,
lasted until ≥42 weeks, or ≥294 days. Late-term preg- or ≥280 days, but is often defined differently in the literature and
nancy is defined as a pregnancy that has lasted 410/7 to should be avoided [1]. All these definitions may have slightly dif-
416/7 weeks of gestation. ferent meanings in the literature, so it is important to be clear
• Late-term and postterm pregnancies have a twofold when using these terms. These definitions and this guideline per-
increase in the risk of macrosomia and subsequent tain to singleton gestations. For multiple gestations, please refer
increase in labor dystocia, operative vaginal delivery, to Chap. 46 in Maternal-Fetal Evidence Based Guidelines.
cesarean delivery, perineal injury, and shoulder dystocia.
• Postterm neonates are at increased risk for seizures, Epidemiology/Incidence
meconium aspiration, 5-minute Apgar scores less than
4, and admission to the neonatal intensive care unit. In 2018, in the United States, the incidence of late-term preg-
Postterm pregnancies are also at increased risk for nancy was 5.90% and of postterm pregnancy was 0.30% [2]. These
intrauterine infection, oligohydramnios, nonreassur- incidences have significantly decreased in the last few years.
ing fetal heart rate tracing (NRFHT), low umbilical
artery pH, and perinatal mortality.
• Pregnancies with risk factors such as maternal (e.g.
hypertension and diabetes) and fetal (growth restriction, The most frequent cause of postterm pregnancy is an error in
etc.) diseases should be delivered at term or as described dating [1, 3]. See Chap. 4 for accurate dating criteria and their
in Chap. 23. benefits, as well as the following sections.
• Prevention of postterm pregnancy can be achieved with
accurate dating by routine first-trimester ultrasound and
with serial membrane stripping starting at 38 weeks.
• There is insufficient evidence to assess the efficacy of ante- Poor (wrong) dating; prior postterm pregnancy, obesity, nulliparity,
partum testing for pregnancies after their due date. Twice- long (>28 days) cycles without early ultrasound, placental sulfatase
weekly fetal testing with nonstress test (NST), or NST and deficiency, anencephaly, and male fetus. Obesity appears to be one
maximum vertical pocket (MVP) of amniotic fluid volume preconceptionally modifiable risk factor for postterm pregnancy [4].
(AFV), or biophysical profile (BPP), has been proposed,
starting at 41 weeks.
• All women should be offered induction of labor for 39 Complications
weeks’ gestation (preferred name of this indication for
Perinatal
induction), as it has been shown to decrease the risks of
Many epidemiologic studies have shown that fetal and neona-
cesarean delivery; of hypertensive disorders of preg-
tal complications increase with gestational age after 41 weeks.
nancy; and of adverse perinatal outcomes, including still-
Meconium aspiration, intrauterine infection, oligohy-
birth, admission to the neonatal intensive care nursery,
dramnios, macrosomia, nonreassuring fetal heart rate trac-
and need for respiratory support, compared to expectant
ing (NRFHT), low umbilical artery pH, and low 5-minute
management up to 40 weeks 5 days. These benefits are simi-
Apgar score have all been associated with postterm pregnancy.
lar for all race/ethnic groups, ages, Bishop scores, and body
Perinatal mortality (fetal and neonatal deaths) is twice as high
mass indexes (BMIs). Induction for 39 weeks’ gestation is
at ≥42 weeks and 6 times as high at ≥43 weeks compared with
also associated with decreased pain in labor and higher
the rate for pregnancies delivered between 39 and 40 weeks [1, 5].
maternal satisfaction and sense of control compared
Two markers of immediate neonatal morbidity, umbilical
to expectant management. Most women do want to be
artery pH <7 and base excess ≥12, have been shown to increase
induced at 39 weeks when offered the option. Induction for
in a continuous manner in pregnancies beyond 40 weeks and
39 weeks’ gestation is also associated with less costs and
increase by odds ratio (OR) 1.65 for pH <7 for pregnancies
other health care system benefits.
between 41 and 42 weeks [6].
Neonatal mortality of normal-weight infants appears to be
Diagnosis/Definition higher for infants born between 41 and 0 days and 41 weeks and 6
days compared with infants born between 38 weeks and 40 weeks
Postterm pregnancy is defined as pregnancy that has lasted until and 6 days (OR 1.37, 95% confidence interval [CI] 1.08–1.73) [7].
≥42 weeks, or ≥294 days, or ≥14 days after the due date (esti- However, these data are mixed and may vary based on whether
mated date of confinement [EDC]) [1]. Late-term pregnancy risk factors such as fetal growth restriction (FGR) are included
268 DOI: 10.1201/9781003102342-22

Management of the Uncomplicated Term Pregnancy 269
in the analysis. In a review of epidemiologic studies published

<14 weeks
between 1990 and 2004, 7 out of 11 studies demonstrated an Ultrasound to establish accurate dating
increased stillbirth risk with postterm pregnancies, and 4 sug-
gested that other issues such as FGR or fetal anomalies had a
greater contribution to the stillbirth rate than did prolonged
pregnancy [8].
Postmaturity syndrome is present in about 10%–20% of neo- ≥37–38 week
nates born postterm. These fetuses have decreased subcutaneous
fat and lack of vernix and lanugo. Postmature neonates are also - Start weekly stripping of membranes
- If risk factor present, manage appropriately1
more likely to have meconium staining of the amniotic fluid, skin,
membranes, and umbilical cord [1].
Maternal 380 – 386 wk

Women giving birth late-term and postterm are at increased risk
of perineal injury, infection, postpartum hemorrhage, and - Counsel regarding induction at 390 - 396 weeks2, 3
cesarean delivery [1]. - Fetal kick counts every day. Clinical assessment of fetal weight
and ultrasound EFW if clinical assessment limited by habitus.
Pregnancy considerations
Every woman should be counseled early in pregnancy that up to 390 – 396 wk
50% of gestations, especially in nulliparous women, last until past Induction
the due date. This is physiologic and natural for humans. The inci-
dence of fetal death is significantly higher than that of neonatal
death at ≥283 days (≥40 weeks and 3 days) [9]. In a large series, FIGURE 22.1 Management of term pregnancy. 1 – Risk factor
delivery at 38 weeks is associated with the lowest risk of perinatal examples include hypertension, diabetes mellitus, FGR, multiple
death, but this risk is low at <1 to 2/1000 up to 41 weeks and 6 days gestation, etc. Please see guideline pertinent to specific risk factor
[10]. It is important to identify maternal (e.g. hypertension for management. 2 – Strongly suggest induction for all women
and diabetes) and fetal (e.g. growth restriction) risk factors between 390 and 396 weeks. 3 – See Chap. 23 for effective induc-
that would necessitate special management, as described in the tion management. Abbreviation: EFW, estimated fetal weight.
specific chapters in Maternal-Fetal Evidence Based Guidelines.
The OR for stillbirths and neonatal mortality increases in gesta-
tions from 40 weeks onward, and this increase is compounded the incidence of postterm pregnancy and of induction for
sevenfold to tenfold when the fetus is growth restricted [11]. postterm pregnancy [4, 12, 13] (see also Chap. 4).
Stripping/Sweeping of membranes
Management (Figure 22.1) Compared with no sweeping, sweeping of the membranes, per-
formed weekly as a general policy in women at term (e.g. weekly
Preconception counseling starting at 37–38 weeks), is associated with reduced duration
Women with prior postterm pregnancy are at increased risk for of pregnancy and reduced frequency of pregnancy continuing
recurrent postterm pregnancy. Prevention strategies, includ- beyond 41 and 42 weeks [14, 15]. To avoid one formal induction of
ing weight loss for obese women, appropriate weight gain labor, sweeping of membranes must be performed in eight women.
during the pregnancy, early initiation of prenatal care, early Risk of cesarean section, maternal, or neonatal infection is
ultrasound screening, and stripping of membranes starting at similar. Serial sweeping of membranes starting at 41 weeks every
37–38, weeks should be discussed [3]. 48 hours also decreases the risk of postterm pregnancy from 41%
to 23%, with efficacy both in nulliparous and multiparous women
Prevention [16]. Discomfort during vaginal examination and other adverse
Routine early ultrasound to reduce effects (bleeding and irregular contractions) are more frequently
postterm pregnancies reported by women allocated to sweeping, but its safety has been
Accurate assessment of gestational age is extremely important confirmed in multiple studies [14–17] (see also Chap. 23).
in improving perinatal morbidity and mortality. First-trimester
ultrasound is the most accurate for pregnancy dating. Early Breast and nipple stimulation to
ultrasound also reduces the number of postterm inductions. reduce postterm pregnancies
Over 40% of women randomized to undergo first-trimester Breast and nipple stimulation daily starting at 39 weeks has not
screening had their gestational age adjusted based on the ultra- been sufficiently studied to ascertain safety, but it does appear to
sound measurement of crown–rump length, whereas the cor- reduce the incidence of postterm pregnancy by 48% [18, 19].
responding number was only 10.9% for women assigned to
second-trimester ultrasound. Furthermore, 4.8% in the first- Antepartum testing
trimester screening group compared with 13% in the second- If a woman with an uncomplicated pregnancy accepts induction
trimester ultrasound group had labor induced for a postterm at 39 weeks, there is no need for earlier antepartum testing. If she
pregnancy (relative risk [RR] 0.37, 95% CI 0.14–0.96), which is a declined induction, there are insufficient data to assess the best
63% reduction in the induction rate for postterm pregnancy mode of fetal monitoring after the due date, as there are no trials
[11, 12]. Compared with no routine early ultrasound, routine to assess the effect of antepartum testing on these pregnancies
early pregnancy (<20 weeks) ultrasound reduces by 32%–39% compared with no testing. Since fetal death rates incrementally
increase after the due date, it seems reasonable to test fetuses There were fewer cesarean sections in the induction group (RR
to assure well-being, especially at ≥41 weeks [1, 4, 9]. The most 0.89, 95% CI 0.81–0.97). Labor induction at 41 weeks also sig-
used options include nonstress testing (NST) (also called car- nificantly reduces the risk of perinatal meconium aspiration syn-
diotocography or CTG), biophysical profile (BPP), and modified drome compared with expectant management (RR 0.50, 95% CI
BPP. Modified BPP includes NST and ultrasound measurement of 0.34–0.73). Other maternal and perinatal outcomes are similar
maximum vertical pocket (MVP) of amniotic fluid volume (AFV). between the groups. It is important to recognize, however, that in
Others have been described, but with even less evidence for effi- general the outcomes are very good with both expectant manage-
cacy. Doppler of any vessel, including the umbilical artery, is not ment and induction, with the absolute perinatal death rate per
effective in the management of postterm pregnancy. Compared 1000 ongoing pregnancies no higher than 1.2/1000 at 42 weeks,
with fetal monitoring using NST and AFV, BPP (computerized increasing up to 6/1000 ongoing pregnancies at 43 weeks [23].
CTG, MVP, fetal breathing, fetal tone, and fetal body movements) About 410 inductions (95% CI 322–1492) would need to be done
is associated with increased incidence of inductions and similar at 41 weeks in order to prevent one perinatal death [21].
outcomes in a small trial in women ≥42 weeks [20]. At ≥41 weeks, Routine induction is more cost-effective than expect-
twice-weekly testing (e.g. with NST and MVP) is recommended ant management [26]. Several studies have shown that patient
[1], but not based on trials (see also Chap. 58 in Maternal-Fetal satisfaction is higher with induction of labor [21, 26, 27].
Evidence Based Guidelines). In addition, an effort should be made Iatrogenic prematurity should be avoided by careful assessment
to assess fetal weight, either clinically or, if this assessment is of gestational age. This risk should be minimal with the advent
limited, by ultrasound, as the known increase in fetal and neona- of widespread early ultrasound use to confirm pregnancy dat-
tal mortality in pregnancies beyond their due date is even higher ing. Planned induction without medical indications at 390/7–40 6/7
in FGR fetuses [11, 21]. weeks has been shown not to be associated with an increase with
cesarean delivery [28]. See also Chap. 23 for other induction risks
Interventions and benefits, as well as management of induction. For women
Induction of labor for ≥39 weeks with a prior cesarean delivery, see Chap. 15.
When compared to expectant management up to 40 weeks and 5
days, induction of labor at 39 weeks (39–394/7) in low-risk nul-
liparous women has been shown to decrease the frequency of References
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2020;2(2):100086. [Survey]
23
INDUCTION OF LABOR
Corina N. Schoen
Key points preferred methods for labor induction when the cer-
vix is <3 cm dilated.
• An early (e.g. <20 weeks) ultrasound examination helps • Vaginal misoprostol 25 mg every 2–4 hours is the
determine accurate gestational age and is associated with a preferred safe dosage and is as effective as PGE2 or any
reduction in the rates of induction of labor for postterm other method; this is also a preferred method of labor
pregnancy. induction.
• Gestational age should be documented accurately before • PGE2 tablet, gel, and insert appear to be as safe and
considering induction. efficacious as each other in terms of tachysystole, CD
• Possible indications for induction of labor and the sug- rates, and neonatal outcomes.
gested best gestational age for induction are listed in Table 23.1. • Other cervical ripening or induction agents are either not
Induction for 39 weeks’ gestation is associated with a sufficiently studied, unsafe, or not as effective as the agents
decrease in hypertensive disorders of pregnancy, cesarean already mentioned.
delivery (CD), and perinatal morbidity and mortality, com- • Oxytocin IV infusion is recommended with favorable cer-
pared to expectant management up to 40 weeks 5 days. vical exam.
• Without indications, induction before 39 weeks should • Oxytocin IV infusion is recommended for prelabor rup-
be avoided. ture of membranes (PROM) and should be started within
• Contraindications to induction of labor include mal- 12 hours, or as soon as feasible, after term PROM.
presentation, umbilical cord prolapse, previous classical • There are insufficient safety data for outpatient use of
uterine incision or transfundal uterine surgery (e.g. from pharmacologic cervical ripening or induction agents.
myomectomy), placenta or vasa previa, active genital her- However, there is emerging evidence that the Foley cath-
pes infection, and any contraindications to vaginal deliv- eter may be an effective and safe method for outpatient
ery, or indication for CD (Table 23.2). cervical ripening.
• Compared to expectant management, induction of labor • Contraction pressures of ≥200 Montevideo units should
can be complicated by a prolonged first stage of labor. be targeted in induction or augmentation of laboring
• Misoprostol should not be used for cervical ripening or patients to achieve adequate labor.
labor induction in women with prior uterine incisions, • While the definition of a failed induction of labor is elu-
given the >5% risk of uterine rupture. In women with prior sive, a failed induction should not be diagnosed until after
uterine incisions, prostaglandin E2 (PGE2) for cervical rip- 18–24 hours of oxytocin after membrane rupture in
ening is associated with an approximately 1.4%–2.5% risk the active phase (usually ≥6 cm in nulliparous women),
of rupture; oxytocin has a 1.1% risk. Cervical ripening assuming reassuring fetal heart pattern.
with the Foley catheter does not appear to be associated • Induced labor should be managed, in general, as spon-
with any additional risk of uterine rupture in patients taneous labor.
undergoing a trial of labor after cesarean section.
• In women with an unfavorable (Bishop score <5, or even Definitions
<9) cervical exam:
• Sweeping of membranes starting at 37–38 weeks Induction of labor is the stimulation of uterine contractions prior
weekly doubles the rate of onset of labor in the next to spontaneous labor in order to achieve childbirth. Cervical rip-
48 hours and decreases the incidence of no spontane- ening is a process that occurs prior to labor in which the cervix is
ous labor by the due date. softened, thinned, and dilated.
• Induction in these women should be done by two
agents, such as Foley balloon (single balloon, Incidence/Epidemiology
inflated to 60–80 mL, with traction) and misopro-
stol (e.g. 25 µg every 2–4 hours). If misoprostol is In 2017, there were 3.86 million births in the United States, of
contraindicated, combine Foley with oxytocin IV which 25.7% were induced [1]. There is evidence for a decreasing
infusion. rate of indicated preterm births (17% decline from 2005 through
• The Foley balloon is associated with less hyper- 2012) [2].
stimulation accompanied by fetal heart rate (FHR)
changes and increased use of oxytocin, but results Basic pathophysiology
in the same number of vaginal deliveries and the same
number of women delivered within 24 hours as all of The cervix functions as the gatekeeper to parturition, main-
the locally applied prostaglandins (prostaglandin E1 taining a fine balance between the integrity of the pregnancy
and E2 [PGE1 and PGE2]). It is therefore one of the and delivery. Histologically, the cervix is composed of mostly
272 DOI: 10.1201/9781003102342-23

Induction of Labor 273
TABLE 23.1: Indications for Induction of Labor with Suggested Timing of Delivery
Gestational Age at Induction Quality of Strength of
Condition (weeksdays) Evidence [135] Recommendation [135]
Obstetric
Intrauterine infection (e.g. chorioamnionitis) At detection Moderate Strong
Abruptio placenta At detection Moderate Strong
39 weeks gestation 390–396 High Strong
Maternal
Chronic hypertension – no medications 380–396 High Strong
Chronic hypertension – controlled on medications 370–396 High Strong
Chronic hypertension – difficult to control (requiring frequent 360–376 Moderate Weak
medication adjustments)
Gestational hypertension 370–376, at diagnosis thereafter High Strong
Preeclampsia – no severe features 370–376, at diagnosis thereafter High Strong
Preeclampsia – severe features 340, at diagnosis thereafter High Strong
Eclampsia At detection Moderate Strong
Diabetes – pregestational, well-controlled 390–396 Moderate Strong
Diabetes – pregestational, poorly controlled 340–386a Low Weak
Diabetes – gestational, well-controlled on diet 390–396 Moderate Strong
Diabetes – gestational, well-controlled on medication 390–396 Moderate Strong
Diabetes – gestational, poorly controlled on medication 340–396a Low Weak
Intrahepatic cholestasis of pregnancy with bile acids ≥100 360–376 Low Weak
Intrahepatic cholestasis of pregnancy with bile acids <100 370–396 Low Weak
Prior stillbirth 390–396 Low Weak
PPROM 340–366 High Strong
Fetal
FGR – singleton, otherwise uncomplicated, normal umbilical 380–396 Moderate Weak
artery Doppler
FGR – singleton, decreased but present diastolic flow in umbilical 370–376 Moderate Weak
artery Doppler
FGR – singleton, absent diastolic flow in umbilical artery Doppler 330–346 Moderate Weak
FGR – singleton, reversed diastolic flow in umbilical 310–326 Moderate Weak
artery Doppler
FGR – twin gestation, dichorionic-diamniotic twins with 350–366 Low Weak
isolated FGR with normal umbilical artery Doppler
FGR – twin gestation, monochorionic-diamniotic twins with 320–346 Low Weak
isolated FGR with normal umbilical artery Doppler
Macrosomia (e.g. EFW >4000 g, or larger for gestational 380–386 High Weak
age >95% percentile)
Twin gestation: dichorionic/diamniotic, uncomplicated 370–376 Moderate Weak
Twin gestation: monochorionic/diamniotic, uncomplicated 360–366 Low Weak
Twin gestation: monochorionic/monoamniotic, uncomplicated 320–346 Low Weak
Oligohydramnios (MVP <2 cm) – isolated but persistent 370–376 Low Weak
Nonreassuring fetal heart tracing (e.g. category III) At detection Low Strong
Fetal death At detection Low Weak
Source: From Berghella V, Bellussi F, Schoen C. Evidence-based labor management: induction of labor (part 2). Am J Obstet Gynecol MFM. 2020:1–9. [III, Review] Ref. [134],
with permission.
Abbreviation: EFW, estimated fetal weight; FGR, fetal growth restriction.
collagen, with some smooth muscle; the stability of these com- Risk factors/Associations
ponents and the ability to become dynamic when stressed on a
physical and molecular level are what changes the cervical status. Factors that may increase the risk for complications associated
This cervical status prior to induction is predictive of induction with induction are nulliparity, no prior vaginal delivery, unfavor-
success, as described later [3]. able cervical exam, postterm, obesity, and a large fetus.
TABLE 23.2: Contraindications to Induction of Labora Prevention

Usual Gestational Age at
A routine early ultrasound examination (e.g. before 20 weeks)
Condition Cesarean (weeksdays)
is associated with a 39% reduction in the incidence of postterm
Obstetrical pregnancies and rates of induction of labor for postterm preg-
Transverse or oblique fetal lie 390–396 nancy by allowing a more precise estimation of exact gestational
(malpresentation) age. An ultrasound performed in the first trimester (6–14 weeks)
More than two prior low-transverse cesarean 380–396 provides the best estimate of gestational age and the most benefit
deliveries in terms of avoiding induction for postterm pregnancy (see also
Placenta previa 360–376 Chap. 4) [12]. Membrane sweeping can also reduce the need of a
Placenta accreta/increta/percreta 340–356 labor induction by about 25% [13] and should be routinely offered
Vasa previa 340–366 to women who do not have a contraindication to vaginal delivery
starting at 37 weeks (Figure 23.1).
Maternal
Prior classical cesarean delivery 360–376
Prior myomectomy requiring cesarean 370–376 Criteria for induction
delivery
Prior uterine rupture 360–376 Workup/Counseling
Active genital herpes infection 390–396 Gestational age should be documented accurately before con-
HIV with viral load >1000 copies/mL 380–386 sidering induction to avoid inadvertent postterm and preterm
Fetal
deliveries. Indications and contraindications need to be carefully
reviewed. Counseling with the patient should include discussion
Nonreassuring fetal testing precluding fetal At diagnosis (individualize
of specific indications, risks (possible complications), and benefits
tolerance to labor for periviable)
of induction.
Umbilical cord prolapse At diagnosis
Other Indications
Any other contraindications to vaginal delivery Depending on diagnosis Once a term gestation has been confirmed, possible indications
Source: From Berghella V, Bellussi F, Schoen C. Evidence-based labor manage- for induction and suggested best timing are shown in Table 23.1
ment: induction of labor (part 2). Am J Obstet Gynecol MFM. 2020:1–9. [14, 15].
[III, Review] Ref. [134], with permission. For more details on the indications, see each specific guideline
a Perform cesarean if/when delivery is indicated. (e.g., Chaps. 15 and 20 in this volume and Chaps. 4, 5, 10, 46, and
48 in Maternal-Fetal Evidence Based Guidelines).
Complications
Gestational age of induction
Complications of inductions include prolonged first stage of labor, The gestational age at which the induction is being considered is
especially in the latent phase [4], leading to increased risk of post- very important. There are some indications for induction before
partum hemorrhage, intraamniotic infection, and endometritis 39 weeks (Table 23.1), but without indications induction before
[5, 6]. Cesarean delivery (CD) risk is not increased with induction 39 weeks should be avoided [14, 16]. In this chapter, induction
of labor compared to expectant management [7, 8]. Preterm (<37 and ripening in the third trimester, usually at or near term, is
weeks) induction is associated with prematurity risks and should reviewed. For second-trimester induction and ripening, see Chap.
only be performed for appropriate maternal or fetal indications. 57 in Maternal-Fetal Evidence Based Guidelines.
The safety of the induced patient can be enhanced through the
use of safety checklists available through the American College Induction at 39 weeks’ gestation
of Obstetricians and Gynecologists (ACOG) [9]. without medical indication
The ARRIVE trial was completed in the United States in 2018,
Pregnancy considerations which randomized 6,106 low-risk nulliparous women to induction
at 390/7–394/7 weeks versus expectant management until at least
The risks and complications of induction of labor should be 405/7 weeks [17]. Although the 20% decrease in the primary out-
weighed against the potential benefits. A successful induction come of perinatal morbidity and mortality was not statistically
has been defined in many ways, but usually is one that achieves significant, induction was associated with a significant reduction
an uncomplicated vaginal delivery within 24 hours. If the active in the risk of CD, maternal hypertensive disease, and respira-
phase is not achieved within 24 hours, this is not a reason per se tory distress in the newborn, and maternal satisfaction was
for CD. Compared with a shorter induction-to-delivery interval, significantly increased and pain significantly decreased [17].
an induction lasting greater than 24 hours is associated with a In a meta-analysis of 34 studies including over 21,000 women,
higher risk for adverse outcomes, with a higher (e.g. 50%) risk of there was a clear reduction (70%) in perinatal mortality when
CD [10]. Neonatal outcomes, including ICU admission, Apgar <7, induction of labor occurred beyond 37 weeks when compared to
and arterial cord pH <7, do not appear to increase with a pro- expectant management [18]. NICU admission and Apgar score <7
longed latent stage as long as fetal status is reassuring [5, 6]. A at 5 minutes were also decreased in this population, by 12% and
minimum of 18–24 hours should be allowed after cervical 27%, respectively [18]. Maternal benefits seen in the ARRIVE trial
ripening and oxytocin administration (optimally with mem- were also confirmed in the meta-analysis data. With 21,030 par-
branes ruptured) prior to diagnosing a failed induction [10, ticipants included in mode of delivery outcome, there was a 10%
11]. After appropriate counseling, this period may be extended, reduction in the risk of CD for induction compared with expect-
assuming a reassuring fetal status. ant management (relative risk [RR] 0.9, 95% confidence interval
Patient selected for induction is

≥39 weeks or meets appropriate Membrane sweeping as an
medical/obstetric indications outpatient starting at 37–38 weeks
Balloon 60–80 mL + Misoprostol 25

mcg every 2–4 hours OR
Balloon + oxytocin infusion
Oxytocin infusion
Amniotomy after balloon expulsion

with regular contractions
Failed induction should only be diagnosed

after cervical ripening AND 18–24 hours of
oxytocin with membranes ruptures
FIGURE 23.1 Induction algorithm to reduce the risk of cesarean delivery and time to delivery.
[CI] 0.85–0.95) [18]. These data indicate women who are low of labor or expectant management after a prior CD, induction at
risk should be given the opportunity to be induced primarily 39 weeks remained associated with a significantly higher chance
for the indications of 39 weeks’ gestation. of vaginal birth after cesarean (VBAC), as well as uterine rup-
ture (odds ratio [OR] 1.31, 95% CI 1.03–1.67 and OR 2.73, 95% CI
Contraindications 1.22–6.12, respectively) [26]. Uterine rupture was not statistically
Induction of labor is contraindicated in the situations shown in different in those women induced at 40 completed weeks com-
Table 23.2 [16]. The supervising physician should use their discre- pared to expectantly managed women; however, there was also
tion in the event of multifetal pregnancy, maternal heart disease, no increase in VBAC odds [26].
prior low-transverse CD, severe hypertension, and abnormal fetal
heart rate (FHR) patterns not necessitating emergent delivery. Time of day for induction
Spontaneous labor has been shown to have a circadian rhythm
Induction of labor after cesarean with a higher occurrence at night due to a higher concentration
The risk of uterine rupture after induction in women with a
of myometrial oxytocin receptors and maternal oxytocin concen-
prior CD deserves special attention (see Chap. 15). Misoprostol
trations. A meta-analysis of three randomized controlled trials
induction in women with a prior CD was associated with a 5.6%
(RCTs) was performed; however, results were not pooled second-
risk of uterine rupture in one of the largest series [19]. Therefore,
ary to substantial heterogeneity between studies [27]. One RCT
misoprostol should not be used for cervical ripening or labor
comparing morning and evening oxytocin inductions showed no
induction in women with prior uterine incisions except
difference in outcomes for women induced in the morning ver-
under very unusual circumstances or management of still-
sus the evening, except for slightly increased neonatal admission
birth in the second trimester (see Chap. 57 in Maternal-Fetal
to the maternity ward, medium care neonatal unit, or ICU (RR
Evidence Based Guidelines). According to retrospective studies,
1.48, 95% CI 1.02–2.14) in the morning group, though the authors
using prostaglandin E2 (PGE2) for cervical ripening in women
could not explain a reason for this effect [28]. The remaining two
who have a history of previous cesarean also increases the risk
RCTs compared prostaglandin induction timing and showed no
of uterine rupture [20–23]. Risk of uterine rupture is approxi-
differences in neonatal outcomes or CD but higher maternal sat-
mately 1.4–2.5% with PGE2 use (with or without oxytocin) [22,
isfaction in morning inductions [27]. Inductions should be timed
23] and about 1.1% with oxytocin alone [23]. Alternatively, cer-
to best accommodate the staffing needs of the labor unit and
vical ripening with the Foley catheter is not associated with
patient preference, given the lack of clear benefit for morning or
any additional risk of uterine rupture in patients undergoing
night inductions.
a trial of labor after cesarean section [24]. Mifepristone 400 mg
orally may outperform Foley to induce labor in a prior cesarean
due to its lack of uterine stimulation, but currently is under- Prediction of successful induction
studied [25]. A patient who has a prior CD, no previous vaginal
delivery, and an unfavorable Bishop score up to 39–40 weeks has Maternal characteristics
more risks (e.g. septicemia, uterine rupture, and hysterectomy) Certain maternal characteristics have been shown to favorably
from induction of labor; these women may elect for repeat CD predict successful induction of labor. A secondary analysis of a
after counseling (Chap. 15) [20–23]. However, in a prospective study investigating vaginal misoprostol versus vaginal dinopro-
observational trial of 12,676 women undergoing either induction stone showed that prior vaginal delivery, lower maternal body
TABLE 23.3: Bishop Score for Cervical Favorability

Score Dilation (cm) Effacement (%) Station Cervical Consistency Position of Cervix
0 Closed 0–3 –3 Firm Posterior
1 1–2 40–50 –2 Medium Midposition
2 3–4 60–70 –1, 0 Soft Anterior
3 5–6 80 +1, +2 – –
mass index (BMI), tall maternal stature, and neonatal birth methods have been compared not only to placebo or no treatment
weight <4000 g were associated with a higher likelihood of a vagi- but also among themselves in different populations and clinical
nal delivery, independent of method. [29]. settings, making for an extensive experience.
Bishop score Combination methods

In 1964, Bishop reported that his pelvic score (Table 23.3) is Compared with prostaglandin alone, the addition of a Foley
inversely proportional to the time from examination to the time catheter to locally applied prostaglandins (PGE1 and PGE2)
at which spontaneous labor begins [3]. Unfavorable (<5) Bishop increases the likelihood of vaginal delivery within 24 hours in
scores at admission for induction of labor are associated with three trials, with a lower likelihood of observing no cervical
twofold to threefold increased risk of CD when compared to change when a balloon catheter is used [42, 45]. There was no
spontaneous onset of labor [3, 4, 30]. Data show a score of ≥9 to difference in CD between the groups in a network meta-analysis
predict a short time until onset of spontaneous labor and there- of 30 trials [42].
fore indicate favorability for induction [29]. A simplified Bishop Compared to Foley alone, Foley with oxytocin reduced the
score might also be considered [31]. In a meta-analysis of mostly total time to delivery, increased delivery within 24 hours, and had
cohort studies aimed primarily to assess Bishop score as a predic- no effect on mode of delivery in a network meta-analysis of eight
tor of cesarean, scores of 4, 5, or 6 were not predictive. A Bishop trials [42]. Either Foley with misoprostol or Foley with oxytocin
score of 8 or 9 had a negative predictive value of 96% for cesarean can be used to significantly reduce total time to delivery [42].
[32]. In an additional meta-analysis that included a larger sample For parturients undergoing an inpatient induction, the
of studies and randomized trials, higher Bishop scores were asso- combination of cervical ripening and induction methods
ciated with a higher rate of vaginal delivery. A Bishop score of 4 has been shown to reduce the time to delivery and should be
had an OR of 2 for vaginal delivery, whereas a Bishop score of 8 considered if there are no other contraindications. Individual
increased the odds of vaginal delivery by 5.5 [33]. A Bishop score methods are described later. In summary, Foley catheter com-
of ≥9 is usually associated with a probability of vaginal delivery bined with either misoprostol or oxytocin is the preferred
after labor induction similar to that after spontaneous labor method of inpatient labor induction for pregnancies without
[16]. other contraindications to receive two agents.
Transvaginal cervical length Mechanical methods

In a systematic review of mostly observational studies, a cervi- Mechanical methods include the following: hygroscopic dila-
cal length (CL) of <30 mm did not predict vaginal delivery; a CL tors (laminaria, Lamicel, or Dilapan), balloon (Foley catheter,
>30 mm did not predict cesarean section [34]. When compared double-balloon catheters), and balloon with extra-amniotic infu-
with Bishop score, there was no significant difference in the pre- sion. Other methods reviewed under this category are membrane
diction of successful labor induction, mode of delivery, vaginal stripping and amniotomy.
delivery within 24 hours of starting induction, or achievement of
the active stage of labor [35, 36]. In nulliparas, a CL cutoff of 30 Hygroscopic (osmotic) dilators (Laminaria,
mm had a sensitivity of 70% and specificity of 74% for predicting Lamicel, or Dilapan)
cesarean [36]. Hygroscopic devices are made either from synthetic or organic
material. Laminaria are used as organic hygroscopic devices,
Fetal fibronectin which are made from cold-water seaweed. Under direct visualiza-
Of five prospective observational trials [37–41], only one showed tion facilitated by a vaginal speculum, Laminaria are placed in
an association with positive fetal fibronectin and successful the cervical canal. Once in the cervix, the device absorbs water
induction [37]. As such, fetal fibronectin is not recommended from surrounding tissues, causing it to slowly swell, dilating the
to predict which patient’s labor induction will result in a suc- cervix. Generally, the Laminaria are left in place for 6–12 hours
cessful vaginal delivery. but less than 24 hours. Sterility cannot be reliable ensured in the
organic product. Polyvinyl alcohol polymer–magnesium sulfate
Induction/Ripening methods (Lamicel) and polyacrylonitrile (Dilapan) were developed as syn-
thetic hygroscopic devices to avoid this issue and allow sterile
Induction of labor is one of the most-studied interventions in insertion into the cervix.
obstetrics, with hundreds of trials reported. Cervical ripening/ Currently, no evidence exists to support using Laminaria
induction agents can be functionally divided into two methods: to decrease either the interval from induction to delivery or
mechanical and pharmacologic. Mechanical methods have the rate of CD when compared to vaginal PGE2, intracervical
been utilized since the days of Hippocrates, 460–360 B.C. Many PGE2, oxytocin, or amniotomy [43]. Laminaria were associated
with less uterine hyperstimulation compared to vaginal PGE2, Compared with vaginal misoprostol, transcervical Foley
but other secondary outcomes were uncertain based on an meta- catheter has been demonstrated to be equivalent for cervical
analysis of >22,000 women (endometritis, meconium staining, ripening. There is a similar risk of CD, chorioamnionitis and
NICU admission, etc.) [43]. other maternal and perinatal outcomes, except a higher inci-
Compared to 60 mL intracervical Foley, Dilapan-S was dence of tachysystole associated with misoprostol (RR 2.9, 95%
noninferior in achieving vaginal delivery with similar maternal CI 1.39–5.81) [51–54]. Foley was associated with a longer time
infectious morbidity. Women reported higher satisfaction with from induction to delivery in two meta-analyses [53, 55]. In a net-
Dilapan-S in one trial [44]. work meta-analyses of 51 RCTs, vaginal misoprostol reduced the
risk of not achieving a vaginal delivery in 24 hours (RR 0.43, CI
Balloon catheter 95% 0.35–0.67) and cesarean section (RR 0.84, 95% CI 0.0.71–
In 1853, Kraus first described a balloon device for preinduction 0.99), but Foley catheter reduced the risk of hyperstimulation (RR
cervical ripening. A vaginal speculum is often utilized to insert 0.15, 95% CI 0.07–0.3) [55].
the Foley catheter in the cervical os, but placement via a digital Compared with dinoprostone (intracervical and vaginal),
examination is also common. The Foley catheter affects cervical Foley catheter had similar rates of not achieving a vaginal deliv-
ripening in two ways: (1) gradual mechanical dilation and (2) sep- ery within 24 hours and CD. Foley catheter was significantly less
aration of the decidua from the amnion, stimulating prostaglan- likely to cause hyperstimulation than vaginal dinoprostone (RR
din release. Many studies have demonstrated the Foley catheter 0.27, 95% CI 0.12–0.52), but not intracervical dinoprostone [55].
to be an effective tool for achieving a favorable cervix [45]. Compared with use with oxytocin for cervical ripening,
Foley use without oxytocin was associated with a lower rate of
Technique CD (RR 0.57, 95% CI 0.38–0.88) [45]. There was no difference in
Optimally, the catheter is placed at a level above the internal cervi- tachysystole with or without FHR changes between groups [45].
cal os, sometimes with the assistance of forceps or a clamp to guide Theoretical risks associated with Foley catheter use include
the catheter. Placement may be done with the aid of a stylette if bleeding, fever, displacement of the presenting part, and prema-
preferred, but it has not been shown to reduce the rate of failed ture rupture of membranes (PROM) (Figure 23.2). However, no
insertion [46]. Rather, reduced insertion failure is associated with randomized trial has shown an increase in these complica-
increased cervical dilation and experience of the practitioner [46]. tions in comparison to other methods. Foley should not be used
Placement should be attempted digitally without a speculum in women with low-lying placentas. Overall, the Foley catheter
first, as this is associated with lower pain score. However, com- is an inexpensive, safe, well-tolerated, and easy tool for cervi-
pared to placement with a speculum, both digital and speculum cal dilation [56]. In a review of over 1200 low-risk women who
methods had a high satisfaction score with women [47]. received the intracervical Foley catheter for cervical ripening,
Once placed above the internal os, the operator uses sterile there were no adverse events necessitating delivery in the pre-
saline or water to inflate the catheter’s balloon. Various sizes induction ripening period [57]. In a meta-analysis of 26 trials
and balloon capacities have been investigated and used; these including 5563 women, there was no increased risk of infectious
include a range from 25 to 80 mL balloons with 14–18 F cathe- morbidity with Foley catheter use [56]. Foley is as effective as
ters. Compared to balloons filled with 30 mL, filling a balloon other methods, including misoprostol, and possibly safer than
to 80 mL resulted in an average decreased time to delivery pharmaceutical methods and should be considered as first
of 2 hours in a meta-analysis of seven studies [48]. Correct line in all inductions (see Chap. 21).
placement is verified by gentle traction on the catheter until the
inflated balloon meets the resistance of the internal os. Vaginal Sequential ripening
exam of the posterior fornix should be performed to palpate the There is no evidence the Foley catheter after pharmacologic rip-
balloon above the level of the internal os. Once the location is ening will reduce time to delivery or CD rate in those women who
verified, gentle traction is applied by taping the distal end of the
catheter to the patient’s inner thigh. Adding weighted traction
has not been shown to increase vaginal delivery overall, vaginal Diagnosis of PROM ≥ 37 weeks confirmed
delivery within 24 hours, or decrease the CD rate [49]. If the
Foley is not expulsed within 12 hours, consideration should be
given to removing it and starting the induction with oxytocin, Start induction within
as leaving it in 24 hours is associated with longer inductions but 6 hours
no reduction in rate of CD [50].
Unfavorable
Efficacy
Compared with no treatment, one trial reported Foley catheters
to have no effect on the risk of CD [45]. Oxytocin Vaginal or oral
Compared with all locally applied prostaglandins (LAPGs), Best evidence
infusion misoprostol
including PGE2 and misoprostol, the rate of CDs is the same
in a meta-analysis of 21 studies (n = 3202) [45]. There was no sig-
nificant difference in vaginal delivery in 24 hours in the Foley Some evidence, but superiority
catheter group [45]. LAPGs were associated with a higher rate to oxytocin not proven
of excessive uterine activity, and the Foley catheter was associ-
ated with an increased need for oxytocin augmentation in labor FIGURE 23.2 Induction for prelabor rupture of membranes
according to a meta-analysis of nine trials [45]. (see Chap. 21).
have not achieved a favorable Bishop score after the initial rip- over single-balloon catheters for the induction of labor. Until
ening method [58]. Serial ripening with repeated doses of dino- further information is available, a Foley catheter should be
prostone similarly have shown increased time to delivery without used over a double-balloon catheter for both efficacy and eco-
affecting the CD rate [59]. Using cervical ripening in sequence nomic concerns.
(as opposed to simultaneous) does not improve obstetric out-
come and should be avoided. Oxytocin is recommended after Membrane stripping (or sweeping)
the initial cervical ripening course is completed. Membrane stripping is the practice of inserting a finger through the
internal os and sweeping to separate the membranes from the lower
Extra-amniotic saline infusion uterine segment. This technique stimulates prostaglandin release,
Extra-amniotic saline infusion (EASI) involves, as the term states, as plasma prostaglandin levels have been observed to increase post-
infusing usually saline through the cervix by a Foley balloon. For stripping. Sweeping the membranes promotes the onset of labor and
information on infusion of PGE2, see the section “Extra-amniotic is found acceptable to a vast majority of women [13].
Prostaglandins.” Compared with no sweeping or a sham procedure, sweeping of
Compared with LAPG, EASI showed no difference in risk to the membranes at term (i.e. weekly starting at 38 weeks) is associ-
delivery >24 hours, CD, or tachysystole (six studies, n = 747) [45]. ated with a slight increase in spontaneous labor (RR 1.21, 95% CI
Compared with PGE2, EASI with an intracervical Foley bal- 1.08–1.34) and reduced frequency of labor induction (RR 0.73,
loon is associated with shorter time intervals to yield a favor- 95% CI 0.56–0.94), although certainty on these outcomes was low
able Bishop score and similar incidence of CD [45, 60–62]. due to heterogeneity and multiple biases [13]. To avoid one formal
Compared with vaginal misoprostol, EASI with an intracervi- induction of labor, sweeping of membranes must be performed
cal Foley balloon and oxytocin is associated with a shorter induc- in eight women. Rates of CD and maternal and neonatal mor-
tion-to-delivery interval in one trial, but no difference in another bidity are similar. Discomfort during vaginal examination and
[63, 64]. There was similar incidence of CD in both trials [63, 64]. other adverse effects (bleeding and irregular contractions) are
Compared with Laminaria, EASI with an intracervical Foley more frequently reported by women allocated to sweeping, but
balloon is associated with a shorter induction-to-delivery are not associated with complications.
interval and fewer CDs for failed induction in one trial [64]. Studies comparing sweeping with prostaglandin adminis-
Compared with Foley only, EASI with Foley catheters has tration (vaginal or intracervical) did not show a difference in
been associated with a shorter induction-to-delivery interval in induction of labor, spontaneous vaginal delivery, cesarean, or
one RCT [65] but not in another larger RCT [66]. spontaneous labor. Sweeping more than once weekly did not
In summary, there is insufficient evidence to use EASI increase the vaginal delivery rate or decrease the need for labor
instead of Foley balloon for cervical ripening. induction. Membrane sweeping also was not more effective than
amniotomy and oxytocin for promoting spontaneous labor,
Double-balloon Foley catheters induction of labor, or cesarean [13].
Double-balloon Foley catheters (Cook Catheter or Atad cath- When used as a means for induction of labor, the woman should
eters) have become more frequently used for mechanical labor be counseled that her chance of going to spontaneous labor after
induction. The catheter is designed specifically for labor induc- one sweeping at term is about 36% in the next 48 hours versus
tion, providing an intracervical and vaginal balloon to compress 17% without sweeping (so doubling the rate of onset of labor) [74].
the cervix in addition to membrane separation to ripen the cer- Possible complications such as bleeding, infection, and ruptured
vix. Both balloons in the Cook catheter are approved to fill to a membranes are not found to be increased with stripping [74]. In
volume of 80 mL in each balloon. nulliparas being induced with PGE2 and oxytocin, the addi-
Compared to PGE2, no difference in CD rates were reported tion of membrane sweeping is associated with a shorter induc-
in five RCTs [67–71]; one RCT of 126 women found a higher rate tion-to-delivery interval and increased vaginal delivery rates
of CD in the dinoprostone group [72]. Time to vaginal delivery in one trial [75]. No differences were noted in nulliparas with
was shorter in the double-balloon group in two out of four RCTs favorable cervices or in multiparas.
reporting on the outcome [68, 69, 71, 72], and delivery within In women attempting trial of labor after cesarean (TOLAC),
24 hours was increased for the double-balloon group in two of weekly membrane sweeping had no effect on spontaneous labor
three trials reporting the outcome [69, 71, 72]. Overall maternal or vaginal delivery rate [76]. Membrane stripping was also found
and neonatal morbidity was similar in both groups, except tachy- to be safe in group B streptococcus (GBS) carriers, without any
systole was more common with PGE2 [72]. There is insufficient cases of neonatal sepsis, death, or serious neonatal morbidity in
evidence to support the use of a double-balloon catheter over a trial of 542 women [77]. There was also no increase in neonatal
PGE2 for labor induction. composite morbidity.
Compared to a single-balloon Foley catheter, there was no
difference in time to delivery, CD, or intrapartum fever in two Amniotomy
meta-analyses of four trials [67, 73]. Additionally, there was a Amniotomy—artificial rupture of the membranes—is another
higher rate of patient discomfort with the double-balloon cath- technique used in labor induction. There is insufficient evidence
eter compared to single-balloon Foley [73]. Time from induction to assess the effectiveness of amniotomy alone [78]. No trials
to delivery was longer in the double-balloon group in one trial compared amniotomy alone with intracervical prostaglandins. If
[68]. There is also a significant cost difference between the cath- performed without cervical ripening or achieving a favorable cer-
eters: single-balloon Foley catheters may cost up to $12–$14 (US) vix, amniotomy may be followed by long intervals before onset of
for large balloon catheters (75 mL), but are cheaper when 30 mL labor. In induced patients, early amniotomy is associated with
balloons are used. The double-balloon catheter costs labor and a shorter duration of labor and no increase in CD in a meta-
delivery units over $200 (US) per unit. There is currently insuffi- analysis of four trials [79]. The rate of intrapartum fever is mixed
cient evidence to support the use of double-balloon catheters in RCTs and warrants additional research [79].
Pharmacologic methods has an OR of 4.40 (95% CI 2.22–7.94) compared to placebo. When

Pharmacologic methods include the prostaglandins—E1: miso- compared to dinoprostone, the CIs cross, but are higher for high-
prostol; E2: dinoprostone; and F2a—as well as mifepristone, dose vaginal misoprostol and slow-release vaginal PGE2 pessary
estrogen, relaxin, oxytocin, etc. (Cervidil) (OR 2.97, 95% CI 1.36–5.73) [81]. Additionally, the cost
of a 50-µg pill of misoprostol is approximately $2 compared to the
Misoprostol dinoprostone vaginal insert at approximately $168 [82].
Misoprostol (Cytotec; PGE1) is an endogenously produced hor- Compared with intracervical PGE2, vaginal misoprostol
mone that acts locally on surrounding tissues. Through complex showed a reduction in the number of failed vaginal deliveries in
molecular actions, PGE1 stimulates uterine contractions and cer- 24 hours and reduced risk of CD [55]. There is a slightly lower risk
vical dilation in a manner akin to the onset of spontaneous labor. of hyperstimulation compared to both high-dose and low-dose
More specifically, PGE1 potentiates calcium ion transport across vaginal misoprostol [55, 81].
the cellular membrane and regulates cyclic adenosine monophos- Compared with oral misoprostol solution and all formula-
phate (AMP) within the uterine smooth muscle cells to trigger tions of PGE2, a network meta-analysis including over 48,000
contractions. PGE1 facilitates cervical ripening by stimulating women showed that oral misoprostol solution had a higher vagi-
the pathway leading to activation of collagenases. Collagenases, nal delivery rate in 24 hours and reduced risk of CD. High-dose
in turn, break down the structural collagen network of the cervix, vaginal misoprostol, then low-dose misoprostol, followed as the
yielding a softer, thinner cervix. most effective treatments [81].
Although it is currently on the market as a 100-mg tablet to pre- In summary, vaginal misoprostol less than or equal to 50 µg
vent peptic ulcers, misoprostol is available and widely used in an every 2 (25 µg) to 6 hours is a safe, effective means for cervical
“off-label” form for preinduction cervical ripening and induction. ripening and more effective than PGE2.
Misoprostol should not be used for cervical ripening or labor
induction in women with prior uterine incisions (e.g. prior CD) Vaginal misoprostol insert
after 28 weeks [16, 19]. For use of misoprostol for induction in A 100-µg vaginal insert (which is equivalent to a 25-µg tablet
the second trimester, see Chap. 57 in Maternal-Fetal Evidence fragment being inserted every 6 hours) had a similar time to vagi-
Based Guidelines. Misoprostol can be administered vaginally, nal delivery as a 10-mg dinoprostone vaginal insert in a random-
orally, buccally, or sublingually. ized trial and similar CD rate [84]. Misoprostol inserts of 50, 100,
and 200 µg have similar rates of vaginal delivery within 24 hours,
Vaginal misoprostol but higher rates of NRFHT requiring CD and tachysystole in the
Vaginal misoprostol is most commonly administered by placing 200-µg group [85]. Although 100 µg of vaginal misoprostol insert
a tablet in the posterior fornix of the vagina. Several studies have has a shorter time to delivery and similar CD rate compared to
focused on the dose administered. Vaginal misoprostol in doses vaginal dinoprostone, the rate of tachysystole was much higher
above 25 µg every 4 hours is more effective (higher success [86]. There was a higher rate of NRFHT and CD secondary to
rate for vaginal delivery within 24 hours of induction, decreased NRFHT in the high-dose misoprostol insert groups [86, 87]. In
need for oxytocin, and decreased induction-to-delivery intervals) summary, there is still insufficient evidence for clinical use of
than conventional methods of labor induction, but with more the misoprostol vaginal insert.
uterine hyperstimulation. Lower doses (25 µg) are like con-
ventional methods in terms of effectiveness and risks. Lower Oral misoprostol
doses of misoprostol compared with higher doses were associ- Compared with placebo in women with PROM, women who
ated with more need for oxytocin augmentation and less uterine received oral misoprostol had a higher likelihood to deliver vagi-
tachysystole, with and without FHR changes, and less meconium nally within 24 hours (RR 0.16, 95% CI 0.05–0.49), needed less
aspiration and less CD for nonreassuring fetal heart rate tracing oxytocin (RR 0.42, 95% CI 0.37–0.49), and had a lower cesarean
(NRFHT) [80, 81]. Therefore, 25 µg of misoprostol (one-quar- section rate (RR 0.72, 95% CI 0.54–0.95) (see Chap. 21) [88].
ter of a 100-µg tablet) given not more frequently than every Compared with vaginal PGE2, low-dose oral misoprostol
3–6 hours has been recommended by the ACOG [16]. (e.g. 20 µg) administered every 2 hours had the same rate of vagi-
Compared with placebo, misoprostol is associated with nal delivery in 24 hours and a significantly lower rate of CD [88,
reduced failure to achieve vaginal delivery within 24 hours (RR 89]. Women given oral misoprostol were also less likely to need
0.51, 95% CI 0.37–0.71) and with increased uterine tachysystole a cesarean section (RR 0.88, 95% CI 0.78–0.99). There was some
without FHR changes (RR 3.52, 95% CI 1.78–6.99) [80, 81]. evidence that they had slower inductions, but there were no other
Compared with vaginal PGE2, vaginal misoprostol is associ- significant differences [88].
ated with a higher rate of vaginal delivery in 12 or 24 hours and Compared with oxytocin, oral misoprostol was associated
similar cesarean and hyperstimulation risk in a meta-analysis of with an increase in meconium-stained liquor in women with rup-
11 studies [82]. There was a reduced need for oxytocin augmen- tured membranes (RR 1.65, 95% CI 1.04–2.6) but lower CD rate
tation with misoprostol compared to vaginal dinoprostone [80]. (RR 0.77, 95% CI 1.04 – 2.6) [88].
These results remain unchanged when a separate meta-analysis by Compared with vaginal misoprostol, oral misoprostol had
Liu et al. analyzed only singleton pregnancies [83]. A later network similar outcomes for vaginal delivery in 24 hours and CD in a
meta-analysis of 92 studies confirmed the shorter time to delivery meta-analysis of 37 RCTs [88]. There were fewer babies with low
with vaginal misoprostol compared to vaginal PGE2, although it Apgar score or postpartum hemorrhage in the oral misoprostol
did also show higher rates of hyperstimulation in vaginal miso- group, but higher rate of meconium-stained fluid [88]. A network
prostol, unlike the prior meta-analysis [55]. However, the risk of meta-analysis, which allows for ranking treatments across stud-
hyperstimulation is primarily dose dependent. Vaginal misopros- ies through indirect comparisons, found that vaginal misopro-
tol <50 µg has an OR of uterine hyperstimulation of 2.75 (95% CI stol had the highest probability of performing best among all
1.36–5.04) compared to placebo [81]. Vaginal misoprostol >50 µg prostaglandins to achieve vaginal delivery in 24 hours, but oral
misoprostol avoided the most CDs [90]. When the informal anal- PGE2 vaginal insert
ysis of both achieving vaginal delivery in 24 hours and avoiding The PGE2 vaginal insert (Cervidil) (also called a slow-release
CD was combined, low-dose (<50 µg) oral misoprostol performed pessary) is a thin, vaginal insert containing 10 mg of dinopro-
best, followed by high-dose, then low-dose vaginal misoprostol stone and delivers roughly 0.3 mg of dinoprostone each hour
[90]. A later network meta-analysis showed that vaginal miso- over a 24-hour period. The insert is placed in the posterior for-
prostol avoided failed vaginal delivery in 24 hours the most, but nix of the vagina and left in place until the desired ripening has
was not different from oral misoprostol for reduced chance of CD occurred, when the insert is removed. Removal should occur at
[55]. Compared with vaginal misoprostol, low-dose titrated oral least 30 minutes prior to starting oxytocin.
misoprostol (20–25 µg) given every 2 hours was shown to cause Compared with PGE2 gel, a PGE2 insert is associated with an
fewer incidences of uterine tachysystole with FHR changes and a increased risk of not achieving a vaginal delivery within 24 hours
higher rate of vaginal delivery in 24 hours [89]. Studies that exam- (RR 1.26, 95% CI 1.12–1.41). There was no change in the risk of cesar-
ine patient satisfaction have shown a definite preference toward ean section (RR 1.07, 95% CI 0.93–1.22). The risks of tachysystole
oral administration [86, 87]. with FHR changes (RR 0.76, 95% CI 0.39–1.49) and without FHR
changes (RR 0.80, 95% CI 0.56–1.15) were not different with the
Sublingual misoprostol two methods of PGE2 administration. The use of sustained-release
Based on only three small trials, sublingual misoprostol appears PGE2 inserts is associated with a reduction in instrumental vaginal
to be at least as effective as when the same dose is administered delivery rates (RR 0.47, 95% CI 0.32–0.68) when compared to vagi-
orally [91]. nal PGE2 gel or tablet. Compared with intracervical PGE2 low dose,
Compared to vaginal misoprostol, a meta-analysis of five tri- intracervical PGE2 high dose has a higher rate of hyperstimulation
als found no difference in vaginal delivery within 24 hours, tachy- with FHR changes but no change in CD rate [93].
systole (when grouped according to dose), or CD for sublingual Compared with dinoprostone insert followed by oxyto-
dosing [92]. There is inadequate data to assess safety, optimal cin, dinoprostone insert started concurrently with oxytocin
dose, and side effects. is associated with a shorter induction-to-delivery interval and
higher incidence of vaginal deliveries within 24 hours in one
Prostaglandin E2 (dinoprostone) small trial [95].
PGE2 is an endogenously produced hormone that acts locally
on surrounding tissues. Such effect is manifested in the smooth Extra-amniotic prostaglandins
muscle of the uterus and gastrointestinal tract. PGE2 can be used There is insufficient evidence to fully assess the effectiveness
for induction of labor via different routes of administration, such of extra-amniotic prostaglandins for induction of labor, with
as vaginal, extra-amniotic, oral, and intravenous. The vaginal enough evidence to discourage its use compared with other
route is the most common route of administration of PGE2 for methods (see also the section “Extra-Amniotic Saline Infusion”).
labor induction. It can be given in different forms, such as tablet, Extra-amniotic placement of prostaglandins was first undertaken
gel, and insert. in the early 1970s and has been largely replaced with cervical or
vaginal placement. Most of the studies used PGE2 (the minor-
PGE2 vaginal gel ity prostaglandin F2α) and gel preparations. Of the primary
Dinoprostone gel (Prepidil) is packaged as a 0.5-mg dose in outcomes, there were significantly fewer women delivered vagi-
a 2.5-mL syringe. A shielded catheter is added to the syringe nally within 24 hours among those induced with extra-amniotic
end to facilitate safe injection, usually intracervically. Under prostaglandin F2α (PGF2α) compared with vaginal misoprostol
direct visualization using a speculum, the syringe contents (RR 2.43, 95% CI 1.42–4.15). Oxytocin was used to initiate or
should be injected into the endocervical canal using sterile augment labor more frequently when compared with vaginal
technique. The patient should remain supine for 30 minutes misoprostol (RR 1.73, 95% CI 1.20–2.49). When extra-amniotic
to minimize leakage from the canal. An alternative method for PGE2 was compared with Foley catheter only, the only differ-
administering the gel is to inject it into the posterior fornix or ence between the groups was that there were fewer cases of unfa-
intravaginal administration. Until achieving a favorable cer- vorable cervix at 12–24 hours following treatment (RR 0.59, 95%
vix, dinoprostone 0.5 mg may be repeated every 6 hours up to a CI 0.41–0.86). There were no other significant differences when
maximum dose of 1.5 mg in a 24-hour period. Once the cervix extra-amniotic prostaglandins were compared with other meth-
is favorable, oxytocin may be initiated for induction 6 hours ods of cervical ripening or induction of labor. Although this
after the last dose. could suggest that extra-amniotic prostaglandins are as effective
Compared with placebo, intracervical PGE2 is associated as other agents, the findings are difficult to interpret because
with a decreased risk of not achieving vaginal delivery within they are based on very small numbers and may lack the power to
24 hours (RR 0.61, 95% CI 0.47–0.79). There was a small, non- show a real difference [96].
significant reduction of the risk of cesarean section when PGE2
was used (RR 0.88, 95% CI 0.77–1.0). The finding was statisti- Oral PGE2
cally significant in a subgroup of women with intact membranes All oxytocin treatments were more likely to achieve vaginal deliv-
and unfavorable cervix (RR 0.82, 95% CI 0.68–0.98). The risk of ery in 24 hours compared to oral PGE2 [97]. Oral prostaglandin
tachysystole with FHR changes was not significantly increased was associated with vomiting across all comparison groups. There
(RR 1.21, 95% CI 0.72–2.05). However, the risk of tachysystole are no clear advantages to oral prostaglandin over other methods
without FHR changes was significantly increased (RR 1.59, 95% of induction of labor [97].
CI 1.09–2.33) [93, 94].
Compared with PGE2 tablets, PGE2 gel has a similar rate of Intravenous prostaglandins
vaginal delivery not achieved in 24 hours, CD, hyperstimulation IV prostaglandins should not be used for induction or cer-
causing FHR changes, and oxytocin use [93]. vical ripening. They are no more effective than IV oxytocin or
vaginal/cervical PGE2 for the induction of labor, but their use is TABLE 23.4: Labor Stimulation with Oxytocin: Examples of
associated with higher rates of maternal side effects (e.g. gastro- Low- and High-Dose Oxytocin Protocols
intestinal, thrombophlebitis, pyrexia) and uterine tachysystole
Starting Incremental Increase Dosage Interval
[98]. No significant differences emerged from subgroup analysis
Regimen Dose (mU/minute) (minute)
or from the trials comparing combination oxytocin/PGF2α and
oxytocin or extra-amniotic versus IV PGE2 [98]. Low dose 0.5–1 1 30–40
1–2 2 15
Oxytocin High dose ~6 ~6 15
In 1948, the posterior pituitary extract oxytocin was first used for 6 6a, 3, 1 20–40
labor induction via IV drip. Oxytocin was then synthesized by du a The incremental increase is reduced to 3 mU/minute in the presence of tachysys-
Vigneaud and associates in 1953; this accomplishment won the
tole and reduced to 1 mU/minute with recurrent tachysystole.
Nobel Prize in Chemistry in 1955. Oxytocin is routinely utilized,
as it is the drug of choice also for augmentation of labor. While
induction of labor is the stimulation of contractions before the significant reduction of the induction to delivery interval and an
spontaneous onset of labor, augmentation is the stimulation of increase in hyperstimulation without specifying FHR changes.
contractions in the face of inadequate contractions following the Table 23.4 shows examples of each regimen (see also Chap. 7).
spontaneous onset of labor. There is insufficient evidence to support the use of high-dose
By increasing intracellular calcium concentration, oxytocin oxytocin over low-dose protocols [100].
stimulates the smooth muscle cells of the breast, vessels, and,
moreover, the uterus. Receptors for oxytocin are expressed in
Prostaglandin F2α
Compared with placebo, vaginal PGF2α has a similar CD rate
cells of the endometrium, liver, pancreas, and breast tissue. After
(RR 0.59, 95% CI 0.31–1.14). Vaginal delivery within 24 hours was
the 13th week of gestation, myometrial cells express oxytocin
not reported in the three trials included in a meta-analysis [93].
receptors as well. Peak expression by the myometrium and endo-
There were insufficient data to make meaningful conclusions for
metrium occurs at term. Oxytocin increases both the amplitude
the comparison of vaginal PGE2 and PGF2α [93]. There are there-
and frequency of contractions, making labor effective. When
fore insufficient data to assess the safety and efficacy of PGF2α
continuously administered IV, oxytocin affects uterine response
for induction.
within 1 minute. Steady-state plasma concentrations are obtained
within 40 minutes. Mifepristone
Overall, comparison of oxytocin with either intravaginal or Compared with placebo, mifepristone-treated women were
intracervical PGE2 reveals that the prostaglandin agents prob- more likely to be in labor or to have a favorable cervix at 48 hours
ably increase the chances of achieving vaginal birth within (RR 2.41, 95% CI 1.70–3.42), were less likely to need augmenta-
24 hours [99]. Compared with expectant management, oxyto- tion with oxytocin (RR 0.80, 95% CI 0.66–0.97), and were less
cin-alone inductions are associated with fewer women failing likely to undergo cesarean section (RR 0.74, 95% CI 0.60–0.92),
to deliver vaginally within 24 hours (8% vs. 54%; RR 0.16, 95% but more likely to have an instrumental delivery (RR 1.43, 95% CI
CI 0.10–0.25), but with the CD rate slightly increased (RR 1.17, 1.04–1.96) and abnormal FHR pattern [101].
95% CI 1.01–1.35). There is a significant increase in the number of Compared to oxytocin, women treated with mifepristone for
women requiring epidural analgesia (RR 1.10, 95% CI 1.04–1.17) PROM after 36 weeks were less likely to have a vaginal delivery
[99]. Compared with vaginal prostaglandins, oxytocin alone within 24 hours (RR 0.66, 95% CI 0.45–0.96) and their babies
is associated with an increase in unsuccessful vaginal deliv- had an increased likelihood of neonatal adverse outcomes with
ery within 24 hours (70% vs. 21%; RR 3.33, 95% CI 1.61–6.89), more NICU admissions (RR 3.56, 95% CI 1.09–11.58) and abnor-
irrespective of membrane status, but there was no difference in mal FHR patterns (RR 4.36, 95% CI 1.02–18.66) in one trial [101].
cesarean section rates [99]. Uterine hyperstimulation was not increased.
Compared with intracervical PGE2 prostaglandins, oxyto- One poor-quality study comparing mifepristone to dinopros-
cin alone is associated with an increase in unsuccessful vaginal tone found no difference in cesarean rate but a smaller change in
delivery within 24 hours (50% vs. 35%; RR 1.47, 95% CI 1.10– Bishop score for mifepristone [102]. There is insufficient infor-
1.96). For all women with an unfavorable cervix regardless of mation available from clinical trials to support the use of
membrane status, the cesarean section rate is also increased (19% mifepristone to induce labor.
vs. 13%; RR 1.37, 95% CI 1.08–1.74) [99].
Compared to vaginal prostaglandin F2α, there was no dif- Estrogen
ference in CD rate (RR 1.19, 95% CI 0.65–2.18). The outcome of Several studies have shown that estradiol given via a variety of
failing to delivery vaginally in 24 hours was not reported in any of routes has the ability to achieve some degree of improved cervical
the three RCTs included in the meta-analysis [99]. ripening with minimal myometrial stimulation [103]. However,
Oxytocin seems to be as effective as prostaglandins in on the whole there were insufficient data to draw any conclu-
women with PROM (see Chap. 21) [99]. sions regarding the efficacy of estrogen as an induction agent,
Compared to low-dose oxytocin regimens (<100 mU in the given small, differing trials with different controls and different
first 40 minutes and <600 mU in the first 2 hours), there were outcomes reported [103]. It also was not shown to improve Bishop
no differences in rates of vaginal delivery not achieved within score when compared to placebo in the outpatient setting [104].
24 hours (RR 0.94, 95% CI 0.78–1.14) or CD (RR 0.96, 95% CI
0.81–1.14). There was no difference in serious maternal or neo- Relaxin
natal morbidity. No trials reported on the number of women who There is insufficient evidence to assess the safety and efficacy
had uterine hyperstimulation with FHR changes. When high- of relaxin as an intervention for induction of labor. There are no
bias studies were removed from the meta-analysis, there was a reported cases of uterine tachysystole with NRFHT in any of the four
small trials [105]. Compared with placebo, relaxin is not associated not significant in women with an unfavorable cervix. The rate of
with differences in CD [105]. In a phase 2 study, there was no dif- postpartum hemorrhage is reduced (0.7% vs 6.0%, RR 0.16, 95% CI
ference in Bishop score between relaxin infusion and placebo [106]. 0.03–0.87). There is no significant difference in the cesarean sec-
tion rate, in the rate of meconium staining, or in uterine tachy-
Dehydroepiandrosterone sulfate systole. The three perinatal deaths were associated just with breast
Dehydroepiandrosterone sulfate (DHEAS) is converted to estro- stimulation (1.8% vs. 0%; RR 8.17, 95% CI 0.45–147.77) [114].
gen by the fetoplacental unit, and it was investigated as a possible Compared with oxytocin alone, breast stimulation had simi-
mechanism for cervical ripening without myometrial contrac- lar rates of women not in labor after 72 hours, cesarean section
tions. One trial of 84 women showed a 6-day difference to onset rates, and meconium staining. Three of the four perinatal deaths
of labor and 4-hour shorter labor course for DHEAS compared to were in high-risk women in the breast stimulation group (17.6%
placebo, but this was only for nulliparous women (n = 40) [107]. vs. 5%; RR 3.53, 95% CI 0.40–30.88) [114]. Until safety issues
Given twice-weekly infusions during the trial, there is insuffi- have been fully evaluated, breast stimulation should not be used
cient evidence on its efficacy and would be quite cumbersome as in high-risk women [114].
a method of outpatient ripening, as one trial that investigated its
use showed poor results when compared with placebo. Castor oil
Castor oil should not be used routinely for induction of labor,
Dexamethasone sulfate given the incidence of maternal side effects and insufficient
There is insufficient evidence to assess the safety and efficacy evidence for efficacy [115]. There was no evidence of a difference
of steroids as induction agents. Compared with oxytocin alone, in caesarean section rate in the two trials reporting this outcome
dexamethasone IM and oxytocin are not associated with sig- (RR 2.04, 95% CI 0.92–4.55). No data were presented on neona-
nificant effects in maternal and perinatal outcomes in one small tal or maternal morbidity. All women who ingested castor oil felt
RCT [108]. Compared to Foley catheter, Foley catheter plus extra- nauseous [115]. One additional small trial (n = 81) found no dif-
amniotic infusion of dexamethasone solution had a significantly ference in labor at 24, 36, and 48 hours after ingestion of castor
shorter time from induction to delivery in one small RCT (11.9 ± oil compared to sunflower oil [116]. However, a sub-analysis of 37
3 hours vs. 14.5 ± 4.8 hours, p < 0.01 [109]. women did show some benefit for onset of labor for multiparous
women. Forty percent of women had an increase in bowel move-
Hyaluronidase ment after ingestion, but there was no increase in meconium
There is insufficient evidence to assess the safety and efficacy staining or abnormal FHR tracing [116].
of intracervical injections of hyaluronidase for cervical ripening.
It is not common practice, and it is an invasive procedure that Enemas and baths
women may find unacceptable in the presence of less invasive There are no trials on enemas or baths for induction of labor.
methods. In one RCT, when compared with placebo for cervi-
cal ripening, intracervical injections of hyaluronidase resulted in Homeopathy
women receiving significantly fewer cesarean sections (RR 0.37, There is insufficient evidence to recommend the use of homeopa-
95% CI 0.22–0.61), less need for oxytocin augmentation (10% vs. thy (e.g. with Caulophyllum) as a method of induction. No ben-
47%; RR 0.20, 95% CI 0.10–0.41), and increased cervical favor- efits were seen in the two small, poor-quality trials [117].
ability after 24 hours (60% vs. 98%; RR 0.62, 95% CI 0.52–0.74).
No side effects for mother or baby were reported in this trial [110]. Sexual intercourse
Compared to Foley catheter, hyaluronidase was associated with a Women randomized to sexual intercourse had similar incidence
higher CD rate and no difference in oxytocin use [111]. of spontaneous labor compared to the control group (RR 1.02,
95% CI 0.98–1.07) [118]. Intercourse is not effective to induce
Nitric oxide donors labor in women with low-risk term pregnancies.
Nitric oxide (NO) donors do not appear currently to be a use-
ful tool in the process of induction of labor. A meta-analysis Summary
including 23 studies compared NO donors with placebo, vaginal
PGE2, intracervical PGE2, vaginal misoprostol, and intracervical Most cases of inpatient inductions who require cervical ripen-
catheter. There is no evidence of any difference between failed ing should be performed with two agents. Evidence supports the
vaginal delivery within 24 hours, CD, or hyperstimulation [112]. combination of Foley catheter (single balloon, inflated to 60–80
There was an increase in nonserious maternal side effects (nau- mL, with or without traction) and misoprostol (e.g. 25 µg every
sea, headache) [112]. 2–4 hours; or 25mcg followed by 50 mcg every 3–4 hours). If
misoprostol is contraindicated, oxytocin IV infusion is recom-
Other methods mended with Foley catheter. Once cervical ripening is completed
Acupuncture (i.e. 12 hours of Foley catheter use, four to six doses of misopro-
There is insufficient and conflicting evidence to assess the effi- stol), oxytocin infusion is recommended. Amniotomy should be
cacy of acupuncture for induction of labor. Compared with a performed once regular contractions are achieved, and usually
sham procedure, the use of acupuncture prior to a scheduled after Foley expulsion and cervix is about >3–5 cm dilated, with
induction is not associated with any difference in the need for the head engaged. If the Bishop score is ≥9 or there is rupture of
induction agents or CD, but had greater cervical change [113]. membranes (ROM), oxytocin IV infusion is recommended.
Breast stimulation Fetal testing during cervical ripening

Compared with no intervention, breast stimulation is associated
with a significant reduction in the number of women not in labor Fetal heart monitoring during cervical ripening depends on the
at 72 hours (63% vs. 94%; RR 0.67, 95% CI 0.6–0.74). This result is agent used. There are no trials to assess the effectiveness and best
modality for monitoring. In general, a nonstress test (NST) should waiting for the priming to work, and overall preferred outpatient
be obtained before any induction or cervical ripening agent is priming when the option was to return to their own home [130].
used to assure fetal well-being. After administration of PGE2 gel Women who are offered outpatient ripening should be of a low-
or tablet, the fetal heart can be monitored continuously for about risk population with reliable transportation back to the hospital
0.5–2 hours, although the proper amount of time for monitoring in case of labor, ROM, decreased fetal movement, or bleeding.
is unclear. After administration of PGE2 insert, the fetal heart The patient should be able to opt for inpatient ripening if desired,
can be monitored continuously for the duration of the insertion receive verbal and written instructions prior to discharge, and
[119]. After administration of misoprostol, the fetal heart should complete 1–2 hours of monitoring prior to discharge with a reas-
be monitored continuously, given the higher chance of contrac- suring fetal tracing.
tions and uterine tachysystole with related NRFHT [120].
Labor management during induction
Outpatient versus inpatient
The patterns by which labor progresses in spontaneous labor and
Induction of labor in outpatient settings appears feasible, but electively induced labor are significantly different [30]. Latent and
the evidence is still insufficient for routine use for most meth- early active phases proceed slower than a spontaneous labor in
ods. Important adverse events are rare [121]. There is insufficient induced labor in which cervical ripening was necessary. Induction
evidence to know which induction agents are most effective and not requiring cervical ripening may be associated with a quicker
safe to use in the outpatient setting. A meta-analysis of seven labor course from 4 to 10 cm [30]. The risk of CD is increased
trials (n = 1610) had high heterogeneity for many outcomes, and during the first stage of labor of an induction needing cervical
many of the prespecified obstetric and safety outcomes were not ripening, mainly because of dystocia. Induction without need for
reported, with high risk of bias and imprecision [121]. There is cervical ripening may have no or only a minor effect on the risk of
limited evidence to assess the safety of outpatient misoprostol cesarean [30]. Applying the same standards of spontaneous labor
for induction of labor. While effective in decreasing the length curves (e.g. Friedman’s curve) to induced patients may lead to an
of gestation and induction-to-delivery interval, the safety of this increased cesarean section rate in induction (see Chaps. 8 and 9).
approach, even at low (25 mg) doses, is still unproven in the three When administering oxytocin, the target is to stimulate uterine
small trials [122–124]. There are insufficient data to assess the activity that is enough to effect cervical change as well as fetal descent
safety of outpatient dinoprostone for induction of labor. In an without compromising the fetus. Minimal criteria for effective uter-
RCT including 827 women, the outpatient dinoprostone group ine activity are three contractions per 10 minutes averaging greater
had more NRFHT and were unable to be discharged home. Over than 25 mmHg above baseline, with five contractions in 10 minutes.
half of the randomized women did not receive the allocated inter- The Montevideo unit was created in 1957 to describe the summation
vention secondary to labor or not requiring ripening [125]. For of the amplitudes of all contractions in a 10-minute window. Uterine
this reason, prostaglandins are not recommended in the out- tachysystole is defined as more than five contractions in 10 minutes.
patient setting. During induction with oxytocin, 91% of patients delivered vaginally
Conversely, there is a large body of evidence that supports achieved 200 Montevideo units without neonatal morbidity in one
the safety of inpatient Foley catheter use, with one of the low- retrospective study [131]. Contraction pressures of ≥200 Montevideo
est risks of hyperstimulation [81]. Although outpatient trials in units should be targeted in induction or augmentation of laboring
Foley catheter ripening are also not powered for safety, there is a patients to achieve adequate labor [131, 132]. Induced labor should
lower risk that intervention will be required [57]. Likewise, in a be managed, in general, as spontaneous labor (see Chaps. 8 and 9).
meta-analysis of 26 studies of mostly inpatient women who were If active phase is not achieved within 24 hours, this is not a reason
ripened with a Foley catheter, this incidence of adverse effects was per se for CD. A failed induction should not be diagnosed until after
0.26%, most of which were reported as pain or discomfort [126]. 18–24 hours of oxytocin after membrane rupture in the active
In a trial of 126 nulliparous women undergoing outpatient ripen- phase (usually 6 cm in a nulliparous patient), assuming reassuring
ing with Foley catheter, an average of 4 fewer hours were spent on fetal heart pattern [11, 133].
the labor and delivery unit. There was no difference in cesarean or
infectious morbidity between the outpatient and inpatient groups
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24
INTRAAMNIOTIC INFECTION AND INFLAMMATION (TRIPLE I)
Victoria Adewale, Cecily May Barber, and Elizabeth Liveright
Key points Definitions/Diagnosis

• Intraamniotic infection and inflammation (triple I) is the A wide range of terminology continues to be used in the litera-
infection and/or inflammation of any combination of the ture to describe intrapartum infection. The term “chorioam-
amniotic fluid, placenta, fetus, fetal membranes, or decidua. nionitis” has traditionally been used to describe infection of
• Triple I is diagnosed by maternal fever (single tempera- the amniotic fluid, placenta, membranes, and/or umbilical cord;
ture of ≥39°C or two temperatures of 38–38.9°C that are however, “intraamniotic infection and inflammation” (triple I)
at least 30 minutes apart) and one or more other clinical may be a more accurate representation of the clinical picture.
criteria: Maternal leukocytosis (white blood cell [WBC] As evidenced by decades of research and intellectual exchange,
count ≥15,000/mm3), purulent cervical drainage, and/or the ongoing clinical challenge of diagnosis and management of
fetal tachycardia (>160 beats per minute for ≥10 minutes) triple I is still disputed [1]. A 2016 National Institute of Child
in the absence of other causes of fever. Health and Human Development (NICHD)–sponsored work-
• Rates of triple I increase with duration of labor and rupture shop of maternal and neonatal experts proposed separating triple
of membranes (ROM) greater than 24 hours. I into three different categories: (1) isolated maternal fever, (2)
• Triple I is associated with increased maternal and neonatal suspected intraamniotic infection, and (3) confirmed intraam-
morbidity. niotic infection [2]. For clinical purposes, the American College
• Rates of cesarean delivery are higher in women with a diag- of Obstetrics and Gynecology (ACOG) recommends using the
nosis of triple I. term “intraamniotic infection” alone because confirmation of
• The clinical diagnosis of triple I may not correlate with his- intraamniotic infection will most commonly be after delivery.
tologic findings in the placenta, which has led to a shift in The clinical and histologic presentation of triple I is heteroge-
separating suspected intraamniotic infection based on clini- neous, and its association with maternal and neonatal morbidity
cal criteria from confirmed intraamniotic infection by Gram varies widely (Table 24.1). Maternal fever is the most important
stain, glucose level, culture results, or placental pathology. and identifiable sign [3]; however, isolated maternal fever may be
• Antibiotics (e.g. ampicillin and single-dose gentamycin) from an extrauterine source or may not be infectious in etiology.
should be given at the time of diagnosis of suspected intra- Isolated maternal fever is defined as any temperature between 38
partum triple I. Because isolated maternal fever is a common and 38.9°C with no other clinical criteria to diagnose intraamni-
occurrence during labor, when it occurs, antipyretics should otic infection, with or without persistent temperature elevation.
be given and a clinical suspicion for triple I should be raised. In line with the most recent ACOG Committee Opinion, the def-
If the fever persists without other clinical signs of triple I, it is inition of suspected intrapartum infection is maternal fever
reasonable to start antibiotics. (≥100.4°F or 38–38.9°C) with at least one of the following cri-
• Antibiotic treatment can generally be stopped after teria: Leukocytosis (white blood cell [WBC] count ≥15,000/mm3),
vaginal delivery. For cesarean, anaerobic coverage purulent cervical drainage, or fetal tachycardia (>160 beats
(clindamycin or metronidazole) should be added intra- per minute for 10 minutes) in the absence of other causes of
partum, and one additional dose of triple I regimen fever [4]. Intraamniotic infection can only be confirmed after
given postpartum. delivery with histologic examination of the placenta or analysis
• Neonates delivered after a triple I diagnosis should be evalu- of the amniotic fluid (such as Gram stain or culture) [4].
ated and treated as per Centers for Disease Control and Ancillary signs of triple I have been identified and quantified
Prevention (CDC) and American Academy of Pediatrics in a number of studies [2]. The presence of maternal tachycardia
(AAP) guidelines. In general, if a maternal fever occurs prior is reported in 50%–80% of cases of triple I, and fetal tachycar-
to the delivery of a neonate <34 weeks, workup and antibi- dia in 40%–70% of cases. Uterine tenderness and foul-smelling
otic treatment are recommended. In neonates ≥34 weeks amniotic fluid are present in 70%–90% of cases, but tenderness
born to mothers with a diagnosis of isolated maternal may be masked by epidural anesthesia [5]. In fact, these clini-
fever or suspected triple I, workup and treatment with cal criteria for triple I diagnosis and ancillary signs correlate
antibiotics are recommended only for ill-appearing poorly with positive bacterial polymerase chain reaction (PCR)
babies, while most can instead be closely observed in the or culture by amniocentesis [6]. Furthermore, studies show that
nursery. Antibiotics are usually continued for 24–48 hours there is a poor relationship between clinical suspicion for triple
and stopped when culture results return as negative. I and histopathologic diagnosis postdelivery. Investigations par-
• There are several preventive techniques shown to decrease ticularly focusing on increasing latency in preterm labor have
rates of triple I. Some of these include antibiotic prophy- shown that other markers of inflammation—amniotic fluid
laxis in prelabor rupture of membranes (PROM), as well WBC count, matrix metalloproteinase-8 (MMP-8), and inter-
as limiting the length of labor—especially with ROM—and leukin-6—may lead to a more accurate diagnosis or better pre-
the number of vaginal examinations. dict adverse outcomes [7, 8].
DOI: 10.1201/9781003102342-24 287

TABLE 24.1: Definition/Diagnosis of Suspected Triple I number of vaginal exams [18–26]. For example, the International
Multicentre Term Prelabor Rupture of Membranes Study (Term
Maternal fever (single temperature of ≥39°C or two temperatures of
PROM) demonstrated that increasing the number of digital
38–38.9°C that are at least 30 min apart) plus at least one of the
vaginal exams, longer duration of labor, and meconium-stained
following:
amniotic fluid were the most commonly identified risk factors for
• Leukocytosis (WBC count ≥15,000/mm3) developing infection. There is some evidence that some of these
• Purulent cervical drainage previously identified risk factors are eliminated by controlling for
• Fetal tachycardia (≥160 beats per minute for ≥10 min) confounders such as length of labor and prolonged rupture [4].
Abbreviation: WBC, white blood cell; min, minutes. The increased risk of triple I in the setting of cervical catheter
use for induction is controversial. A meta-analysis of several RCTs
Epidemiology demonstrated that the use of transcervical Foley catheters for
induction of labor was not associated with increased infectious
Triple I incidence ranges from 0.6%–19.7%, and a meta- morbidity [27]. In PROM alone, a recent multicenter randomized
analysis of high-quality studies showed a pooled incidence of controlled trial (RCT) showed that a Foley catheter in addition
3.9% (95% confidence interval [CI] 1.8–6.8). This includes not to oxytocin does not shorten time to delivery; however, it does
only the United States but several other countries around the increase the incidence of triple I [28]. Furthermore, another mul-
world [9]. This chapter focuses on triple I at term (≥37 weeks). ticenter RCT demonstrated that delayed pushing in the second
The incidence of triple I in preterm births may be as high as 40% stage results in higher rates of triple I compared to immediate
in deliveries under 27 weeks’ gestation. The rate is higher in cesar- pushing (6.7% vs. 9.1%; between-group difference, −2.5% [95% CI,
ean section, with as many as 12% of cesarean deliveries having a −4.6% to −0.3%], p = 0.005) [25].
clinical diagnosis of triple I [10].
In women with prelabor rupture of membranes (PROM), the
reported incidence is higher. The Term PROM study showed a
Complications
rate overall of 7% in women with rupture of membranes prior to Maternal
active labor [11]. In women with PROM greater than 24 hours, the Intrauterine infection is associated with increased risk of cesar-
rates of infection may be as high as 40% [12]. ean delivery and endometritis, as well as postpartum hemor-
rhage, need for blood transfusion, intensive care unit (ICU)
Pathophysiology admission, and need for hysterectomy (Table 24.2). The dura-
tion of triple I has been shown to be associated directly with
Triple I is largely considered to be an acute inflammation that blood transfusion and ICU admissions. Fortunately, infection
is due to an ascending polymicrobial infection from the cervix rarely lasts greater than 24 hours after delivery, particularly when
after membrane rupture. Additional routes have been proposed, given a dose of antibiotics postpartum (see “Management” sec-
including hematologic dissemination from the gastrointestinal tion). Treatment failure, defined as persistent fevers after receiv-
(GI) tract, retrograde spread from the peritoneal cavity via the ing one postpartum dose of antibiotics, is reported to be from 2%
fallopian tube, and iatrogenic spread through medical procedures to 6%. The patients likely to have treatment failures had either
[13]. In this setting, the most common bacteria implicated are undergone cesarean delivery, had prolonged rupture of mem-
Ureaplasma, Urealyticum, and Mycoplasma. Other bacteria often branes, or were obese [29].
isolated in amniotic fluid cultures are Gardnerella, Bacteroides, The risk of cesarean section is approximately twofold to three-
group B streptococcus, and Escherichia coli [14]. Rarely, hematog- fold higher for a woman meeting clinical criteria for triple I [30,
enous spread is the source, as in the case of Listeria infection [15]. 31]. The increased risk is thought to be due to decreased uter-
Triple I can be diagnosed histologically based on placental ine contractility and subsequent dysfunctional labor. Decreased
evaluation; however, a clinical diagnosis may not be confirmed
by histologic studies. It has been reported that up to one-third
of clinical diagnoses may not have corresponding histologic
TABLE 24.2: Selected Possible Complications Associated
findings [16]. A number of grading systems have been proposed
with Triple I
to describe the histologic severity of triple I, and they include
depth and location of neutrophil infiltration of the placenta. A Maternal
number of inflammatory markers may be associated with the
• Cesarean delivery
clinical syndrome and histologic diagnosis of triple I, including
• Endometritis
cytokines such as interleukin (IL)-1-alpha, IL-1-beta, IL-6, and
• Postpartum hemorrhage
IL-8, among others. It is suggested that microorganisms invad-
• Need for blood transfusion
ing the amniotic space stimulate these inflammatory cytokines,
• ICU admission
which favors the migration of neutrophils and ultimately pro-
• Need for hysterectomy
duces the histologic diagnosis of triple I [17].
Neonatal
Risk factors
• Pneumonia
Risk factors for developing triple I include longer duration of • Meningitis
labor, prolonged rupture of membranes, meconium-stained • Sepsis
amniotic fluid, use of internal fetal monitoring, group B • Risk of cerebral palsy or bronchopulmonary dysplasia
streptococcus (GBS) colonization, nulliparity, bacterial vagi- • Death
nosis, delayed pushing in the second stage, and increased Abbreviation: ICU, intensive care unit.
Intraamniotic Infection and Inflammation (Triple I) 289
uterine contractility may also lead to higher rates of postpartum TABLE 24.3: Antibiotic Treatment for Triple I
hemorrhage due to atony; risk of postpartum hemorrhage after
Recommended Regimens
vaginal delivery may be up to 80% more likely, and 50% more
likely after cesarean section [32]. The international multicenter • Ampicillin and gentamicina or
PPROMT trial showed that with PPROM close to term—between • Cefazolin and gentamicin or
34 and 36.6 weeks—women who were managed expectantly had • Clindamycin or vancomycin and gentamicin
higher rates of hemorrhage (RR 0.6, 95% CI 0.4–0.9), intrapartum • Add clindamycin (or metronidazole) for cesarean section
fever (RR 0.4, CI 0.2–0.9), use of postpartum antibiotics (RR 0.8,
CI 0.7–1.0), and longer hospital stays (p <0.0001) compared with Duration
those who were delivered within 24 hours [33] (see Chap. 20).
• Initiate treatment at time of diagnosis and continue intrapartum
• Vaginal delivery: Stop postpartum
Neonatal
• Cesarean: Single additional dose of chosen antibiotic regimen
Triple I is associated with increased rates of bacteremia, sep-
postpartum
sis, and mortality in neonates, as well as an increased risk of
• No indication for prolonged treatment in absence of clinical
cerebral palsy [34]. A neonatal sepsis rate of 8% when born
indications
with triple I has been reported; the mortality rate of neonates
born to mothers with triple I was 1.4/1000 as compared to
Benefits
0.8/1000 of neonates born to mothers without infection [35].
Intrapartum fever has been shown to increase transient neonatal • Decreased rate of neonatal bacteremia, pneumonia, and sepsis
adverse effects, including neonatal seizures and encephalopathy • Shorter maternal hospital stay
[36–39]. These risks are present in both term and preterm infants, • Lower rates of persistent maternal fever
though the relative risk is greater preterm. It is posited that the a Dosing recommendations: Ampicillin 2 g IV every 6 hours, gentamicin 5 mg/kg
fetal inflammatory response is a contributing factor to cerebral every 24 hours, cefazolin 2 g IV every 8 hours, clindamycin 900 mg IV every
palsy. Studies show that elevated levels of inflammatory cyto- 8 hours, vancomycin 1 g IV every 12 hours.
kines were present in the amniotic fluid of mothers of children
with cerebral palsy [40].
Recent studies emphasize that an association with cerebral intrapartum antibiotics. These studies most consistently have
palsy be differentiated from the risk of cerebral palsy when dis- shown decreased rates of neonatal bacteremia and sepsis, and
cussing triple I. One large meta-analysis delineated that clinical also decreased rates of maternal febrile morbidity and length
diagnosis of triple I was not a risk factor for cerebral palsy; how- of postpartum stay [43, 44]. These data are exclusively from
ever, an association was found. There was no association between cohort studies; there still have been no RCTs to date compar-
histologically diagnosed triple I and cerebral palsy in preterm ing intrapartum antibiotics to no treatment/placebo for women
neonates, likely due to other factors related to preterm birth con- with triple I. A recent analysis showed that the sensitivity and
tributing to the neonate’s outcome [41]. specificity of the NICHD criteria for suspected triple I to predict
Complications from triple I have also been explored in chil- confirmed triple I were 71.4% (95% CI 61.4%–80.1%) and 40.5%
dren beyond the neonatal and infant years. Using NICHD data (95% CI 33.6%–47.8%), respectively. Furthermore, the incidence
on magnesium for prevention of cerebral palsy in early preterm of adverse clinical infectious outcomes was similar between the
delivery, an observational cohort study demonstrated that there isolated maternal fever group and the suspected triple I group
were no significant differences in Mental Developmental Index (11.8% in suspected triple I group, 9.5% in isolated fever group,
scores between children of mothers with or without triple I P = 0.5), suggesting that febrile women not meeting criteria for
(19.1% versus 17%). This study did, however, show that neonates suspected triple I are still at risk and may benefit from antibiotics
diagnosed with sepsis had decreased Mental Development Index [45]. Because isolated maternal fever is a common occurrence
scores at age 2 (absolute risk reduction [ARR] 1.36, CI 1.04–1.78). during labor, when it occurs, antipyretics should be given and
Therefore, though exposure to triple I does not result in measur- a clinical suspicion for triple I should be raised. If the fever
able neurocognitive delays in children, a known complication of persists without other clinical signs of triple I, it is reason-
triple I, neonatal sepsis, was significantly associated with this able to start antibiotics, given evidence that the new criteria may
outcome [42]. not be inclusive enough to treat all those women and newborns
who have potential to benefit from antibiotics. Furthermore, pro-
spective, randomized controlled studies are still needed to better
Management qualify the management of isolated maternal fever [4].
Once triple I has been diagnosed at any gestational age, the rec- The source of triple I is thought to originate in the vaginal flora;
ommended management is prompt delivery, with intrapartum coverage is therefore recommended to target beta-lactamase–
antibiotics. Currently, expectant management without delivery producing aerobes and anaerobes. Ampicillin and gentamicin
for triple I is contraindicated, unless an amniocentesis is done and are the antibiotics most commonly used when the diagnosis of
triple I is ruled out (e.g. amniotic fluid with glucose >15 mg/dL; triple I is made in labor, based largely on clinical consensus, in
negative Gram stain; negative culture). the absence of data supporting other regimens [46]. Twenty-four-
hour dosing of the aminoglycoside is equally effective as 8-hour
Intrapartum dosing with the advantages of increased bactericidal effects,
Initiation of antibiotics at the time of diagnosis is the stan- decreased nephrotoxicity, and decreased cost [47]. The two RCTs
dard of care for treatment of triple I (Table 24.3). This rec- identified in a Cochrane review showed no statistically significant
ommendation is supported by several studies demonstrating difference in maternal or neonatal outcomes when clindamycin
decreased maternal and fetal morbidity with administration of was added to ampicillin and gentamicin [48, 49].
For patients undergoing cesarean section, anaerobic cover- TABLE 24.4: Selected Strategies for Prevention of Triple I
age through antepartum addition of clindamycin or metro-
• Decreasing length of labor
nidazole to ampicillin and gentamycin is associated with fewer
• Decreasing length of time of rupture of membranes (ROM)
wound infections postpartum [50].
• Antibiotic prophylaxis in labor if ROM to delivery >12 hours
Antipyretics should be considered when maternal fever is
• Decreasing number of digital exams
present.
Delivery antibiotic therapy. Antibiotics are usually continued for about

Triple I itself does not necessitate cesarean section, unless 48 hours and stopped when culture results return as negative.
otherwise motivated by standard obstetric indications, though
there is an increased rate of cesarean delivery in the setting of triple
I as described earlier. Time from initiation of antibiotic treatment Prevention
to delivery has not been shown to affect outcomes; it is therefore
Several interventions are associated with the prevention of triple I
not recommended to expedite delivery for triple I alone.
(Table 24.4).
Postpartum Antibiotic prophylaxis for prevention of triple I in preterm
For women who had a vaginal delivery, antibiotics do not need PROM (PPROM) has been consistently shown to yield benefit for
to be continued postpartum, as shown by RCTs comparing anti- the neonate (see Chap. 20). Even in women with term PROM,
biotics vs. placebo. The cure in these cases is the delivery itself. antibiotic prophylaxis, especially in women expected to have
In women who had a cesarean delivery, ACOG recommends at latency from PROM to delivery >12 hours, has been associated
least a single dose of the chosen antibiotic regimen after deliv- with a significant reduction in the rates of triple I and endome-
ery to decrease postpartum maternal morbidity, as the mode tritis [59] (Chap. 21). This benefit is extended to women with
of delivery itself significantly increases the risk for postpartum GBS isolated from vaginal flora, as shown in the PPROMT and
maternal endometritis and wound infection. However, prolonged PPROMEXIL studies [25].
treatment has not been shown to improve outcomes [51–54]. Modifiable risk factors for triple I in term pregnancies present
the opportunity for prevention, particularly length of ruptured
Neonatal management membranes and length of labor [60].
Maternal diagnosis of triple I can be associated with serious Techniques used to shorten active labor have been shown to
implications for evaluation and management of the newborn, decrease maternal infectious morbidity. Decreasing length of
even for well-appearing term infants. The NICHD, Centers for labor, especially when ROM occurs, inherently decreases other
Disease Control and Prevention (CDC), and American Academy risk factors associated with triple I, such as increased number of
of Pediatrics (AAP) all recommend laboratory testing and anti- digital exams.
biotic treatment for well-appearing infants born to mothers with Perineal hygiene, in addition to prolonged supine positioning
either suspected or confirmed triple I [55, 56]. This often results and digital exams, are suggested contributing factors to triple I
in separation from the mother, admission to a neonatal intensive [61]. A Cochrane review and another larger meta-analysis, how-
care unit (NICU), and potential exposure to drug-resistant bacte- ever, showed no evidence that vaginal chlorhexidine during
ria in the NICU setting. labor prevents triple I or neonatal infection and showed only a
In addition to these health costs, the financial implications statistically insignificant trend toward a decrease in postpar-
of triple I management of well-appearing infants has been tum endometritis [62, 63]. Prophylactic antibiotics to reduce
estimated at $10,424,400 (treating all infants diagnosed each vaginal infections have been shown to lower rates of bacterial
day for 2 days) [35]. A “sepsis calculator” has been suggested vaginosis and trichomonas, without a decrease in the risk of triple
as a tool to limit unnecessary treatment of well-appearing I or preterm birth [64, 65]. Two small trials showed that intrapar-
neonates. The calculator combines categorical (GBS status, tum amnioinfusion may decrease maternal temperature, but did
intrapartum antibiotic treatment) and continuous variables not show consistent improvements in maternal or neonatal out-
(peak febrile temperature, duration of ruptured membranes, ges- comes [66, 67]. A recent Cochrane review reinforced that there is
tational age) with the neonate’s clinical presentation (clinically insufficient evidence for amnioinfusion in reducing perinatal and
ill, equivocal, or well-appearing) during the first 6–12 hours of maternal morbidity and mortality [68].
life. Studies have demonstrated that the incidence of early-onset
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during labour on maternal and neonatal infections? A systematic review 67. Monahan E, et al. Amnioinfusion for preventing puerperal infection: A pro-
of randomized trials with meta-analysis. BMC Pregnancy Childbirth. spective study. J Reprod Med. 1995;40:721–723. [I]
2018;18:139. [Meta-analysis, 11 RCTs] 68. Hofmeyr GJ, et al. Amnioinfusion for chorioamnionitis. Cochrane Library.
64. Goldenberg RL, et al. The HPTN 024 Study: The efficacy of antibiotics 2016;8:13–814. [Meta-analysis, 1 RCT]
to prevent chorioamnionitis and preterm birth. Am J Obstet Gynecol.
2006;194(3):650–661. [I]
25
MECONIUM
Meike Schuster and Justin S. Brandt
Key points neonatal depression [1]. Confirming such clinical impressions,

meconium passage was formally recognized to be associated
• Meconium-stained fluid becomes more common with with increased perinatal morbidity and mortality in the 1975
advancing gestational age and occurs in over 25% of preg- Collaborative Study of Cerebral Palsy.
nancies past 42 weeks.
• Meconium-stained amniotic fluid (MSAF) is due to a com- Diagnoses/Definitions
bination of increased fetal bowel motility and decreased
clearance of meconium by the fetus or placenta. Meconium is the intestinal fecal content of the fetus and is com-
• Meconium aspiration syndrome (MAS) occurs in about posed of mucopolysaccharides, blood by-products, hair, and
5% of MSAF cases, and, of these, approximately 4% of squamous cells. The diagnosis of MSAF is made clinically on the
affected neonates die. basis of appearance (i.e. greenish or brownish staining) or by his-
• Risk factors include pregnancy after 39 weeks, acute fetal topathologic examination of the placenta. Particularly in the pre-
acidemia, intrauterine infection, placental dysfunction term gestations, a clinical impression of MSAF may be false and
leading to chronic hypoxia, uterine hyperstimulation, and instead reflect staining by another mechanism (i.e. hemosiderin).
prolonged labor. Meconium aspiration syndrome (MAS) is defined as neonatal
• The most common ultrasound findings are ascites, respiratory distress requiring supplemental oxygen in the pres-
dilated loops of bowl, calcifications, echogenic bowel, and ence of MSAF without other causes of respiratory distress. MAS
polyhydramnios. is classified as shown next.
• MAS is associated with neonatal morbidity and mortal-
ity, especially in a low-resource setting.
• Discolored amniotic fluid <24 weeks (i.e. at genetic amnio-
centesis) is not due to meconium staining, but may be asso- The incidence of MSAF increases with gestational age. In a ret-
ciated with intraamniotic bleed or infection. rospective cohort study of 499,096 singleton births, the reported
• The presence of meconium or the change in thickness of rates of MSAF were 5.1% in preterm gestations (<36 weeks), 16.5%
meconium at term may be associated with possible nonre- in term gestations (37–42 weeks), and 27.1% in postterm gesta-
assuring fetal status and should prompt evaluation. tions (>42 weeks) (Figure 25.1) [2]. Meconium in placental mac-
• Induction of labor for 39 weeks’ gestation is beneficial rophages is documented in about 17%–19% of term placentas, and
in reducing the risk of MAS. clinical evidence of MASF is present in about 12% (7%–22%) of
• Amnioinfusion for MSAF is not associated with term deliveries [3]. However, there is poor concordance between
improvements in perinatal outcomes in settings with histologic and clinical evidence of meconium presence, probably
standard perinatal surveillance, but this intervention due to the persistence of old meconium in macrophages after
may be associated with improvements in perinatal out- its clearance from the amniotic fluid, as well as new release of
comes in resource-poor settings. meconium by the fetus before uptake by placenta macrophages
• There appears to be little benefit to the use of antibiotics [4]. Moreover, there is discordance among histopathologists in
during labor for MSAF and should be reserved for indica- the definition of the presence of placental meconium [5]. In sum-
tions such as group B streptococcus (GBS) prophylaxis and mary, meconium-stained fluid becomes more common with
chorioamnionitis. advancing gestational age and occurs in over 25% of pregnan-
• Oropharyngeal and nasopharyngeal suctioning prior cies past 42 weeks.
to delivery of the shoulders is not necessary and doesn’t
improve outcomes.
• Routine endotracheal intubation of nonvigorous new-
borns with MSAF should be avoided and discouraged. Although regular fetal bowel movements occur as early as the
• The use of meconium and sections of the umbilical cord second trimester [6], meconium does not become green (i.e. con-
appear to be equivalent for the evaluation of in utero expo- tains biliverdin pigments) until 22–24 weeks.
sure to drugs, alcohol, and environmental factors, and In term and postterm fetuses, physiologic increased moti-
either may be used for this purpose. lin levels or pathologic increases mediated by fetal stress from
hypoxia, infection, or cord compression may lead to meconium
Historic notes passage. Pregnancies >38 weeks show higher rates of MSAF and
macrosomia, and these markers of neonatal morbidity and mor-
Meconium is a term derived from the Greek “mekoni,” which tality are associated with MAS [3].
means poppy juice or opium. Aristotle reportedly observed that Aspiration of meconium can lead to respiratory compro-
meconium-stained amniotic fluid (MSAF) was associated with mise due to chemical pneumonitis associated with inhibition of
DOI: 10.1201/9781003102342-25 293

40.0%
35.0%
30.0%
25.0%
20.0%
15.0%
10.0%
5.0%
0.0%
24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44
Gestational Age - Completed Weeks
FIGURE 25.1 Percentage of births with meconium-stained fluid according to gestational age. (Adapted from Ref. 2.)
surfactant function, inflammation, and obstruction. However, neonatal sepsis in the presence of MSAF); placental dysfunc-
respiratory compromise in the presence of meconium is more tion leading to chronic fetal hypoxia (e.g. fetal growth restric-
commonly due to other processes (such as chronic or acute tion, preeclampsia, oligohydramnios); uterine tachysystole
asphyxia or intrauterine infection) than damage from meconium (e.g. with misoprostol); and prolonged labor (every 2-hour
aspiration itself [7]. Factors such as intrauterine growth restric- increase in duration of labor is associated with a 30% increase in
tion, postmaturity (>40 weeks), nonreassuring fetal heart rate the risk of MSAF) [10, 11]. The multiplicity of risk factors and the
tracing, and caesarean birth have been associated with higher possible coexistence of independent risk factors (e.g. meconium
rates of MAS [8]. For example, hypoxia may stimulate colonic and oligohydramnios) may explain why MSAF has inconsistently
activity and fetal gasping, leading to meconium aspiration. In been associated with lower umbilical artery pH at birth.
such cases, meconium is not causative of the respiratory compro-
mise, but rather a manifestation of underlying chronic or acute Complications
processes leading to fetal compromise. MAS occurs in about 5%
of MSAF cases, and, of these, approximately 4% of affected Because the intrauterine processes underlying accumulation
neonates die [9]. of meconium can jeopardize the fetus, MSAF and MAS can be
associated with increased risk of fetal acidemia, neonatal sei-
Symptoms zures, neonatal intensive care unit (NICU) admission, neonatal
sepsis, respiratory distress, neonatal encephalopathy, cerebral
Symptoms of neonatal MAS include respiratory compromise, palsy, and neonatal death [3, 9, 12–14]. MAS is associated
with tachypnea, cyanosis, and reduced pulmonary compliance. with neonatal morbidity and mortality, especially in a low-
In some cases, pulmonary hypertension develops [9]. resource setting.
Classification of meconium Pregnancy management

aspiration syndrome
Prenatal diagnosis of meconium
• Mild: Supplemental oxygen <40% for <48 hours peritonitis (Figure 25.2)
• Moderate: Supplemental oxygen ≥40% or for ≥48 hours Meconium peritonitis (MP) is a chemical peritonitis that occurs
• Severe: Need for intubation (or primary pulmonary in utero from perforation of the intestines and is associated with
hypertension) cystic fibrosis, viral infections, and intestinal obstruction [15–17].
Incidence of MP is approximately 3.7 per 10,000 [18]. One study
Risk factors reported a prenatal diagnosis rate of 64.9%, with ascites being the
most common finding, followed by dilated bowel loops, cal-
Postterm pregnancy; acute fetal acidemia; intrauterine infec- cifications, echogenic bowel, and polyhydramnios [19]. Fetal
tion (as suggested by higher rates of histologic acute chorio- MRI may assist in the diagnosis and planning for postnatal surgi-
amnionitis, clinical chorioamnionitis and endometritis, and cal repair of intestinal obstructions causing MP [20–22].
Meconium 295
Meconium Stained Amniotic Fluid

(MSAF)
Prenatal Occurrence Prevention
Ultrasound finding of
dilated bowels, Avoid risk factors such as fetal
calcifications, echogenic acidemia, infection, chronic fetal
bowel or hypoxia due to placental
polyhydramnios dysfunction, uterine
tachysystole, or prolonged labor
Amniocentesis – most
often break-down Use best obstetrical
products of intra-uterine Management estimate for
or intra-amniotic pregnancy dating to
bleeding avoid delivery post
due date
Institutional policies
regarding routine
induction of labor
Fetal/Neonatal may reduce adverse
neonatal outcomes
- Oro – and such as MAS
Nasopharyngeal
suction does not
decrease the incidence Maternal
of MAS, need for
mechanical ventilation - Amnioinfusion does not reduce the
or other risk of MAS or neonatal morbidity,
morbidity/mortality except in low resource setting
and should not be - Antibiotics improve outcomes in the
performed in the setting of infection but should not
setting of MSAF be used in MSAF cases
- Routine endotracheal
intubation at birth in
meconium stained
neonates does not
improve outcomes and
is no longer
recommended
FIGURE 25.2 Suggested management of meconium-stained amniotic fluid.
Meconium at genetic amniocentesis Meconium in the late preterm and

Discolored amniotic fluid <24 weeks (i.e. at genetic amnio- early term fetus <39 weeks
centesis) is not due to meconium staining, but may be asso- MSAF in the late-preterm and early-term fetus should prompt
ciated with intraamniotic bleed or infection. In this situation, evaluation for intrauterine infection and fetal hypoxia, as the
evaluation for such causes of discolored amniotic fluid may be finding is unlikely to be physiologic at these gestational ages.
considered, including microbiologic studies on amniotic fluid;
Kleihauer-Betke testing on maternal blood; careful sonographic Meconium at ≥39 weeks
examination for evidence of retroplacental or intraamniotic Although fetal stress due to infection, hypoxia, and other causes
bleeding; and assessment of placental implantation by evaluating may provoke meconium passage, MSAF in the term, late-term, or
placental thickness, dimensions, echotexture, and cord insertion. postterm fetus may reflect normal physiology and maturation
of the gastrointestinal tract. Progression in meconium consis- of fetal heart rate decelerations, 5-minute Apgar score less than 7,
tency in labor from no/little meconium to the presence of thick presence of meconium below the vocal cords, and need for neo-
meconium, or the occurrence of meconium in the setting of cat- natal ventilation or NICU admission.
egory II fetal heart rate tracings should elicit further evaluation, In a subgroup analysis that included three studies performed in
as these findings are associated with higher rates of fetal acide- settings with limited perinatal surveillance capabilities, amnio-
mia and lower Apgar scores at 5 minutes [23–25]. The presence infusion for MSAF was associated with a significant reduction
of meconium and fetal distress or the change in thickness in MAS (RR 0.17, 95% CI 0.05–0.52) and perinatal mortality (RR
of meconium is associated with possible fetal distress and 0.24, 95% CI 0.11–0.53), as well as reductions in cesarean delivery
should prompt evaluation. for nonreassuring fetal testing, 5-minute Apgar score less than 7,
neonatal ventilation or NICU admission, and neonatal encepha-
lopathy, compared with no amnioinfusion.
Prevention In summary, amnioinfusion for MSAF is not associated
Prevention of meconium passage and of MAS may be accom- with improvements in perinatal outcomes in settings with
plished by reducing the rate of postterm deliveries. Early ultra- standard perinatal surveillance, but this intervention may
sound dating, stripping of membranes at ≥37-38 weeks, and be associated with improvements in perinatal outcomes in
induction of labor at 39 weeks decrease the incidence of post- resource-poor settings.
term pregnancies (see Chap. 23). Avoidance of fetal hypoxia may
also reduce MSAF, but there is a lack of evidence-based strategies Maternal antibiotics
to achieve this aim. Induction has been shown to reduce the risk There is insufficient evidence to assess the effectiveness of anti-
of MAS. In a meta-analysis of 11 randomized controlled trials biotics for women with meconium in labor. A meta-analysis
(RCTs) that included term pregnancies and compared a policy of (including two RCTs, both of which utilized ampicillin-
routine labor induction at or shortly after 41 weeks versus expect- sulbactam, n = 362) found that antibiotic prophylaxis in women
ant management, there was a 23% reduction in the risk of MAS in with MSAF is associated with a significant decrease in the risk
the induction group versus expectant management group (rela- of chorioamnionitis (RR 0.36, 95% CI 0.21–0.62) compared with
tive risk [RR] 0.77 95% confidence interval [CI] 0.62–0.96) [26]. normal saline, but is not associated with a significant reduction
The ARRIVE trials, an RCT of 6096 patients, compared induction in the incidence of neonatal sepsis (RR 1.00, 95% CI 0.21–4.76),
of labor vs. expectant management and showed an overall 20% NICU admission (RR 0.83, 95% CI 0.39–1.78), and postpartum
reduction in perinatal composite adverse outcomes (RR 0.80, 95% endometritis (RR 0.50, 95% CI 0.18–1.38) [31]. No serious adverse
CI 0.64–1.00), which included MAS, birth trauma, respiratory effects were reported. In summary, based on the limited evi-
support, perinatal death, and other averse neonatal outcomes dence available, there appears to be little benefit to the use
[27]. In summary, induction of labor for 39 weeks’ gestation of antibiotics during labor for MSAF, and they should be
reduces the risk of MAS (see also Chap. 22) [28, 29]. reserved for indications such as group B streptococcus (GBS)
prophylaxis and chorioamnionitis.
Management techniques used Neonatal [28, 29]

in the setting of MSAF Oropharyngeal and nasopharyngeal suctioning
Although obstetric providers commonly suction the oropharynx
Amnioinfusion and nasopharynx before delivery of the shoulders or the “first cry,”
Amnioinfusion is instillation of isotonic fluid, typically normal there is insufficient evidence to support this practice. Indeed, an
saline, into the uterus via an intrauterine pressure catheter in a RCT of n = 2514 infants with MSAF who were randomized to
woman with dilated cervix and ruptured membranes. A “typical” suctioning versus no suctioning demonstrated no reduction in
approach involves instillation of 500 mL of normal saline over the incidence of MAS, need for mechanical ventilation for MAS,
a period of 30 minutes. Amnioinfusion may be considered >34 any other associated morbidities, or neonatal mortality [32, 33].
weeks. For amnioinfusion in the presence of variable decelera- Another RCT that included over 500 infants was performed in a
tions, see Chap. 11; for amnioinfusion for preterm prelabor rup- resource-poor community and also demonstrated no advantage
ture of membranes (PPROM), see Chap. 20; for amnioinfusion of prenatal suctioning versus expectant management [34]. In
for oligohydramnios without PPROM, see Chap. 59 in Maternal- summary, it appears that oropharyngeal and nasopharyngeal
Fetal Evidence Based Guidelines. suctioning prior to delivery of the shoulders is not necessary
The efficacy of amnioinfusion to “dilute” meconium, relieve and doesn’t improve outcomes.
cord compression, and reduce associated neonatal morbidity has
historically been controversial. A recent meta-analysis on this Endotracheal intubation
topic included 14 RCTs [30]. Results were reported separately for A policy of routine endotracheal intubation at birth with MSAF
clinical sites with and without capabilities for perinatal surveil- in neonates who are otherwise vigorous does not improve neo-
lance. The main outcome in the RCTs was usually occurrence of natal outcomes over routine resuscitation [35]. Neither the
MAS. Under standard perinatal surveillance, amnioinfusion for American Academy of Pediatrics (AAP) nor the American
MSAF was not associated with a reduction in MAS (RR 0.52, 95% Heart Association recommends routine endotracheal suction-
CI 0.26–1.06), perinatal deaths (RR 1.00, 95% CI 0.29–3.45), or ing for nonvigorous infants [36, 37]. In 2015, the AAP’s Neonatal
the combined outcome of perinatal death and severe morbidity Resuscitation Program issued updated guidelines, which dis-
(RR 1.13, 95% CI 0.88–1.47), compared with no amnioinfusion. couraged routine intubation of nonvigorous fetuses born through
There was considerable heterogeneity among studies for several MSAF after an RCT showing that the rate of MAS and neonatal
secondary outcomes, such as presence of heavy meconium stain- mortality was equal in those who were intubated and those who
ing, caesarean delivery for nonreassuring fetal testing, occurrence were not [38, 39]. Several studies have since evaluated the impact
Meconium 297
of this change in management. Comparing outcomes of intubated 4. Incerti M, Locatelli A, Consonni S, Bono F, Leone BE, Ghidini A. Can pla-
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of MAS, inhaled nitric oxide and extracorporeal membrane oxy- 5. Poggi SH, Salafia C, Paiva S, Leak NJ, Pezzullo JC, Ghidini A. Variability
genation (ECMO), and morbidity and mortality, but lower rates in pathologists’ detection of placental meconium uptake. Am J Perinatol.
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vs. 3.1%) [40–44]. One RCT following the change in recommen- 6. Ramon y Cajal CL, Martinez RO. Defecation in utero: A physiologic fetal
function. Am J Obstet Gynecol. 2003;188(1):153–156. [II-2, Prospective
dation found an increased risk of MAS (RR 1.4, 95% CI 0.792 –
study, n = 240]
2.470) and death (13.6% vs. 7.5%, p < 0.05) in those nonvigorous 7. Ghidini A, Spong CY. Severe meconium aspiration syndrome is not caused
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26
MALPRESENTATION AND MALPOSITION
Alexis C. Gimovsky, Andrea Dall’Asta, Giovanni Morganelli, and Tullio Ghi
Key points • Compared with planned vaginal delivery (VD), planned

CD for the term breech fetus is associated with a small
• Malpresentation, including breech, transverse and oth- decrease in perinatal death and a reduction in serious
ers, is associated with uterine anomalies, fibroids, pla- neonatal morbidity, but no difference in death or neuro-
centa previa, grand multiparity, contracted maternal developmental delay at 2 years after delivery.
pelvis, pelvic tumors, prematurity (the earlier the ges- • There is insufficient evidence to assess if outcomes of the pre-
tational age, the higher the incidence of malpresentation), term breech-presenting fetus are affected by mode of delivery.
multiple gestation, polyhydramnios, short umbilical • Planned VD of the second nonvertex twin by breech
cord, fetal anomalies (e.g. anencephaly, hydrocephalus), extraction is a reasonable management option by expert
abnormal fetal motor ability, and prior breech delivery. operator, as neonatal and maternal morbidities at planned
• Complications of breech presentation include congenital CD or VD are equivalent.
anomalies, preterm birth (PTB), birth trauma, low Apgar • Manual rotation of the persistent occiput posterior or trans-
scores, and low pH, regardless of mode of delivery. Cord verse malposition of the cephalic presentation to the occiput
prolapse, head hyperextension, and head or arm entrap- anterior position in the second stage is associated with a non-
ment are more common with vaginal breech delivery. significant 14% decrease in operative (OVD and CD) delivery.
• External cephalic version (ECV) is a safe and effec-
tive intervention for malpresentation. Urgent cesarean Definitions
delivery (CD) for nonreassuring fetal heart rate tracing
(NRFHT) and placental abruption occur in <0.5% of ECVs. Presentation: Fetal body part that is in the lower uterine segment
• ECV is to be avoided with any contraindications to (lowest in the uterus and closest to the cervix).
vaginal delivery such as placenta previa, or prior classi- Malpresentation: Clinical entities where the presenting part is
cal uterine incision. ECV is relatively contraindicated in not the fetal vertex (Figure 26.1), such as the following: Breech
rupture of membranes, oligohydramnios, known uterine presentation (Figure 26.2); transverse/oblique lie, compound
or fetal anomaly, unexplained uterine bleeding, or active presentation (Figure 26.3); shoulder presentation (Figure 26.4);
phase of labor. and cephalic malpresentations secondary to deflexed fetal head:
• ECV reduces the incidence of noncephalic birth by 54% Sinciput (Figure 26.5), brow (Figure 26.6), and face (Figure 26.7)
and CD by 37%. Because ECV is associated with a very low presentations.
incidence of adverse events and with a significant decrease
in CD, all women at or near term with nonvertex pre-
sentations should be offered an ECV. Success rates range
Malpresentation
between 50% and 70%. Success is increased with higher Symptoms
parity, transverse or oblique lie, nonengaged presenting Maternal impression of fetal presentation based on fetal move-
part, relaxed uterus, palpable fetal head, larger fore-bag ment is suggestive but overall unreliable for predicting fetal
and maternal weight less than 65 kg. presentation.
• Compared with ECV at term, ECV before term (e.g.
34–35 weeks) reduces noncephalic presentation at birth Epidemiology/Incidence
but does not reduce the rate of CD and may be associ- Breech presentation complicates 3%–4% of all pregnancies at
ated with an increase in the incidence of PTB. About term (≥37 weeks) [1]. Its incidence is inversely proportional to
360/7–366/7 weeks is generally considered to be the opti- gestational age, with an incidence of about 25% at 28 weeks, 11%
mal time for attempted ECV. at 32 weeks, and 5% at 34 weeks [2]. In 2003, 87% of all breech
• Tocolysis with betamimetics prior to attempt at ECV is presentations resulted in cesarean delivery (CD); this is similar
associated with fewer failures of ECV and fewer CDs. to 1990 (90%), but much increased from 1970 (12%) [3, 4]. Breech
• Anesthetic-dose neuraxial blockade (usually with spi- as an indication for CD accounts for 15% of all CDs and adds $1.4
nal) is associated with a 63% increase in the success rate billion to U.S. obstetric costs [4].
of ECV. Transverse lie is reported to complicate less than 1% of the
• ECV should be performed, after appropriate counseling pregnancies at term [5]. Oblique lie is usually transitory and con-
and consent, in a facility with ready availability for ultra- verts into longitudinal or transverse lie in early labor [5].
sound and for emergency CD. Sinciput, brow, and face presentations represent the three
• There is inconsistent evidence that moxibustion at point “classical” variants of cephalic malpresentation and are char-
BL67 alone or in combination with acupuncture is associ- acterized by a progressive deflexion from vertex presentation.
ated with higher success rates of external cephalic ver- These malpresentations are quite rare with reported incidences
sion, especially when performed in China. of 1/600–1/2000 for face presentation [5] and 1/380–1/800 for
DOI: 10.1201/9781003102342-26 299

FIGURE 26.1 Vertex presentation.
brow presentation [6]. Sinciput presentation is likely to be under-

estimated, given its subtlety, but its incidence is largely unknown.
Classifications (see Figure 26.8

for a detailed algorithm)
Breech (Figure 26.2)

Fetus presents in longitudinal lie with head not in the lower uter-
ine segment.
Fetal breech presentation is further classified as follows:
• Complete: Flexion of the fetal hips and knees

• Incomplete: Extension of one or both hips (includes
footling)
• Frank: Flexion at the hips and extension at the knees
Transverse
The fetal longitudinal axis is perpendicular to the long axis of the
uterus. The fetus can either present “back up” (fetal small parts
present to the cervix) or “back down” (fetal spine or shoulder
present to the cervix).
Oblique
The fetal longitudinal axis is diagonal to the long axis of the
uterus.
Face (Figure 26.7)

The fetal head is hyperextended so that the fetal occiput is in con-
tact with the fetal back and the mentum (chin) is presenting. The
fetal chin may be anterior or posterior relative to the maternal
pubic symphysis. FIGURE 26.2 Breech presentation. (a) Footling breech; (b)
complete breech; (c) frank breech.
Brow (Figure 26.6)
The presenting part is the portion of the fetal head between the
orbital ridge and the anterior fontanelle. The fetal head is posi- fontanelle. Sinciput represents a mild form of deflexion of the
tioned midway between full flexion and extension. fetal head in the cephalic-presenting fetus.
Sinciput (Figure 26.5) Compound (Figure 26.3)

The presenting part is the portion of the fetal head between the Simultaneous presentation of a prolapsing fetal extremity and the
brow and the posterior fontanelle, corresponding to the anterior presenting part.
Malpresentation and Malposition 301
FIGURE 26.3 Compound presentation.
FIGURE 26.5 Sinciput presentation.
Shoulder (Figure 26.4)

The fetal shoulder is the presenting part.
Both maternal and fetal factors can lead to malpresentation,
including uterine anomalies, fibroids, placenta previa, grand
multiparity, contracted maternal pelvis, pelvic tumors, pre-
maturity (the earlier the gestational age, the higher the incidence
of malpresentation), multiple gestation, polyhydramnios, short
umbilical cord, fetal anomalies (e.g. anencephaly, hydrocepha-
FIGURE 26.4 Shoulder presentation. lus), abnormal fetal motor ability, and prior breech delivery.
FIGURE 26.6 Brow presentation.

FIGURE 26.7 Face presentation.
There is a 9% risk of recurrence of malpresentation in subsequent
pregnancies following a prior breech delivery.
independent of delivery mode. Incidence of cord prolapse is the
Complications same with frank breech as with vertex presentations (<1%), 5%
Incidence of congenital anomalies (up to 6%), premature with complete breech, 15% with footling breech, and is inversely
birth (PTB), birth trauma, low Apgar scores, and low pH are proportional to gestational age (GA). Head hyperextension
increased with breech presentation compared with vertex pre- (associated with spinal cord injury) and head or arm entrapment
sentation, regardless of mode of delivery. Breech presenta- are associated with breech presentation, particularly with vagi-
tion may be both a sign and a consequence of fetal compromise, nal breech delivery. Presentation at birth does not seem to affect
FIGURE 26.8 Malpresentations and malpositions. Denominator: The fetal reference point used in defining position. It is usually
a prominent bony landmark at the circumference of the presenting part. For example, occiput for vertex, sacrum for breech, mentum
for face, and acromion for shoulder presentation. Fetal lie: Orientation of the long axis of the fetus to the long axis of the uterus;
Longitudinal orientation: Fetus and the mother’s dorsal column are parallel; Transverse orientation: Fetus at 90 degrees to mother’s
dorsal column; Oblique orientation: Fetus is neither parallel nor 90 degrees to the mother’s dorsal column, but is in transition between
longitudinal and transverse lie. Fetal presentation: The lowermost structure of the fetus in the maternal pelvis. In the longitudinal lie,
the fetal presentation can be either cephalic or breech. In the transverse lie, the presentation is usually the fetal back or shoulder; in
the oblique lie, it is usually the shoulder or the arm. Fetal attitude: Degree of extension-flexion of the fetal head; the relation of various
parts of the fetus to each other. For example, in the cephalic presentation: Vertex: Head is maximally flexed; Sinciput (military): Head
is partially flexed; Brow: Head is partially extended; Face: Head is maximally extended. Breech presentation can be further defined
based on the attitude or flexion of the hip and knee joints: Frank breech: Flexion at the hip and extension at the knees; Complete
breech: Flexion at both the hip and knee joints; Footling breech: One or both hips and knees in a partial or intermediate extension.
Fetal position: This is a description of the relation of the presenting part of the fetus to the maternal pelvis. In a longitudinal lie with
a vertex presentation, the occiput of the fetal calvarium is the landmark used to describe the position. Direct occiput anterior: When
the occiput is facing the maternal pubic symphysis. Right or left occiput anterior: If the occiput is between the ischial spines and the
symphysis. Occiput transverse: If the occiput is located halfway between the promontorium of the sacrum and the symphysis; Right or
left occiput posterior: The occiput approaches the sacrum. Direct occiput posterior: When the occiput is straight down (i.e. facing the
sacrum or coccyx). In cases of breech presentation, the fetal sacrum is used for position. With transverse and oblique lies, the shoulder
structures (acromion) can be used for the description of position. For a fetus in cephalic presentation and face or brow presentation,
FIGURE 26.8 (Continued)

the mentum is used for position. In a compound presentation, one or more extremities of the fetus will present in addition to the vertex
or breech. Asynclitism: Malalignment of the head in relation to the axis of the birth canal; when one of the fetal parietal bones pre-
cedes the sagittal suture in the birth canal. Abbreviations: ROA, right occiput anterior; DOA, direct occiput anterior; LOA, left occiput
anterior; LOT, left occiput transverse; ROT, right occiput transverse; ROP, right occiput posterior; DOP, direct occiput posterior; LOP,
left occiput posterior; RSA, right sacrum anterior; DSA, direct sacrum anterior; LSA, left sacrum anterior; LST, left sacrum transverse;
RST, right sacrum transverse; RSP, right sacrum posterior; DSP, direct sacrum posterior; LSP, left sacrum posterior. At term: In bold,
normal; in red, abnormal.
adult intellectual performance. Cesarean or vaginal delivery for Contraindications

breech presentation does not differ in terms of long-term adult Any contraindications to vaginal delivery such as placenta
intellectual performance [7]. previa or prior classical uterine incision are considered con-
Transverse lie does not allow for the vaginal delivery of a term fetus, traindications to ECV. There are no trials on ECV in multiple
and the neglected transverse lie may lead to uterine rupture [5]. gestations, so the safety and efficacy of this procedure cannot
Cephalic malpresentations are estimated to account for be assessed in this population. Relative contraindications are
approximately one-third of cesarean deliveries performed due to rupture of membranes, oligohydramnios, known uterine or
labor arrest [8–11]. fetal anomaly, unexplained uterine bleeding, or active phase
of labor [1, 28]. ECV in women with premature rupture of mem-
Workup branes has been studied in a systematic review of 13 cases. There
Fetal presentation should be assessed by Leopold maneuvers at was a 46.1% success rate, with a 33.3% incidence of cord prolapse.
each prenatal visit starting at ≥34 weeks of gestation. If the clini- ECV in the setting of premature rupture of membranes should
cian is unsure, a vaginal examination or an ultrasound may be indi- only be considered in a setting with immediate access to emer-
cated to assess fetal presentation. Consideration should be given gent CD [29]. ECV in women with prior CDs are associated with
to a routine fetal position check by ultrasound at 36 weeks. comparable success rates to those of women without prior cesar-
In the cephalic-presenting fetus, the identification of mal- ean deliveries, and no reports of uterine rupture have been noted,
presentations of the fetal head is most important in the context but there is insufficient data to assess the safety of this manage-
of labor abnormalities. In such conditions, the use of intra- ment [1].
partum ultrasound is recommended by the guidelines of the
International Society of Ultrasound in Obstetrics and Gynecology Efficacy
[12], and several manuscripts have described the sonographic fea- Compared with no ECV, ECV at term is associated with a sta-
tures of the malpresentations of the fetal head and their clinical tistically significant and clinically meaningful 58% reduction
role in the context of labor dystocia [13–24]. Intrapartum ultra- in noncephalic birth (relative risk [RR] 0.42, 95% confidence
sound can also be useful in the assessment of abnormal second interval [CI] 0.29–0.61) and a 42% decrease in CD (RR 0.58, 95%
stage of labor (see Chap. 9). CI 0.40–0.82) [30]. There are no significant differences in Apgar
score ratings <7 at 5 minutes (RR 0.63, 95% CI 0.29–1.36), low
External cephalic version (see Figure 26.9 for umbilical artery pH levels (RR 0.65, 95% CI 0.17–2.44), neonatal
suggested management) admission (RR 0.80, 95% CI 0.48–1.34), perinatal death (RR 0.39,
Definition 95% CI 0.09–1.64), or time from enrollment to delivery compared
Procedure performed by application of pressure and maneuvers with no ECV [30]. Because ECV is associated with a very low inci-
to the maternal abdomen, with the goal to turn the fetus to a dence of adverse events and with a significant decrease in CD, all
cephalic presentation, thus increasing the likelihood of vaginal women at or near term with nonvertex presentations should
delivery [1]. be offered an ECV.
Success rates of ECV average 58%, with a range of 25%–80%
Complications [1]. Success is increased with higher parity and with transverse
While the rate of short-term fetal bradycardia can be as high as or oblique lie (vs. breech). Lower amniotic fluid volume, anterior
20%, the rate of the need for urgent CD for nonreassuring fetal placenta, and high maternal body mass index (BMI) may decrease
heart rate tracing (NRFHT) after an external cephalic version the success rate [1]. A meta-analysis showed that multiparity,
(ECV) is about 1/600 [25]. Placental abruption (<1%) and onset nonengagement of the breech, a relaxed uterus, a palpable
of labor are uncommon complications. Rare fetal deaths follow- fetal head, and maternal weight less than 65 kg were predictors
ing attempts at version have not been determined to be a result of of successful ECV [31]. One model for predicting the probability
the procedure [1]. Femur fracture has been reported. In a meta- of success of ECV found that maternal BMI, size of fore-bag, and
analysis, there was a 4.7% risk of transient abnormal cardioto- parity were independent contributing factors of successful ECV
cography, 0.21% risk of abnormal cardiotocography leading to with a prediction accuracy of 91.9% [32]. After successful ECV,
emergency CD (with good neonatal outcomes), and 0.35% risk the chance of spontaneous version to breech is low, but under-
of emergency CD. Other risks included 0.24% risk of stillbirth, studied. The chance of spontaneous version after failed ECV is
0.18% risk of placental abruption, 0.18% risk of cord prolapse, and about 6.6% in one study [33].
0.19% risk of fetal death. These complications were not found to
be directly related to the ECV procedure. Vaginal bleeding related Timing of version
to ECV occurred in 0.34% of patients, and rupture of membranes Compared with no ECV, ECV before term reduces noncephalic
related to ECV occurred in 0.22% of patients [26]. An additional births [34–37]. Compared with ECV at term, ECV before term
retrospective review showed a 3.32% risk of spontaneous rever- reduces noncephalic presentation at birth, but does not reduce
sion to breech [27]. the rate of CD and may be associated with an increase in the
Confirmed breech presentation

at 36 weeks of gestation
Review contraindications
Obtain informed consent
Nonstress test
(ensure reactivity)
Betamimetic tocolysis
(e.g., terbutaline 25 µg SQ)
Consider spinal anesthesia
Cephalic version attempt
Successful Unsuccessful
Spontaneously
converts to vertex
Remains breech
No further
attempts at
version
Continues vertex
Trial of labor
Cesarean
delivery at 39
weeks
FIGURE 26.9 Suggested management of breech presentation. (Adapted from Ref. 1.)
incidence of PTB. There is insufficient evidence to assess the noncephalic presentation at birth (57% vs. 66%) and slightly lower
best GA at which to perform ECV. In general, the later the GA, CD (65% vs. 72%) [34–37]. In the largest randomized controlled
the lower the success rate, but there are reports of successful ECV trial (RCT) to date, compared with ECV at >37 weeks, ECV at
in women in term labor. About 36 weeks is generally consid- 34 0/7–356/7 weeks was associated with a decrease in the incidence
ered to be the optimal time for attempted version. At 36 weeks, of noncephalic presentation at birth (41% vs. 49%; RR 0.84, 95% CI
there is felt to be adequate room to turn the fetus while minimiz- 0.75–0.94), but no difference in rates of CD (52% vs. 56%; RR 0.93,
ing the risk of return to breech presentation following a success- 95% CI 0.85–1.02) or risk of PTB (6.5% vs. 4.4%; RR 1.48, 95% CI
ful ECV. Additionally, if delivery becomes necessary, a 36-week 0.97–2.26) [38].
infant has a low rate of respiratory distress syndrome or other
complications of prematurity compared to a fetus of <36 weeks Tocolysis
GA. Compared with ECV at 370/7–380/7 weeks, ECV at 34 0/7–360/7 Tocolysis with betamimetics prior to attempting ECV is associ-
weeks is associated with nonsignificant trends for slightly lower ated with 30% fewer ECV failures, a 32% reduction in noncephalic
presentations at birth, and 23% fewer CDs [39]. A common toco- Inhalational anesthesia
lytic used is terbutaline with a dose of 25 mg subcutaneously In a systematic review of anesthesia and analgesia for ECV, the
once, 10–15 minutes before ECV. Other different betamimetics visual analog scores (VASs) of pain were also significantly lower
have been used with no evidence as to the best one or its dosage with inhalational anesthesia. The VAS of patient satisfaction was
and timing [39]. One RCT of adjusted doses of intravenous salbu- significantly higher with intravenous anesthesia [51].
tamol tocolysis prior to ECV increased success rates, decreased
the CD rate, and was well tolerated [40]. Tocolysis can also be Systemic opioids
used with success in a second ECV attempt on the same day after There is limited evidence that systemic opioids improve success
a first ECV attempt has failed [41]. rates for ECV. One RCT of 60 women showed that the frequency
Nifedipine as a uterine relaxant for ECV has also been evalu- of CD was similar in the opioid (remifentanil) group vs. placebo
ated. In a randomized, double-blind, placebo-controlled trial (RR 0.9, 95% CI 0.20–4.27) 318). In one RCT comparing spinal
of 320 participants, nifedipine did not significantly improve anesthesia, systemic opioid (remifentanil) and control (no anes-
the success of ECV [42]. In two RCTs evaluating oral nifedipine thesia/analgesia) for ECV success, ECV was most successful in
versus subcutaneous terbutaline tocolysis for ECV, there was the spinal anesthesia group (83%) versus opioid (64%) and control
higher ECV success with terbutaline (52.2%–58.1% for terbu- (64%). Pain relief was highest with spinal anesthesia, followed by
taline vs. 34.1%–39.5% for nifedipine), fewer CDs, and no dif- opioid and then control. Incidence of CD for fetal bradycardia
ference in neonatal outcomes, although more side effects were was similar among the groups [52].
noted with terbutaline (maternal palpitations and tachycardia) In a systematic review, compared to control, ECV with neuraxial
[43–45]. anesthesia has a significantly higher ECV success rate; however, the
Nitroglycerin has been studied as an agent to improve odds of maternal hypotension increase significantly. All anesthesia
ECV success rates. In four small trials, sublingual nitro- interventions provide a significant reduction of procedure-related
glycerin was associated with significant side effects and was pain. Intravenous anesthesia had a significantly higher score in
not found to be effective [39]. One RCT demonstrated that patient satisfaction and lower odds of NRFHRT pattern [51].
treatment with intravenous nitroglycerin increased the rate
of successful ECV in nulliparous women (24% compared to Hypnosis
8%, p = 0.04) but not in multiparous women [46]. In one trial, There is one RCT on hypnosis versus neurolinguistic program-
terbutaline 25 mg subcutaneous 5 minutes prior to ECV was ming for pain relief during ECV, and both groups reported a simi-
found to have a significantly higher ECV success rate than lar degree of relief [39].
nitroglycerin [47].
ECV procedure
Fetal acoustic stimulation Given the possible complications, it is prudent to perform ECV
Fetal acoustic stimulation to the fetal head for 1–3 seconds in in a facility with ready availability of emergency CD. Consent
midline fetal spine positions is associated with fewer failures should be obtained after counseling regarding possible complica-
of ECV at term in a very small study [28, 39, 48]. Eleven of 12 tions, alternatives (CD), prognosis, and explanation of the actual
ECVs were successful following stimulation [48]. The crossover procedure. A nonstress test should be performed before and
arm (patients who failed version without stimulation) were then after ECV. Anesthesia is usually not necessary and has not been
stimulated, and 8 of 10 patients were successfully verted, for a absolutely proven to benefit outcomes. Betamimetic prophylactic
total of 19 of 22 successful versions (86%) [47]. The success rate tocolysis should be given (e.g. terbutaline 25 µg subcutaneously
in the control group in this study was lower than expected (8%) 5–10 minutes prior to procedure). There are no trials comparing
[47]. The evidence is limited and is insufficient to make a other technical aspects of ECV. One or two operators can be used.
recommendation. When the fetal back is accessible to palpation with no intervening
placenta, the stimulation of the Galant or the stepping or walking
Neuraxial anesthesia fetal reflexes have been suggested to improve the outcome of ECV
There is evidence that regional anesthesia affects ECV success. [53]. Frequent, if not continuous, ultrasound guidance to assess for
ECV failure, noncephalic births, and CDs were reduced in two fetal well-being and presentation is suggested. Rh-negative women
trials with epidural but not in three trials with spinal analgesia should receive anti-D immunoglobulin. There is no evidence to
[39]. ECV success rates increased from 33% to 59% with epidural support immediate induction after successful ECV.
in one study and from 32% to 69% in another [4, 49]. Potential There are no trials to evaluate the potential effects of hydration
bias in both studies lies in that the care provider was not blinded or transabdominal amnioinfusion on the success rate of sponta-
to placement of the epidural [4, 49]. It is important to note that neous version or ECV.
the control groups had lower success rates than expected; the In summary, regarding ECV, and as supported by the American
average success rate in the literature, which is mostly without College of Obstetricians and Gynecologists (ACOG) and the Royal
anesthesia, is about 58%. All patients in both studies received College of Obstetricians and Gynaecologists (RCOG), all women who
terbutaline prior to attempt at ECV. It has been postulated that are near term with breech presentations or transverse/oblique lie
large-volume preloading with epidural may increase the amni- should be offered ECV due to the benefit of a significant decrease
otic fluid volume [39]. The use of spinal anesthesia has not been in CD and the small risk of an adverse event. Tocolysis increases the
associated with any benefit in the success of ECV in some RCTs chance of a successful ECV [1, 54]. ACOG also supports the use of
[28, 39]. However, a meta-analysis including nine RCTs, of which neuraxial anesthesia to increase the success rate of ECV [1].
seven used spinal and two used epidural anesthesia for ECV ver-
sus controls, demonstrated anesthetic-dose neuraxial blockade Moxibustion and/or acupuncture
(usually spinal) is associated with a 63% increase in the suc- Moxibustion is a form of traditional Chinese medicine that
cess rate of ECV [50]. uses heat generated by burning herbs, most often Artemisia
vulgaris, to stimulate the acupuncture point BL67 (Zhiyin in (excluding fetal anomalies) or serious neonatal morbidity [66].
Chinese) [55–59]. There is inconsistent evidence to assess if the This reduction is less for countries with high national perina-
use of moxibustion converts a breech to a cephalic presentation. tal mortality rates [67]. Planned CD is associated with a 71%
Differences in interventions (e.g. moxibustion alone or with acu- reduction (from 1.15% to 0.26%) in perinatal or neonatal death
puncture) make it difficult to perform a satisfactory meta-analy- (excluding fetal anomalies) [66]. This reduction was similar for
sis. Moxibustion may reduce the need for ECV by 53% and reduce countries with low and high national perinatal mortality rates.
the incidence of nonvertex presentation at term by 35%–70% in One death could be prevented for every 112 CDs planned [66].
Chinese trials [56, 57]. In two trials performed in Italy, moxi- A secondary analysis [68] of the short-term outcomes of the
bustion was not well tolerated by 22% of women and therefore Term Breech Trial [67] looked at factors associated with adverse
not effective [58]. Moxibustion was not effective when used with outcomes. The lowest morbidity was found in patients with
acupuncture [59]. Moxibustion may decrease the use of oxyto- planned CD prior to the onset of labor. In a planned vaginal
cin before or during labor for women who had vaginal deliveries breech delivery, labor augmentation and a second stage greater
and might reduce noncephalic presentation at birth and CD com- than 60 minutes are associated with less optimal outcomes [68].
pared to acupuncture [55]. A meta-analysis performed compil- Factors not shown to affect outcome included induction, par-
ing data from six studies of both Western and Chinese databases ity, use of continuous electronic fetal monitoring, or epidural
shows that moxibustion at point BL67, alone or in combination [68]. A “skilled clinician” at the delivery was associated with
with acupuncture, is associated with higher rates of cephalic lower adverse outcomes. “Skilled clinician” was best described
version of 72.5%, compared with 53.2% in the control group (RR by the clinicians themselves rather than by years of experience
1.36, 95% CI 1.17–1.58). These data should be viewed with cau- or being a licensed obstetrician [68].
tion, given the high degree of heterogeneity of the studies [60]. No Three months after delivery, women allocated to the planned
significant differences were found in the safety of moxibustion CD group reported 38% less urinary incontinence, 89% more
compared with other techniques. A recent RCT of 328 women abdominal pain, and 68% less perineal pain [69].
showed no beneficial effect of moxibustion to facilitate ECV Two years after delivery, there was no difference in the com-
compared to controls when looking at the percentage of fetuses in bined outcome “death or neurodevelopmental delay.” Of 463
breech presentation at 37 weeks (72.0% vs. 63.4%; RR 1.13, 95% CI vaginal delivery patients followed at 2 years, there were only 6
0.98–1.32 [61]. It might be that acupuncture and not moxibustion deaths and 7 children with neurodevelopmental delay (2.8%),
(especially not at home) is beneficial [59], although a recent trial compared with 2 and 12 of 457 patients (3.1%) in the CD group
of acupuncture with a heating needle moxibustion technique [70]. The authors postulate that there was no difference seen at
(smokeless) showed no benefit [62]. the 2-year follow-up (vs. immediate neonatal outcome) because
the study was underpowered, the predictive value was low for
Maternal change in posture an association of measures of early morbidity with later death
Maternal changes in position such as knee–chest and others and adverse neurodevelopmental outcomes, and planned CD is
have been suggested as a means to correct breech presentation in perhaps only reducing the risk of perinatal mortality/morbid-
pregnancy. There is insufficient evidence from the small trials ity associated with fetal hypoxemia [70]. Maternal outcomes at
reported so far to support the use of postural management for 2 years were also very similar, with constipation significantly
breech presentation [63]. Meta-analysis could not be undertaken, more common in the CD group (27% vs. 20%), while self-reported
since study designs and outcomes measured were different [64]. incontinence was not significantly different (18% vs. 22%) [71].
Postural management is not associated with a significant effect Incontinence was different (16% vs. 25%) if comparing women
on the rate of noncephalic births, either for the subgroup in which who actually planned and had a CD versus those who planned
no ECV was attempted or for the group overall (RR 0.98, 95% CI and had a vaginal delivery [71].
0.84–1.15). No differences were detected for CDs (RR 1.10, 95% CI These results are from the Term Breech Trial [67] and its second-
0.89–1.37). To date there is no solid evidence for this practice ary analyses and follow-up [67–71]. These outcomes are based on
[63, 64]. deliveries done by “clinicians who were regarded as experienced at
vaginal breech delivery” [67–71]. As the number of vaginal breech
Delivery outcomes deliveries decreases, physician skill will continue to diminish,
It is important to note that the rate of CD after ECV is still about with the potential to make vaginal delivery less safe. While it is
double that of pregnancies presenting with spontaneous cephalic estimated that >90% of babies presenting nonvertex are currently
presentation due to higher incidences of dystocia and NRFHT delivered by CD, there might still be a role for vaginal delivery
after successful ECV [65]. for the woman who declines scheduled CD or who presents in
advanced labor. Postdates pregnancy [72], parity [73], and fetal leg
Mode of delivery position [74] showed no association with the outcome of intended
breech vaginal delivery. A prospective study of 1054 women with
Singleton intended breech vaginal delivery showed that a birth weight above
Term breech 3.8 kg is associated with an increased rate of CD but no difference in
Three RCTs [66], including one large study (the Term Breech terms of neonatal and maternal morbidity [75]. ACOG reaffirmed
Trial) [67], have compared a policy of planned CD to a policy of in 2018 and RCOG in 2017 that the decision of mode of delivery
planned trial of labor to attempt a vaginal delivery. CD occurs in depends on the experience of the health care provider [76, 77]. CD
about 45% of women allocated to a vaginal delivery protocol and is the preferred mode due to the limited experience of most physi-
>90% in those allocated to a CD protocol. cians, but planned vaginal delivery of a term singleton fetus may be
At 4–6 weeks after delivery, compared with planned vagi- considered under specific hospital protocols [76, 77]. All women
nal delivery, planned CD is associated with a 67% decrease with breech presentation with a large fetus (>3500 g estima-
in perinatal or neonatal death (RR 0.33, 95% CI 0.19–0.56) tion), unfavorable pelvis, hyperextended head, incomplete
or footling breech presentation, NRFHT, severe fetal growth Twins

restriction, or lack of experienced obstetrics or anesthesiology Breech external cephalic version
providers should have a CD. of the presenting twin
There is a small amount of data regarding ECV of the nonce-
Technical aspects phalic-presenting twin in dichorionic twin pregnancies [90].
Cesarean breech delivery: There are no trials to assess technical In a systematic review of 23 patients and attempted ECV of the
aspects of breech (or other malpresentation) CD. There is insuf- nonpresenting twin, successful ECV occurred in 57% of women
ficient evidence to assess if intraabdominal version during CD and 48% of women had a successful vaginal delivery. No adverse
before uterine incision affects outcomes. events occurred in this small series [91]. ECV in twin gestations
Vaginal breech delivery: There are several technical sugges- is insufficiently studied to make a conclusion about safety and
tions for assisting a vaginal breech delivery, including the adop- efficacy [92, 93].
tion of upright or “hands and knees” position instead of supine
position [78]; none are based on trials. There is insufficient evi- Breech delivery of the nonpresenting twin
dence to assess if clinical/radiologic pelvimetry affects outcomes (See also Chap. 46 in Maternal-Fetal Evidence Based Guidelines.)
in the management of breech presentation. One RCT and a cohort Pregnancies at ≥35 weeks with vertex/breech presentation in
study showed that prelabor MRI is helpful in predicting the risk twin gestations <7 cm dilation have similar Apgar scores and
of emergency caesarean section in women with vaginal intended incidence of neonatal morbidity in the second twin delivered by
breech delivery by allowing the identification of the abnormali- vaginal or cesarean birth [93]. There was no incidence of birth
ties of the pelvimetry [79] and the measurement of the obstetric trauma or intraventricular hemorrhage in any of the 27 breech
conjugate [80]. deliveries of the second twin [93]. Maternal febrile morbidity
A double setup is suggested: A vaginal delivery should be orga- and length of stay were increased in the CD group [93]. In the
nized in the operating room and ready for possible CD. largest RCT that randomized women with twin pregnancies to
Other suggestions are as follows: Minimal intervention until planned CD or planned vaginal delivery, there was a large num-
the abdomen up to the umbilical cord is delivered and prevention ber of women with a noncephalic second twin. There was no sta-
of head extension with prophylactic Mauriceau maneuver and tistically significant difference seen in composite fetal or neonatal
proper use of Pipers forceps, if necessary. There is not enough evi- morbidity, even when evaluating for interaction with fetal pre-
dence to evaluate the effects of expedited vaginal breech delivery sentation, comparing perinatal morbidity in planned CD versus
(breech delivery from umbilicus to delivery of the head within planned vaginal delivery (odds ratio [OR] 1.16, 95% CI 0.77–1.74).
one contraction) on perinatal outcomes [81]. Morbidity included birth trauma, seizures, and assisted ventila-
The same management options exist for transverse/oblique tion. There were also no significant differences noted in serious
lie as for breech. Fetal ECV, and CD if persistent malpresenta- maternal morbidity (OR 0.86, 95% CI 0.65–1.13) [94]. In a second-
tion, are the standards of care, with limited trial evidence. ary analysis of this study of women with a cephalic-presenting
twin in spontaneous labor, again no difference was noted in neo-
Preterm breech natal or maternal outcomes based on delivery route [95]. Vaginal
There is insufficient evidence to assess if outcomes of the predelivery of the second nonvertex twin is a sound option.
term breech-presenting fetus are affected by mode of delivery. Attempt at vaginal twin delivery of the second twin, especially for
Very little prospective data, mostly nonrandomized, exist regard- a second twin with an estimated fetal weight (EFW) of >1500 g,
ing vaginal versus CD of the premature breech infant [1]. Two should be performed with adequate experience of the obstetri-
trials aimed at assessing this question failed to randomize the cian, as well as with continuous availability of expert anesthesia
planned sample sizes. After 17 months of patient recruiting at 26 in or very close to an operating room. Total breech extraction of
different hospitals, only 13 women had been randomized, making the second twin is associated with shorter maternal stay, lower
it impossible to confer any conclusions in one study [82]. The Iowa neonatal pulmonary disease, infection, and intensive care nurs-
premature breech trial was somewhat more successful, recruiting ery stay compared with cephalic version [82, 84]. There are no
38 patients over 5 years, but had insufficient data for meaningful trials for twins presenting with first twin nonvertex (about 26%
conclusions [83, 84]. In a meta-analysis of randomized trials (n = 1) of twins). Recommendation for CD under this circumstance is
and observational studies (n = 14), CD was associated with a 41% based mostly on data from singleton gestations.
decrease in neonatal death and a 49% decrease in intraventricular
hemorrhage between 230/7 weeks and 276/7 weeks, with the most Preterm twins
benefit seen at 23 weeks and 0 days to 24 weeks and 6 days [85]. There are no RCTs of planned CD vs. vaginal delivery of preterm
A retrospective cohort study evaluating morbidity and mortality twins less than 34 weeks with malpresentation of the second
of periviable breech fetuses in relation to the mode of delivery twin. A retrospective cohort study of vertex/nonvertex twins
showed an almost fourfold and threefold higher chance of sur- with a trial of vaginal delivery between 24 and 28 weeks of ges-
vival in the event of CD performed at 23 and 24 weeks of gesta- tation showed a high incidence of emergency CD for the deliv-
tion, respectively [86]. A secondary analysis of a prospective study ery of the second twin but no difference in the risk of adverse
of 390 women with breech fetus and spontaneous onset of labor outcomes compared to those submitted to CD at paired gesta-
or preterm prelabor rupture of membranes (PPROM) between tion [96]. In a meta-analysis of three observational studies on
26 and 34 weeks of gestation showed no benefit of planned CD delivery mode of extremely preterm (24 weeks and 0 days to 27
in improving neonatal outcomes [87]. Outcomes in premature weeks and 6 days) cephalic/noncephalic twin gestations, neo-
breech infants are mainly related to prematurity, with unclear natal death and severe brain injury were not different between
conclusions regarding the preferred mode of delivery, as the methods of delivery [97]. There are insufficient data to make a
majority of data is observational [88, 89]. recommendation.
Triplets
Because vaginal delivery of triplets is usually associated with an
increased risk for stillbirth or neonatal and infant deaths as com-
pared with CD, cesarean delivery is the route of choice, even
if some small series have recently reported similar outcomes for
trial of labor or CD for triplets.
Malposition
Definitions
Position
Relationship of presenting part (usually occiput for head) to pel-
vic outlet.
Malposition
Fetal position that is not occiput-anterior for cephalic presenta-
tions (or sacrum anterior for breech presentations).
Asynclitism
Malalignment of the head in relation to the axis of the birth canal;
when one of the fetal parietal bones precedes the sagittal suture
in the birth canal (Figures 26.10 and 26.11) [98].
Compound presentation
When an extremity prolapses alongside the presenting part in the
birth canal
Occiput posterior (OP) (Figure 26.12) is the most common fetal
malposition. Only 5% of term fetuses are OP at time of delivery,
but about 23% are OP at the beginning of labor [99].
OP position is associated with African American race, advanced
maternal age, postterm pregnancy, birth weight >4000 g, and epi-
dural anesthesia [100]. In a meta-analysis evaluating epidural vs.
no epidural/analgesia in labor, malposition was higher in women
in the epidural group (RR 1.40, 95% CI 0.98–1.99), although this
was not statistically significant [101].
Diagnosis
Fetal malposition can be detected by provider digital exam, as
well as by transabdominal ultrasound. Digital (manual) vaginal
examination correctly detects OP position about 80% of the
FIGURE 26.10 Anterior asynclitism.
time, while transabdominal ultrasonographic examination of
fetal head position during the second stage of labor is correct
>99% of the time. The use of transabdominal ultrasound to of malposition of the presenting part of the fetus in a small trial,
locate the exact position of the fetal head should be mandatory but assuming the hands and knees posture for 10 minutes twice
when this knowledge influences management [102]. Additionally, daily in the last weeks of pregnancy had no effect on the baby’s
ultrasound has the ability to predict persistent OP position dur- position at delivery or any of the other pregnancy outcomes
ing labor: Sensitivity and specificity of intrapartum ultrasound measured in a larger trial [104]. One study evaluated the use of
for prediction of persistent OP position were about 0.85 and 0.83, the hands and knees position in labor involving 147 women in
respectively. Sensitivity and specificity increased after 4 cm cervi- labor at term who assumed the position for a period of at least
cal dilation to about 0.92 and 0.85, respectively [103]. 30 minutes. There was no significant reduction in OP or occiput-
transverse positions at delivery or reduction of operative deliv-
Management eries. However, there was a significant reduction in back pain
Hands and knees posture [105]. An RCT studied women with OP fetal position during labor
The effect of hands and knees posture to correct malposition has who were placed in the hands and knees position in first-stage
been evaluated both before (for prevention) and during labor. labor at term for at least 10 minutes, which showed no benefit of
There are trials on the effect of the hands and knees posture rotation to occiput anterior (OA) [106]. In summary, the hands
before labor [104]. Compared to a sitting position, 10 minutes in and knees posture does not seem to be effective in preventing
the hands and knees position is associated with a lower likelihood or treating malposition.
FIGURE 26.12 Occiput posterior.
(Table 26.1) [108–113]. Over 80% of labors end up spontaneously

without OP position at the beginning of the second stage, so
manual rotation should not be done before the second stage.
If fetal head position is assessed at the beginning of the sec-
ond stage, it should be assessed by ultrasound; digital diagno-
sis of fetal head position is wrong in at least 20 of cases. There
seems to be a nonsignificant 14% decrease in OD associated
with manual rotation of OP fetuses performed at the begin-
ning of the second stage (Table 26.1). The number of manual
rotations needed to avoid an OD (number needed to treat) is
13.2. Manual rotation seems to have a higher chance of being
beneficial when the fetal head is flexed (OP position, vertex pre-
sentation) [108–113]. When assisted by ultrasound to detect the
location of the fetal spine, manual rotation success was improved
and spontaneous vaginal delivery (SVD) rate was improved with-
out adverse neonatal effects in an RCT [114].
Operative delivery from malposition (OP)

There is insufficient evidence to make a recommendation on how
OVD is performed from OP or if forceps or vacuum delivery is
FIGURE 26.11 Posterior asynclitism. more successful.
Lateral asymmetric decubitus position Ultrasound

In a recent RCT that evaluated the influence of ultrasound on diag-
Lateral asymmetric decubitus position, or lying on the side oppo-
nosis of fetal head malposition and subsequent mode of delivery,
site the fetal spine with the inferior leg positioned in the axis of
using transabdominal ultrasound in active labor did not improve
the body and the upper leg in hyperflexion, has been proposed
management of labor or increase the incidence of operative deliv-
as a maneuver to help rotate a fetus from OP to OA. In an RCT
ery (CD + operative vaginal delivery) (RR 1.24, 95% CI 1.08–1.43)
of term women with singleton fetuses and ruptured membranes
and did not decrease maternal and neonatal morbidity [115].
with ultrasound-confirmed OP position, for women who were
placed in the lateral asymmetric decubitus position on the side
opposite that of the fetal spine for at least 1 hour during the first Anesthesia
stage of labor, OA rates did not differ at complete dilation or at For vaginal breech delivery, an anesthesiologist skilled at the phar-
birth and rate of CD was not different [107]. macology of uterine relaxation (e.g. nitric oxide) should be present.
Manual rotation
Persistent fetal OP position has been historically considered a References
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TABLE 26.1: RCTs on Manual Rotation vs. No Rotation of the Malpositioned Fetal Head in the Second Stage of Labor
Study Year Origin N Head Position Sham Control OD OVD CD
Graham [94] 2014
Australia 30 OP Yes 13/15 vs. 12/15 4/15 vs. 3/15 9/15 vs. 9/15
Broberg [95] 2016
United States of 65 OP No 10/33 vs. 8/32 8/33 vs. 7/32 2/33 vs. 1/32
America
Phipps (POPOUT) [96] 2021 Australia 264 OP Yes 79/127 vs. 90/127 57/127 vs. 68/127 22/127 vs. 22/127
Blanca (PROPOP) [97] 2021 France 257 OP No 37/126 vs. 54/131 N/A N/A
Phipps (TURNOUT) [98] NP/C Australia 160 OT Yes N/A N/A N/A
Verhaeghe [99] NP/C France 238 OP No N/A N/A N/A
Total 1014 139/301 (46.2%) vs. 69/175 vs. 78/174 33/175 vs. 32/174
164/305 (53.8%)
RR, 95% CI 0.86, 0.73–1.01 0.88, 0.68–1.14 1.03, 0.64–1.64
Note: Data are presented manual rotation versus control.
a Data are presented as manual rotation versus control.
Abbreviations: RCT, randomized controlled trial; NP/C, not published; recruitment complete; N/A, not available; OD, operative delivery; OVD, operative vaginal delivery; CD,
cesarean delivery; OP, occiput posterior position; OT, occiput transverse; RR, relative risk; CI, confidence interval.
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27
SHOULDER DYSTOCIA
Julia Burd
Key points • Initial responses to shoulder dystocia involve asking for

help and, as first maneuvers, use of McRobert maneuver
• Risk factors for shoulder dystocia include prior shoulder and suprapubic pressure (Figure 27.1).
dystocia (recurrence risk ∼1%–15%), maternal diabetes • Second-line maneuvers include direct fetal manipula-
mellitus, obesity, postterm pregnancy, labor induction, tion, such as delivery of the posterior arm (considered
epidural anesthesia, labor abnormalities (e.g. prolonged to be the most effective internal maneuver), then rota-
second stage), operative vaginal delivery, and fetal mac- tion of fetal shoulders. One-third of shoulder dystocia
rosomia (Table 27.1). cases require the use of more than two maneuvers. See
• In 50% of shoulder dystocia cases, no risk factors are Figure 27.1 for suggested management of shoulder dystocia.
identified. Therefore, clinicians should be ready for pos-
sible shoulder dystocia at every delivery. Diagnosis/Definition
• In 40%–60% of shoulder dystocia cases, birth weight is
<4000 g. Shoulder dystocia is diagnosed when additional obstetric
• Maternal complications of shoulder dystocia include maneuvers are required following failure of gentle downward
obstetric anal sphincter injuries (OASI) and postpartum traction on the fetal head to effect delivery of the shoulders
hemorrhage. in a cephalic-presenting neonate. Retraction of the delivered
• A perinatal complication of shoulder dystocia is brachial fetal head against the maternal perineum (“turtle sign”) is an
plexus impairment (BPI), which occurs in 4%–40% indication of a possible shoulder dystocia [1]. Shoulder dysto-
of shoulder dystocia cases; up to 90% are transient. cia pertains only to vertex presentation. A quantitative definition
Approximately one-half of cases of BPI occur without doc- of shoulder dystocia has been proposed as a prolonged head-to-
umented shoulder dystocia. body delivery time >60 seconds [2]. This definition categorizes
• Other perinatal complications of shoulder dystocia include 10% of vaginal deliveries as having a shoulder dystocia, while only
fractures, hypoxic-ischemic encephalopathy, long-term 25%–45% of these cases were diagnosed as such by the delivering
neurologic disability, and even death. provider [3]. Shoulder dystocia remains a subjective clinical
• Preconception prevention of maternal obesity and dia- diagnosis by the delivering provider, and this may account for
betes, as well as prenatal prevention of excessive weight some of the variability in the frequency of reported shoulder
gain, decrease the incidence of shoulder dystocia, mainly dystocia across various populations and different studies.
by prevention of fetal macrosomia.
• In women with prior shoulder dystocia, clinicians should
review recurrence risk (1%–15%), which risk factors
(Table 27.1) are present in the current pregnancy, and pos- The incidence of shoulder dystocia is about 1% (range 0.2%–
sible complications. If several significant risk factors are 3%) [1].
still present, the woman may opt for cesarean delivery. If
risk factors are not present (except for prior shoulder dys-
tocia), the woman may decide after counseling for either
trial of labor or cesarean delivery. Shoulder dystocia results from size discrepancy between the
• Induction of labor at term for suspected fetal macro- fetal shoulders and the pelvic inlet that results in impaction of
somia (estimated fetal weight [EFW] ≥4000 g) in women the anterior shoulders behind the maternal pubis symphysis
without diabetes is associated with a similar incidence of or the posterior shoulder on the sacral promontory (uncom-
cesarean or operative vaginal delivery compared to expect- mon), or both (rare) [4]. Persistent anterior-posterior location
ant management, a significant decrease in fetal frac- of the fetal shoulders at the pelvic brim occurs most often due
tures, and higher incidences of hyperbilirubinemia and to increased resistance between the fetal skin and vaginal walls
phototherapy. Induction at ≥38 weeks would prevent the (e.g. fetal macrosomia), a large fetal chest relative to the bipari-
neonatal complications and can be considered. etal diameter (e.g. infants of diabetic mothers), and when truncal
• In pregnancies with EFW >5000 g in nondiabetic and rotation does not occur (e.g. precipitous labor) [1].
>4500 g in diabetic women, the American College of
Obstetricians and Gynecologists (ACOG) suggests that
a planned cesarean delivery (without labor attempt) Risk factors/Associations
may be considered to avoid shoulder dystocia. Table 27.1 lists antepartum and intrapartum risk factors associ-
• In women with EFW >3800 g, prophylactic McRobert ated with shoulder dystocia. These risk factors individually or in
maneuver and suprapubic pressure are associated in combination have a poor predictive value for shoulder dystocia.
one randomized controlled trial (RCT) with a trend In 50% of cases, no risk factors are identified. The two risk
towards a decreased rate of shoulder dystocia.
314 DOI: 10.1201/9781003102342-27

Shoulder Dystocia 315
TABLE 27.1: Factors Associated with Shoulder Dystocia TABLE 27.2: Relationship between Increasing Birth Weight
and Maternal Diabetes and the Development of
Antepartum Intrapartum
Shoulder Dystocia
Multiparity Labor induction and/or augmentation
Birth Weight (g) No Diabetes Maternal Diabetes
Postterm gestation Labor abnormalities
Prolonged first stage 4000–4250 5.25% 12.2%
Short second stage 4250–4500 9.1% 16.7%
Prolonged second stage 4500–4750 14.3% 27.3%
Maternal obesity Epidural 4750–5000 21.1% 34.8%
Maternal diabetes Operative vaginal delivery [forceps or
Source: Data from Ref. [5].
vacuum] especially mid-pelvic station
Prior shoulder dystocia
Prior macrosomic child abdominal diameter) have demonstrated a correlation between
elevated asymmetry and shoulder dystocia [13–16].
Excessive gestational weight gain
Fetal macrosomia
Source: Data from Ref. [1].
Complications
Maternal
Maternal complications involve increased post-partum blood
factors for shoulder dystocia most studied are maternal diabe- loss and vaginal lacerations. Retrospective studies have noted an
tes and fetal macrosomia. The frequency of shoulder dystocia increase in obstetric anal sphincter injuries (OASIs) with fetal
increases with higher birth weight (Table 27.2) [5]. However, it manipulation during shoulder dystocia, increasing with internal
should also be remembered that 40%–60% of cases occur with maneuvers and more than four maneuvers (Table 27.3) [17, 18].
birth weight <4000 g, and of deliveries with birth weight
>4000 g, only 3.3% develop shoulder dystocia [4, 6, 7]. Multiple Perinatal
studies, including those using advanced statistical models, have Brachial plexus impairment
been unable to discriminate labor patterns (e.g. prolonged first The most common major complication of shoulder dystocia is neo-
and/or second stage) in a manner that improves intrapartum natal brachial plexus impairment (BPI), which occurs in 4%–40%
management to predict and avoid shoulder dystocia [8–12]. In a of cases of shoulder dystocia. In one of the largest series, the rate
study, the statistical model that best predicted shoulder dysto- was 16.8% (Table 27.3) [19]. Most cases of BPI are unilateral (right
cia with injury included maternal height and weight, gestational > left) and involve the C5–C6 roots (Erb-Duchenne palsy).
age, parity, and birth weight and was able to identify 50.7% of Table 27.4 describes the most common palsies associated with
cases with a false-positive rate of 2.7% [12]. Recent studies exam- shoulder dystocia. Most fully recover spontaneously, with physical
ining ultrasound asymmetry (ratio of biparietal diameter and therapy, or, in some situations, respond to neurosurgical treatment.
CALL FOR HELP
McRobert's Maneuver
1ST LINE
Suprapubic Pressure
Delivery Posterior Arm 2ND LINE

Consider episiotomy to facilitate maneuvers as needed
Fetal Rotational Maneuvers

(Wood's or Rubin's)
If all maneuvers fail, consider

repeating prior steps
Gaskin Maneuver (ALL FOURS)
Zavanelli, Clavicular fracture, or symphiotomy 3RD LINE
FIGURE 27.1 Suggested management algorithm for shoulder dystocia.

TABLE 27.3: Maternal and Newborn Complications of Umbilical artery pH

Shoulder Dystocia Reported at a Single Large In a study of 134 cases of shoulder dystocia, mean umbilical pH
Tertiary Care Center was not clinically different from cases without shoulder dysto-
Complication Frequency
cia, and there was no association between head-to-body deliv-
ery intervals and umbilical pH, base excess, or 5-minute Apgar
Maternal scores [29]. However, another study of 200 cases of shoulder dys-
Postpartum hemorrhage 11% tocia noted that the umbilical artery pH dropped 0.01 per min-
Fourth-degree laceration (either extension of episiotomy 3.8% ute for the head-to-body delivery interval (HBDI). They found an
or extension of laceration) overall 2.5% rate of hypoxic-ischemic encephalopathy: The risk
Vaginal lacerations 19.3% was 0.5% if HBDI was <5 minutes compared to 23.5% if HBDI was
Cervical tear 2% ≥5 minutes [30].
Perinatal
Any fetal injury 24.9% Demise
Brachial plexus injury 16.8% In a review of 56 cases of fatal shoulder dystocia reported to the
Clavicular fracture 9.5% Confidential Inquiry into Stillbirths and Deaths in Infancy between
Humeral fracture 4.2% 1994 and 1995 from England, Northern Wales, and Ireland, the
approximate incidence of fatal shoulder dystocia is 0.025 per 1000
Source: Data from Refs. [7, 19].
deliveries. In 47% of these cases, the head-to-body ratio was less
Permanent BPI is very rare and occurs in 1–2 out of every than 5 minutes and greater than 10 minutes in 20% [31].
10,000 births. Signs and symptoms of BPI are a limp or unmov-
ing paralyzed arm; lack of muscle control in the arm, hand, or Management
wrist; and lack of feeling or sensation in the arm or hand. Neonatal
BPIs can occur without shoulder dystocia: In a recent literature
Principles
Shoulder dystocia is an obstetrical emergency and cannot be
review of neonatal BPI with and without shoulder dystocia, approx-
reliably predicted. Thus, prompt recognition and response are
imately 45% of BPI cases in the United States and 47% outside
essential to optimizing outcomes once it develops. Obstetricians
the United States were not associated with shoulder dystocia at
should be trained and ready to manage this complication at every
delivery [20]. In fact, it is estimated that one half of all BPIs occur
delivery. Therefore, it is imperative that shoulder dystocia train-
in the absence of shoulder dystocia and up to 4% of BPIs are associ-
ing occurs early and that at least one clinician experienced in the
ated with cesarean delivery [21, 22]. At least three studies provide
management of shoulder dystocia is present at every delivery.
evidence that BPI (both transient and permanent) can occur with
cesarean delivery. Gherman et al. reported the finding of 17 cases Prevention
of BPI (6 permanent) associated with cesarean delivery with 12- to
Preconception
29-month follow-up [6, 23]. Chang et al. described 30 cases of BPI
Preconception prevention of maternal obesity (relative risk [RR]
with cesarean delivery (out of a total 387 cases) where 60% were
of shoulder dystocia 1.63, 95% confidence interval [CI] 1.33–1.99)
persistent at 1 year [24]. Torki et al. found 8 cases of severe BP inju-
[32] and diabetes, as well as prenatal prevention of excessive
ries in 43,337 deliveries, 1 following a cesarean section [25]. These
weight gain, decrease the incidence of shoulder dystocia, mainly
data indicate that some cases of neonatal BPIs are unrelated to
by prevention of fetal macrosomia.
clinician-applied forces and are due to a combination of mecha-
nisms such as endogenous labor forces, the impaction and pressure Prediction
effects of the shoulder dystocia itself, and/or in utero compression Women with prior shoulder dystocia have a 1%–15% risk of recur-
or maladaptation [26, 27]. External maneuvers such as excessive rence [33–35]. In women with a prior shoulder dystocia, coun-
lateral traction are most likely responsible for some cases of BPI seling should include review of prior delivery events, including
from shoulder dystocia, but not all. severity of injury of prior child, which risk factors (Table 27.1) are
present in the current pregnancy, and possible short-term and
Fractures
long-term complications of cesarean delivery. The suspected size
Fractures of the clavicle and humerus have also been associated
of recurrent pregnancy related to the size of the first pregnancy
with shoulder dystocia (up to 10.4%) and the maneuvers to resolve
was noted to be the most important risk factor for recurrent
it. Both humeral and clavicular fractures heal well with conserva-
shoulder dystocia (odds ratio [OR] 7–12) [36]. If several signifi-
tive therapy [28].
cant risk factors are still present, the woman may opt for cesarean
TABLE 27.4: Types of Brachial Plexus Impairments delivery. However, given that at least 85% of women will not have
a recurrent shoulder dystocia and cesarean delivery does have
Palsy Description Level Frequency
surgical risks, a woman with a prior shoulder dystocia after coun-
Erb palsy (also known Paralysis of flexion, C5, C6 >98% seling may choose to pursue vaginal delivery [1].
as Erb-Duchenne abduction, internal and
palsy) external rotation of the Antepartum
forearm Fetal macrosomia has been noted to be an independent risk factor
Klumpke palsy Paralysis of the thumb, C8, T1 <1% for shoulder dystocia in a meta-analysis (>4000 g OR 9.54 [6.76–
fingers, and pronation of 13.46], >4500 g OR 15.64 [11.31–21.64]) [37]. This risk prediction
the forearm is complicated by the known limitations of prenatal ultrasound to
Complete brachial Both Erb and Klumpke C5–T1 <1% accurately estimate fetal weight, especially with increased fetal size
plexus palsy [38, 39]. Only at high estimated fetal weights (EFWs) (>5000 g in
nondiabetic and >4500 g in diabetic women) does the American
College of Obstetricians and Gynecologists (ACOG) suggest In a small RCT of 40 women, compared to lithotomy position,
planned cesarean delivery (without labor attempt) be consid- the use of the McRobert maneuver was associated with the same
ered to avoid shoulder dystocia [39]. incidence (7.1 vs. 7.7%) of shoulder dystocia in both prophylac-
Labor induction for women with suspected macrosomia as tic and lithotomy groups. The forced used in traction of the fetal
an intervention to decrease the rate of shoulder dystocia has head during vaginal delivery was the same in each group [48]. In
been tested in four clinical trials including 1190 women [40–44]. another RCT, in 185 women likely to give birth to a large baby
Women with EFW either >95% for gestational age or with macro- (EFW >3800 g), McRobert maneuver and suprapubic pressure
somia usually defined as EFW >4000 g, who were randomized to were associated with a trend for a lower rate of shoulder dysto-
labor induction ≥38 weeks, had a similar incidence of cesarean cia compared to controls with no prophylactic maneuvers (9% vs.
delivery (26.6% vs. 29.4%; RR, 0.90, 95% CI 0.75–1.09), operative 21%; RR 0.44, 95% CI 0.17–1.14). There were significantly more
vaginal delivery (13.0% vs. 15.2%; RR 0.86, 95% CI 0.65–1.13), cesarean sections in the prophylactic group, and when these were
spontaneous vaginal delivery (60.3% vs. 55.4%; RR 1.09, 95% CI included in the results, significantly fewer instances of shoulder
0.99–1.20), shoulder dystocia (2.4% vs. 4.2%; RR 0.57, 95% CI dystocia were seen in the prophylactic group (RR 0.33, 95% CI
0.30–1.08), intracranial hemorrhage (0.6% vs. 0.4%; RR 1.48, 95% 0.12–0.86). In this study, 13 (18%) women in the control group
CI 0.20–12.57), brachial plexus injury (0.0% vs. 0.3%; RR 0.21, required therapeutic maneuvers after delivery of the fetal head
95% CI 0.01–4.28), Apgar score <7 at 5 minutes (0.7% vs. 0.5%; RR compared to 3 (5%) in the treatment group (RR 0.31, 95% CI 0.09–
1.51, 95% CI 0.25–9.02), cord blood pH <7 (0.2% vs. 0.4%; RR 0.44, 1.02). One infant in the control group had a BPI (RR 0.44, 95% CI
95% CI 0.06–2.97), and mean birth weight (mean difference [MD] 0.02–10.61), and one infant had a 5-minute Apgar score less than
–134.41 g, 95% CI –317.27 to 48.46) compared to women expec- 7 (RR 0.44, 95% CI 0.02–10.61) [49, 50].
tantly managed. The induction group had a significantly lower
time to delivery (MD –7.55 days, 95% CI –8.20 to –6.89), lower Therapy
birth weight ≥4000 g (30.7% vs. 61.8%; RR 0.50, 95% CI 0.42– There are no interventional trials in human subjects that com-
0.59), lower birth weight ≥4500 g (3.2% vs. 14.8%; RR 0.21, 95% pare the safety or effectiveness of various shoulder dystocia
CI 0.11–0.39), lower incidence of fetal fractures (0.3% vs. 2.0%; therapeutic maneuvers [50]. Thus guidelines are based on obser-
RR 0.17, 95% CI 0.03–0.79), and a significantly higher incidence vational data and/or expert opinion. The most important feature
of hyperbilirubinemia (8.8% vs. 2.9%; RR 3.03, CI 1.60–5.74) and of the response to shoulder dystocia is that it should be a coor-
phototherapy (11.0% vs. 6.6%; RR 1.68, CI 1.07–2.66) compared to dinated and orderly application and progression of obstetric
the expectant management group [43]. maneuvers (Figure 27.1) [1, 51]. Table 27.5 describes maneuvers
A qualitative systematic review of induction of labor versus employed to relieve shoulder dystocia [4, 52]. Fundal pressure
expectant management for women with diabetes included one should always be avoided in shoulder dystocia, as it may worsen
randomized trial and four observational studies. The random- impaction of the fetal shoulder(s).
ized controlled trial (RCT) of 200 women found women induced After diagnosis of shoulder dystocia, the delivery provider
at 38 weeks or with confirmed fetal lung maturity demonstrated should call for help. This includes utilizing the assistance of other
larger fetuses in the expectant management group but was only caregivers present in the delivery room as well as alerting other
able to demonstrate three shoulder dystocias, all in the expectant obstetric, pediatric, and/or anesthesia providers on the labor and
management group [45]. The authors draw the conclusion from delivery unit. Most authorities recommend McRobert as the ini-
the four observational studies that there is a potential reduc- tial maneuver since it is easy to perform, is effective, and has a
tion in both macrosomia and shoulder dystocia with induction low complication rate. McRobert alone is effective in 40%–90%
of labor but that further study is required [46]. A recent RCT of of cases. Suprapubic pressure is often done in direct conjunction
induction of labor at 39 weeks versus expectant management in by nursing personnel (Figure 27.2). In a series of 134 cases, more
patients with gestational diabetes (n = 425) indicated similar rates than one-third of patients required more than two maneuvers to
of cesarean section (RR 1.06; 95% CI 0.64–1.77; p = 0.81) and sim- relieve the shoulder dystocia [16]. In another series of 231 shoulder
ilar rates of shoulder dystocia (induction vs. experimental group 3 dystocia cases, 57.9% of cases responded to Mc Robert and supra-
[1.4%] vs. 1 [0.5%], RR 2.96 CI 0.31–28.21, p = 0.62) [47]. pubic pressure alone and had a median duration of 29 seconds [53].
In summary, cesarean delivery is recommended for macroso- If McRobert combined with suprapubic pressure is not suc-
mia at an EFW of >5000 g in nondiabetic and >4500 g in dia- cessful, direct fetal manipulation is attempted next. In a very
betic women. Induction of labor at term for suspected fetal large series (2018 shoulder dystocia cases), delivery of the poste-
macrosomia (EFW ≥4000 g or EFW >95% for gestational age) rior shoulder (Figure 27.3) was associated with the highest rate of
in women without diabetes is associated with a similar inci- delivery (84%) compared to all other maneuvers (24%–72%) [54].
dence of cesarean delivery and shoulder dystocia compared Delivery of the posterior arm decreases the bisacromial diameter
to expectant management, a significant decrease in fetal by approximately 2 cm and makes the arm available for additional
fractures, and higher incidences of hyperbilirubinemia and rotational maneuvers, if necessary [55]. Compared with other
phototherapy. Induction at ≥38 weeks would prevent some maneuvers, delivery of the posterior arm has also been noted in
neonatal complications and can be considered; however, it is models to cause the least stretch of the anterior brachial plexus
not recommended by ACOG [1]. There is inadequate evidence to compared to lithotomy alone [56]. Other helpful fetal manipula-
recommend for or against induction of labor in patients with dia- tion interventions are either the Wood corkscrew (Figure 27.4) or
betes to prevent shoulder dystocia. Rubin maneuver (Figure 27.5). Some argue for axillary traction as
an effective maneuver for relieving shoulder dystocia: The index
Intrapartum finger is placed in the axilla of the posterior shoulder, the thumb
Prophylactic McRobert maneuver prior to the development of on the shoulder, and the middle finger is used to apply pressure
shoulder dystocia has not been shown to decrease subsequent to keep the arm in contact with the fetal body. Using significant
shoulder dystocia in women at low risk for this complication [48]. force, the posterior shoulder is delivered. A retrospective study in
TABLE 27.5: Description of Various Obstetric Maneuvers to Resolve Shoulder Dystocia

Characteristics
Maternal or Fetal
Maneuver Manipulation Type Description
McRobert Maternal First line Hyperflexion and abduction of the maternal hips (knee to abdomen position).
This causes cephalad rotation of the symphysis pubis and flattening of the
lumbar lordosis, freeing the impacted shoulder.
Suprapubic pressure Maternal First line Pressure directed posteriorly in an attempt to force the anterior shoulder
under the symphysis pubis. It also may include lateral pressure from either
side of the maternal abdomen or alternating between sides using a rocking
pressure.
It works by reducing the fetal bisacromial diameter and rotating the anterior
shoulder into the oblique pelvic diameter.
Delivery of posterior arm Fetal Second line The delivery attendant places their hands in the vagina and applies pressure
at the antecubital fossa in order to flex the fetal forearm. The arm is
subsequently swept out over the infant’s chest and delivered over the
perineum. Rotation of the fetal trunk to bring the posterior arm anteriorly is
sometimes required.
Fracture of the humerus can occur with grasping and pulling directly on the
fetal arm, as well as application of pressure onto the mid-humeral shaft.
Rubis Fetal Second line Pressure is applied to the posterior surface of the most accessible part of the
fetal shoulder to effect shoulder adduction.
It works by rotating the fetal shoulder into the oblique pelvic diameter.
Wood Fetal Second line Pressure is applied onto the anterior surface of the posterior shoulder in
order to abduct the posterior shoulder.
It works by rotating the fetal shoulder into the oblique pelvic diameter.
Gaskin Maternal Second line Patient is rolled from her existing position onto her hands and knees.
(Knee–chest, or all fours) It works through the downward force of gravity and/or a favorable change in
pelvic diameters, which causes disimpaction of the fetal shoulder.
Intentional fracture of clavicle Fetal Third line This works by decreasing the fetal bisacromial diameter.
Zavanelli (cephalad replacement) Third line Cephalic replacement of the fetal head from the vagina back into the uterus
and then delivery by cesarean section.
Symphysiotomy Maternal Third line Surgical or traumatic separation of the pubis symphysis to facilitate
disimpaction of the fetal shoulders.
Auckland, New Zealand, found that this was the most commonly and fetal complications may be considered after repeat failure
used rotational maneuver with the highest success rate with no of these first- and second-line interventions. Third-line maneu-
difference in maternal and neonatal outcomes between groups vers include intentional fracture of the fetal clavicle, Zavanelli
[57]. Regardless of chosen maneuvers, the need for successive (cephalic replacement), and symphysiotomy.
maneuvers is associated with higher rates of neonatal injury;
10% with three maneuvers, 16% with four maneuvers, and 23% Counseling and documentation
with five or more [54].
Since shoulder dystocia is a bony dystocia, routine episiotomy After completion of all necessary medical interventions (e.g.
is not advised. In a systematic literature review including 14 repair of maternal lacerations or treatment of hemorrhage), the
studies of 9769 cases of shoulder dystocia, there was no reported delivery provider should sit down with the patient and her
benefit of episiotomy to prevent or assist with the management of family to review the delivery events, the management steps per-
shoulder dystocia [58]. However, episiotomy can be considered formed, and the need for close newborn follow-up to evaluate for
to allow the delivering provider space for internal maneuvers. any neonatal injuries. Open and honest communication with
If these steps all fail, one can repeat the sequence of ini- the mother and family after delivery is recommended.
tial maneuvers, potentially with an alternative delivering It is important to document in the medical record all
provider, and/or attempt placement of the patient in the “ALL maneuvers used in detail, including which shoulder was ante-
FOURS” position (Gaskin maneuver) to repeat the maneuvers rior, and the time from delivery of head to complete delivery of
(Figure 27.1). In cases of intractable shoulder dystocia, a tech- the body (Figure 27.6) [60, 61].
nique called posterior axilla sling traction (PAST) has been
described. The PAST technique makes use of a sling (e.g. suc- Anesthesia
tion catheter or firm urinary catheter) that is placed around
the posterior axilla and then used to provide traction to either An anesthesiologist should be present during cases of shoulder
deliver the posterior shoulder or rotate it [59]. More aggressive, dystocia to ensure adequate analgesia and prompt preparation for
“heroic” maneuvers which have very high frequency of maternal cesarean delivery if needed.
FIGURE 27.2 McRobert Maneuver and suprapubic pressure.

Hyperflexion and abduction of the maternal hips, causing cepha-
lad rotation of the symphysis pubis and flattening of the lumbar
lordosis, opening space for delivery. Suprapubic pressure directed FIGURE 27.4 Woods corkscrew maneuver. Initial pressure
posteriorly in an attempt to force the anterior shoulder under the exerted on the anterior surface of the posterior shoulder facili-
symphysis pubis. It also may include lateral pressure from either tates rotation of the posterior shoulder anteriorly (upper). With
side of the maternal abdomen or alternating between sides using a concurrent synchronized downward pressure, the shoulder
rocking pressure. (Image by Henry Lerner, Wikimedia Commons “screws” though the maternal pelvis, disimpacting the previously
with Creative Commons license.) impacted shoulder (lower). (Reproduced from Ramsey PS, Ramin
KD, Field CS, et al. Shoulder dystocia: Rotation maneuvers revis-
ited. J Repro Med. 2000;45:85–88 Ref. 70, with permission.)
(a)
(b)
(c)
FIGURE 27.3 (a) Delivery of the posterior arm. (b) Hand placed in the vagina to apply pressure at the antecubital fossa in order to
flex the fetal forearm. (c) The arm is subsequently swept out over the infant’s chest and delivered over the perineum. (From Regional
Perinatal Outreach Program of Southwestern Ontario & the Southwestern Ontario Perinatal Partnership, Perinatal Manual of
Southwestern Ontario, “Shoulder dystocia”, with permission.)
(b)
(a)
(c)
FIGURE 27.5 Rubin maneuver. (a) and (b) Pressure is exerted on the posterior surface of the most accessible part of the shoulder to
facilitate abduction and disimpaction of the anterior shoulder. (c) Further rotation and adduction toward the fetal chest reduces the
bisacromial diameter and results in the movement of the shoulders in a transverse position, facilitating passage of the anterior side of
the shoulder beneath the pubic arch. (Reproduced from Ramsey PS, Ramin KD, Field CS, et al. Shoulder dystocia: Rotation maneuvers
revisited. J Repro Med. 2000;45:85–88 Ref. [70], with permission.)
Neonatal/Infant follow-up Training/Simulation

Table 27.4 describes the most common palsies associated with Multiple nonrandomized studies have shown the benefits of shoulder
shoulder dystocia. It is important to underscore that causation dystocia training on neonatal outcomes. In a single-center “before
has never been proven between shoulder dystocia and palsies, and and after” study conducted in Jamaica, New York, between 2003–
many palsies develop in babies delivered without shoulder dysto- 2006 (pre) and 2006–2009 (post), training decreased the rate of BPI
cia. Erb palsy is by far the most common (>98%) and the one associated with shoulder dystocia from 30% (pre) to 10.67% (post)
with the best prognosis (90% rate of full spontaneous recov- even after adjusting for confounding factors [63]. Another “before
ery). For 65% of patients with Klumpke palsy, full spontaneous and after” study in the United Kingdom showed a reduction in neo-
recovery can be expected, whereas in patients with a complete natal injury at birth after shoulder dystocia: (9.3% vs. 2.3%; RR 0.25;
BPI, <50% will have this recovery. If sustained injury occurs, the 95% CI 0.11– 0.57) [64]. This same group noted over 12 years contin-
evidence is mixed for the efficacy of surgery [62]. ued reduction in BPI (pretraining 24/324 [7.4%], early training 6/262
1. Antepartum documentation:
a. Prior shoulder dystocia? Yes no
b. Estimated fetal weight ____________
2. Mode of vaginal delivery
a. Spontaneous
b. Vacuum
c. Forceps
3. How was the shoulder dystocia diagnosed? Turtle sign
Failure to deliver shoulders with gentle downward pressure
Other ____________________________________________
4. Time fetal head delivered? ________________
5. Time body delivered? ________________
________________
6. Total duration of shoulder dystocia (in minutes and seconds):
7. What shoulder was under the pubis symphysis (anterior) at delivery: Left Right Unknown
8. Please describe the obstetrical maneuvers were attempted, their order, and who performed:
Maneuver Order By whom

McRobert's (Hip flection) 12345678 _________________________
Suprapubic 12345678 _________________________
Delivery of posterior arm 12345678 _________________________
Rubin's (Anterior scapula) 12345678 _________________________
Wood's (Posterior scapula) 12345678 _________________________
Episiotomy 12345678 _________________________
Extension of Episiotomy 12345678 _________________________
Gaskin's (Knee-chest, all fours) 12345678 _________________________
Other _______________ 12345678 _________________________
Other _______________ 12345678 _________________________
Other _______________ 12345678 _________________________
Additional delivery comments: ___________________________________________________________________________
_________________________________________________________________________________________________
9. Was fundal pressure performed: Yes No
If yes, by whom and what was reason: _____________________________________________________________________
10. Who were the health care providers present at delivery?
Primary delivery attendant: ____________________________

CNM: ____________________________
Resident (s) [include PGY year]: ____________________________
Nurse 1: ____________________________
Nurse 2: ____________________________
Nurse 3: ____________________________
Pediatrician: ____________________________
Anesthesiology: ____________________________
Other providers (please add name and role): ________________________________________________________________
11. Birth weight (grams) ___________

12. Was baby moving his/her extremities: Left right Comment: _________________________________
13. Was XRAY ordered for evaluation any bony fractures? YES NO
14. Were umbilical cord gases ordered? YES NO
15. Confirm that notes (e.g. medical, nursing, anesthesia, etc) are consistent YES NO
16. Has delivery note been dictated? YES NO
17. Family counseled YES NO
18. Debriefing with appropriate personnel involved YES NO
19. Follow-up about condition of neonate in nursery YES NO
Signatures:
_____________________ _____________________ _______________________________

Primary Delivery Provider Primary delivery nurse Other care providers in attendance
FIGURE 27.6 Suggested checklist for documentation of delivery complicated by shoulder dystocia.
[2.3%], and late training 7/562 [1.3%]) [65]. In a university hospital 18. Gauthaman N, Walters S, Tribe IA, et al. Shoulder dystocia and associ-
setting in Chicago, the effects of a shoulder dystocia protocol were ated manoeuvres as risk factors for perineal trauma. Int Urogynecol J.
2016;27(4):571–577. [II-2, Swedish Birth Registry study of 959,559 births]
studied in three periods (6 months prior to training, 6 months during 19. Gherman RB, Ouzounian JG, Goodwin TM. Obstetric maneuvers for
training, and 6 months post-training). Over the three periods, com- shoulder dystocia and associated fetal morbidity. Am J Obstet Gynecol.
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p <0.001), and there was a decrease in BPI at delivery (10.1%, to 4%, to 20. Chauhan SP, Blackwell SB, Ananth C V. Neonatal brachial plexus
palsy: Incidence, prevalence, and temporal trends. Semin Perinatol.
2.6%; p = 0.03) and BPI at neonatal discharge (7.6%, to 3%, to 1.3%; p =
2014;38(4):210–218. [Review]
0.04) [60]. Multiple RCTs on simulation training demonstrate higher 21. Gherman RB, Ouzounian JG, Miller DA, et al. Spontaneous vaginal deliv-
rates of successful delivery, improved timeliness, less application of ery: A risk factor for Erb’s palsy? Am J Obstet Gynecol. 1998;178(3):423–
force, and improved patient communication during drills on pelvic 427. [II-2]
models [66–68]. Both the Joint Commission in the United States and 22. Sandmire HF, DeMott RK. Erb’s palsy without shoulder dystocia. Int J
Gynecol Obstet. 2002;78(3):253–256. [Review]
the Royal College of Obstetricians and Gynecologists recommend 23. Gherman RB, Goodwin TM, Ouzounian JG, et al. Brachial plexus palsy
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ing, and recommendations for management of shoulder dystocia 24. Chang KWC, Ankumah NAE, Wilson TJ, et al. Persistence of neonatal bra-
chial plexus palsy associated with maternally reported route of delivery:
have demonstrated improved recognition and management of
Review of 387 cases. Am J Perintaol.2016;33(8):765–769. [II-2]
shoulder dystocia cases and decrease in BPIs [60, 69]. 25. Torki M, Barton L, Miller DA, et al. Severe brachial plexus palsy in women
without shoulder dystocia. Obstet Gynecol. 2012;120(3):539–541. [III-3]
26. Sandmire HF, DeMott RK. Controversies surrounding the causes of bra-
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28
POSTPARTUM HEMORRHAGE, RETAINED PLACENTA, AND UTERINE INVERSION
Amy C. Hermesch and Jorge E. Tolosa
Key points Etiology

Common:
• Primary postpartum hemorrhage (PPH) is defined as
blood loss ≥1000 mL within 24 hours after birth. • Uterine atony: Lack of efficient uterine contraction (most
• Gravimetric methods for quantifying blood loss, common, accounts for 80%)
including weighing of pads and sponges, and the use • Retained placenta
of calibrated under-buttock drapes, as well as blood • Genital tract trauma: Vaginal, cervical, and vulvar
loss calculators, are recommended for the diagnosis of
PPH. Less common:
• The most common complications of the third stage of labor
are postpartum hemorrhage (PPH), retained placenta, and • Uterine rupture
uterine inversion. Timely diagnosis, physical exam, IV • Uterine inversion
access, anesthesia, appropriate use of blood products, nurs- • Retroperitoneal hematoma
ing support and teamwork are important for the manage- • Consumptive coagulopathy
ment of third-stage complications. • Inherited or acquired bleeding disorders
• In cases of PPH, one should perform uterine massage,
explore for and repair any vaginal or cervical lacerations, Risk factors
and manually explore the uterus. At term, the uteroplacental circulation has a blood supply of
• Oxytocin 20–80 IU in 500–1000 cc normal saline given as 600–800 cc/minute. The blood volume expansion of 1.5–2.0 L
a fast IV infusion, 10 IU slow IV push, or 10 IU IM should in pregnant women provides a physiologic reserve for blood loss
be used as a primary uterotonic for PPH. Pharmacologic at delivery. Cessation of placental site blood flow is due mostly
therapy with a combination of oxytocin, misoprostol, to effective myometrial contractions. Most major hemorrhage
tranexamic acid, methergine, and/or prostaglandin F2α occurs within the first hour postpartum. Resources available to
should be employed quickly without delay after PPH is treat PPH vary greatly by setting (academic center versus com-
diagnosed. munity hospital). Location of planned delivery should be con-
• Misoprostol, tranexamic acid, methergine (except in sidered carefully for patients at high risk for PPH. Risk factors
women with hypertension), and prostaglandin F2α (except that contribute to decreased myometrial contractions include the
in women with asthma) are all effective for the treatment of following:
PPH and can be used in combination. Misoprostol may be
particularly helpful in low-resource settings. • Maternal factors:
• There is insufficient evidence with RCTs to assess other • First pregnancy
interventions for the treatment of PPH. • Maternal obesity
• There is insufficient evidence with RCTs to recommend • Previous PPH: 10% recurrence risk
pharmacologic agents for the treatment of retained • High parity
placenta. • Coagulopathy
• Thrombocytopenia
• Antepartum bleeding: Placenta previa, abruption
Postpartum hemorrhage • Chorioamnionitis
Definitions • Uterine fibroids
While controversial, the American College of Obstetrics and • Overdistension: Macrosomia, multiple gestation,
Gynecology (ACOG) defines primary postpartum hemorrhage polyhydramnios
(PPH) as blood loss ≥1000 mL within 24 hours after birth [1]. • Uterine tocolytics: Magnesium, nitroglycerin, anesthetic gas
Secondary PPH is defined as excessive blood loss after 24 hours • Labor factors:
and <12 weeks postpartum. There is no single definition for PPH • Precipitous delivery
that has been agreed upon internationally, and multiple guide- • Prolonged labor: First stage >24 hours
lines from various national and expert authorities exist (Table • Prolonged oxytocin use and/or maximum of ≥40–50
28.1). Recent initiatives have focused on reassessing the existing cc/minute (prolonged labor)
PPH definitions in an effort to improve clinical management and
outcomes [2, 3]. Complications
The most reliable estimates of global mortality for mothers in
Incidence childbirth are reported to be between 250,000 and 300,000 annu-
Approximately 5%–15% of deliveries are complicated by PPH. ally [4]. This number has decreased significantly over the past
324 DOI: 10.1201/9781003102342-28

Postpartum Hemorrhage, Retained Placenta, and Uterine Inversion 325
TABLE 28.1: Definitions for Postpartum Hemorrhage

Guidelines Postpartum Hemorrhage (PPH) Definition
World Health Organization (2017) Blood loss of ≥500 mL within 24 h after birth.
Severe PPH: blood loss ≥1000 mL in 24 h after birth
American College of Obstetricians and Gynecologists (2017) Blood loss of ≥1000 mL within 24 h after birth
Royal Australian and New Zealand College of Obstetricians and Blood loss ≥500 mL during puerperium and
Gynaecologists (2017) severe postpartum hemorrhage ≥1000 mL
Royal College of Obstetricians and Gynaecologists (2016) Primary PPH: blood loss of 500–1000 mL in the absence of clinical signs of shock
Major PPH: blood loss of ≥1000 mL
Society of Obstetricians and Gynaecologists of Canada (2018) Any amount of bleeding threatening hemodynamic instability
Abbreviation: h, hour.
2 decades. Many of these deaths result from complications of the of blood loss (EBL). Visual EBL has consistently been shown to
third stage of labor [4]. Ninety-nine percent of maternal deaths result in underestimation of large-volume blood loss (>1000 mL)
occur in low- and middle-income countries where maternal mor- by up to 30%–50% and overestimation of small-volume blood loss
tality remains unacceptably high. In sub-Saharan Africa, the risk [6, 7]. These types of EBL errors have been shown to occur simi-
of maternal death is very high, at 1:31, with at least 25% of those larly among providers at all levels of training [7]. Formal training
deaths due to hemorrhage [5], while in high-income countries, in visual blood loss estimation improves accuracy for a time, but
a woman’s lifetime risk of death during or following pregnancy skills tend to decline after several months [8].
is 1:4300. Secondary PPH is a significant contributor to mater- Some obstetric centers have adopted gravimetric methods for
nal death mainly, but not only, in low-income countries. PPH quantifying blood loss, including weighing of pads and sponges
has other serious complications, including hypovolemic shock, and the use of calibrated under-buttock drapes. One study dem-
disseminated intravascular coagulopathy (DIC), renal fail- onstrated that visual assessment of blood loss underestimated that
ure, hepatic failure, and adult respiratory distress syndrome calculated by weighing of pads and sponges by approximately 30%
(ARDS). [9]. Another randomized controlled trial (RCT) showed that in a
simulated environment, visual blood loss estimation using non-
Diagnosis calibrated drapes resulted in underestimation by 15%–40%
Regardless of the PPH definition being utilized, the appropriate (greater error with larger volumes), whereas use of calibrated
management relies upon the clinician’s assessment of risk for drapes resulted in <15% error at all volumes [10].
PPH (Table 28.2) and timely recognition of excessive blood loss. Blood loss calculators can be utilized by care teams to facili-
However, the assessment of peripartum blood loss has classically tate accurate quantification of blood loss after both cesarean
been determined by a provider’s subjective visual estimation and vaginal deliveries. Examples of calculation tools that can be
integrated into an electronic medical record system can be found
TABLE 28.2: Example of Stratification System by Maternal through the California Maternal Quality Care Collaborative
Risk Factors for PPH (CMQCC) website (www.cmqcc.org/resources-tool-kits/toolkits/
PPH Risk Risk Factors Preparation
ob-hemorrhage-toolkit) and OB hemorrhage toolkit resources.
In summary, gravimetric methods for quantifying blood loss,
Low No previous CD Type and screen including weighing of pads and sponges, and the use of cali-
Singleton pregnancy brated under-buttock drapes, as well as blood loss calculators,
4 or fewer prior VDs are recommended for the diagnosis of PPH.
No bleeding disorder
No prior PPH Management (Figure 28.1)
Medium Prior CD Type and screen or type Primary PPH
Multiple gestation and crossmatch The management of PPH begins with a diagnosis of PPH and
> 4 prior VDs obtaining help in a multidisciplinary fashion, including obste-
Chorioamnionitis tricians, nurses (including charge nurse), anesthesia, and the
Polyhydramnios blood bank. The early identification of risk factors is the first step
Macrosomia to facilitating increased surveillance, adequate preparation, and a
Abruption more rapid response to hemorrhage if it does occur (Table 28.2).
Prolonged labor (>24 h) Risk factors should be evaluated in the prenatal period and reas-
Prior PPH sessed throughout the intrapartum and postpartum course.
Large uterine fibroids A commonly accepted approach to the evaluation and treat-
High Placenta previa Type and crossmatch ment of primary PPH includes:
Suspected placenta accreta Consider alerting blood
Coagulopathy bank • Obtain help
Platelets <50,000 • Ensure adequate access with large-bore IV (may need two
Multiple risk factors (see earlier) sites)
Source: Modified from Ref. [25]. • Monitor vital signs serially
Abbreviations: CD, cesarean delivery; VD, vaginal delivery; PPH, postpartum hemor- • Consider placing a Foley catheter to empty the bladder and
rhage; h, hour. monitor urine output
FIGURE 28.1 Suggested management protocol for primary postpartum hemorrhage. °Can be considered first-line in resource-poor
settings, no IV access, or if contraindications to other medications, and also as an adjunct to first-line oxytocin in high-risk cases.
*Consider transfer to operating room for complicated vaginal repairs or any cervical laceration requiring repair. **Consider contra-
indications to methergine [hypertension] and prostaglandin F2α [asthma]. ***Consider uterine balloon tamponade in particular if
aggressive multiple agents [use all uterotonic and antifibrinolytic therapies] fail to control PPH. Abbreviations: IV, intravenous; CBC,
complete blood count; T&S, type and screen, INR/PTT, international normalized ratio/partial thromboplastin time; IU, international
units; IM, intramuscular.
• Obtain laboratory tests: Complete blood count with platelets, ultrasound-guided sharp or suction curettage. Administer
blood type, antibody screen, fibrinogen, fibrin split products, uterotonic drugs:
prothrombin time, and partial thromboplastin time • Oxytocin 20–80 IU in 500 or 1000 cc of normal
saline (NS), fast IV infusion; or 10 IU IM
The first two critical steps in evaluating excessive bleeding • Misoprostol 800–1000 mcg per rectum (side effects:
are (1) to obtain labs and (2) to perform a thorough physical Chills, fever) or 400–600 mcg buccal
exam to identity the etiology of PPH. Although uterine atony • Tranexamic acid (TXA) 1 g in 10 mL IV (100 mg/mL)
accounts for 80% of PPH, failure to identify an alternative diag- at 1 mL per minute; second dose may be given if
nosis could result in delayed surgical intervention or correc- bleeding continues after 30 minutes
tion of underlying coagulopathy. Vaginal or cervical lacerations • Methergine 0.2 mg IM every 15 minutes for 2 doses,
should be explored and repaired. then every 2–4 hours: Consider contraindications,
Primary management of uterine atony: including hypertension
• Prostaglandin F2α (carboprost tromethamine,
• Vigorous uterine massage until firm Hemabate) 0.25 mg IM every 15–90 minutes up to
• Manually explore the uterus and remove any retained 8 doses (maximum 2 mg): Consider contraindica-
clots or placenta. If unable to do so manually, consider tions, including asthma
TABLE 28.3: Blood Products

Product Volume (mL) Contents Effect (per unit)
Whole blood a 400–500 RBCs, leukocytes, platelets, and plasma Increase Hgb by 1 g/dL or Hct by 3%
Packed red blood cells 250–400 RBCs, leukocytes Increase Hgb by 1 g/dL or Hct by 3%
Platelets 50 Platelets, plasma, small number of RBCs, and leukocytes Increase platelet count by 5000–10,000 mm3
Fresh frozen plasma 200–250 Fibrinogen, antithrombin III, clotting factors, plasma Increase fibrinogen by 5–10 mg/dL
Cryoprecipitate 20–40 Fibrinogen, factor VIII, vWF, factor XIII Increase fibrinogen by 5–10 mg/dL
a Can be used initially in MTP instead of recombined products.
Abbreviations: RBC, red blood cells; WBC, white blood cells; Hgb, hemoglobin; Hct, hematocrit; vWF, von Willebrand factor.
Limited evidence exists on which to base a protocol with observational data. The first technique uses a mini-sponge tam-
respect to the order of administration of uterotonics and ponade device, a type of trauma gauze, that provides mechani-
antifibrinolytics for the treatment of PPH following vaginal cal compression of the uterine cavity [16]. The second device is
delivery. It is also important to note that the literature on the an elliptical loop that creates a vacuum within the uterus [17].
management of intraoperative and postpartum hemorrhage Randomized controlled studies comparing these devices to cur-
at the time of cesarean section is limited compared to vaginal rently used uterine balloon tamponade devices will be essential to
delivery. Findings have been generalized to cesarean deliver- determine how to incorporate these in current clinical practice.
ies based on the assumption that they are likely to be beneficial. If pharmacologic therapies and balloon/tamponade are
Traditionally, oxytocin and ergot alkaloids (e.g. methergine) are not effective in stopping PPH, other interventions should be
used as first-line agents due to their pharmacokinetic profile considered:
and speed of action, with prostaglandin F2α and misoprostol
employed as adjunctive therapies. There are many RCTs directly • Compression sutures
comparing oxytocin, ergot alkaloids, and prostaglandin F2α to • Uterine artery ligation
either placebo or to each other for treatment of PPH. Based on a • Uterine artery embolization
recent systematic analysis, the addition of misoprostol to conven- • Hysterectomy
tional injectable uterotonics conferred no added benefit with an
increase in side effects [11]. Compared with oxytocin, misoprostol Soon after the diagnosis of PPH, need for blood products and
is less effective in the primary treatment of PPH. Studies compar- hemostatic drugs should be assessed:
ing misoprostol to ergot alkaloids have demonstrated conflicting
results, and the studies are small and heterogeneous. Thus, there • Transfusion of blood and blood products as necessary
is no compelling evidence to suggest an alteration in medical (Table 28.3).
management at this time. However, it is important to note that • Hemostatic drugs.
rectal or buccal misoprostol may be an appropriate first-line • Factor VIIa: A single RCT demonstrated that recom-
agent in the setting of no IV access, patients with contraindi- binant human FVIIa may reduce the need for surgical
cations to other uterotonics, or in resource-poor settings. In intervention for severe PPH that has failed medical
addition to uterotonic medications, a growing body of evidence management [18]. This RCT was small and not pla-
supports antifibrinolytic agents (i.e. TXA). A large international cebo-controlled or blinded. Thus, larger blinded and
randomized trial demonstrated a reduction in the risk of death placebo-controlled trials are needed to assess efficacy
due to bleeding when TXA was administered (compared to pla- and safety.
cebo) early during PPH diagnosis [12]. A systematic review and • If stable, consider pelvic arterial embolization done by
meta-analysis showed a reduced risk of hysterectomy after PPH interventional radiology (IR).
following vaginal delivery [13]. Together, these studies provide • If unstable (there are no high-quality RCTs investigating
evidence that early administration of TXA in adjunct with other the following techniques):
uterotonic agents is reasonable and supported by the World • Consider massive transfusion protocol (see Figure 28.2).
Health Organization (WHO) [14]. In summary, pharmacologic • Laparotomy: Uterine artery ligation, compression
therapy with a combination of oxytocin, misoprostol, TXA, sutures, internal iliac artery ligation.
methergine, and/or prostaglandin F2α should be employed • Bimanual uterine compression.
quickly without delay after PPH is diagnosed (Figure 28.1). • Aortic compression (temporary) and pelvic packing.
Secondary management of uterine atony (refractory uterine • Hysterectomy.
atony):
A nonpneumatic antishock garment (NASG) is a neoprene
• Uterine balloon tamponade compression suit fastened around the body to reduce bleeding
and reverse shock, to be used as a hemodynamic temporizing
Failed medical pharmacologic management of uterine measure during transfer to a higher-level treatment facility.
atony is typically followed by intrauterine tamponade device Massive hemorrhage may exceed the clinical care team’s abil-
placement. The most common device is a uterine balloon, with ity to “keep up,” leading to hemodynamic instability and shock
a high success rate—87.1%—in the setting of uterine atony [15]. frequently in the presence of acidosis, hypothermia, and coagu-
Advantages of the uterine balloon include simplicity and mini- lopathy. Damage control surgery during obstetrics is defined as
mal requirement for local resources and training. Alternative abdominopelvic packing [19]. This can be utilized after arterial
uterine tamponade techniques have recently shown promising bleeding has been controlled. After packing, coagulopathy can
Complications
Hemorrhage, infection, and genital tract trauma.
Etiology
• Preterm birth: Inversely proportional to gestational age
• Cord avulsion: Incidence up to 3% with controlled cord
traction, especially by inexperienced operators
• Placenta accreta (see Chap. 29)
Management
• Obtain adequate anesthesia.
• Attempt manual placental extraction.
• One hand is placed over the abdomen to stabilize
the uterine fundus, while the other hand is placed
through the cervix into the uterus. The placenta is
gently separated from the uterus starting at the supe-
rior placental edge. If possible, the placenta should be
removed intact.
• Consider ultrasound to ascertain all placental tissue has
been removed.
• The ultrasonographic appearance of the uterus imme-
diately following delivery is variable. The sensitivity
and positive predictive value of ultrasound for the
detection of retained products of conception are
relatively low (44% and 58%, respectively). The speci-
ficity and negative predictive value are better (92% and
87%, respectively) [21].
• Palpate and massage the fundus until firm.
• Proceed to the operating room for curettage under ultra-
sound guidance if unsuccessful extraction or excessive
bleeding.
• Consider diagnosis of placenta accreta.
Pharmacologic agents
In the past, pharmacologic interventions have been used in the
management of retained placenta. The rationale was that stimu-
lating uterine contractions with oxytocin or prostaglandins, or
cervical relaxation with nitroglycerin, would facilitate spontane-
FIGURE 28.2 Suggested massive transfusion protocol. ous placental delivery and avoid further invasive interventions.
*Depending on institutional availability and blood blank protocol, However, a systematic analysis incorporating 16 RCTs and 1683
whole blood may be used initially in MTP instead of recombined patients identified no differences in the need for manual pla-
blood components. Abbreviations: INR, international normalized cental extraction with oxytocin (intraumbilical), prostaglan-
ratio; pRBC, packed red blood cells; FFP, fresh frozen plasma. dins (e.g. F2α, E2, or misoprostol), or nitroglycerin [22]. The
greatest number of studies investigated intraumbilical admin-
istration of oxytocin. They concluded that there is no evidence
supporting the use of intraumbilical oxytocin for retained
be corrected and interventional radiology can be utilized if the placenta and that there has not been adequate evaluation of other
patient is stable and if it is available. Additional expertise and pharmacologic interventions by RCT. Therefore, there is insuf-
resources can be called on for surgical and transfusion support. ficient evidence to recommend pharmacologic agents for the
treatment of retained placenta.
Secondary PPH
There is insufficient evidence to make recommendations for Antibiotics
the management of secondary PPH [20]. Management similar There is insufficient evidence to assess the effects of pro-
to that for PPH is suggested, with high suspicion for retained phylactic use of antibiotics following manual removal of the
placenta. placenta [23]. The WHO recommends single-dose penicillin
or first-generation cephalosporin based on one retrospective
Retained placenta study [14, 24].
Definition
Placenta undelivered ≥30 minutes after infant delivery. Uterine inversion
Incidence Definition
Between 0.5% and 3%. The collapse of the uterine fundus into the uterine cavity.
Incidence 5. Hogan MC, Foreman KJ, Naghavi M, et al. Maternal mortality for 181 coun-
tries, 1980-2008: A systematic analysis of progress towards Millennium
Approximately 1 in 2500 deliveries.
Development Goal 5. Lancet. 2010;375(9726):1609–1623. [Review]
6. Stafford I, Dildy GA, Clark SL, Belfort MA. Visually estimated and calcu-
Risk factors lated blood loss in vaginal and cesarean delivery. Am J Obstet Gynecol.
• Excessive umbilical cord traction 2008;199(5):519 e1–7. [II-3]
• Fundal pressure 7. Dildy GA 3rd, Paine AR, George NC, Velasco C. Estimating blood loss:
• Fundal cord insertions Can teaching significantly improve visual estimation? Obstet Gynecol.
2004;104(3):601–606. [II-3]
• Abnormal placentation 8. Toledo P, Eosakul ST, Goetz K, Wong CA, Grobman WA. Decay in blood
loss estimation skills after web-based didactic training. Simul Healthc.
Management 2012;7(1):18–21. [II-1]
There are no randomized trials to determine the optimal manage- 9. Al Kadri HM, Al Anazi BK, Tamim HM. Visual estimation versus gravi-
ment for uterine inversion. Suggested management may include metric measurement of postpartum blood loss: A prospective cohort study.
Arch Gynecol Obstet. 2011;283(6):1207–1213. [II-2]
the following:
10. Toledo P, McCarthy RJ, Hewlett BJ, Fitzgerald PC, Wong CA. The accuracy
of blood loss estimation after simulated vaginal delivery. Anesth Analg.
• Obtain assistance from other obstetricians or experienced 2007;105(6):1736–1740. [II-1]
providers and nursing staff. 11. Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic Z. Treatment
• Obtain adequate anesthesia. for primary postpartum haemorrhage. Cochrane Database Syst Rev.
2014(2):CD003249. [I]
• Consider immediate transfer to the operating room. 12. WOMAN Trial Collaborators. Effect of early tranexamic acid adminis-
• Obtain large-bore IV access. tration on mortality, hysterectomy, and other morbidities in women with
• IV fluid therapy. post-partum haemorrhage (WOMAN): An international, randomised,
• If placenta has not yet delivered, avoid separation to reduce double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105–2116.
[RCT, n = 20,020]
bleeding.
13. Della Corte L, Saccone G, Locci M, et al. Tranexamic acid for treatment
• Consider uterine-relaxing agents. of primary postpartum hemorrhage after vaginal delivery: A systematic
• Nitroglycerin 50–500 mg orally or inhaled per anes- review and meta-analysis of randomized controlled trials. J Matern Fetal
thesia – usually preferred as first line. Neonatal Med. 2020;33(5):869–874. [I]
• Magnesium sulfate 4–6 g IV bolus. 14. WHO Guidelines for the Management of Postpartum Haemorrhage and
Retained Placenta. WHO Guidelines Approved by the Guidelines Review
• Terbutaline IV 0.25 SQ. Committee. Geneva, Switzerland: WHO; 2009. [III]
• Manual manipulation of the uterus. 15. Suarez S, Conde-Agudelo A, Borovac-Pinheiro A, et al. Uterine balloon
• Manually reduce the uterine fundus by placing the tamponade for the treatment of postpartum hemorrhage: A systematic
hand through the cervix into the uterine cavity and review and meta-analysis. Am J Obstet Gynecol. 2020;222(4):293 e1–e52. [I]
16. Rodriguez MI, Bullard M, Jensen JT, et al. Management of postpartum
applying gentle pressure to the inverted fundus. Cup
hemorrhage with a mini-sponge tamponade device. Obstet Gynecol.
the uterus in the palm with the fingers posteriorly and 2020;136(5):876–881. [II-3]
thumb anteriorly (no use of fist). 17. D’Alton ME, Rood KM, Smid MC, et al. Intrauterine vacuum-induced
• Once the fundus has been manually replaced, administer hemorrhage-control device for rapid treatment of postpartum hemorrhage.
uterotonic therapy (oxytocin) followed by methergine to Obstet Gynecol. 2020;136(5):882–891. [II-3]
18. Lavigne-Lissalde G, Aya AG, Mercier FJ, et al. Recombinant human FVIIa
maintain uterine tone and prevent reinversion. for reducing the need for invasive second-line therapies in severe refractory
• Surgical intervention: Laparotomy (rarely needed). postpartum hemorrhage: A multicenter, randomized, open controlled trial.
• Huntington procedure: Clamps are placed on the J Thromb Haemost. 2015;13(4):520–529. [I]
round ligaments 2 cm deep in the inversion and gentle 19. Pacheco LD, Lozada MJ, Saade GR, Hankins GDV. Damage-control surgery
for obstetric hemorrhage. Obstet Gynecol. 2018;132(2):423–427. [Review]
upward traction applied. Repeat clamping as necessary.
20. Alexander J, Thomas P, Sanghera J. Treatments for secondary postpartum
• Haultain procedure: A vertical incision is made in the haemorrhage. Cochrane Database Syst Rev. 2002(1):CD002867. [Meta-
posterior portion of the inversion ring to increase its analysis, no RCTs]
size and to reposition the uterus. 21. Carlan SJ, Scott WT, Pollack R, Harris K. Appearance of the uterus by ultra-
• Uterotonic agents when uterus is repositioned. sound immediately after placental delivery with pathologic correlation. J
Clin Ultrasound. 1997;25(6):301–308. [II-2]
• If present, treat PPH or retained placenta as described under 22. Duffy JM, Mylan S, Showell M, Wilson MJ, Khan KS. Pharmacologic inter-
‘Postpartum hemorrhage’ or ‘Retained placenta’, above. vention for retained placenta: A systematic review and meta-analysis.
Obstet Gynecol. 2015;125(3):711–718.[Meta-analysis: 16 RCTs, n = 1683, I]
23. Chongsomchai C, Lumbiganon P, Laopaiboon M. Prophylactic antibiot-
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Database Syst Rev. 2014(10):CD004904. [Meta-analysis, 0 RCTs, I]
1. Committee on Practice B-O. Practice Bulletin No. 183: Postpartum hemor- 24. Criscuolo JL, Kibler MP, Micholet S, et al. The value of antibiotic prophy-
rhage. Obstet Gynecol. 2017;130(4):e168–e86. [III] laxis during intrauterine procedures during vaginal delivery. A comparative
2. Menard MK, Main EK, Currigan SM. Executive summary of the reVITAL- study of 500 patients. J Gynecol Obstet Biol Reprod. 1990;19(7):909–918.
ize initiative: Standardizing obstetric data definitions. Obstet Gynecol. [RCT, n = 500]
2014;124(1):150–3. [III] 25. California Maternal Quality Care Collaborative Obstetric Hemorrhage
3. Abdul-Kadir R, McLintock C, Ducloy AS, et al. Evaluation and management Toolkit Version 2.0 03/24/15. https://www.cmqcc.org/resource/3322/
of postpartum hemorrhage: Consensus from an international expert panel. download. [III]
Transfusion. 2014;54(7):1756–1768. [III]
4. Lozano R, Wang H, Foreman KJ, et al. Progress towards Millennium
Development Goals 4 and 5 on maternal and child mortality: An updated
systematic analysis. Lancet. 2011;378(9797):1139–1165. [II-1]
29
PLACENTAL DISORDERS
Daniele Di Mascio and Francesco D’Antonio
placenta that comes within 0.1–2.0 cm of the internal os, but

Placenta previa does not cover it [1].
The terms “complete” (when the placenta entirely covers the
internal os), “partial” or “incomplete” (when the placenta covers
Key points the internal os only in part), or “marginal” (when placental tis-
• Placenta previa is defined as a placental tissue that covers sue reaches the internal os, not covering it) traditionally used to
the internal cervical os. characterize placenta previa should be avoided, as these belong
• Low-lying placenta is defined as a placenta that comes to the “pre-ultrasound” period, when the diagnosis was made by
within 0.1–2.0 cm of the internal os, but does not cover it. physical examinations. Moreover, many studies have used these
• The major risk factor for placenta previa is a previous terms to signify different conditions. When the placenta does not
cesarean delivery. cover the internal os, rather than use ambiguous language, it is
• The majority of cases of placenta previa are usually detected best to describe the distance of the tip of the placenta from the
at the mid-trimester ultrasound and are labelled “previa” internal os [1].
with the presence of placental tissue completely extending
over the internal cervical os. Epidemiology/Incidence
• Transvaginal ultrasound should be preferred, as it can be
safely performed in women with placenta previa, and it is The overall prevalence rate of placenta previa ranges from 4.0
more accurate than the transabdominal approach. to 5.2 per 1000 births, and the prevalence significantly changes
• The most common symptom of placenta previa is antepar- according to the regional area, with higher prevalence among
tum, painless bleeding in the second or early third trimester. Asian studies (12.2 per 1000 pregnancies) compared with those
• The risk that a placenta previa diagnosed in the antepar- coming from North America (2.9 per 1000 pregnancies), Europe
tum period remains a placenta previa at the time of delivery (3.6 per 1000 pregnancies), and sub-Saharan Africa (2.7 per 1000
depends on several factors, especially gestational age (GA) pregnancies) [2, 3].
at detection, the placental distance from or extent of over- The frequency of placenta previa is higher earlier in gestation,
lap of the internal os, and the a priori risk of placenta previa but many of these cases will resolve. The likelihood of resolution
related to other risk factors (e.g. prior cesarean delivery). is inversely proportional to gestational age (GA) at the time of
Most placenta previas diagnosed before the third trimester examination (Figure 29.1) [4].
do not remain placenta previas at the time of delivery.
• Women who have the inferior edge of the placenta ≥1 cm Risk factors
from the internal os at around 20 weeks usually do not
require further ultrasounds for placental location. The major risk factor for placenta previa is a previous cesarean
• All patients with the inferior placenta edge <1 cm from delivery: A prior cesarean delivery increases the risk of placenta
the internal os or overlying the os at around 20 weeks previa by about 47%, as shown by both cohort and case-control
should be rescanned at least once at approximately studies [5–7], and this risk increases as the number of previous
32–35 weeks’ gestation to reassess for placental location. cesarean deliveries increases (Figure 29.2), with prelabor cesar-
• All patients with prior cesarean delivery and placenta ean associated with a significantly increased risk of previa in the
previa that extends anteriorly should have evidence of second delivery [8].
placenta accreta assessed ultrasonographically. Other well-known risk factors for placenta previa are any
• Women with a placenta previa should be delivered by cesar- other uterine surgery (e.g. myomectomy, dilation and evacua-
ean. If the placental lower edge is within 1–19 mm of the tion [D&E], dilation and curettage [D&C], and hysteroscopy),
internal os, a trial of labor can be attempted, but the risk smoking, maternal age, multiparity, cocaine abuse, and multiple
of significant bleeding during labor may be higher, espe- pregnancies [1]. In particular, a large retrospective cohort study
cially in those with a distance of only 1–10 mm. of singleton and twin pregnancies showed that dichorionic twin
• The optimal GA for delivery of an asymptomatic woman pregnancies were more likely to have placenta previa compared
(i.e. a woman without acute bleeding) with placenta previa with monochorionic (odds ratio [OR]: 3.3) or singleton pregnan-
is unknown, but many experts recommend planned cesar- cies (OR: 1.5) [9].
ean delivery at approximately 360/7–376/7 weeks.
Diagnosis
Definition
The assessment of the position of the placenta is one of the rec-
Placenta previa is defined as a placental tissue that covers the ommended minimum requirements for basic mid-trimester fetal
internal cervical os, while low-lying placenta is defined as a anatomic survey [10]. Thus, the majority of cases of placenta
330 DOI: 10.1201/9781003102342-29

Placental Disorders 331
FIGURE 29.1 Persistence of placenta previa until delivery stratified by gestational age at ultrasound detection, type of previa, and
prior cesarean delivery. All data presented as %; incomplete previa defined as inferior edge of the placenta partially covering or reach-
ing the margin of the internal os. (Data from Ref. [4].)
previa are usually detected at the mid-trimester ultrasound Symptoms and complications
and are labelled “previa,” with the presence of placental tissue
completely extending over the internal cervical os, or as “low- The most common symptom of placenta previa is antepartum,
lying placenta” when the edge is within 2 cm of the internal os. painless bleeding in the second or early third trimester, which
In this scenario, the Eunice Kennedy Shriver National Institute occurs in more than half of women with placenta previa [21]. In
of Child Health and Human Development recommend to always some cases, bleeding might also present as painful, mostly as a
describe the location of the edge of the placenta when writing the consequence of uterine contractions due to partial placental sep-
ultrasound report [11]. aration. Finally, a small proportion of patients might not present
When considering transabdominal ultrasound, a prospective any bleeding until labor [1].
cohort study of 1214 women aiming at evaluating the distance Placenta previa is associated with both maternal and perinatal
from the placental edge to the internal os (placenta–cervix dis- morbidity. Maternal morbidity is mainly associated with either
tance) showed that a transabdominal placenta–cervix distance antepartum or postpartum hemorrhage, which might occur,
cutoff of 4.2 cm had a sensitivity of 93.3% and a specificity of respectively, in up to 52% and 22% of cases of placenta previa [20,
76.7% for detection of placenta previa, with a 99.8% negative 21]. When comparing women with normal location of the pla-
predictive value at a screen-positive rate of 25.0%, while a cutoff centa, those affected by placenta previa are at significantly higher
of 2.8 cm had a sensitivity of 86.7% and a specificity of 90.5%, risk of perinatal morbidity, mainly related to preterm birth before
with a 99.6% negative predictive value at a screen-positive rate 37 weeks, admission to the neonatal intensive care unit (NICU),
of 11.4% [12]. and both perinatal and neonatal death [22].
However, transvaginal ultrasound (TVU) should be pre- Intuitively, the incidence of both maternal and perinatal
ferred, as it can be safely performed in women with placenta morbidity is lower in cases of low-lying placenta, but there is
previa, and few studies—including a randomized controlled still a risk that is higher in women with placental edge at 1–10
trial—demonstrated that the transvaginal approach is more mm compared with 11–20 mm from the internal cervical os
accurate than the transabdominal, with a sensitivity of 87.5%, a (Table 29.1) [23].
specificity of 98.8%, and a negative predictive value 97.6% [13–15].
Moreover, in women with placenta previa, transvaginal cervi- Management
cal length also allow to predict antepartum bleeding and emer-
gency delivery, and in particular, a cervical length ≤30 mm, as Principles
well as a decrease in cervical length, was associated with a sig- Placenta location should be assessed at the time of the fetal
nificantly higher incidence of antepartum hemorrhage and anatomic survey (usually 18–24 weeks). If placenta previa is
emergency cesarean delivery (CD) before 34 weeks of gestation suspected by transabdominal examination, TVU should be
when placenta previa was “complete.” Women with a change in performed for confirmation of the diagnosis (Figure 29.3). A
the transvaginal cervical length more than 6 mm between the single antenatal ultrasound that detects a placenta previa, how-
second and third trimester are considered to be at higher risk of ever, may not indicate that a placenta previa will be present at
emergency CD [16–19]. delivery, as the relative position of the placenta with respect to
FIGURE 29.2 (a) Risk (%) of placenta accreta (in cases with previa) stratified by number of prior cesarean deliveries. (b) Risk of (%)
placenta accreta (in cases with no previa) stratified by number of prior cesarean delivery. All data presented as %; CD, cesarean deliv-
ery. (Data from Ref. [7].)
the internal os will change as gestation progresses [4]. The reason postulated as a contributing factor to this apparent positional
for this change in relative position is not placental migration, but change. This phenomenon has been cited as the reason that vasa
likely due to the growth and development of the lower uterine previa can be seen in this setting (i.e. when an initially diagnosed
segment. Atrophy of placental cells overlying the os also has been placenta previa resolves).
TABLE 29.1: Selected Outcomes with Low-Lying Placenta Workup

According to Placental Edge to Internal os Distance Examination
Digital examination should NOT be performed. Because of the
Distance between Placental
reliability of ultrasound for diagnosis of previa, the technique of
Edge and Internal
double-setup examination is unnecessary. If employed, double-
Cervical os
setup examination should be performed in a setting with the abil-
1–10 mm 11–20 mm ity to proceed in a prompt fashion with CD if indicated.
Cesarean delivery 75% 31%
Ultrasound
Antepartum hemorrhage 29% 3% TVU is the gold standard for the diagnosis of placenta previa
Postpartum hemorrhage 21% 10% (Figure 29.4). Most previas diagnosed before the third trimester
Postpartum hemorrhage >1000 mL 8% 10% resolve (Figure 29.1). If a placenta previa “resolves” but remains
Source: From Vergani P, Ornaghi S, Pozzi I, et al. Placenta previa: Distance to inter- proximate to the internal cervical os, a woman still may have an
nal os and mode of delivery. Am J Obstet Gynecol. 2009;201:266.e1–5. Ref. increased risk of third-trimester bleeding, intrapartum hemor-
[23], with permission. rhage, and CD [23, 24].
Suspected Placenta Previa on

TAU 18–24 Weeks
TVU
Placenta Previa, Distance ≥10mm

or Distance <10mm
Repeat TVU ~32 Weeks Trial of labor *
Placenta Previa Distance 1–9mm
Planned CD Discuss trial of labor,

at approximately 37 possible repeat TVU ~35
weeks weeks
FIGURE 29.3 Management of suspected placenta previa. Abbreviations: Distance, distance between placental edge to internal
cervical os; TAU, transabdominal ultrasound; TVU, transvaginal ultrasound; CD, cesarean delivery. *After discussion with the couple
and if no contraindication.
Women who have the inferior edge of the placenta >1 cm Prenatal care
from the internal os at around 20 weeks usually do not require All patients with placenta previa and antenatal bleeding in the
further ultrasounds for placental location, as they are exceed- third trimester should be advised about pelvic rest (no vaginal
ingly unlikely to have a placenta that is low-lying or a previa at penetration). Pelvic rest recommendations in women with previa
delivery. Women who have the inferior placental edge overlap- placenta that is near but not overlapping the internal os should
ping the internal os by ≥25 mm at around 20 weeks have been be individualized and based on bleeding during the pregnancy,
reported to usually have persistence of previa even by term as well as the distance between the placenta and the internal
(Figure 29.1) [25, 26]. os. There is insufficient evidence to support the use of routine
All patients with suspected placenta previa in the second tri- bed rest in women with placenta previa or to be certain who
mester should be rescanned at approximately 32–35 weeks’ ges- are optimal candidates, when asymptomatic, for hospitalization
tation to assess for persistence of placenta previa (Figure 29.3). [28]. Moreover, while pelvic rest, i.e. nothing per vagina, is often
Additionally, even if a placenta previa is no longer present, suggested, there is no evidence for its effectiveness. There is no
measuring the distance from the placental edge to the internal evidence to support the use of autologous blood donation/trans-
os in the third trimester can help estimate the risk of bleed- fusion for placenta previa [29].
ing with a trial of labor [23, 24]. All patients with prior CD (or
other uterine surgery) and placenta previa that extends ante- Therapy/Interventions
riorly should have evidence of placenta accreta assessed ultra- Management at home versus hospitalization
sonographically (see the section “Placenta Accreta Spectrum There has been no evidence of any clear advantage to a policy
Disorders”) [7, 27]. of home versus routine hospital care, with similar maternal and
controlled trial of 217 women [30]. Given the limited data, pes-
sary cannot be recommended for use in women with placenta
previa.
Tocolysis
There is insufficient evidence to assess the benefits of tocolysis for
treatment of preterm labor (PTL) specifically in women with a pla-
centa previa. It is reasonable to consider tocolysis, as for women
without a placenta previa, if PTL is diagnosed and a course of
steroids has not yet been administered [31]. Acute bleeding with
instability of the mother or fetus is considered a contraindication
to tocolysis.
Steroids
In case of antenatal bleeding, a course of corticosteroids should
be administered to women who are eligible and are managed
expectantly if delivery is likely within 7 days, the GA is between
34 0/7 and 366/7 weeks of gestation, and antenatal steroids have not
previously been administered [32].
FIGURE 29.4 Transvaginal ultrasound showing anterior
placenta previa, with placental edge covering over the inter- Anti-D immune globulin
nal Os. (Courtesy of the Division of Maternal Fetal Medicine, For prevention of RhD alloimmunization, anti-D immune glob-
Department of Obstetrics and Gynecology, Northwestern ulin to D-negative should be administered to women who have
University Feinberg School of Medicine.) Abbreviations: IO, bleeding from placenta previa.
internal os; EO, external os.
Antepartum testing
There are insufficient data to assess the usefulness of routine
antenatal testing in improving outcomes, and this strategy is
fetal outcomes demonstrated in the trials that do exist. The only presently not indicated.
difference is that compared to hospitalization, management at
home—not surprisingly—has been associated with a reduced
Delivery
Timing: There is insufficient evidence to be certain of the opti-
length of stay in the hospital [28]. There are limited data to allow
mal GA of delivery for women with placenta previa who are not
certainty as to who are the optimal candidates for inpatient man-
acutely bleeding, although experts have recommended approxi-
agement. Women who traditionally have been more likely to
mately 360/7–376/7 (Figure 29.3) [32]. In the setting of acute bleed-
be managed in the hospital even though they are not acutely
ing, the timing of delivery depends upon individualization of
symptomatic are those who have had recurrent episodes of
patient circumstances, taking into account GA, amount of bleed-
antepartum hemorrhage (e.g. three or more episodes of bleed-
ing, and other comorbidities.
ing); have other medical complications that increase their risks
Mode: Delivery of women with a placenta previa should be by
(e.g. congenital cardiac disease); or are unable to easily access the
cesarean. A recent randomized controlled trial aiming at evalu-
hospital in an emergency (e.g. lack of telephone at home and far
ating the role of interventional radiology before CD showed that
distance from an adequate care facility).
the use of prophylactic internal iliac artery balloon occlusion
Often, after an initial antenatal bleeding episode related to pla-
did not reduce postpartum hemorrhage or have any effect on
centa previa, if several days of no further bleeding have occurred
maternal or neonatal morbidity [33]. Preoperative ultrasonog-
and there is no other indication for hospitalization, women may
raphy to assess placental location is useful in determining
be managed as outpatients.
the optimal place for the uterine incision. Those with a low-
Cervical cerclage lying placenta not covering the internal os but within 20 mm
Cervical cerclage has not been proven to be an effective inter- of it may have a trial of labor offered, with individual circum-
vention for women with placenta previa [28]. Although the meta- stances (e.g. the presence of antepartum bleeding) and the risk
analysis in the Cochrane review that evaluated cervical cerclage of bleeding at delivery taken into consideration (Figure 29.3). In
in the setting of placenta previa revealed that women randomized a series, 26/28 (93%) women who had a placental edge–to–cervi-
to cerclage had a reduced length of inpatient hospitalization, as cal os distance of 1–20 mm and who underwent a trial of labor
well as reduced risks of a small-for-gestational-age (SGA) birth delivered vaginally [23]. Women with a placental edge that is
or delivery <34 weeks, the benefits were evident in studies with within 1 cm of the internal os can have uncomplicated vagi-
lower methodological quality, and thus there is not yet sufficient nal deliveries, although their risk of bleeding and requiring
evidence to justify this intervention. a cesarean is higher than in those women whose placenta is
10–20 mm distant from the os (risks of cesarean are 75% and
Cervical pessary 31%, respectively) (Figure 29.1) [23]. As such, depending upon
Compared with progesterone alone, the use of the Arabin cervi- the distance of the placental edge from the internal os, as well
cal pessary combined with progesterone in patients with placenta as other factors, these patients (i.e. those with a placenta not
previa significantly reduced the rate of preterm delivery <34 covering the internal os but that is 2 cm or less from the internal
weeks and bleeding during pregnancy in a recent randomized os prior to delivery) should have their circumstances discussed
and be delivered in facilities with the capacity to perform emer- Definition

gent operative delivery if necessary [23]. In women with the pla-
centa 2 cm or more from the internal os, a trial of labor should PAS disorders represent a heterogeneous group of conditions
be encouraged. characterized by an abnormal invasion of trophoblastic tissue
through the myometrium and uterine serosa [1]. The nosography
of abnormal placentation was recently updated, and the new term
“placenta accreta spectrum disorders” is now preferred to over-
Placenta accreta spectrum disorders
come possible confounding terms like “morbidly adherent pla-
centa” that technically excludes the severe forms of the disease, or
Key points “placental adhesive disorders” and “abnormally invasive placenta-
tion,” which ignore clinical and pathologic diagnostic standards.
• Placenta accreta is diagnosed when anchoring placental
villi are attached to myometrium rather than decidua, but
without completely invading it; placenta increta is diag-
Classification
nosed when chorionic villi penetrate the myometrium, PAS disorders are commonly classified according to the degree of
while the diagnosis of placenta percreta is considered when invasion of the trophoblastic tissue through the myometrium and
chorionic villi penetrate through the myometrium to the uterine serosa. Placenta accreta is diagnosed when anchoring
uterine serosa and/or adjacent organs. placental villi are attached to myometrium rather than decidua,
• The incidence of placenta accreta spectrum (PAS) disorders but without completely invading it; placenta increta is diagnosed
significantly increased in the last decades, and the greatest when chorionic villi penetrate the myometrium, while the diag-
contribution to the increasing pattern of PAS epidemiology nosis of placenta percreta is considered when chorionic villi
is represented by the rising rates of CDs. penetrate through the myometrium to the uterine serosa and/
• In addition to placenta previa and CD, several other risks or adjacent organs [34]. However, some authors have cast doubt
factors have been described to be associated with myo- on this anatomy-based classification: It is retrospective; it does
mectomy, uterine curettage, hysteroscopy, multiparity, not consider the topography of placental invasion, which is one
advanced maternal age, obesity, and assisted reproductive of the main determinants in predicting the surgical outcome; and
techniques. it does not easily fit the clinical evidence that different degrees
• Ultrasound is the gold standard imaging approach to of placental invasion coexist in the same uterine specimen, mak-
diagnose PAS. ing a precise histopathologic classification extremely challeng-
• Antepartum diagnosis significantly reduces intrapar- ing. For this reason, the International Federation of Gynecology
tum blood loss and units of red blood cells and fresh frozen and Obstetrics (FIGO) recently proposed a clinical based stag-
transfused, but most of all, it might allow to organize deliv- ing upon the difficulties in placental detachment during delivery
ery with a multidisciplinary team in a tertiary center with and the gross visualization of invasion during surgery, which goes
the proper expertise. from grade 1 (complete placental separation at the third stage,
• The diagnostic accuracy of MRI in detecting the depth of with normal adherence of placenta) to grade 6 (placental tissue
placental invasion is similar to ultrasound, and it might be seen to have invaded through the serosa of the uterus and infil-
useful to delineate the topography of placental invasion trating the parametrium or any organ other than the urinary
and to better evaluate the posterior placenta. bladder) (Table 29.2) [35].
• PAS is associated with a high burden of adverse maternal
outcomes and particularly severe life-threatening hem-
orrhage, need for blood transfusion, damage to adjacent Etiopathology
organs, and death.
• There are limited randomized trials to assess the The etiopathology of PAS has not been entirely elucidated yet,
efficacy of different surgical interventions in or the but it has been postulated that an abnormal decidualization pro-
approaches to the management of placenta accreta (e.g. cess, particularly in the case of prior uterine surgery, can cause
balloon catheterization by interventional radiology, ure- an excessive trophoblastic infiltration through the myometrium
teral stents, etc.). Planned cesarean hysterectomy may that might extend also beyond the serosa in the most severe cases.
be beneficial in cases in which the diagnosis is highly Also, other biologic factors linked to angiogenesis and inflamma-
suspected, especially for the woman who does not desire tion processes have been claimed to play a role in the develop-
further fertility. ment of PAS [36].
• The American College of Obstetricians and Gynecologists
(ACOG) recommends planned delivery between 34+0 Epidemiology/Incidence
and 35+6 weeks of gestation for stable (no bleeding or pre-
term labor) patients, while the Society for Maternal-Fetal A recent meta-analysis including 7001 cases of PAS of 5,719,992
Medicine (SMFM) suggests delivery between 34 and 37 births showed that the overall prevalence of PAS was 0.17%. In
weeks of gestation for stable women with placenta accreta. this review, the incidence of placenta accreta, increta, and per-
• Women with PAS should deliver in tertiary centers that creta was 63%, 15%, and 22%, respectively [37]. The incidence of
could provide a multidisciplinary team with significant PAS significantly increased in the last decades, and the great-
experience in managing PAS. est contribution to the increasing pattern of PAS epidemiol-
• Cesarean hysterectomy with placenta left in situ is cur- ogy is represented by the rising rates of CDs (see “Risk Factors”
rently the gold standard surgical management of PAS next). The role of CDs in increasing the prevalence of PAS dis-
disorders. orders is supported by strong epidemiologic data. Different
TABLE 29.2: Clinical Grading to Assess and Categorize Placental Adherence or Invasion at Delivery
Grade Definition
1 At cesarean or vaginal delivery: Complete placental separation at third stage. Normal adherence of placenta
2 (A) Cesarean/laparotomy: No placental tissue seen invading through the surface of the uterus. Incomplete separation with uterotonics and
gentle cord traction, and manual removal of placenta required for remaining tissue and parts of placenta thought to be abnormally adherent
(B) Vaginal delivery: Manual removal of placenta required and parts of placenta thought to be abnormally adherent
3 (A) Cesarean/laparotomy: No placental tissue seen invading through the surface of the uterus. No separation with uterotonics and gentle
cord traction with manual removal of placenta required and the whole placental bed thought to be abnormally adherent
(B) Vaginal delivery: Manual removal of placenta required and the whole placental bed thought to be abnormally adherent
4 Cesarean/laparotomy: Placental tissue seen to have invaded through the serosa of the uterus but a clear surgical plane can be identified
between the bladder and uterus to allow nontraumatic reflection of the urinary bladder at surgery
5 Cesarean/laparotomy: Placental tissue seen to have invaded through the serosa of the uterus and a clear surgical plane cannot be identified
between the bladder and uterus to allow nontraumatic reflection of the urinary bladder at surgery
6 Cesarean/laparotomy: Placental tissue seen to have invaded through the serosa of the uterus and infiltrating the parametrium or any organ
other than the urinary bladder
Source: From Jauniaux E, Chantraine F, Silver RM, et al; FIGO Placenta Accreta Diagnosis and Management Expert Consensus Panel. FIGO consensus guidelines on pla-
centa accreta spectrum disorders: Epidemiology. Int J Gynaecol Obstet. 2018;140:265–273. Ref. [35], with permission.
worldwide evidences point out a parallel rise of PAS disorders it might allow health care providers to organize delivery with a
and rate of CDs [35]. Furthermore, the increasing rate of CDs not multidisciplinary team in a tertiary center with the proper exper-
only increases the overall risk of PAS, but significantly shifts the tise. Ultrasound is the gold standard imaging approach to
epidemiology towards the more advanced forms of the disease, diagnose PAS (Figure 29.5). A recent meta-analysis of 20 studies
including increta and percreta. This change is unambiguously including more than 3000 patients showed that the sensitivity for
outlined by the marked differences in the distribution of the dif- depth of placental invasion was 90.6%, 93%, and 81.2%, respec-
ferent subtypes of PAS in the case series antecedent to the 1980 tively, and the specificity was 97.1%, 98.4%, and 98.9%, respec-
and the more recent cohort studies [35]. tively (accrete, increta, percreta). Due to the high specificity, a
negative ultrasound almost excludes PAS; moreover, diagnosis
Risk factors and staging of myometrial invasion are accomplished effectively.
However, about 20% of women with placenta percreta remain
Placenta previa and previous CD are the major determinants undiagnosed, underscoring the need for developing more accu-
of PAS and act as independent risk factors. Indeed, the risk of PAS rate prediction models to detect abnormal invasive placenta [46].
dramatically increases with the number of prior cesareans, but In order to improve diagnostic accuracy, the European Working
this effect is much more evident when in the presence of placenta Group on Abnormally Invasive Placenta proposed a standardiza-
previa, with a prevalence ranging from 3% after one cesarean to tion of the PAS imaging descriptors (Table 29.3) that were unified
67% after five or more CDs in women with placenta previa under a common heading, ultimately providing unambiguous
(Figure 29.2) [7, 38]. The detrimental effect of CDs on the risk of definitions and with specific reference to the ultrasound modality
abnormal placentation can be further differentiated according to (grayscale or color Doppler ultrasound) [47]. Prenatal diagnosis
the characteristics of the surgical procedure, i.e. by distinguish-
ing whether it was a prelabor or intrapartum CD, with the latter
conferring a significantly reduced risk for PAS in later pregnan-
cies [8]. In addition to placenta previa and CD, several other risk
factors have been described to be associated with myomectomy,
uterine curettage, hysteroscopy, multiparity, advanced maternal
age, obesity, and assisted reproductive techniques, where altered
endometrial status and receptivity possibly hamper the mecha-
nisms of placental implantation [39–44]. However, epidemiology
cannot conclusively help in identifying patients at high risk of
PAS, as this condition can occur even in the absence of any clas-
sical risk factor. Therefore, despite the importance of the patient
clinical profile, diagnostic imaging maintains a pivotal role in
PAS assessment and prediction.
Diagnosis
The importance of an appropriate screening in the management FIGURE 29.5 Transvaginal ultrasound showing loss of normal
of PAS is clearly outlined by the evidence of a recent meta-anal- hypoechoic retroplacental zone and multiple vascular lacunae
ysis aimed at evaluating the influence of prenatal diagnosis of with turbulent blood flow within anterior placenta concern-
PAS on maternal outcome that indicate how antepartum diag- ing for placenta accreta. (Courtesy of the Division of Maternal
nosis significantly reduces intrapartum blood loss and units of Fetal Medicine, Department of Obstetrics and Gynecology,
red blood cells and fresh frozen transfused [45], but most of all, Northwestern University Feinberg School of Medicine.)
TABLE 29.3: Ultrasonographic Signs for Placenta Accreta Spectrum Disorders

Grayscale ultrasound signs are:
• Loss of clear zone, defined as a loss or irregularity of hypoechoic plane in myometrium underneath placental bed (“clear zone”).
• Placental lacunae, defined as the presence of numerous lacunae, often containing turbulent flow visible on grayscale imaging.
• Bladder wall interruption, defined as loss or interruption of bright bladder wall (hyperechoic band or “line” between uterine serosa and bladder lumen)
• Myometrial thinning, defined as thinning of myometrium overlying placenta to <1 mm or undetectable.
• Placental bulge, defined as the deviation of uterine serosa away from expected plane, caused by abnormal bulge of placental tissue into neighboring
organ, typically bladder; uterine serosa appears intact but outline shape is distorted.
• Focal exophytic mass, defined as placental tissue seen breaking through uterine serosa and extending beyond it; most often seen inside filled
urinary bladder.
Two-dimensional color Doppler signs are:
• Uterovesical hypervascularity, defined as the striking amount of color Doppler signal seen between myometrium and posterior wall of bladder.
• Subplacental hypervascularity, defined as the striking amount of color Doppler signal seen in placental bed.
• Bridging vessels, defined as vessels appearing to extend from placenta, across myometrium and beyond serosa into bladder or other organs; often
running perpendicular to myometrium.
• Placental lacunae feeder vessels, defined as vessels with high-velocity blood ﬂow leading from myometrium into placental lacunae, causing
turbulence upon entry.
Three-dimensional ultrasound plus power Doppler signs are:
• Uterovesical hypervascularity, defined as intraplacental hypervascularity in a complex, irregular arrangement of numerous placental vessels,
exhibiting tortuous courses and varying calibers
• Placental bulge (as in 2D)
• Focal exophytic mass (as in 2D)
• Uterovesical hypervascularity (as in 2D)
• Bridging vessels (as in 2D)
Source: From Collins SL, Ashcroft A, Braun T, et al. European Working Group on Abnormally Invasive Placenta (EW-AIP). Proposal for standardized ultrasound descriptors
of abnormally invasive placenta (AIP). Ultrasound Obstet Gynecol. 2016;47:271–275. Ref. [47], with permission.
of PAS is commonly performed during the second and third tri- considering that ultrasound rendered 27% of false-positive diag-
mester of pregnancy, while there are limited data on the possibil- noses of implantation disorder when in the presence of posterior
ity of a first-trimester diagnosis. In a retrospective analysis of 105 placenta previa, while MRI rendered no false-positive diagnoses.
women with PAS confirmed at delivery, a low implantation of the This result was validated by other reports, leading to the current
gestational sac was already detectable at 6–9 weeks and was pres- statement that posterior placentas are better evaluated by MRI
ent in almost 80% of cases at 11–14 weeks; also, most of the previ- when in the presence of a suspected invasion [50, 51]. The most
ously mentioned ultrasonography signs were already present at common MRI signs associated with PAS are intraplacental T2
the time of the nuchal scan, but their prevalence did increase with dark bands, uterine bulging, heterogeneous placental signal
advancing pregnancy [48]. Overall, in high-risk patients, abnor- intensity, focal interruption of the myometrium, tenting of
mally invasive placenta can be searched at the time of the nuchal the bladder, abnormal intraplacental vascularity, and focal
scan, while a longitudinal assessment during the third trimester exophytic mass [52, 53].
accurately identifies the severity of the disorder.
Ultrasound remains the primary imaging modality for detect- Symptoms and complications
ing and evaluating PAS, while magnetic resonance imaging
(MRI) might be a complementary diagnostic tool to perform in The first clinical manifestation of PAS generally occurs at deliv-
women suspected to be affected by severe types of PAS in order to ery, with a massive, life-threatening hemorrhage usually associ-
delineate the topography of placental invasion. In a recent meta- ated with repeated attempts at manual placental separation.
analysis of 20 studies involving 1080 pregnancies undergoing PAS is associated with a high burden of adverse maternal
MRI mainly for the ultrasound suspicion of PAS, the sensitivity outcomes and particularly severe life-threatening hemorrhage,
of MRI for detecting placenta accreta, increta, and percreta need for blood transfusion, damage to adjacent organs, and
was, respectively, 94.4%, 100%, and 86.5%, while the sen- death [35].
sitivity was, respectively, 98.8%, 97.3%, and 96.8%, with the Composite maternal morbidity (including hysterectomy dur-
accuracy of MRI being significantly affected by the opera- ing CD, delayed hysterectomy, transfusion of ≥10 units of packed
tors’ expertise and experience [49]. Thus, these findings showed red blood cells, septic shock, acute kidney injury, cardiovascular
that the diagnostic accuracy of MRI in detecting the depth failure, maternal transfer to intensive care, or death) is particu-
of placental invasion is similar to ultrasound, which might larly higher in the case of placenta percreta compared with pla-
be partially explained by the fact that studies on ultrasound centa accreta (86% versus 27%) [54].
diagnosis of PAS include longitudinal assessment of women Finally, pregnancies complicated by PAS are at increased
that could improve the diagnostic accuracy of ultrasound in risk for perinatal adverse outcomes—mostly preterm birth and
detecting PAS. An additional role for MRI can be inferred by SGA—but it seems that the occurrence of adverse outcomes is
not significantly associated with the severity of placental invasion incision should be made, if possible, away from the placenta,
(placenta accreta versus increta or percreta) [55, 56]. the position of which can be determined by ultrasound before-
hand. Intraoperative ultrasound with a sterile cover over the
probe placed on the exposed uterus may be helpful if preoperative
Management ultrasound is not informative. While there are different potential
Time of delivery approaches for managing placenta accreta after delivery of the
A general consensus about the optimal time of delivery in women baby by cesarean, many experts would recommend that if there
with PAS is still lacking, as no randomized controlled trial has is proven placenta accreta (e.g. placenta directly visualized in the
been specifically designed with this aim. The indications from serosa), highly suspected accreta by history and radiologic studies
different international societies range between 34 and 37 weeks (e.g. multiple prior CDs, placenta previa, and several ultrasono-
of GA, mainly as a result of differences in balancing maternal graphic findings of placenta accreta), or if the mother plans no
risks versus the problems connected to fetal immaturity. The more childbearing (e.g. has requested tubal ligation), a reason-
American College of Obstetricians and Gynecologists recom- able course of action is to avoid disturbing the implantation of
mends planned delivery between 34+0 and 35+6 weeks of ges- the placenta and proceed with a hysterectomy while the placenta
tation for stable (no bleeding or preterm labor) patients, while the remains attached. The long-standing main point in the technique
SMFM suggests delivery between 34 and 37 weeks of gestation for of cesarean hysterectomy is the avoidance of any form of placenta
stable women with placenta accreta. manipulation, as avoiding attempted placental removal is associ-
The International Society for Abnormally Invasive Placenta ated with reduced maternal morbidity in women with suspected
recommends delivery at ≥36+0 weeks in asymptomatic women placenta accreta [59].
and no history of preterm birth or at about 34+0 weeks in women During hysterectomy, the uterine serosa overlying the pla-
with a previous preterm birth, multiple episodes of minor bleed- centa should not be dissected, including trying to avoid blad-
ing, or a single episode of substantial bleeding [34, 57]. der dissection. The blood supply to the placenta is not just from
the uterine arteries but also from many collateral vessels. Care
Preparation and place of delivery should be given to dissection of this extensive blood supply by
If placenta accreta is suspected, appropriate counseling and attempting uterine artery dissection laterally and then continu-
preparations should be made (Table 29.4). The patient (and family ing down without incising the placenta. Total hysterectomy is
members if available) should be counseled regarding risks, com- generally necessary, as subtotal hysterectomy may leave in part
plications, and management. The possible need for hysterectomy of the lower segment, where the placenta is abnormally attached
as a lifesaving procedure should be discussed with the patient. and causing bleeding if a previa is present.
Plans for future reproduction should be discussed and weighed If the diagnosis is possible but not certain and the patient
against the risk of retaining the uterus. desires to make attempts at avoiding hysterectomy despite
Labor and delivery staff (nursing and anesthesia), as well as having been counseled regarding the risks, it is not unreason-
the blood bank, should be notified regarding delivery plans. As able to wait for signs of placental separation, although abnor-
suggested by the International Society for Abnormally Invasive mal adherence or significant hemorrhage should be ascertained
Placenta, women with PAS should deliver in tertiary centers and acted upon promptly. If spontaneous placental delivery fails,
that could provide a multidisciplinary team with significant the operator must decide if either manual placental removal in
experience in managing PAS and that can provide antenatal diag- pieces or hysterectomy is the next intervention, based on sev-
nosis and preoperative planning; this team should be available eral factors, including the degree of invasiveness and amount of
24 hours a day, 7 days a week, to ensure that expertise is avail- bleeding.
able for emergency situations; the multidisciplinary team should, If only a small area of the placenta is adherent and a focal area
at a minimum, include an experienced obstetrician (often of the placental bed is bleeding, sewing over this area with
maternal-fetal medicine specialist), anesthesiologist with sutures can be considered, but usually these are in the very
expertise in complex obstetric cases, surgeon experienced low uterine segment and cervix and often continue to bleed
with complex pelvic surgery (often a gynecologic oncologist), despite suturing or uterotonics. Some have suggested ligation
urologist (with experience of open urologic surgery especially of the pelvic vessels (such as the internal iliac artery) in the set-
ureteric reimplantation), neonatologist, and interventional ting of significant hemorrhage, although this may not be benefi-
radiologist. There should be on-site, rapid access to the follow- cial, given the many collateral vessels, and may incur risks as well.
ing in case of emergency: Colorectal surgeon, vascular surgeon, Pelvic packing has been used in some cases as a measure to tem-
hematologist, adult intensive care facilities, NICU facilities, porarily lessen bleeding and allow attainment of hemodynamic
massive transfusion facilities, and intraoperative blood sal- stability. Hysterectomy may be necessary if uterine bleeding can-
vage (cell salvage) services [57]. not be controlled, hopefully before massive blood loss and cardio-
Maternal morbidity is greatly decreased when women with vascular instability. When bleeding is from the lower part of the
placenta accreta deliver in tertiary care hospitals with multidis- uterus in the setting of an accreta and placenta implanted low in
ciplinary teams, as shown by the reduced evidence of massive the uterus (e.g. a previa), total hysterectomy is desirable, as subto-
transfusions and early reoperation [58]. tal hysterectomy may not control bleeding. Gravid hysterectomy
has been associated with an incidence of maternal mortality of
Mode of delivery up to 7%, with a 90% incidence of transfusion, 28% incidence of
postoperative transfusion, and a 5% incidence of ureteral injuries
Cesarean hysterectomy with the placenta left in situ is cur- or fistula formation [60, 61].
rently the gold standard surgical management of PAS dis- In rare cases, a woman who has not completed childbear-
orders. General intraoperative considerations include the ing may strongly want to avoid hysterectomy. There are several
possibility of a planned vertical skin incision. The uterine case reports of expectant (also called “conservative”) or medical
TABLE 29.4: Preparations in Cases of Suspected Placenta Accreta

OUTPATIENT PROCEDURES
• Maternal-fetal medicine (MFM) and GYN oncology consultations as outpatient

• Interventional radiology (IR), urology, and anesthesia consultations as outpatient
• Prenatal care and ultrasounds with MFM. Specify:
• Placenta location
• Relevant ultrasound findings
• Relevant MRI findings
• Obstetric history
• No. of prior cesarean deliveries
• Other prior uterine surgery
• Latest hemoglobin (within 4 weeks of surgery; aim for >10 mg/dL)
• Betamethasone at 33.5 weeks
• Third-trimester MRI if posterior placenta or concern for percreta
• Delivery:
• Timing: 34–36 weeks
• Designate and make aware primary surgical team (e.g. one MFM and one Gyn Oncology attending, at least; the presence of one urologist is useful)
• Cesarean hysterectomy in main operating room
• Arrange for cell saver
INPATIENT PROCEDURES
• Admit the day before

• Type and cross: 10 units packed red blood cells (pRBCs), 7 fresh frozen plasma (FFP), in room
• Blood bank to be notified
• Order the blood products before the case, not same day
• Clear liquid diet/consider bowel preparation if concern for bowel involvement
DAY OF SURGERY
• Labor and delivery for IV placement at 6 am

• If IR involved:
• Fetal heart monitoring before IR
• Preop for IR by 7 am. First case.
• Heparin 5000 units SQ ×1: needs to be given prior to going to IR
• Tylenol 950 mg, Lyrica 150 mg: needs to be given prior to going to IR
• Preop balloon catheters (consider only)
• Fetal heart monitoring after IR
• Transfer directly from IR suite to main operating room
• Unasyn 3 g IV before ureteral stents
• Cell saver in room
• Surgical intensive care unit (SICU) bed on hold
INTRA-OP
• Regional anesthesia preferred before delivery of baby; then possibly general anesthesia as per gyn oncology and anesthesia preference
• Positioning: Lithotomy in Allen stirrups
• Sequential compression devices (SCDs) placed
• Urology: open-ended ureteral catheters
• Vertical skin incision
• C-section, evaluate need for hysterectomy
• Hysterectomy
• If hysterectomy not done, and placenta left in situ:
• After operating room, to IR for gel foam embolization
• After discharge will follow with MFM for weekly ultrasounds
• High potential for infection, need for hysterectomy at a later date
POST-OP
• SICU: if necessary, decide intraoperatively which level of care is appropriate
• Possible post-op embolization with IR
Individual practices and circumstances will vary. This example does not indicate that certain evaluations or consultations are anticipated or expected in
all cases.
Abbreviation: MRI, magnetic resonance imaging.
management in the setting of placenta accreta. In these circum- • The optimal GA for delivery of an asymptomatic woman
stances, the placenta is left in situ and the cord ligated close to (i.e. a woman without acute bleeding) with vasa previa is
its origin, either with no therapy or with an adjunctive therapy unknown, but many experts recommend planned cesar-
such as methotrexate and/or arterial embolization. There is no ean delivery at approximately 340/7–356/7 weeks.
proven efficacy for methotrexate; therefore, it is not actually rec-
ommended. Antibiotic prophylaxis has been suggested, given the Definition
risk of infection, as have short-term uterotonics for postpartum
hemorrhage prevention, but there are no trials of these interven- Vasa previa consist of fetal blood vessels, unprotected by the
tions. Follow-up is also not based on good evidence, but serial umbilical cord or placental tissue, that run through the mem-
ultrasounds (to monitor involution and decrease in placental branes and over the internal os.
vascularity) and quantitative human chorionic gonadotrophin
(HCG) levels have been proposed. If HCG levels plateau or uter-
ine size or placental vascularity does not decrease by 72 hours,
Classification
methotrexate has been given as 1 mg/kg on alternate days for a Two types have been described: Type I, when there is a vela-
total of four to six doses, or according to HCG levels and ultra- mentous cord insertion, and type II, when the placenta con-
sonographic findings [62]. Women on methotrexate should be tains a succenturiate lobe or is multilobed and fetal vessels
monitored with liver function tests (LFTs), platelet counts, and connecting the two placental lobes course over or near the
creatinine levels. However, conservative management, espe- internal os [67].
cially for placenta percreta, has been associated with signifi-
cant morbidity, including severe vaginal bleeding in 53%, sepsis
in 6%, secondary hysterectomy in 19%, and death in 0.3% of cases,
although a subsequent pregnancy can be achieved in 67% of cases The incidence of vasa previa is about 1/2500–1/5000 deliveries, but
[63]. Thus, conservative management might be considered when is higher in assisted reproductive technology pregnancies, in bilo-
PAS is discovered at surgery in a hemodynamically stable patient bate or succenturiate placenta, and in multiple gestations [1, 68].
with no skilled team or hospital resources available or for patients
who desire to preserve fertility, but only after an extensive coun-
seling that balances the high maternal morbidity and mortality Risk factors
risks with the outcomes on future fertility. As also discussed in “Epidemiology/Incidence,” risk factors for
vasa previa are represented by the placenta in the lower uterine
Interventional radiology
segment (e.g. low-lying, or previa earlier in pregnancy), vela-
Although a recent meta-analysis of 15 studies including 958
mentous cord insertion, succenturiate or bilobed placenta,
women with PAS provided low-quality evidence that inter-
and multiple gestations [68].
ventional radiology procedures might be associated with lower
estimated blood loss and need for transfusion [64], the only
two randomized controlled trials evaluating the role of pre- Screening and diagnosis
cesarean prophylactic internal iliac artery balloon occlusion
for suspected placenta accreta did not show any significant TVU with color Doppler is the standard for the diagnosis of vasa
improvement in terms of mean number of packed red blood previa (Figure 29.6). Women with risk factors that are judged to
cell units transfused or in the calculated blood loss, as well increase their risk of vasa previa (low-lying placenta, or previa,
as in the number of women with blood loss greater than 2500 velamentous cord insertion, succenturiate or bilobed pla-
mL, number of plasma products transfused, and duration of centa, and multiple gestations) should be screened with TVU
surgery [65, 66]. Furthermore, in one of these studies, hospital- for this condition, usually at the time of the 20-week anatomy
ization costs and the incidence of postoperative fever were signifi- ultrasound or in general when these ultrasound diagnoses
cantly higher in the balloon group [65]. are made (Table 29.5). Vasa previa is diagnosed if a vessel is
visualized over the cervix with color Doppler demonstrating
a rhythm consistent with the fetal heart rate. The American
Institute of Ultrasound in Medicine (AIUM) and ACOG recom-
Vasa previa mend that the placental cord insertion site be documented when-
ever technically possible [69]. A recent systematic review showed
a high accuracy of TVU color Doppler (median detection rate
Key points
• Vasa previa consists of fetal blood vessel(s), unprotected
TABLE 29.5: Conditions Which Warrant Transvaginal
by the umbilical cord or placental tissue, that run through
Ultrasound with Color Doppler Screening for Vasa
the membranes and over the cervical internal os.
Previa
• Risk factors for vasa previa are represented by placenta
in the lower uterine segment (e.g. low-lying, or previa • Low-lying placenta
earlier in pregnancy), velamentous cord insertion, suc- • Second-trimester placenta previa
centuriate or bilobed placenta, and multiple gestations. • Velamentous cord insertion
• TVU with color Doppler is standard for the diagnosis • Succenturiate or bilobed placenta
of vasa previa. • Multiple gestations
• Vasa previa are commonly asymptomatic unless membranes • In vitro fertilization pregnancies
rupture, at which time vaginal bleeding may be noted. Source: Adapted from Ref. [68].
of 93% and specificity of 99%), but also noted that the quality are undiagnosed (3% versus 56%) [71]. The Apt test may be used to
of the available studies was relatively poor [70]. Thus, not all vasa distinguish between fetal and maternal sources of vaginal bleed-
previa will be detected prenatally, even by adequate examinations ing, although this test may be of little use in many clinical situ-
and experienced operators using color Doppler. Women whose ations with bleeding from a vasa previa, as bleeding can lead to
vasa previa has been diagnosed prenatally have been reported to rapid deterioration of the fetal status and require urgent delivery
have lower perinatal mortality than those with vasa previas that before an Apt test can be completed.
(a)
(b)
FIGURE 29.6 Ultrasound images showing vasa previa. (a) Left lateral placenta with a posterior succenturiate lobe. (b) Transvaginal
ultrasound with color Doppler showing vessels visualized over the cervix. (Courtesy of the Division of Maternal Fetal Medicine,
Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine.)
(Continued)
(c)
FIGURE 29.6 (Continued) Ultrasound images showing vasa previa. (c) Color Doppler of vessel overlying the cervix demonstrates a
rhythm consistent with the fetal heart rate.
Symptoms and complications patients who were managed as an outpatient [74]. It is reasonable
to consider administration of antenatal corticosteroids at 28–33
Vasa previa are commonly asymptomatic unless membranes weeks of gestation, if indications do not develop prior, to prepare
rupture, at which time vaginal bleeding may be noted. Perinatal for the possible need for urgent preterm delivery [75]. Women
morbidity (e.g. neonatal anemia) and mortality (up to 56%) due with vasa previa should be delivered by cesarean at a center capa-
to acute fetal hemorrhage are among the most frightening com- ble of providing immediate neonatal blood transfusion if needed
plications of this condition [71]. In a minority of cases, suspected [76]. Timing of delivery is controversial, with suggestions for CD
second-trimester vasa previa resolves over time, as shown in a anywhere between 340/7 and 356/7 weeks, although earlier when
recent retrospective cohort study in which 14–39% of antenatally preterm prelabor rupture of membranes (PPROM), PTL, or sig-
diagnosed cases of vasa previa resolved spontaneously later in nificant bleeding occurs [1].
gestation [72, 73].
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30
PLACENTAL ABRUPTION
John F. Visintine
Key points • Stage 2 abruption (nonreassuring fetal status): Rapid

delivery is indicated typically by cesarean. With fetal
• Approximately 0.2%–1% of all pregnancies are complicated demise, vaginal delivery is also indicated (unless oth-
by placental abruption. erwise contraindicated).
• Nearly 50% of women with placental abruption have no • Stage 3 abruption (maternal compromise, often with
identifiable risk factors. Risk factors include abruption in a DIC): Vaginal delivery or cesarean, highly dependent
prior pregnancy, maternal hypertensive disorders, smoking, on maternal condition.
cocaine use, polyhydramnios, multiple gestation, preterm
and term premature rupture of membranes, chorioamnio- Definition/Diagnosis
nitis, elevated maternal serum alpha-fetoprotein (MS-AFP),
pregnancy-associated plasma protein-A (PAPP-A) ≤5th Placental abruption (also called abruptio placentae) is defined as
percentile, leiomyoma, subchorionic hematoma, vaginal a premature separation of a normally implanted placenta. The
bleeding <20 weeks, previous cesarean delivery, abdominal diagnosis is a clinical diagnosis of exclusion, based usually on
trauma, subclinical hypothyroidism, anti-thyroglobulin, vaginal bleeding and abdominal pain in the second or third tri-
and anti-thyroperoxidase antibodies. The association with mester unexplained by other etiologies (see also “Etiology/Basic
thrombophilias has, for the most part, not been confirmed Pathophysiology”).
by prospective studies.
• Complications include antepartum and postpartum hem-
orrhage, disseminated intravascular coagulopathy (DIC),
Signs and symptoms
and acute renal failure, as well as growth restriction, pre- Signs and symptoms are shown in Table 30.1 [1, 2]. About 10%–
term delivery, fetal hypoxia and/or exsanguination, and 31% of abruptions present with only concealed (occult) bleeding.
perinatal mortality. Occasionally, the presenting sign is fetal death.
• The diagnosis of placental abruption is primarily clini-
cal. History, physical exam, laboratory tests, and ultra-
sonographic studies guide management. Ultrasound is
primarily useful in ruling out other causes of third-trimes- • Approximately 0.2%–1% of all pregnancies are compli-
ter bleeding. cated by placental abruption [3–5]. The incidence in the
• The following clinical staging system can be used in the United States has increased, especially in the African
management of placental abruption: American population, the ethnic group at highest risk in
• Stage 1: No evidence of maternal or fetal compromise particular for severe abruption [3].
• Stage 2: Nonreassuring fetal status or fetal death, no • About 60% of abruptions occur preterm, and 50% occur
evidence of maternal compromise prior to labor.
• Stage 3: Maternal systemic involvement: Severe hem- • The incidence of abruption is possibly highest at 24–26
orrhage, hemodynamic shock, or DIC, with or without weeks (up to 9 per 100 births) [6].
fetal compromise • There is over a 5% recurrence risk in a subsequent preg-
• Placental pathology has been shown to confirm the pres- nancy for women with a history of an abruption [4].
ence of abruption in 25% of those with an acute clinical
abruption and in 60% of those with a chronic clinical
abruption. Genetics
• Prompt delivery is indicated if placental abruption is A genome-wide association study identified several candidate
diagnosed late-preterm or term. However, if less than 34 genes associated with placental abruption. The strongest associa-
weeks, expectant management for stage 1 abruptions may tion was with the FLI-1 gene (a megakaryocyte-specific transcrip-
allow time for glucocorticoid administration. Maternal or tion factor). Genes involved in lipid metabolism, cell signaling,
fetal compromise may necessitate delivery. A decision-to- mitochondrial biosynthesis, and oxidative phosphorylation are
delivery interval of 20 minutes or less is associated with a also associated with the risk of placental abruption [7]. The asso-
substantial reduction of neonatal morbidity and mortality in ciation with thrombophilias has not been confirmed in pro-
placental abruption with nonreassuring fetal heart testing. spective studies. See “Risk Factors/Associations” and Chap. 29
• Mode of delivery is dependent primarily on the condition in Maternal-Fetal Evidence Based Guidelines. A recent study
of the mother and fetus. evaluating ischemic placental disease (preeclampsia, placental
• Stage 1 abruption (no evidence of maternal or fetal abruption, and small for gestational age [SGA]) found a correla-
compromise): In most cases, vaginal delivery is tion with a family history of preeclampsia, suggesting a familial
indicated. inheritance [8].
DOI: 10.1201/9781003102342-30 345

TABLE 30.1: Clinical Findings in Women with Placental

Abruption
Clinical Findings %
Vaginal bleeding 67–78
Uterine tenderness or abdominal/back pain 52–66
Nonreassuring EFM category II/III 60–78
Uterine contractions >5 per 10 minutes 17
Source: Data from Refs. [1, 2].
Abbreviation: EFM, electronic fetal monitoring.
The etiology is not completely understood, but appears to occur
as the result of two mechanisms: Mechanical separation or as the
end result of defective deep placentation [9]. Placental separa-
tion occurring in association with mechanical trauma or rapid
decompression of a distended uterus is believed to occur due
to shearing forces resulting from a change in the surface area of a
relatively elastic uterine wall in relation to an inelastic placenta.
Blunt trauma to the uterus resulting in abruption or rupture of
membranes with rapid decompression of an overdistended uterus
resulting in abruption are examples of this mechanism. FIGURE 30.1 Couvelaire uterus noted at the time of cesarean
Evidence in support of a defective deep placentation mecha- delivery due to a placental abruption.
nism comes from placental bed biopsies from cases of placental
abruption, which show an absence of physiologic trophoblas-
tic invasion, dilated vessels, and recent thrombosis of spiral this pathologic finding in the early 20th century (Figure 30.1)
arteries [10]. These changes are seen not only in abruption but [16]. The pathologic diagnosis of a placental abruption often
also in preeclampsia, fetal growth restriction (FGR), and pre- does not correlate with the clinical diagnosis. In a large series
term prelabor rupture of membranes (PPROM), suggesting that of placental pathologic evaluations, a placental abruption, defined
placental abruption represents one manifestation of a long- as an adherent clot with disruption of the underlying tissue, was
standing pregnancy disorder [9]. Moreover, abnormalities in demonstrated in 3.8% of specimens, which is higher than the gen-
circulating angiogenic factors have been observed in women who erally accepted incidence based on a clinical diagnosis (0.2%–1%)
subsequently developed placental abruption. In a nested case- [17]. Most of those “abruptions” called by pathologists do not have
control study, serum levels of the proangiogenic factor placental clinical diagnosis of abruption, and many clinical abruptions
growth factor (PIGF) were lower, and levels of the potent inhibi- have no pathologic evidence of abruption. This chapter has been
tor of PIGF, soluble FMS-like tyrosine kinase-1 (sFlt-1), were structured around a clinical definition of abruption. A retrospec-
increased [11]. tive review of abruption cases diagnosed on clinical grounds or
The resultant hemorrhage and initiation of the clotting cas- by pathologic criteria were analyzed based on risk factors, acute
cade is believed to play a major role in increasing uterine activity, (cocaine use, trauma <12 hours from delivery) or chronic (hyper-
PPROM, and ultimately preterm birth (PTB). Thrombin has been tension, preeclampsia, acute chorioamnionitis, trauma occurring
found to be a potent uterotonic factor, comparable to both oxy- >12 hours prior to delivery). Placental pathology confirmed the
tocin and prostaglandin F2-alpha [12]. Thrombin has also been presence of abruption in only 25% of those with acute risk fac-
demonstrated to increase interleukin-8 expression in decidual tors for abruption and 60% of those with chronic risk factors
cells. The subsequent neutrophilic infiltration of the decidua is for abruption [18].
believed to result in release of elastase and matrix metallopro-
teinases, and ultimately PPROM [13]. A functional progesterone Classification
withdrawal mediated by thrombin has also been demonstrated in
the decidual cells from those with an abruption, which may also At least since the early 1950s, clinicians have sought to
play a role in resultant PTB [14]. develop a useful clinical classification system to guide man-
Gross pathology findings associated with placental abrup- agement decisions [19]. Yet to date, a uniformly accepted clas-
tion include adherent retroplacental clot with depression or sification system for placental abruption does not exist. The
disruption of the underlying placental tissue. Microscopic clinical classification system originally published by Page in 1954
changes associated with abruption resulting in perinatal mortal- has been used by several authors as a means of grouping placental
ity include thrombosed arteries and necrosis of the decidua abruptions in those that can be potentially managed conserva-
basalis and large, recent infarcts and stromal fibrosis in the tively (grade 0 and 1) and those that require more aggressive man-
terminal villi of the placental parenchyma [15]. Severe cases of agement (grades 2 and 3) [20, 21]. The inclusion of clinical data
abruption can result in hemorrhagic infiltration between myo- obtained after delivery (gross or pathologic placental evaluation)
metrial fibers that extends to the serosal surface, giving the into these grading systems limits the usefulness for the everyday
uterus a dark purple discoloration, also known as Couvelaire clinician faced with an urgent management decision with grave
uterus in honor of the French obstetrician who first described consequences.
Placental Abruption 347
TABLE 30.2: Clinical Staging for Placental Abruption

Stage Disease Extent Maternal Clinical Findings Fetal Clinical Findings
I • Clinically recognized abruption • No signs of maternal systemic complications • No signs of NRFT
• We include concealed abruptions,
diagnosed by imaging as stage I.
II • Clinically recognized abruption, with placental • No signs of maternal systemic complications • NRFT or fetal death
dysfunction (local complication) • FGR
III • Clinically recognized abruption, with maternal • Maternal systemic complications: • No signs of NRFT, or NRFT,
systemic complications (serious nature) • DIC or fetal death
• Maternal hemodynamic instability
• Other system involvement
Abbreviations: NRFT, nonreassuring fetal testing; FGR, fetal growth restriction; DIC, disseminated intravascular coagulation.
A more recent classification defines severe abruption as at • Multiple gestation: 1.2% risk of abruption in twins, 1.5%
least one maternal (disseminated intravascular coagulation [DIC], in triplets [31].
hypovolemic shock, blood transfusion, hysterectomy, renal failure, • PPROM: OR 3.5 [32]. Evidence of old decidual hemorrhage
or in-hospital death), fetal (nonreassuring fetal status, intrauterine can be found in nearly 40% of placentas from patients with
growth restriction, or fetal death), or neonatal (FGR, PTB) com- PPROM [33].
plication. Using these criteria, two-thirds of placental abrup- • Chorioamnionitis: OR 9 [32]. Neutrophil infiltration of
tions are defined as severe (overall abruption rate 9.6/1000, the fetal membranes and cervix is seen in premature rup-
severe abruption 6.5/1000). It should be noted that the definition ture of membranes (PROM), and chorioamnionitis is asso-
of placental abruption in this study does not include abruptions ciated with placental abruption [13].
only identified through pathologic evaluation of the placenta. The • Leiomyomas detected at second-trimester ultrasound are
author recognizes that this definition cannot be used prospec- associated with a small increase in the risk of abruption
tively due to inclusion of outcome measures, but may guide further (OR 2.1) [34].
research toward a better understanding of the disease [5]. • Ultrasound-detected subchorionic hemorrhage before
We use a staging system in our clinical practice which employs 22 weeks of gestation results in an increased risk of placen-
many of the elements of the earlier grading systems but only tal abruption (OR 2.6) [34].
allows for data clinically available prior to delivery (Table 30.2). • Vaginal bleeding <20 weeks is associated with an
While staging systems are necessarily arbitrary, the advantage increased risk of abruption (relative risk [RR] 1.6) [35].
for the clinician is that they allow for integration of the clinical • Unexplained elevated maternal serum alpha-fetoprotein
findings at presentation (history, physical exam, laboratory and (MS-AFP) in the second trimester: OR 6–10 for placental
imaging studies) into a system that allows for tailoring of treat- abruption [36, 37].
ment and estimation of prognosis [22]. • Pregnancy-associated plasma protein-A (PAPP-A) ≤5th
percentile in the first trimester is associated with placental
Risk factors/Associations abruption (OR, 1.9) [38].
• Inherited thrombophilias have been associated with
Nearly 50% of women with placental abruption have no identifi- abruption in case-control studies [39, 40]. However, most
able risk factors [23]: prospective studies have shown no increased risk of
abruption [41–43]. A retrospective cohort study compar-
• History of an abruption in a prior pregnancy: The risk of ing thromboprophylaxis with heparin for women with an
recurrence is about 5%–17% [24]. After two abruptions, the inherited thrombophilia demonstrated no difference in
risk of recurrence is about 25%. rates of abruption or other adverse outcomes regardless of
• Maternal hypertensive disorders: Associated with up treatment [44]. But one large prospective cohort study did
to almost 50% of grade 3 abruption cases. In particular, demonstrate an increased risk of abruption for women with
chronic hypertension (incidence 1.5%–2.5%, odds ratio the prothrombin gene mutation 20210A (OR 12), but not
[OR] 2.8), superimposed preeclampsia (about 3%), and for factor V Leiden mutation, MTHFR C677T or A1298C
severe preeclampsia (OR 4.1) are associated with placental mutations, or thrombomodulin gene mutation [45].
abruption [25, 26]. • Advanced maternal age: It is unclear if there is an asso-
• Abdominal trauma is a recognized cause of placental ciation with abruption, as the data are conflicting [46, 47].
abruption, but is responsible for only 1% of cases [27]. See • Thyroperoxidase antibodies have been associated with an
also Chap. 41 in Maternal-Fetal Evidence Based Guidelines. increased risk of placental abruption in two large cohort
• Smoking: 90% increase in abruption in women who smoke studies (OR 1.5–3.4) [48, 49]. An association with abrup-
compared with controls. Smoking is responsible for 15%– tion was also seen with thyroglobulin antibodies (OR
25% of episodes of abruption [25]. 1.4–1.7) [49]. The association with abruption was con-
• Cocaine: 1.9% rate of abruption [28]. firmed in a cohort of low-risk women with subclinical
• Previous cesarean delivery is associated with an increased hypothyroidism [50].
risk of abruption in subsequent pregnancies (OR 1.3) [29]. • Elevated uterine artery pulsatility index (PI) >90th percen-
• Polyhydramnios has been associated with placental tile is associated with an increased risk of placental abrup-
abruption in patients >37 weeks’ gestation [30]. tion RR 2.7 (2.7–12) [51].
Complications Management (Figure 30.2)

• Maternal Evidence-based decisions involving the clinical management of
• Serious maternal complications (pulmonary edema, placental abruption are limited by a paucity of level I data [56].
acute respiratory failure, acute heart failure, acute Only one randomized controlled trial (RCT) has been conducted
myocardial infarction, cardiomyopathy, puerperal to address the clinical management of abruption, specifically the
cerebrovascular disorder, coma, and amniotic fluid use of magnesium sulfate [57]. However, most recommendations
embolism) occur at a higher ratio for women with for management are based on expert opinion or, at best, retro-
severe abruption (141.7/10,000 births) compared to spective case-control studies. High-quality data from random-
those with a mild abruption (33.3/10,000 births) or ized treatment trials for hypertensive disorders in pregnancy
nonabruption (15.4/10,000 births) (Table 30.3) [5]. provide some guidance regarding prevention strategies for abrup-
• Antepartum hemorrhage remains a leading cause of tion due to the close association of these disorders.
maternal mortality. For pregnancies ending in still-
birth, hemorrhage related to placental abruption is the Prevention
leading cause of maternal mortality [52]. • Women supplemented with vitamin C alone or in combina-
• DIC was first reported to occur in association with tion with other supplements compared with placebo or no
placental abruption by De Lee in 1901 [19]. The devel- control were at decreased risk of having a placental abrup-
opment of DIC is thought to be due to a release of tion (RR 0.64, 95% confidence interval [CI] 0.44–0.92) in a
thromboplastins, as well as consumption of coagu- Cochrane review [58].
lation factors secondary to an enlarging hematoma. • Women supplemented with vitamin E in combination
Nearly 30% of patients who present with a severe with other supplements compared with placebo were at
abruption develop DIC. decreased risk of having a placental abruption (RR 0.64,
• Acute renal failure is a potential maternal complica- 95% CI 0.44–0.93) in a Cochrane review [59].
tion associated with abruption. Fortunately, the inci- • A reduction in the risk of placental abruption was demon-
dence of acute renal failure appears to be decreasing, strated with prenatal vitamin C and E supplementation
possibly due to improved medical management. in smokers (RR 0.09; 95% CI 0.00–0.87) but not in non-
• Postpartum hemorrhage secondary to uterine atony smokers (RR 0.92; 95% CI 0.52–1.62). This study was not
is associated with abruption, as is postpartum anemia included in the Cochrane reviews cited earlier [60].
and infection. • The use of magnesium sulfate for women with pre-
• Perinatal eclampsia was shown to reduce the risk of placental abrup-
• Perinatal mortality (both fetal and neonatal deaths) tion (RR 0.64; 95% CI 0.5–0.83) [61].
varies from 4 to 12/1000 [53]. This high perinatal mor- • Smoking cessation counseling, avoidance of cocaine,
tality with abruption is attributable, in part, to its asso- and, if possible, avoidance of other risk factors may pre-
ciation with preterm delivery. vent placental abruption.
• Of the excess perinatal deaths, about 55% can be • Routine delivery at 39 weeks may reduce the risk of
attributed to prematurity. The other is associated placental abruption in a low-risk population [62]. This
with fetal hypoxia and/or exsanguination or growth secondary analysis of data from a multicenter RCT of ami-
restriction. nosalicylic acid (ASA) for reduction of preeclampsia risk
• Among abruption cases from a large multicenter case- found that over 30% of placental abruptions occurred at 39
control study, 60% were found to be small for gesta- weeks and beyond.
tional age; the authors concluded that this association • Systematic reviews of early intervention (delivery) trials for
was primarily due to preterm birth [54]. preeclampsia provide secondary analysis data regarding
• Of children with spastic quadriplegic or dyskinetic the relative risk of abruption, with mixed results.
cerebral palsy, 5.7% are associated with placental • No difference in risk of placental abruption (RR 0.64,
abruption [55]. 95% CI 0.17–2.34) with planned early delivery versus
expectant management from 34 weeks to term [63].
• Of note, a large nationwide cohort study demonstrated
a reduction in placental abruptions RR 0.35 (0.25–
TABLE 30.3: Severe Abruption Is Clinically Defined as ≥1 of 0.49) in the 6 years after adoption of HYPIAT-1–driven
the Following Maternal, Fetal, or Neonatal Findings guidelines for delivery of preeclampsia at term [64].
Maternal Fetal Neonatal • A reduction in the risk of placental abruption (RR
0.42, 95% CI 0.18–0.96) with planned early delivery
DIC NRFT PTB complications
versus expectant care for severe preeclampsia between
Hypovolemic shock FGR SGA complications
24 and 34 weeks’ gestation [65].
Blood transfusion Fetal death Neonatal death • A large meta-analysis for treatment of CHTN in preg-
Hysterectomy nancy (including 5 RCT’s with over 1000 women reporting
Renal failure abruption data) demonstrated a lower risk of placental
In-hospital death abruption when treated with antihypertensives. The use
Note: See Ref. [87] for more information. of nifedipine and methyldopa were associated with signifi-
Abbreviations: DIC, disseminated intravascular coagulation; NRFT, nonreassuring cantly lower placental abruption rates (odds ratio, 0.29
fetal testing; FGR, fetal growth restriction; PTB, premature birth; SGA, small for ges- [95% confidence interval, 0.15–0.58] and 0.23 [95% confi-
tational age. dence interval, 0.11–0.46], respectively) [66].
Clinical Diagnosis of Abruption

Vaginal Bleeding and/or Uterine
Tenderness (not otherwise
explained)
Preterm Late Preterm/Term

<34 weeks' ≥34 weeks' Gestation
Gestation
Stage II Stage III

Non-Reassuring Maternal Systemic
Stage I
Fetal Status Involvement: Delivery
No Fetal or Maternal
or Fetal Death Severe Hemorrhage any Stage I, II, III
Compromise
or, Hemodynamic
Shock, or
DIC
Expectant Management Delivery

Fetal Monitoring
Maternal Monitoring Maternal Stabilization
Steroids for Fetal Maturity Treatment of shock,
Serial Fetal Ultrasound blood product
replacement, supportive care
And
Close Fetal Surveillance
Expectant Management If undelivered and stable

if stable Delivery at 34–37 weeks
Delivery for
Non-Reassuring Fetal Status
or
Maternal Deterioration
FIGURE 30.2 Management of placental abruption.

• A recent multicenter RCT evaluating treatment of chronic Workup
hypertension (CHTN) in pregnancy with labetalol or • The diagnosis of an abruption is made clinically
methyldopa or no medication demonstrated a reduced risk (vaginal bleeding with abdominal pain and/or uter-
of abruption for those who were treated [67]. ine tenderness). Nonreassuring fetal testing, uterine
• Intensive fetal surveillance for women with an elevated tachysystole, and coagulopathy are often present as
uterine artery PI >90th percentile was not associated with well. Pathologic evaluation of the placenta may confirm
an increased risk of placental abruption [51]. the diagnosis in some cases (25% of acute and 60% of
chronic abruptions), but the absence of pathologic find-
Preconception counseling ings does not exclude an abruption [18]. Placental abrup-
Women with risk factors should be counseled regarding the risk tions may be occult. At times presenting as preterm labor,
factors (Table 30.3) and complications of placental abruption, they may go undiagnosed until after delivery with exami-
as well as interventions for its prevention. In addition, counsel- nation of the placenta. If a pathologic diagnosis (rather
ing should be provided for women with a history of a placental than clinical diagnosis) of placental abruption is used, the
abruption, as they are at significant increased risk of recurrence incidence of placental abruption is 3.8% [17] compared to
(5%–17%) [24]. For those with a history of two or more placental around 1% in epidemiologic studies that employ a clinical
abruptions, delivery at 37 weeks has been recommended [6]. diagnosis.
• History and physical exam, as well as appropriate labora- containing red cells in the maternal circulation and to
tory and ultrasonographic studies, guide management. attempt to quantitate the extent of fetal-maternal hemor-
Routine assessment should be conducted, including vital rhage (FMH) [75]. More recently, flow cytometry has been
signs, oxygenation status, and urine output. Laboratory found to be a sensitive test for the detection of fetal red
assessment may include a hematocrit, platelet count, cells in the maternal circulation [76]. Both of these tests
coagulation studies (prothrombin time [PT], partial use normal maternal and fetal blood volume estimates to
thromboplastin time [PTT], and fibrinogen), blood type quantify the amount of FMH; in the presence of signifi-
and screen, or crossmatch, serum creatinine, and a drug cant maternal hemorrhage, quantitative results may not be
screen. Other causes of third-trimester bleeding must be as reliable. While the KB test has often been included in
excluded. The differential diagnosis includes placenta the laboratory workup of abruption, it appears to be a low-
previa, vasa previa, cervical lesions (for example, malig- yield test. In a recent retrospective study of women with a
nancy), and vaginal lesions. clinical abruption who were screened with KB, only 3 of 65
• An ultrasound examination is useful primarily in exclud- were positive (sensitivity 4.4%) [77]. An earlier retrospec-
ing placenta previa or vasa previa. The sensitivity and tive study reported no positive KB tests out of 27 cases
specificity of ultrasound in the diagnosis of placental of abruption confirmed by pathology [78]. While FMH as
abruption were 24% and 96%, respectively [68]. Of note, a result of or related to placental abruption has been well
a placental abruption was defined in this study by clinical described, the clinically utility of these tests for the diag-
signs or symptoms or by placental examination. So while nosis or management of an abruption is an open question.
ultrasound is very helpful in ruling out other causes of
third-trimester bleeding, it lacks the sensitivity needed General principles
to reliably detect placental abruption [68]. The echo- Once the diagnosis of placental abruption has been made, atten-
genicity of the collection of blood of an abruption depends tion should be focused on ensuring maternal and fetal well-being.
on the time the ultrasound was performed relative to the Maternal status should be addressed, with attention paid to signs
onset of symptoms [69]. Acute hemorrhage is hyperechoic or symptoms of hemorrhage, hypovolemic shock, and DIC. The
to isoechoic compared with the placenta. Resolving hema- frequency of repeated evaluations is dependent primarily on the
tomas become hypoechoic within 1 week and sonolucent acuity and severity of the abruption. Preparations should be made
within 2 weeks. in anticipation of potential maternal complications. This should
• Computed tomography (CT) has been used to identify include intravenous access; two large-bore peripheral lines will
abruptions in trauma patients. A retrospective study of allow for rapid fluid or blood component replacement. The avail-
pregnant trauma patients who were evaluated with CT ability of blood or blood components may be lifesaving; therefore,
found a high sensitivity (86%) and specificity (98%) in the close cooperation with blood banking services is essential.
detection of placental abruption [70]. In a retrospective Fetal status is typically assessed with continuous electronic
review of pregnant trauma patients, as placental enhance- fetal monitoring, at least in the acute setting. For women with a
ment on CT imaging decreased, the presence of clinical chronic abruption, once clinically stable, intermittent monitor-
findings of placental abruption were found to increase. ing may be a consideration.
The authors found that clinical signs and/or symptoms Tocolytic use is generally discouraged due to maternal
of abruption were significantly more likely with placental safety concerns. Multiple retrospective studies have evaluated
enhancement on CT imaging <50% and that the likeli- tocolytic use (mostly magnesium sulfate) in the setting of placen-
hood of delivery for abruption increased as the placental tal abruption, without suggestion of increased maternal risk and
enhancement decreased to less than 25% [71]. possible pregnancy prolongation [79–82].
• Magnetic resonance (MR) imaging has also been used Magnesium sulfate as a tocolytic for women with a mild (stage I)
to identify placental abruption. In a prospective series of abruption prior to 34 weeks was not found to be effective, as
60 consecutive patients with clinical suspicion of abrup- reported in a well-designed but underpowered RCT. Thirty women
tion, ultrasound imaging and MR imaging were compared. were enrolled, short of the 48 planned. While there was no signifi-
Placental abruption (defined as adherent clot or fibrin by cant prolongation in pregnancy with the use of magnesium sulfate,
placental examination at delivery) was found in 19 patients. we cannot conclude with certainty that this treatment is ineffective
Abruption was identified in 10 of the 19 patients (52%) due to the small study size. The authors recognize that significant
with ultrasound and in all 19 (100%) with MR imaging power was not achieved and that with the relatively high rate of
(p = 0.002) [72]. This study underscores the relative abil- pregnancy prolongation in the placebo group, it was recognized
ity of imaging modalities to identify retroplacental collec- that a much larger study population would in actuality be need.
tions, but the presence or absence of adherent placental Further enrollment was not attempted due to changes in clinical
clot does not always correlate with a clinical abruption. practice as a result of the BEAM trial. Of note, while adverse out-
• A vaginal speculum examination should be performed to comes due to tocolysis in the face of abruption were not primary
rule out cervical or vaginal sources of bleeding. outcome measures, safety concerns were not raised in the trial [57].
• Laboratory findings: A prolonged PT, prolonged PTT,
hypofibrinogenemia, and thrombocytopenia can occur Timing of delivery (Figure 30.2)
in women with abruption for whom DIC develops.
D-dimer, a fibrin degradation product, has been evalu- Level I evidence is not available on delivery decisions [56, 83].
ated as a diagnostic tool for abruption in two small stud-
ies with conflicting results [73, 74]; at present, the data do Term placental abruption: ≥37 weeks
not support its routine use. The Kleihauer-Betke (KB) test • Delivery is recommended by most authors [6]. Rapid labor
has been used for over 50 years to detect fetal hemoglobin often ensues as a result of an abruption.
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31
POSTPARTUM CARE
Elena R. Magro-Malosso, Sarah K. Dotters-Katz, and Daniele Di Mascio
epidural anesthesia, and persistent occiput posterior presenta-

Early postpartum care after vaginal delivery tions [4].
Workup
Repair of obstetric lacerations Careful physical examination of the obstetric laceration is cen-
tral to define the anatomic defect, its right depth, and degree. A
Key points digital rectal examination is also recommended if an occult
• Obstetric lacerations are very frequent, affecting 53%–79%
anal sphincter injury is suspected [5]. There is some evidence to
of all vaginal deliveries.
suggest that the use of endoanal ultrasound (EAUS) prior to
• Forceps delivery followed by vacuum delivery, regardless
perineal repair is associated with reduced risk of severe anal
of the use of episiotomy, is the strongest risk factor for
incontinence but an increase in the incidence of perineal pain at
obstetric anal sphincter injuries (OASIS) and repeated
3 months postpartum. However, more research is needed to fully
OASIS, with subsequent anal and fecal incontinence.
evaluate the intervention before the routine use of EAUS on the
• A first-degree laceration may heal by secondary intention
labor ward could be supported [6].
if it is not bleeding or if it does not distort the anatomy.
A first-degree laceration may heal by secondary intention if
When the first-degree laceration is repaired, the use of
it is not bleeding or if it does not distort the anatomy. When the
adhesive glue achieves cosmetic and functional results
first-degree laceration is repaired, the use of adhesive glue achieves
equal to traditional suturing.
cosmetic and functional results equal to traditional suturing [7].
• Second-degree lacerations (as well as higher order) involv-
Higher-order lacerations must be repaired. The repair of a
ing the perineal muscles need to be repaired. The con-
second-degree laceration requires approximation of the vaginal
tinuous suturing techniques and rapidly absorbing
tissue identifying the apex of the laceration, the perineal muscles
synthetic materials are recommended.
(transverse perineal muscles and bulbocavernosus muscle), and
• The two methods for repairing the external anal sphincter
the perineal skin [8]. Use of continuous suturing techniques
(EAS) are the end-to-end method and the overlap.
and rapidly absorbing synthetic materials for repair of second-
• Prophylactic antibiotic therapy prevents perineal wound
degree lacerations is recommended [9, 10].
infections in third- and fourth-degree lacerations
There are currently no controlled studies that compare the
(single-dose, second-generation cephalosporin—cefotetan
various techniques or various suture materials for anal mucosa
or cefoxitin, 1 g intravenously).
repair. Traditionally, the anal mucosa is approximated using
• Postoperative laxative regimens (e.g. oral lactulose) fol-
closely spaced interrupted or running sutures with delayed
lowing the primary repair OASIS are suggested to avoid
absorbable materials 4/0 or 3/0 polyglactin. The indications on
constipation.
the injury repair technique of the internal anal sphincter (IAS)
• Limited data support the effectiveness of local cooling
are limited. The IAS is identified as a glistening, white, fibrous
treatments for treating perineal pain.
structure placed between the rectal mucosa and the external anal
Epidemiology/Incidence sphincter (EAS). The IAS may be retracted laterally, and place-
Obstetric lacerations are very frequent, affecting 53%–79% of all ment of Allis clamps on the muscle ends facilitates repair with
vaginal deliveries. They usually involve the perineum and, less continuous 2/0 polyglactin sutures [8].
commonly, the labia, clitoral area, and vaginal walls. Two methods for repairing the EAS are recognized. In the
end-to-end method, the torn ends of the EAS are approximated
Classification and sutured. In the overlap method, the torn ends of the EAS
Perineal lacerations are generally classified into four grades are brought together and sutured by overlapping one end of the
according to the severity of the lesion: First-degree lacerations muscle over the other in a double-breasted fashion [11]. The over-
involve the perineal skin only, second-degree lacerations involve lapping repair results in a larger surface area of tissue contact
the perineal muscle as well, while third- and fourth-degree lac- between the two torn ends, and it is only possible when a full-
erations involve the anal sphincter complex and are referred to as length and full-thickness disruption and 1–1.5 cm of torn muscle
obstetric anal sphincter injuries (OASIS) (Table 31.1). on either end are present. Therefore, the overlap method should
not be used to repair grade 3a tears and partial grade 3b tears, as
Risk factors these should be repaired by the end-to-end technique. There is
Forceps delivery followed by vacuum delivery, regardless of the no consensus on which technique to use to repair the EAS, and
use of episiotomy, is the strongest risk factor for OASIS and the choice is currently left to the preference of the physician [12].
repeated OASIS, with subsequent anal and fecal incontinence (AI Neither the repair method nor the suture material used (polygla-
and FI) [1–3]. Other risk factors for severe perineal lacerations ctin 2/0 versus polydioxanone 3/0) seem to affect overall morbid-
during childbirth include high birth weight, median episiotomy, ity, which instead is reduced if anal sphincter repair is performed
primiparity, Asian ethnicity, labor induction, labor augmentation, by appropriately trained staff [13].
354 DOI: 10.1201/9781003102342-31

Postpartum Care 355
TABLE 31.1: Perineal Lacerations An episiotomy is performed to enlarge the vaginal orifice by a
controlled incision in the perineum and facilitate difficult deliv-
First degree Injury to perineal skin only
eries. Since 2006 in the United States the percentage of episioto-
Second degree Injury to perineum involving perineal muscles but not
mies is declining, when the ACOG recommended a restrictive
involving anal sphincter
episiotomy use. The episiotomy rate dropped from 17.3% to
Third degree Injury to perineum involving anal sphincter complex
11.6% from 2006 to 2012 [21]. The current evidence does not
3a: Less than 50% of external anal sphincter thickness torn
justify routine episiotomy. A meta-analysis including 12 RCTs
3b: More than 50% external anal sphincter thickness torn
(6177 women) compared selective versus routine use of episiot-
3c: Both external anal sphincter and internal anal
omy. Women in labor, for whom a vaginal birth was intended,
sphincter torn
were evaluated in 11 RCTs (5375 women). In this group, a policy
Fourth degree Injury to perineum involving anal sphincter complex of selective episiotomy resulted in 30% fewer women experi-
(external anal sphincter and internal anal sphincter) and encing severe perineal/vaginal trauma (relative risk [RR] 0.70,
anal epithelium 95% confidence interval [CI] 0.52–0.94). Both selective and rou-
Source: Adapted from American College of Obstetricians and Gynecologists. tine episiotomies have little or no effect on neonatal outcome
Obstetric Data Definitions (version 1.0). Washington, D.C.: American (Apgar score less than 7 at 5 minutes), perineal infection, dys-
College of Obstetricians and Gynecologists; 2014. http://www. pareunia, and long-term urinary incontinence (UI). Subgroup
acog.org/-/media/Departments/Patient-Safety-and-Quality-Improvement/ analyses by parity (primiparas versus multiparas) and by surgical
2014reVITALizeObstetricDataDefinitionsV10.pdf. method (midline versus mediolateral episiotomy) did not identify
any modifying effects. One trial examined selective episiotomy
Therapy compared with routine episiotomy in women where an operative
If antibiotics are unnecessary for repair of first- and second- vaginal delivery was intended in 175 women and did not show
degree lacerations, in the case of third- or fourth-degree lac- a clear difference in severe perineal trauma between the restric-
erations, prophylactic antibiotic therapy may reduce the tive and routine use of episiotomy, but the analysis was under-
incidence of perineal wound infections associated with them. powered. This review thus demonstrates that in women where no
The only randomized controlled trial (RCT) that compared the instrumental delivery is intended, selective episiotomy policies
effect of prophylactic antibiotic (single-dose, second-generation result in fewer women with severe perineal/vaginal trauma [22].
cephalosporin—cefotetan or cefoxitin, 1 g intravenously) with Episiotomies, like obstetric lacerations, that involve the muscle
placebo found a rate of postpartum perineal wound complica- layer need to be stitched by continuous suturing techniques and
tions (wound disruption and purulent discharge) in third- or preferably with rapidly absorbing synthetic sutures [9, 10]. There
fourth-degree perineal tears at 2 weeks of 8% and 24% in the treat- are no clear indications that prophylactic antibiotics reduce
ment and the control groups, respectively [14]. Although the data the incidence of episiotomy wound dehiscence with infection
derive from a small trial with high rate of loss to follow-up, they or without infection, and therefore no recommendation can be
are the best available data on which to base a recommendation. made [23].
The Royal College of Obstetricians and Gynaecologists (RCOG)
and the American College of Obstetricians and Gynecologists
(ACOG) support the use of broad-spectrum antibiotics to reduce
Pelvic floor disorders
the incidence of postoperative infection for third- and fourth- Key points
degree lacerations [15, 16]. • Pelvic floor disorders (PFDs) define a variety of interrelated
Postoperative laxative regimens (e.g. oral lactulose) are sug- clinical entities that include pelvic organ prolapse (POP),
gested to avoid constipation and the potential risk of perineal UI, and FI.
laceration breakdown, and when compared with a constipating • Increasing parity is strongly associated with UI.
regimen, are associated with a significantly earlier and less pain- • There is no evidence that labor alone, in the absence of
ful bowel motion, as well as discharge [17]. Routine prescribing of vaginal delivery, represents a risk factor for UI, FI, or POP.
a stool-bulking agent in addition to a laxative in the immediate • Vaginal delivery is associated with an increased risk of
postnatal period for women who have sustained anal sphincter PFDs, particularly with UI.
injury at vaginal delivery is not recommended because of more • There is no evidence to recommend episiotomy for the pre-
frequent incontinence in the immediate postnatal period com- vention of PFDs.
pared with laxative alone [18]. Evidence for the effectiveness of • Operative vaginal delivery with forceps, but not vacuum
topically applied local anesthetics for treating perineal pain is not delivery, is associated with POP and UI, while both forceps
compelling, and there are limited data that support the effective- and vacuum are risk factors for AI.
ness of local cooling treatments (ice packs, cold gel pads, cold/ • There is no evidence to recommend planned cesarean
iced baths) [19, 20]. delivery for the prevention of PFDs.
• Antenatal pelvic floor muscle training (PFMT) prevents
Episiotomy UI in late pregnancy and in the mid-postnatal period,
while its role to reduce UI in incontinent women (treat-
Key points ment) appeared uncertain.
• Episiotomies should be avoided if at all possible. A policy
of selective episiotomy results in 30% fewer women expe- Definition
riencing severe perineal/vaginal trauma. Pelvic floor disorders (PFDs) define a variety of interrelated clini-
• Episiotomies, like obstetric lacerations, that involve the muscle cal entities that include pelvic organ prolapse (POP), UI, and FI.
layer need to be stitched by continuous suturing techniques They are more common in adult women and strongly associated
and preferably with rapidly absorbing synthetic sutures. with pregnancy and childbirth [24].
Epidemiology/Incidence associated with an increase of AI symptoms [44]. The only avail-

The mean prevalence of UI during pregnancy is approximately able RCT that compares vacuum- and forceps-assisted delivery to
41%, whereas this disorder affects one-third of women during determine the effects of either mode of delivery on anal sphincter
the first 3 months of postpartum [25, 26]. function found that significantly more women complained of
Symptoms related to altered anal continence after preg- altered continence following forceps-assisted delivery com-
nancy are reported in 3%–4% of women, with FI reported pared with vacuum-assisted delivery [45].
in up to 25% of primiparous women at 6 weeks postpartum
[27]. Although the data about POP among pregnant women Cesarean delivery
are limited, in nulliparous pregnant women, the Pelvic Organ There is no evidence to recommend elective cesarean delivery for
Prolapse Quantification (POP-Q) stage appears to increase the prevention of PFDs [46].
during pregnancy and does not change significantly following
delivery. In the postpartum period, POP-Q stage may be higher
Management
PFMT is commonly recommended during pregnancy and after
in women delivered vaginally compared to women delivered by
the birth to prevent or treat UI. A recent Cochrane review of 38
cesarean [28].
trials involving 9892 women showed that compared with usual
Risk factors/Associations care, continent pregnant women performing antenatal PFMT
Parity (for prevention) may have had a lower risk of reporting UI in
A national survey of 1261 women in the United States reported late pregnancy (62% less) and in the mid-postnatal period (more
that the impact of increasing parity is strongly evident in UI: than 3–6 months postpartum) (29% less), while there was insuf-
Nulliparous (6.5%), one birth (9.7%), two births (16.3%), and ficient information available for the late (more than 6–12 months)
three or more births (23.9%). Regarding POP, parity is associ- postnatal period to determine effects at this point. In the same
ated with a small but significant increase: Nulliparous (0.6%), meta-analysis, compared with usual care, the role of antenatal
one birth (2.5%), two births (3.7%), and three or more births PFMT to reduce UI in incontinent women (treatment) appeared
(3.8%). However, the increase of FI according to parity is not uncertain in late pregnancy, in the mid and late postnatal peri-
significant: Nulliparous (6.3%), one birth (8.8%), two births ods. When a mixed population was considered (women with or
(8.4%), and three or more births (11.5%) [29]. without UI), antenatal PFMT appeared to decrease UI risk in late
pregnancy and the mid-postnatal period but not in late postpar-
Labor tum. Regarding AI, the few data available showed considerable
Although data on the role of labor in the development of PFDs are uncertainty about the efficacy of PFMT. It is possible that the
controversial, there is no evidence that labor alone, in the absence effects of PFMT might be greater with targeted rather than mixed
of vaginal delivery, represents a risk factor for UI [30, 31] or FI [32, prevention and treatment approaches and in certain groups of
33]. No difference in prolapse between women who had undergone women [47].
cesarean before or after labor have been reported [34].
Vaginal delivery Pain control

Vaginal delivery is associated with an increased risk of PFDs,
particularly with UI. A meta-analysis investigating the long-
Key points
• Nonsteroidal antiinflammatory drugs (NSAIDs), includ-
term impact of delivery mode on stress urinary incontinence
ing aspirin, are better than placebo for relief of pain due to
(SUI) and urgency urinary incontinence (UUI) showed that
uterine cramping after vaginal birth.
vaginal delivery compared with cesarean delivery is associ-
• Aspirin and acetaminophen are both effective as peri-
ated with an almost twofold increase in the risk of long-term
neal pain relievers, although NSAIDs are more effective
SUI, with an absolute increase of 8%, and an effect that is
compared to acetaminophen.
largest in younger women [35]. Furthermore, a registry-based
• Local cooling pain relievers, such as ice packs, have been
national cohort study of 5236 women who had one singleton
shown to be associated with a significant reduction of peri-
delivery 20 years previously reported that vaginal delivery,
neal pain at 24–72 hours, compared with no treatment.
compared with cesarean delivery, was associated with a 67%
• When a standard dose of an NSAID is insufficient, a multi-
increased risk of UI and with an almost doubled risk of symp-
modal approach including NSAIDs, acetaminophen, and a
tomatic POP (14.6% versus 6.3%) [36, 37]. The role of vaginal
milder opioid (if needed) can be considered as a reasonable
delivery in the development of AI has not yet been clarified;
next step.
the current evidence is based only on conflicting observa-
• Pain after vaginal delivery might be caused by contractions
tional data [38–40].
of the uterus or by perineal injuries.
Episiotomy
There is no evidence to recommend episiotomy for the preven- Nonsteroidal antiinflammatory drugs (NSAIDs), including
tion of PFDs [41]. aspirin, are better than placebo and probably even better than
opioids for relief of pain due to uterine cramping after vaginal
Operative vaginal delivery birth. [48].
There is some evidence that operative vaginal delivery with for- When considering perineal pain, aspirin and acetaminophen
ceps, but not vacuum delivery, is associated with POP and UI are both effective as pain relievers, although NSAIDs are more
[42, 43]. Forceps and other instrumented delivery represent a risk effective to achieve pain control at 4 and 6 hours when compared
factor for AI according to the available data. A comparative sys- to acetaminophen [49–51].
tematic review of 12,237 women found that instrumental deliv- Some nonpharmacologic methods have been suggested to
ery compared with spontaneous vaginal delivery is significantly control postpartum pain, and in particular perineal pain, after
Postpartum Care 357
TABLE 31.2: Recommendations for Early Post-Vaginal Early ambulation—preferably after sitting up for a few minutes
Delivery Care in bed to prevent hypotension—should start about 4 hours after
cesarean delivery and should last approximately 5–10 minutes,
• Continuous suturing techniques and rapidly absorbing synthetic
according to the woman’s feelings, three times a day. Early
materials for second-degree (or high-order) lacerations
ambulation, particularly when involved in a broader spectrum of
• Prophylactic antibiotic therapy in third- and fourth-degree
ERAS policies, has been associated with earlier intestinal sounds,
lacerations
gas passage, and bowel movements, but is also strongly recom-
• Avoidance of episiotomy, unless absolutely necessary
mended to prevent venous thromboembolism [54–56].
• Pelvic floor muscle training before delivery to prevent urinary
Early oral feeding with both fluids and food within 6–8 hours
incontinence
after cesarean delivery improves the return of gastrointestinal
• Nonsteroidal anti-inflammatory drugs or acetaminophen to reduce
function (shorter passage of flatus, bowel movements, and sounds)
postpartum pain
and does not increase the occurrence of gastrointestinal complica-
• Local cooling pain relievers for perineal pain
tions (no nausea, vomiting, diarrhea, abdominal distension, mild
ileus symptoms) compared with delayed oral intake [57, 58].
vaginal delivery. Among them, local cooling pain relievers, such Likewise, chewing gum in the immediate postoperative period
as ice packs, have been shown to be associated with a significant and then at least three times per day for about 15 minutes after
reduction of perineal pain at 24–72 hours, compared with no treat- cesarean delivery is a well-tolerated intervention that enhances
ment. However, this evidence to support the effectiveness of local early recovery of bowel function, as it has been associated with
cooling treatments (ice packs, cold gel pads, cold/iced baths) for the early recovery of bowel motility and significantly less incidence of
perineum following vaginal delivery to relieve pain is limited [20]. ileus, fewer number of episodes of nausea or vomiting, lower mean
When a standard dose of an NSAID is insufficient, a multi- time to first flatus or first bowel sounds, shorter length of stay, and
modal approach including NSAIDs, acetaminophen, and a milder therefore significantly higher maternal satisfaction [59, 60].
opioid (if needed) can be considered as a reasonable next step [52]. Lastly, a bladder catheter is usually used during cesarean deliv-
In summary, for early post–vaginal delivery care, we suggest eries, although it is a common cause of discomfort in the early
the interventions in Table 31.2. postoperative period. There is insufficient evidence to assess the
routine use of indwelling bladder catheters in women under-
going cesarean delivery so far. However, as many institutions
Early postpartum care after still use a bladder catheter during cesarean delivery, immediate
cesarean delivery removal after surgery, at least in women undergoing elective
cesarean delivery, should be encouraged to reduce postopera-
tive bacteriuria, dysuria, urinary frequency and urgency, and to
Enhanced recovery after surgery strategies hasten postoperative ambulation time, time until the first void-
ing, and length of hospital stay [61, 62].
Key points
• Early ambulation should start about 4 hours after cesar-
ean delivery and should last approximately 5–10 minutes
Pain control
several times a day to hasten intestinal recovery and pre- Key points
vent venous thromboembolism. • NSAIDs are associated with lower pain scores at 12 and
• Early oral feeding with both fluids or food within 24 hours, lower pain with movement at 24 hours, signifi-
6–8 hours after cesarean delivery improves the return of cantly less opioid consumption, and less drowsiness/seda-
gastrointestinal function and does not increase the occur- tion. Scheduled NSAIDs should be given initially around
rence of gastrointestinal complications. the clock, starting during cesarean, and not as desired by
• Chewing gum three times a day immediately after the woman.
cesarean delivery is a well-tolerated intervention that • Scheduled acetaminophen for 48 hours around the clock
enhances early recovery of bowel function. after cesarean delivery is effective in reducing opioid use
• If used, immediate removal of the bladder catheter after compared to as-needed administration.
cesarean should be encouraged to reduce urinary discom- • Epidural morphine—and neuraxial opioids in gen-
fort and infections. eral—are significantly associated with a reduction in pain
scores and postoperative morphine request during the first
Enhanced recovery after surgery (ERAS) is a clinical approach 24 hours compared to systemic opioid analgesia.
towards perioperative care that has been utilized for about • A transverse abdominis plane (TAP) block could be
30 years in many surgical fields in order to achieve at least three effective for women not receiving neuraxial morphine.
main objectives: Increasing patient satisfaction, improving qual- • Perioperative administration of gabapentin is associated
ity, and reducing costs for the health care system [53]. with lower pain scores at 24-hour movements and with a
ERAS strategies have also been successfully applied to obstet- higher pain control satisfaction at 12 and 24 hours.
ric care, and in particular after cesarean delivery, thus resulting • Systemic opioids should be reserved for treating break-
in shorter length of hospital stay, reduced opioid consumption, through pain when pain control obtained by the combina-
and unchanged visual analog pain scores at the time of hospital tion of neuraxial opioids and nonopioid adjuncts becomes
discharge when these policies are properly accomplished [53]. inadequate.
ERAS procedures after cesarean delivery usually involve multi-
modal analgesia (see “Pain Control”), early ambulation, early oral Pain after cesarean delivery might significantly affect the
feeding, and expeditious removal of the bladder catheter, if used. early hours of a woman’s motherhood experience. In the 2018
guidelines on postpartum pain management, the ACOG recom- It is uncertain whether covering surgical wounds that are
mends a stepwise, multimodal strategy to provide individualized healing by primary intention with wound dressings reduces
pain control for women in the postpartum period. the risk of surgical site infections (SSIs) [69]. Studies on the
In the United States, 1 in 300 opioid-naive patients exposed to timing of the wound dressing removal after cesarean delivery are
opioids after cesarean delivery will become persistent users of also limited. Epithelialization is an essential component of wound
opioids, thus highlighting the importance of a proper and timely healing and typically occurs in the 48 hours after surgery. Data
approach to control postpartum pain [52]. from three small RCTs showed no significant differences between
NSAIDs are among the most common pain relievers, usually early (up to 48 hours after surgery) and delayed dressing (beyond
administered as part of multimodal pain control after cesarean 48 hours) removal from non-Cesarean surgical wounds in terms
delivery. of incidence of SSIs, wound dehiscence, or serious adverse events
A meta-analysis of 22 RCTs comparing NSAIDs to control within 30 days [70]. Additionally, a recent RCT of 320 women
showed that women in the NSAID group had lower pain scores at observing postsurgery dressing removal showed no increased
12 and 24 hours (when NSAIDs were administered via the intrave- wound complications with removal at 6 hours instead of 24 hours
nous/intramuscular route, but not via oral or rectal routes), lower after a scheduled cesarean delivery. In this same study, women’s
pain with movement at 24 hours, significantly less opioid con- satisfaction was significantly increased when dressings were
sumption, and less drowsiness/sedation, while no difference was removed at 6 hours after the cesarean delivery, allowing them
reported in terms of nausea or vomiting [63]. Scheduled NSAIDs to care for their personal hygiene earlier [71].
should be given initially around the clock, starting during cesarean A multicenter RCT of 869 low-risk obstetric women compared
(e.g. ketorolac, then ibuprofen) and not as desired by the woman. wound dressing removal at 24 hours versus 48 hours post–caesar-
Scheduled acetaminophen around the clock for 48 hours ean delivery with a modified 1-day ASEPSIS score. Higher scores
after cesarean delivery has been reported to be effective in reduc- were associated with more severe disruption of healing. The
ing opioid use compared to as-needed administration in women wound scoring was similar in the groups at discharge and first-
who received spinal anesthesia containing intrathecal morphine week evaluation, while at 6 weeks postsurgery, the wound scor-
[64], and these data were confirmed also in an RCT of 104 women ing was significantly less in the 48-hour (3.9%) versus the 24-hour
that showed that compared to placebo, intravenous acetamino- group (9%; p = 0.002) [72]. Further studies targeting wound com-
phen after cesarean delivery was associated with a significant plications are necessary to define the timing of dressing removal
decrease in oral narcotic consumption for pain control [65]. after cesarean.
Epidural morphine—and neuraxial opioids in general—are The proper technique for the removal of adhesive dressings
significantly associated with a reduction in pain scores and post- in obstetrics and gynecology has also been studied. By using
operative morphine request during the first 24 hours compared a slow rate of removal in the direction of hair growth, the
to systemic opioid analgesia, but it also increased the incidence of proper angle of traction (an ideal angle of 150–180 degrees to
nausea and pruritus compared with systemic opioids [66]. the skin), countertraction with an index finger, and adhesive
The transverse abdominis plane block (TAP block) involves solvents when necessary, patients experience much less pain
using a blunt-tip needle to inject anesthetic in the plane between with dressing removal, and skin injury can be avoided [73].
the internal oblique and transversus abdominis muscles to tar- There is currently no evidence of harm from early (within
get the peripheral nerves innervating the lower abdomen, usually 48 hours of surgery) postoperative bathing or showering in
performed under ultrasound guidance. After cesarean delivery, women with closed surgical wounds, because clinically signifi-
TAP block is effective, but the evidence is currently stronger only cant increases or decreases in SSIs cannot be ruled out [74].
for women not receiving neuraxial morphine [67].
Due to the lack of robust evidence of efficacy, the ACOG does Sutures
not recommend gabapentin as a first-line treatment for pain
management after cesarean delivery, although it might be rea- Key points
sonable in case of a history of chronic pain or uncontrolled pain • Absorbable subcuticular sutures, when compared with
[52]. Moreover, perioperative administration of 600 mg of gaba- staples, are associated with fewer wound complications
pentin has been shown to be associated with a lower pain score at and therefore should be preferred to reapproximate the
24-hour movements and with a higher pain control satisfaction skin at cesarean delivery.
at 12 and 24 hours in healthy pregnant women undergoing spinal • If staples are used nonetheless for skin closure of a trans-
anesthesia for cesarean delivery at term [68]. verse incision, they should be removed at least 4 or more
When focusing on systemic opioids, the ACOG guidelines on days after the cesarean to reduce the risk of skin separation
postpartum pain management suggest reserving parenteral or and the need for reclosure.
oral opioids for treating breakthrough pain when pain control • In women with risk factors for wound complications, such
obtained by the combination of neuraxial opioids and nonopioid as those with diabetes mellitus or obesity, and in vertical
adjuncts becomes inadequate [52]. incisions, staple removal timing should increase up to 7–10
days.
Dressing removal
Absorbable subcuticular sutures, when compared with
Key points staples, is associated with fewer wound complications and
• Dressing removal at 6 hours after a scheduled cesarean therefore should be preferred to reapproximate the skin at
delivery is not associated with an increased risk of wound cesarean delivery [75]. A planned secondary analysis of an RCT
complications. of 746 women in which sutures and staples were compared for
• Women’s satisfaction is higher with early dressing removal, transverse skin closure after cesarean showed that more women
allowing them to care for their personal hygiene earlier. appear to prefer sutures, as they are less painful, are considered
Postpartum Care 359
to have a better appearance, and are associated with fewer wound Extensive discussion of indications for anticoagulation during
complications [76]. If staples are used nonetheless for skin clo- pregnancy is beyond the scope of this section. Similarly, manage-
sure of a transverse incision, they should be removed at least ment of these women in the postpartum period also is beyond
4 days after the cesarean to reduce the risk of skin separation the scope. Finally, evaluation and management of acute VTE is
and the need for reclosure [77]. In women with risk factors for covered in Chaps. 29 and 30 in Maternal-Fetal Evidence Based
wound complications, such as those with diabetes mellitus or Guidelines. However, in this section we will review evidence for
obesity, and in vertical incisions, staple removal timing should postpartum thromboprophylaxis among women without prior
increase up to 7–10 days, as the wound is under more tension. In VTE history and without known thrombophilia.
an RCT including 295 obese women with subcutaneous wound
depth ≥2.0 cm and skin staple closure of a transverse incision, the Thromboprophylaxis
rate of superficial wound dehiscence was 15.2% in the early skin Pneumatic compression devices should be used for all post-
staple removal group (after 3 postoperative days) versus 11.5% in partum women, independent of mode of delivery, until the
the delayed skin staple removal group (between postoperative day patient is fully ambulatory. However, this is based on expert
7 and postoperative day 10), although this difference was not sta- opinion and extrapolated from gynecology and general surgery
tistically significant. Until other trials can establish the noninfe- literature [84]. Evidence is limited in pregnancy. However, the
riority of early staple removal, delayed removal should remain the Society for Maternal-Fetal Medicine (SMFM) and ACOG do rec-
standard in the obese patient [78]. ommend their use starting at the time of cesarean delivery and
High-risk conditions, such as women with a body mass index until the patient is fully ambulatory [85, 86]. These can be contin-
(BMI) of more than 35 kg/m2, urgent cesarean delivery, preterm ued to be used while the patient is in bed for the duration of the
prelabor rupture of the membranes (PPROM), and chorioam- postpartum stay.
nionitis, are associated with wound healing complications, Low-molecular-weight heparin (LMWH) is recommended
regardless of timing of both the dressing and staple removal over heparin for postpartum pharmacologic anticoagulation
(see also Chap. 14) [79]. by the Society of Obstetricians and Gynecologists of Canada
(SOGC), RCOG, SMFM, and the American College of Chest
Physicians, while ACOG notes both are safe [84–88]. While nei-
Postpartum thromboprophylaxis ther compound crosses the placenta, LMWH has a better safety
Key points profile, lower incidence of bleeding, and lower rates of heparin-
• Venous thromboembolism (VTE) risk in the first week induced thrombocytopenia, as well as having less frequent dosing
postpartum is 100-fold higher than during pregnancy. requirements [89, 90]. Both are compatible with breastfeeding.
• Pneumatic compression devices are recommended for In the setting of postpartum prophylactic pharmacologic anti-
all postpartum women, independent of mode of deliv- coagulation, agents such as warfarin and other newer oral anti-
ery, until the patient is fully ambulatory. coagulants are generally not used, nor well studied. In general,
• Low-molecular-weight heparin (LMWH) is recom- though, warfarin is compatible with breastfeeding, while other
mended over heparin for postpartum pharmacologic newer oral agents such as fondaparinux are not recommended
anticoagulation. with breastfeeding.
• When a patient meets criteria for postpartum antico- For a patient where pharmacologic anticoagulation is indi-
agulation, it should in general not be started prior to cated, the optimal time between delivery and initiation is unclear.
4–6 hours after vaginal delivery or 6–12 hours after However, increased bleeding has been shown when anticoagu-
cesarean delivery. lation is started between 5 and 24 hours after vaginal delivery
• Insufficient evidence exists to guide recommendations and 12 and 36 hours after cesarean delivery [91]. ACOG sug-
about the duration of postpartum thromboprophylaxis. gests in general waiting 4–6 hours after vaginal delivery and
6–12 hours after cesarean delivery prior to starting any anti-
Epidemiology/Incidence coagulation [86].
Venous thromboembolism (VTE) occurs in 0.5–2/1000 pregnan- The presence of an epidural catheter can also affect the timing
cies, with half of those occurring postpartum [80, 81]. VTE risk of initiation. The American Society of Regional Anesthesia and
in the first week postpartum is 100-fold higher than during Pain Medicine recommend waiting at least 2 hours after the
pregnancy [82]. removal of an epidural catheter prior to initiation of prophy-
A history of VTE or thrombophilia confers the biggest risk of lactic pharmacologic anticoagulation [92]. SOGC and RCOG
VTE. In women without these two risk factors, most data sug- recommend waiting 4 hours prior to initiation of prophylactic
gest that no single risk factor increases the risk more than 1% pharmacologic anticoagulation after removal of a neuraxial cath-
[83]. However, when women present with multiple risk factors, eter [84, 87, 93].
the cumulative risk may suggest the need for postpartum throm-
boprophylaxis. All of the following other factors have been asso- Candidates for postpartum
ciated with an adjusted odds ratio (aOR) of >4 for VTE in the pharmacologic thromboprophylaxis
postpartum period: Immobility for >1 week in the antepartum A Cochrane review from 2014 including 840 women attempted
period (aOR 40.1), postpartum infection after vaginal delivery or to assess the safety and efficacy of VTE prophylaxis in the early
cesarean delivery (aOR 20.2 and 6.2, respectively), postpartum postpartum period. The authors of that review concluded that
hemorrhage with or without surgery (aOR 12.0 and 4.1 respec- more rigorous and larger RCTs were needed [94]. A more recent
tively), pre-eclampsia with fetal growth restriction (aOR 5.8), placebo-controlled RCT was attempted but had to be stopped
maternal lupus (aOR 8.7), blood transfusion (aOR 7.6), maternal early due to futility recruiting [95]. Thus, while no high-quality,
sickle cell disease (aOR 6.7), multiple gestation (aOR 4.2), and large-scale trials exist, it is clear that universal postpartum phar-
BMI >30kg/m2 (aOR 5.3) [83]. macologic intervention is likely to cause harm [96].
TABLE 31.3: Risk-Based Recommendations for Postpartum tissue if the wound thickness is >2 cm, and skin closure
Pharmacologic Thromboprophylaxis with sutures.
• Mild, nonpurulent cellulitis without systemic signs of
High-Risk Moderate-Risk Factors Low-Risk Factors
infection should be treated with antistreptococcal anti-
Factors (Need ≥1) (Need ≥2) (Need ≥3)
microbial agents; if purulent drainage or exudates
Postpartum BMI >30a,b Age >35a,c accompany cellulitis, empiric therapy should include ade-
infectiona Smoking >10 cigarettes per Parity >2a quate coverage for methicillin-resistant Staphylococcus
Blood loss >1 L daya,b Multiplesa,c aureus.
and surgerya Pre-eclampsiaa,b Abruptiona
BMI >40b Growth restrictiona Assisted reproductive Diagnosis/Definition
Cesarean in setting of labora technologya Wound complications include several surgical morbidities that
Blood loss >1 La,b PPROMa can prolong postoperative pain and convalescence, lead to read-
Maternal lupusa,b Cesarean deliveryac mission, and contribute to rising health care costs. Complications
Sickle cell diseasea,b Maternal cancera that can affect the wound after a cesarean delivery include hema-
Stillbirtha,b toma, seroma, dehiscence, infection, and rarely, necrotizing fasci-
Preterm deliverya,b itis. The diagnosis of wound complications is clinical and posted
Gestational diabetesa in the presence of the classical signs of infection.
Inflammatory bowel diseasea,b
Heart failure/maternal cardiac Symptoms/Signs
diseasea,b Characteristic signs of wound infection are erythema, edema,
heat, discharge, and induration of the incision; fever and leuko-
a Based on SOCG guidelines.
cytosis may be systemic evidence of this condition. Hematoma
b Based on RCOG guidelines.
c Considered moderate risk factor by RCOG.
and seroma present as a collection of blood and serum, respec-
Abbreviations: BMI, body mass index; PPROM, preterm prelabor rupture of the
tively, both of which can cause dehiscence and act as a nidus for
membranes. the development of wound infection [98]. Necrotizing fasciitis is
a rare but serious infection of the deep soft tissue that results in
At this time, some experts suggest that the decision for post- progressive destruction of the muscle fascia and overlying subcu-
partum pharmacologic thromboprophylaxis be an opportunity taneous fat. Severe pain, wooden-hard induration of the subcuta-
for shared decision-making among women without prior or cur- neous tissues, bullous lesions, skin necrosis or ecchymosis, and
rent VTE [83]. In contrast, SOGC and RCOG have given specific elevated serum creatine kinase level are usually observed [99].
risk-based guidelines for recommending postpartum pharma- Computed tomography or magnetic resonance imaging may help
cologic thromboprophylaxis (Table 31.3). However, SMFM does in the diagnosis of necrotizing fasciitis, which will be confirmed
recommend the institution develop their own protocols with at the time of repeat surgery.
respect to postpartum pharmacologic thromboprophylaxis for
women undergoing cesarean delivery [85]. Epidemiology/Incidence
Insufficient evidence exists to guide recommendations about The rate of postpartum wound complications in the literature
the duration of postpartum thromboprophylaxis for women ranges from 2.8% to 26.6% [100] with a percentage of 1%–2% for
without prior VTE or known thrombophilia. Expert opinion sug- primary cesarean delivery [101] and a higher percentage for
gests anywhere from only while hospitalized to 6 weeks postpar- repeat cesarean deliveries.
tum [84, 87]. Prophylactic LMWH dosing is 40 mg daily. However,
Microbiology
this is often weight-based, and doses of 60 mg daily can be consid-
In the first 24–48 hours, the most common pathogens asso-
ered for women weighing 100–150 kg, and 80 mg daily for those
ciated with wound infections are group A or B beta-hemo-
weighing more than 150 kg [97]. Alternatively, subcutaneous hepa-
lytic Streptococcus, while later infections usually involved
rin can be considered at a dose of 10,000 units twice a day.
Staphylococcus epidermidis or aureus, Enterococcus faecalis,
Escherichia coli, and Proteus mirabilis [102].
Postpartum wound complications
Risk factors
Key points Risk factors for the development of SSIs following cesarean
• Wound complications include hematoma, seroma, dehis- delivery in decreasing order of significant risk are listed in
cence, infection, and rarely, necrotizing fasciitis and occur Table 31.4 [103].
in 1%–2% of primary cesarean deliveries.
• Characteristic signs of wound infection are erythema, Workup
edema, heat, discharge, and induration of the incision; Examination of the surgical site is central when a woman pres-
fever and leukocytosis may be systemic evidence of this ents with signs and symptoms possibly related to wound compli-
condition. cation. The area of the wound should be carefully examined and
• In the first 24–48 hours, the most common pathogens potentially marked to assess for spread over time. A sterile swab
associated with wound infections are group A or B beta- can be used to investigate any open areas and the dimensions of
hemolytic Streptococcus. the separation of tissues. Superficial infection such as celluli-
• Effective interventions to decrease SSI include pro- tis can be treated with antibiotics alone and does not require
phylactic antibiotic use before skin incision, no hair incision and drainage. If the wound has purulent drainage, exu-
removal or hair removal using clippers, use of preopera- date or separation, incision and drainage to remove abscess, exu-
tive vaginal cleansing, suture closure of subcutaneous date, and hematoma is needed [103].
Postpartum Care 361
TABLE 31.4: Risk Factors for Surgical Site Infection Postpartum endometritis
Variables Relative Risk or Odds Ratios
Key points
Subcutaneous hematoma 11.6 • Postpartum endometritis refers to an infection of the
Chorioamnionitis 5.6–10.6 decidua, typically polymicrobial, that occurs in about 1%–3%
American Society of Anesthesiologists 5.3 of vaginal births and up to 27% of cesarean deliveries.
class 3 or greater • The diagnosis is clinical and suspected if the patient devel-
Tobacco 5.3 ops puerperal fever, usually accompanied by abdominopel-
Incision length >16.6 cm 4.9 vic pain and purulent or foul-smelling lochia.
Prenatal visit <7 4 • Cesarean delivery is the most important risk factor for
Body mass index >35 kg/m2 3.7
postpartum maternal infection, especially when per-
formed after a prolonged labor with ruptured membranes.
Corticosteroid 3.1
• Routine blood cultures in women with uncomplicated
Body mass index >30 kg/m2 2.0–2.8
endometritis are not recommended, since empiric treat-
Subcutaneous tissue thickness >3 cm 2.8
ment with a broad-spectrum antibiotic is usually effective.
Second stage (vs. first stage) 2.8 • Effective prevention measures able to reduce the incidence
Teaching service 2.7 of postpartum endometritis in women who are undergoing
No antibiotic prophylaxis 2.6 cesarean delivery include vaginal preparation with antisep-
Pregestational diabetes 1.4–2.5 tic solution and antibiotic prophylaxis within 60 minutes
Operating time ≥38 minutes 2.4 prior to making the skin incision.
Hypertensive disease/pre-eclampsia 1.7–2.3 • The gold standard for the treatment of postpartum endo-
Duration of labor >12 hours 2.0 metritis is the combination of clindamycin 900 mg IV
Nulliparity 1.8 every 8 hours plus gentamicin 5 mg/kg IV every 24 hours.
Twin 1.6
Premature rupture of membrane 1.5
Postpartum endometritis refers to an infection of the decidua,
Gestational diabetes 1.5
typically polymicrobial, that may extend into the myometrium
Blood loss (every 100 mL) 1.3
or involve the parametrial tissues. The diagnosis is clinical and
Previous cesarean delivery 1.3 suspected if the patient develops fever in the absence of any other
Emergency delivery 1.3 cause. Puerperal febrile morbidity is defined as an oral temperature
Rupture of membranes (each hour) 1.02 ≥38°C (100.4°F) on any 2 of the first 10 days postpartum or a single
Source: From Ref. [103] under Creative Commons License. oral temperature of 38.7°C (101.6°F) in the first 24 hours [113].
Symptoms/Signs
Prevention Puerperal fever is usually accompanied by abdominopelvic
Effective interventions to decrease SSI include prophylactic anti- pain and purulent or foul-smelling lochia. Additional findings
biotic use before skin incision [104], no hair removal or hair observed in some women are chills, headache, malaise, and/or
removal using clippers instead of razors [105], use of preop- anorexia. Uterine involution can be delayed in the case of endo-
erative vaginal cleansing especially in women with ruptured metritis, particularly if the myometrium is involved (endomyo-
membranes [106], suture closure of subcutaneous tissue if the metritis), and excessive bleeding can occur.
wound thickness is >2 cm [107], and skin closure with sutures
instead of with staples [108]. Evidence-based bundles in women Epidemiology/Incidence
who undergo cesarean delivery are associated with a significant It is the most common postpartum infection, occurring in 1%–3%
reduction in SSI [109]. of vaginal births and in up to 27% of cesarean births [114. Data
derived from a review of Maternal-Fetal Medicine Unit Network
Therapy publications involving over 70,000 cesarean deliveries reported
Wound infection needs early antibiotic intervention. Mild, a rate of endometritis of around 6% for primary cesarean deliv-
nonpurulent cellulitis without systemic signs of infection ery performed before labor and around 11% for primary cesarean
should be treated with antistreptococcal antimicrobial delivery performed during labor [101].
agents, such as cephalexin, dicloxacillin, penicillin VK, amoxi-
cillin/clavulanate, or, in cases of penicillin allergy, clindamycin Etiology/Basic pathophysiology/Microbiology
[110]. If purulent drainage or exudate accompanies cellulitis, Infections are usually polymicrobial and related to a mixture of
empiric therapy should include adequate coverage for meth- two to three aerobes and anaerobes that ascend from the lower
icillin-resistant S. aureus [111]. Options for oral antibiotics genital tract to the uterus, colonizing the decidua, within 6
include clindamycin, trimethoprim–sulfamethoxazole, and tet- weeks of the birth. The most common pathogens isolated from
racycline (doxycycline or minocycline). Reclosure of disrupted the endometrium include E. coli and other aerobic gram-negative
laparotomy wounds can be accomplished with a high likelihood organisms such as Klebsiella pneumoniae, Enterobacter, and
of success (>80%) and a small number of recurrent abscesses, Proteus species; aerobic gram-positive organisms, including
seromas, and minor wound separations. Compared with healing group B Streptococcus and other Streptococcus species such as
by secondary intention, reclosure results in a faster healing time Enterococcus and S. aureus; and coagulase-negative anaerobes
(16–18 days versus 61–72 days) and fewer number of postopera- such as Bacteroides and Prevotella species, Peptostreptococcus
tive visits [112]. species, and the gram-variable Gardnerella vaginalis [115, 116].
TABLE 31.5: Risk Factors for Postpartum Endometritis TABLE 31.6: Recommendations for Early Post-Cesarean
Delivery Care
Maternal Conditions Intrapartum and Postpartum
Conditions • Early ambulation 5–10 minutes several times a day starting from
4 hours after CD
Malnutrition Multiple vaginal examinations
• Early oral feeding within 6–8 hours after CD
Severe anemia Prolonged rupture of the
• Chewing three times a day immediately after CD
membranes
• Immediate removal of catheter, if used
Diabetes Severe meconium staining in
• Postoperative analgesia with scheduled NSAIDs or acetaminophen
liquor
for 48 hours given around the clock
Obesity (body mass index >30 kg/m2) Cesarean delivery • Dressing removal at 6 hours after a scheduled CD
HIV infection Manual extraction of placenta • Absorbable subcuticular suture to reapproximate the skin
Altered vaginal microflora (e.g. bacterial • Pneumatic compression devices during postpartum, regardless of
vaginosis, vaginal group B streptococci mode of delivery, until the woman is fully ambulatory
colonization) • LMWH for postpartum pharmacologic anticoagulation 6–12 hours
Source: Data from Refs. [122–124]. after CD in women meeting criteria for anticoagulation
• Early antibiotic therapy for postpartum wound infection and
Risk factors/Associations postpartum endometritis
Cesarean delivery is the most important risk factor for postpar- Abbreviations: CD, cesarean delivery; LMWH, low-molecular-weight heparin.
tum maternal infection, especially when performed after a pro-
longed labor with ruptured membranes [117, 118]. An increased (iodine-based solutions or chlorhexidine-based solutions) imme-
incidence of endometritis following cesarean delivery has also diately before cesarean delivery [106], antibiotic prophylaxis
been reported in association with bacterial vaginosis [119]. For within 60 minutes prior to making the skin incision [128], and
vaginal birth, the presence of bacterial vaginosis, prolonged rup- spontaneous placental extraction [128].
ture of membranes, and multiple vaginal examinations during
labor are associated with an increased risk of endometritis [118, Therapy
120]. The most common maternal, intrapartum, and postpartum Antibiotic treatment that includes coverage for aerobic and
conditions associated with an increased risk of postpartum endo- anaerobic pathogens likely to be causing endometritis should be
metritis are listed in Table 31.5 [121–123]. administered promptly. The gold standard for the treatment
of postpartum endometritis is the combination of clindamy-
Complications cin 900 mg IV every 8 hours plus gentamicin 5 mg/kg IV
Endometritis is still an important cause of maternal deaths world- every 24 hours [114]. The combination of ampicillin-sulbactam
wide, although the use of antibiotics has considerably reduced its (3 g every 6 hours) and gentamicin (1.5 mg/kg every 8 hours) is
incidence [114]. Serious complications of postpartum endometri- as effective and well tolerated as a combination regimen using
tis include peritonitis, pelvic abscess, and septic thrombophlebi- clindamycin plus gentamicin and therefore could be used in case
tis, which can be associated with septic pulmonary emboli. of clindamycin resistance [129]. The treatment should be con-
tinued until the woman is afebrile for (usually) 24–48 hours
Workup and the pelvic pain disappears. In case of persistent fever for
The white blood cell (WBC) count is elevated, but this can be a nor- more than 48 hours of antibiotic therapy, the addition of ampi-
mal finding in postpartum women secondary to the physiologic cillin or penicillin to the regimen can be an effective approach
leukocytosis of pregnancy and the effects of labor, while a rising, because of the presence of resistant organisms, such as entero-
rather than falling, neutrophil count postpartum is suggestive of cocci, in about 20% of cases [130]. If the woman has not improved
an infectious process [124]. Routine blood cultures in women despite the adjustment of the initial antibiotic therapy, other eti-
with uncomplicated endometritis are not recommended, since ologies of fever should be considered. Ultrasound may demon-
empiric treatment with a broad-spectrum antibiotic is usually strate the retained tissue fluid collection such as pelvic abscess
effective. However, in some selected cases, such as endometritis or infected hematoma [131]; computed tomography (CT) or
complicated by sepsis or failure of the initial antibiotic therapy, magnetic resonance imaging are helpful if septic pelvic throm-
women with an increased risk for bacterial endocarditis, or bophlebitis or ovarian vein thrombosis is suspected. For women
immunocompromised women, the detection of bacteremia with with negative imaging, the likelihood of a drug fever should be
blood cultures can be useful to tailor antibiotic treatment [125]. considered [132].
Endometrial bacterial cultures are challenging to obtain without In summary, for early post–cesarean delivery care, we suggest
contamination through the cervix and rarely provide information the interventions in Table 31.6.
that affect treatment decisions [126]. There are no characteristic
sonographic findings associated with postpartum endometritis
[127]. In the differential diagnosis it is necessary to consider other Other postpartum issues for both
postpartum febrile episodes such as SSI, engorgement, mastitis, vaginal and cesarean delivery
breast abscess, and less frequently, a viral syndrome, appendicitis,
pyelonephritis, atelectasis, or pneumonia.
Postpartum ultrasound
Prevention
Effective prevention measures able to reduce the incidence of Key points
postpartum endometritis in women who undergo cesarean • The upper limit of normal for endometrial thickness
delivery include vaginal preparation with an antiseptic solution was 25 mm up to 7 days postpartum and continued to
Postpartum Care 363
decrease during the puerperium period, as all other uterine skin-to-skin on the mother’s chest and remain there,
measurements gradually do. undisturbed, until the first feeding is accomplished.
• Endometrial stripe thickness and ultrasound presence of • Treatment for mastitis begins with frequent removal
echogenic material in the uterine cavity should not be used of milk, hydration, and analgesia. Healthy term infants
as clinical predictors for abnormal bleeding complications, can continue to feed on the affected side. Antibiotics are
since they may be common findings in the early postpar- used if conservative management is ineffective or the
tum period. patient is acutely ill.
• There is limited evidence that galactagogues increase milk
Postpartum ultrasound is not routinely performed in every production in placebo-controlled trials. Optimal breast-
institution, although it is considered a useful tool when a sus- feeding education can increase milk supply among women
picion for placental pathology arises during the postpartum with low production.
course. A recent, large systematic review including 3106 women • Most medications are compatible with breastfeeding,
undergoing transabdominal and/or transvaginal ultrasound or a safe alternative medication exists. The physiology of
from day 1 to a maximum of 6 weeks postpartum provided the placenta differs from the breast, and providers should
clinical guidance for the sonographic evaluation of women not extrapolate drug safety information from pregnancy to
with an uncomplicated postpartum course. The upper limit lactation.
of normal (95th percentile) for endometrial thickness was • Breastfeeding is contraindicated in the setting of an infant
25 mm up to 7 days postpartum and continued to decrease with classic galactosemia, active maternal use of illicit
(18 mm at 14 days, 12 mm at 4 weeks, and 9 mm at 6 weeks) simi- drugs, maternal medications that are contraindicated in
larly, regardless of parity or mode of delivery. All other uterine breastfeeding, or maternal infection with T-cell lympho-
measurements also gradually decreased during the puerpe- tropic virus type I or II (e.g. HTLV). Recommendations for
rium period similarly, regardless of parity or mode of delivery breastfeeding in the setting of maternal HIV or tuberculo-
[133]. Endometrial stripe thickness and ultrasound presence of sis vary by region. Women with HIV in the United States
echogenic material in the uterine cavity should not be used as are advised not to breastfeed because of the risk of mater-
clinical predictors for the development of abnormal bleeding nal-infant transmission and the availability of safe artifi-
complications, since they may be normal findings in the early cial feeding. Breastfeeding is temporarily contraindicated
postpartum ultrasound [134]. during perinatal maternal Varicella infection or from a
breast with an active herpetic lesion.
Breastfeeding
Definition
Key points Breastfeeding is the physiologic form of infant nutrition. It is
• In normal reproductive physiology, lactation follows preg- defined as the infant receiving any amount of human milk.
nancy. For the infant, use of artificial breast milk sub- Exclusive breastfeeding is defined as receiving human milk alone
stitutes is associated with increased acute and chronic for nutrition while mixed feeding is defined as receiving both
disease risk. For mothers, never or curtailed (e.g. short- human milk and infant formula. It should be noted that breast-
term) breastfeeding is associated with increased risks of feeding is synonymous with nursing, but also includes bottle-
malignancy and metabolic disease. feeding pumped breastmilk to the baby.
• All major medical organizations recommend 6 months
of exclusive breastfeeding, with continued breastfeed- Breastfeeding physiology
ing through 1–2 years, or longer as mutually desired by Secretory differentiation occurs during pregnancy, as placental
mother and infant. hormones stimulate development of mammary alveoli. After
• Infant demand drives maternal milk supply. To ensure ade- birth, secretory activation occurs as progesterone levels fall and
quate milk production, encourage frequent, on-demand milk production increases from 50 mL/day to approximately
feeding in response to infant cues, continuing until the 500 mL/day in the first 2–3 days after birth. Positive feedback
infant is satisfied. via infant stimulation of the breast causes secretion of prolac-
• Prenatal and postnatal lay and/or professional support and tin from the anterior pituitary and oxytocin from the poste-
evidence-based physician training improve breastfeeding rior pituitary. Prolactin stimulates continuous milk synthesis,
duration and exclusivity. whereas oxytocin stimulates intermittent milk secretion, when
• Maternity care practices affect breastfeeding initiation myoepithelial cells contract to transfer milk from the alveoli to
and duration. Implementation of the United Nations the areola. If milk is not removed regularly, negative feedback
International Children’s Emergency Fund (UNICEF)/ downregulates prolactin receptors and reduces production.
World Health Organization (WHO) Baby Friendly Hospital Frequent, on-demand feeding is essential to establish and main-
Initiative (BHI) improves breastfeeding duration, intensity, tain lactation [135].
and infant health outcomes.
• Prenatal treatment of inverted nipples does not increase Health effects of infant feeding
breastfeeding success. Infants who are artificially fed face higher risks of infectious
• Distribution of formula company marketing materials and morbidity and chronic disease than infants who are breastfed.
samples adversely affects breastfeeding outcomes. Formula An Agency for Healthcare Research and Quality (AHRQ) meta-
company materials should not be distributed in health care analysis of outcomes in developed countries found that artifi-
facilities. cially fed infants faced a 2.0-fold risk of otitis media, a 3.6-fold
• At birth, early skin-to-skin contact increases breast- risk of pneumonia, and a 2.8-fold risk of gastrointestinal infec-
feeding duration. Healthy infants should be placed tion compared with infants who were exclusively breastfed [136].
Artificial feeding is also associated with a 1.8- to 3.7-fold risk of TABLE 31.7: Successful Breastfeeding Recommendations
sudden infant death syndrome (SIDS), a 1.1- to 1.4-fold risk of
Offer additional breastfeeding support to women who have had a
child obesity, and a 1.5-fold risk of type 2 diabetes compared
narcotic/general anesthetic, a caesarean, or delayed contact with their
with breastfeeding. Artificial or mixed feeding is also associated
baby.
with higher risks of asthma compared with exclusive breastfeed-
Ensure breast pumps are available for women who have been separated
ing. Among preterm infants, artificial feeding is associated with
from their babies, and give instruction on how to use them.
a 5% absolute increased risk of necrotizing enterocolitis com-
Encourage unrestricted breastfeeding frequency and duration.
pared with being fed mother’s milk [136].
Reassure women about breast milk supply and help them gain
For mothers, artificial feeding is similarly associated with
confidence.
increased health risks. Compared with women who have breast-
fed, parous women who have never breastfed or weaned early Advise women that babies will stop feeding when satisfied.
face higher rates of breast cancer [137, 138], particularly triple- Advise women of the signs that a baby is successfully feeding:
negative breast cancer, ovarian cancer, retained gestational • Swallowing is audible and visible.
weight gain [139], type 2 diabetes [140–143], hyperlipidemia • There is a sustained rhythmic suck.
[144], metabolic syndrome [145, 146], hypertension [142, 147], • The arms and hands are relaxed.
and myocardial infarction [142, 148]. • The mouth is moist.
• Regular soaked/heavy nappies.
Optimal duration of exclusive breastfeeding Reassure women that they may feel the following:
Six months of exclusive breastfeeding, compared with 3–4 • Brief discomfort at the start of feeds in the first few days; this is not
months of exclusive breastfeeding with mixed feeding through uncommon but should not persist.
6 months, reduces infant risk of gastrointestinal and respira- • Softening of their breast during the feed.
tory tract infections without any adverse effect on infant growth.
• No compression of the nipple at the end of the feed.
For mothers, longer exclusive breastfeeding was associated with
• Relaxed and sleepy.
delayed resumption of menses and, in one small study, with
greater maternal weight loss [149]. Attachment and Positioning
Advise women of the following signs of good attachment and
Infant feeding recommendations positioning:
All major medical organizations [150–153] recommend exclu- • The baby’s mouth is wide open.
sive breastfeeding for the first 6 months of life. The World • There is less areola visible underneath the chin than above the
Health Organization (WHO) recommends continued breastfeed- nipple.
ing up to 2 years of age or beyond [153]. The American Academy • The baby’s chin is touching the breast, the lower lip is rolled down,
of Pediatrics (AAP) recommends continued breastfeeding for and the nose is free.
at least the first year of life, continuing for as long as mutually • There is no pain.
desired by mother and child. If the baby is not attaching effectively, advise teasing the baby’s lips with
the nipple to open the mouth.
Promoting breastfeeding
Antenatal interventions can increase breastfeeding initiation and
duration (Table 31.7) [154]. Breastfeeding education improves for hospital staff are similarly associated with improved breast-
initiation rates among low-income U.S. populations. In sub- feeding outcomes. Health care providers who work with mothers
group analyses, one-on-one, needs-based, informal education and infants should receive comprehensive breastfeeding training.
sessions were more effective than generic, formal antenatal ses-
sions [155]. Both lay and professional support for mothers after The Baby Friendly Initiative
birth improves breastfeeding duration and exclusivity, with the Maternity care affects breastfeeding outcomes. The Baby Friendly
strongest effects found with proactive, face-to-face, lay support Initiative (BFI) is WHO-developed set of maternity care rec-
involving four to eight contacts. A U.S. Preventative Services Task ommendations designed to increase initiation and duration of
Force (USPSTF) review similarly found that interventions to pro- breastfeeding. The BFI requires maternity centers to implement
mote and support breastfeeding increase initiation, duration, and the Ten Steps to Successful Breastfeeding (Table 31.8) [162].
exclusivity of breastfeeding, and interventions that include both Each country is responsible for establishing processes and pro-
prenatal and postnatal components may be most effective [156]. cedures for a maternity center designation as baby friendly [162].
Proactive, integrated prenatal and postnatal support for breast- In a cluster-randomized trial in Belarus, BFI implementation
feeding mothers improves breastfeeding duration and intensity. improved breastfeeding exclusivity at 3 months (43.3% versus
6.4%, p < 0.001) and 6 months (7.9% versus 0.6%, p = 0.01) and
Training of providers increased any breastfeeding rates at 12 months (19.7% versus
Breastfeeding education and knowledge among health care pro- 11.4%). Infants born in intervention hospitals had lower rates
viders is inconsistent [157–159]. A meta-analysis found that train- of gastrointestinal illness and atopic eczema in the first year of
ing breastfeeding support personnel using the WHO/UNICEF life [163]. Observational studies in the United States have found
breastfeeding training course [160] increases the duration of a dose–response association between implementation of BFI
exclusive breastfeeding. In a cluster-randomized trial, imple- steps and maternal achievement of breastfeeding goals [164, 165].
mentation of a breastfeeding training curriculum for residents Cohort studies suggest that the Ten Steps are particularly effec-
improved provider knowledge, practice patterns, and confidence tive among women with lower education, suggesting that BFI
and increased exclusive breastfeeding rates at 6 months (odds maternity care can reduce socioeconomic disparities in breast-
ratio [OR] 4.1) compared with control sites [161]. Interventions feeding [166].
Postpartum Care 365
TABLE 31.8: The Ten Steps to Successful Breastfeeding infant is ready to feed and offer help if needed [162]. Routine
procedures, such as weighing, bathing, and vitamin K and
Every facility providing maternity services and care for newborn infants
eye prophylaxis, should be avoided during the first hour, or
should:
be performed on the mother’s chest. Skin-to-skin care during
1. Have a written breastfeeding policy that is routinely communicated
procedures, such as a heel lance, appears to reduce infant pain.
to all health care staff.
Skin-to-skin is also feasible following cesarean section.
2. Train all health care staff in skills necessary to implement this policy.
3. Inform all pregnant women about the benefits and management of
Anticipatory guidance to support normal physiology
breastfeeding.
Human milk production is driven by infant demand.
4. Help mothers initiate breastfeeding within a half-hour of birth.
Therefore, frequent feeding, on demand in response to infant
5. Show mothers how to breastfeed and how to maintain lactation
feeding cues, continuing until the infant is satisfied, is a cor-
even if they should be separated from their infants.
nerstone of breastfeeding success [179], although a recent meta-
6. Give newborn infants no food or drink other than breast milk unless
analysis did not identify trials comparing baby-led feeding with
medically indicated.
scheduled breastfeeding [180]. NICE clinical guidelines have out-
7. Practice rooming in—allow mothers and infants to remain together
lined anticipatory guidance for successful breastfeeding. A small
24 hours a day.
pilot study found that early, limited supplementation with hydro-
8. Encourage breastfeeding on demand.
lyzed formula for infants with ≥5% weight loss increased exclu-
9. Give no artificial teats or pacifiers (also called dummies or soothers)
sive breastfeeding rates at 1 week and 3 months postpartum [181];
to breastfeeding infants.
several trials to test whether these findings can be replicated are
10. Foster the establishment of breastfeeding support groups and refer
underway (NCT02313181 and NCT02221167).
mothers to them on discharge from the hospital or clinic.
Source: From Declercq E, Labbok MH, Sakala C, et al. Hospital practices and wom- Management of breastfeeding complications
en’s likelihood of fulfilling their intention to exclusively breastfeed. Am J Engorgement
Pub Health. 2009;99(5):929–935. Ref. [164], with permission.
Breast engorgement typically occurs between 2 and 5 days post-
The National Institute for Health and Clinical Excellence (NICE) partum. A meta-analysis found insufficient evidence to support
postnatal care guideline recommends that all health care providers any single treatment strategy for engorgement [182]. Cold packs
implement a structured program that encourages breastfeeding, and cabbage leaves may be helpful, and acupuncture was asso-
using the BFI as a minimum standard (Table 31.7) [154]. ciated with some improvement in symptoms. NICE guidelines
recommend breast massage, continued breastfeeding, and
Breastfeeding in clinical care analgesia for symptom relief [154].
Antenatal breast exam
Clinical guidelines recommend evaluation of breast anatomy Mastitis
as part of prenatal care [151, 167]. However, there are no RCTs Mastitis is defined as acute inflammation of connective tissue
regarding the effects of an antenatal breast exam on breastfeed- within the breast, which may or may not be accompanied by
ing outcomes or maternal satisfaction [168]. There is no evidence infection [183]. Interventions to prevent mastitis have not proven
that antenatal manipulation for inverted nipples improves breast- effective [184]. A Cochrane meta-analysis (2 RCTs, n = 125
feeding outcomes [169, 170]. patients) concluded that there is insufficient evidence to support
treatment with antibiotics. An RCT suggests that Lactobacilli
Avoiding commercial infant feeding materials strains isolated from breast milk may be effective for the treat-
In randomized trials, provision of formula company materials ment of mastitis [185].
and gift packs during prenatal care [171] or during the maternity Clinical guidelines emphasize effective milk removal, hydra-
hospitalization [172–174] reduces exclusive breastfeeding. In a tion, and analgesia as key elements of clinical management of
time-series design study, changing from formula marketing dis- mastitis. Healthy term infants may continue to breastfeed on the
charge packs to noncommercial packs was associated with higher affected breast. If symptoms do not improve with conservative
breastfeeding rates, but more than one-third of women in the management or the woman is acutely ill, antibiotics are recom-
noncommercial cohort received formula samples, demonstrating mended. Penicillinase-resistant penicillins (e.g. dicloxacillin)
that policy implementation is challenging [175]. Formula com- are preferred [186].
pany marketing materials should not be distributed in the
health care setting. Breastfeeding and maternal medications
Most medications are compatible with breastfeeding, or a
Skin-to-skin contact at birth safe alternative medication exists. The physiology of the pla-
Early skin-to-skin contact improves breastfeeding outcomes. centa differs from that of the maternal breast and infant gut, so
Skin-to-skin contact is defined as placing the naked infant prone the provider should not assume that a drug’s pregnancy safety
on the mother’s bare chest, with the infant’s back covered with profile applies to breastfeeding. Many drug databases utilized
a warm blanket, ideally beginning immediately after birth. In a by commercial pharmacies do not contain accurate informa-
Cochrane meta-analysis, early skin-to-skin contact increased tion on drug safety in lactation [187]. The National Library of
breastfeeding at 1–4 months after birth (RR 1.27) and increased Medicine’s LactMed database (https://www.ncbi.nlm.nih.gov/
the duration of total breastfeeding by about 6 weeks [176]. Based books/NBK501922/) provides a comprehensive set of mono-
on these data, the NICE [177], AAP [178], and ACOG [151] rec- graphs on medication safety in lactation. Decisions about
ommend that all healthy infants be placed skin-to-skin at birth. medication use in lactation should consider the risks and
Infants should remain with their mothers for at least 1 hour, benefits of maternal treatment or nontreatment, the risk of
and providers should encourage mothers to recognize when the drug transfer to the infant, and the risks to mother and infant
of discontinuing breastfeeding [188]. Maternal providers should their infants, but expressed milk can be provided to
collaborate with the pediatric provider regarding counseling the infant.
about medication use in breastfeeding. • Mothers with HIV infection in settings where safe
artificial feeding is available (see later).
Milk expression
If mothers and infants are separated, milk expression is neces- Tuberculosis
sary to maintain supply and provide milk to the infant. Evidence The AAP lists active, untreated tuberculosis as a contraindication
suggests that early initiation of milk expression, simultaneous to breastfeeding. According to AAP guidelines, the infant may
pumping of both breasts, breast massage, relaxation techniques, continue to receive expressed milk while the mother is treated,
and expressing milk after kangaroo (i.e. skin-to-skin) mother care but mother and infant should be separated until the mother is
improve milk production among neonatal intensive care unit treated for a minimum of 2 weeks and is documented to be no
(NICU) mothers [189–194]. longer infectious. The WHO recommends continued breastfeed-
ing in the setting of maternal tuberculosis. The infant should be
Galactagogues treated with 6 months of isoniazid preventive therapy, followed
There is limited evidence to support pharmacotherapy for low by immunization with bacillus Calmette-Guerin (BCG) [207].
milk supply [195, 196]. Two small randomized, placebo-controlled,
blinded studies have found that domperidone increases milk sup- HIV
ply among mothers of preterm infants [197, 198]. Domperidone is Artificial infant feeding is efficacious in preventing maternal-child
not approved by the U.S. Food and Drug Administration (FDA) transmission of HIV, but RCTs in regions of the world where access
for any indication. Routine use of metoclopramide in the early to clean water is limited demonstrate similar mortality and mal-
postpartum period does not improve milk production [199, 200]. nutrition among breastfed and artificially fed infants. If infants are
In two studies among women with low milk supply who received breastfed, early exclusive breastfeeding and extended antiretrovi-
education on optimal breastfeeding [201, 202], metoclopramide ral prophylaxis reduce the risk of HIV transmission [208].
provided no additional benefit compared with placebo. The AAP Women with HIV in the United States are advised not to
notes that galactagogues have a limited role in facilitating lacta- breastfeed because of the risk of maternal-infant transmission
tion; mothers experiencing milk production difficulties should and the availability of safe artificial feeding [26].
undergo assessment by a lactation specialist and be offered non- The WHO recommends that national or subnational health
pharmacologic measures to increase supply [188]. authorities determine recommendations regarding infant feeding
for HIV-positive mothers, balancing HIV prevention with pro-
Maternal diet during lactation tection from other causes of child mortality [209]. In countries
In two small trials, maternal dietary restrictions during lacta- where breastfeeding is recommended, antiretroviral prophylaxis
tion did not reduce the incidence of atopic eczema or the sever- for mothers and infants reduces HIV transmission. Exclusive
ity of existing disease [203]. Maternal supplementation with breastfeeding is recommended for the first 6 months, continu-
long-chain polyunsaturated fatty acids (LCPUFAs) during lac- ing through 1 year. When mothers decide to stop breastfeeding,
tation does not improve infant neurodevelopmental outcomes. they are advised to wean gradually, over 1 month, and mothers or
In two studies, LCPUFA supplementation increased infant infants receiving antiretroviral prophylaxis should continue for 1
head circumference [204]. A meta-analysis found limited evi- week after breastfeeding is fully stopped.
dence for LCPUFA supplementation during pregnancy and/or
lactation to reduce allergic diseases in children [205]. There is
insufficient evidence to recommend LCPUFA supplementation Contraception
during breastfeeding.
Key points
Contraindications • Postpartum educational interventions can increase
Breastfeeding is contraindicated in the setting of the following: contraceptive use and delay repeat pregnancy.
• Intrauterine device (IUD) placement <48 hours postpar-
• Infant with classic galactosemia (galactose-1-phosphate tum is not associated with infectious morbidity, but expul-
uridyltransferase deficiency) sion rates are higher than with placement >4 weeks. Since
• Maternal medications: many women do not present for postpartum follow-up,
• Mothers with current, active illicit drug use, in the overall IUD use is highest when inserted in the immedi-
absence of a coordinated treatment plan among mater- ate postpartum period.
nal and infant providers [206] • Postpartum tubal ligation (PPTL) is highly effective.
• Mothers requiring medications that are contraindi- However, the risk of regret is higher for PPTL than for
cated in breastfeeding interval TL.
• Maternal infectious disease: • Postpartum placement of the contraceptive implant shows
• Mothers who are human T-cell lymphotropic virus promise as an additional long-acting option for women early in
type I or II positive (e.g. HTLV) the postpartum period, with potentially less lactogenic effects
• Mothers with untreated brucellosis • Lactation amenorrhea is an effective, but not perfect, method
• Mothers with active herpetic lesions on the breast(s). of contraception, until the infant is 6 months old, begins
Mothers can continue to breastfeed on the unaffected complementary feeding, or the mother’s menses resume.
breast and provide expressed milk from the affected • Barrier methods are preferred during lactation compared
breast. with hormonal contraception because of theoretical effects
• Mothers with Varicella onset within 5 days before of hormonal methods on milk supply and hormone expo-
until 48 hours after delivery should be separated from sure for the infant.
Postpartum Care 367
Background TABLE 31.10: WHO Guidelines for Intrauterine Devices

Sexual activity is resumed by about 53% of women within Breastfeeding Not breastfeeding
6 weeks postpartum, with 41% attempting vaginal sex. By
8 weeks, about 65% attempt vaginal sex, rising to 8%–95% by Levonorgestrel-releasing (LNG) 2 1
3 months [210]. Women with uncomplicated vaginal births IUD, <48 hours postpartum
resume sex earlier compared to women who had perineal lac- Copper-bearing (Cu) IUD, <48 hours 1 1
erations, assisted vaginal births, or cesarean deliveries [211]. postpartum
However, by 1 year, sexual function returns to near pre-preg- LNG-IUD or Cu-IUD >48 hours to 3 3
nancy levels independent of mode of delivery [212]. Two-thirds <4 weeks
of women have unmet contraceptive needs after childbirth >4 weeks 1 1
[213]. Educational interventions during the postpartum hospi- Puerperal sepsis 4 4
talization increase contraceptive use compared with no inter-
Source: From World Health Organization. Medical Eligibility Criteria for Contraceptive
vention. Home visit programs reduce repeat pregnancies among
Use, 5th ed. Geneva: World Health Organization; 2015. Ref. [217], with
teenagers [214]. permission.
1: A condition for which there is no restriction for the use of the contraceptive
Contraceptive guidelines method.
A detailed review of contraception is beyond the scope of this 2: A condition where the advantages of using the method generally outweigh the
book. The WHO has published detailed guidelines regarding tim- theoretical or proven risks.
ing of initiation of postpartum contraception and other relative 3: A condition where the theoretical or proven risks usually outweigh the advantages
and absolute contraindications. Postpartum recommendations of using the method.
for healthy women are summarized in Tables 31.9 and 31.10. The 4: A condition that represents an unacceptable health risk if the contraceptive method
full guidelines are available online [215]. is used.
Intrauterine devices
TABLE 31.9: WHO Guidelines for Postpartum Contraception: IUDs are highly effective methods of contraception. Unfortu
Hormonal Contraception nately, less than 50% of women who express interest in an IUD
postpartum actually receive one [216]. Immediate postpartum
Progestin- Combined Hormonal placement has been shown to be safe and allows women to access
Only Methodsa Contraceptivesb contraception during the maternity hospitalization, though it is
Breastfeeding associated with an increased risk of expulsion compared with
<6 weeks postpartum 3/2c 4 delayed insertion [217, 218]. In an RCT of postplacental versus
delayed insertion, women randomized to postplacental inser-
>6 weeks to <6 months 1 3
tion were more likely to have a device inserted (98% versus 90.2%,
postpartum (primarily
p = 0.20). There were no differences between groups in IUD use
breastfeeding)
at 6 months postpartum (84.3% versus 76.5%). However, among
>6 months postpartum 1 2
women who were ineligible for the study and were advised to fol-
Not Breastfeeding
low up for IUD placement as part of routine postpartum care,
<21 days postpartum 1 (i) Without other risk only 26.8% were using an IUD at 6 months postpartum [219].
factors for VTE: 3 These results were confirmed in a more recent Cochrane review,
(ii) With other risk factors with IUD use at 6 months twice as likely, though expulsion was
for VTE: 3/4 four times more likely [220]. These results suggest that women
>21 days to 42 days 1 (i) Without other risk undergoing postplacental placement are more likely to use
factors for VTE: 2 an IUD than those advised to follow up for placement during
(ii) With other risk factors routine postpartum care. Immediate postplacental IUD place-
for VTE: 2/3 ment has been classified as category 1 or 2 by the Centers for
>42 days 1 1 Disease Control and Prevention’s U.S. Medical Eligibility Criteria
Source: From World Health Organization. Medical Eligibility Criteria for for Contraceptive Use [221].
Contraceptive Use, 5th ed. Geneva: World Health Organization; 2015. Ref.
[217], with permission. Implants
Abbreviation: VTE, venous thromboembolism. The contraceptive implant is another highly effective form of
1: A condition for which there is no restriction for the use of the contraceptive method. long-acting reversible contraception that can be placed imme-
2: A condition where the advantages of using the method generally outweigh the diately postpartum. The implant can be placed in the delivery
theoretical or proven risks. room immediately after delivery. However, unlike the IUD, it can
3: A condition where the theoretical or proven risks usually outweigh the advantages also be placed anytime during the delivery admission. Though
of using the method. theoretical concerns about lactogenesis in the setting of early
4: A condition that represents an unacceptable health risk if the contraceptive method
exposure to exogenous progesterone have been raised, a recent
is used.
a Progestogen-only pills, levonorgestrel and etonogestrel implants, depot medroxy-
RCT showed women who had the implant placed immediately
progesterone acetate, and norethisterone enanthate.
postpartum showed no difference in lactogenesis or inability
b Combined oral contraceptives, combined contraceptive patch, combined contra- to breastfeed [222]. Similar to concerns about low attendance, the
ceptive vaginal ring, and combined injectable contraceptives. postpartum visit, and financial barriers mentioned with regard
c 3: Depot medroxyprogesterone or norethisterone enanthate, 2: All other progesto- to the IUD, immediate postpartum placement of the implant
gen-only methods. alleviates those concerns. While an IUD cannot be placed in the
setting of intraamniotic infection, this is not a contraindication rates at 3 and 6 months postpartum compared with insertion
to immediate postpartum implant placement. at 6–8 weeks. A study comparing insertion at 6–8 weeks of the
LNG-IUD with the Cu T380A IUD found no differences in
Postpartum sterilization breastfeeding outcomes, infant growth, or development [237].
Sterilization is the most commonly used form of contraception WHO recommendations regarding timing of IUD insertion are
worldwide. Postpartum partial salpingectomy has a 1-year listed in Table 31.10.
failure rate of 0.6/1000 and a 10-year failure rate of 7.5/1000, The contraceptive implant is a progesterone-only option
which compares favorably with other sterilization methods [223, that can be placed immediately postpartum. Theoretical con-
224]. In a small RCT, operative times were shorter with postpar- cerns regarding the effect on lactogenesis and lactation exist, but
tum Filshie clip placement compared with the Pomeroy tech- level 1 data have not confirmed them. In a RCT comparing early
nique, but failure rates were not evaluated [225]. Another larger insertion (1–3 days postpartum) to standard insertion (n = 69),
RCT with 1400 women compared postpartum titanium clips to there was no difference in hours to lactogenesis (mean difference,
partial salpingectomy (Pomeroy technique); though this study –1.4 hours, 95% CI –10.6 to 7.7 hours) or lactation failure (risk
did not assess operative time, it did find that pregnancy probabil- difference 0.03, 95% CI –0.02 to 0.08) between the two groups
ity at 2 years was 0.017 and 0.004 for clips and salpingectomy, [238]. There was no difference in the percentage of women par-
respectively (p = 0.04) [226]. Maternal age <30 increases risk of tially or completely breastfeeding at 3 or 6 months. Women with
regret and request for tubal reversal [227]. Risk of regret is higher early insertion were more likely to be contracepting at 3 months.
among women undergoing postpartum tubal ligation (PPTL) A second small RCT (n = 24) used deuterium to index milk inges-
compared with interval tubal ligation (TL). Other risk factors for tion among healthy, term newborns of mothers randomized to
regret include ligation at the time of C-section, abrupt decision to immediate postpartum ENG implant placement or 6-week place-
undergo PPTL, and sterilization performed for obstetric indica- ment [239]. Participation was limited to nonobese women who
tions [228]. had previously breastfed for at least 3 months. No differences
In a cohort study of women planning postpartum sterilization, were found in milk intake. Therefore, the implant is also a good
one-third did not receive the procedure prior to hospital dis- contraceptive choice in women breastfeeding.
charge. Of these women, 47% were pregnant within 1 year, com-
pared with 22% of women who had not planned a postpartum
sterilization [229]. Women who desire but do not undergo post- Postpartum mood and anxiety disorders
partum sterilization are at high risk for unplanned pregnancy.
Key points
Among women who desired PPTL but did not receive it, the post-
• See Chap. 21 in Maternal-Fetal Evidence Based Guidelines
partum implant is an equally efficacious option (though less long
for details of management of mood disorders in pregnancy.
acting) that can be placed during the delivery hospitalization.
• One in seven women experience perinatal depression,
In recent years, some practices have begun to perform sal-
making it the most common complication of pregnancy.
pingectomy instead of TL. The rationale for this is prevention
• Risk factors include history of maternal anxiety or
of future tubal disease, decreased risk of ectopic pregnancy,
depression, lack of social support, traumatic birth expe-
and opportunity to decrease the risk of ovarian cancer [230].
rience, infant admission to neonatal intensive care, and
Additionally, no significant difference in length in hospital stay;
breastfeeding problems.
readmissions; blood transfusions; or postoperative complica-
• Routine screening is recommended at least once during
tions, infections, and fevers have been identified in cases of cesar-
perinatal care.
ean with and without salpingectomy [231]. While many have
• Positive screens require additional evaluation. If depres-
raised concerns about the surgical safety of this procedure, given
sion is diagnosed, referral and follow-up to ensure treat-
the increased blood supply, multiple studies, including two RCTs,
ment occurs are essential.
demonstrated no statically significant difference in blood loss and
intraoperative and postoperative complications for opportunistic Definition
salpingectomy compared to standard TL at the time of cesarean Perinatal depression (PND) is an episode of moderate or severe
delivery [232–233]. Based on these data, this approach can be major depressive disorder (MDD) beginning either during preg-
considered in the appropriately counseled patient. nancy or within 4–6 weeks after delivery [240, 241]. Perinatal
generalized anxiety disorder (GAD) is episode of GAD that
Contraception during breastfeeding occurs during pregnancy or 4–6 weeks postpartum.
Breastfeeding reduces fertility and prolongs amenorrhea after
childbirth. In the first 6 months after birth, cohort studies sug- Symptoms/Signs
gest that 0%–7.5% of women who are fully breastfeeding and In addition to typical depression symptoms of sadness, despair,
amenorrheic become pregnant [234, 235]. To maintain effective disrupted sleep and appetite, women with postpartum depression
protection against pregnancy, another method of contraception often experience prominent anxiety symptoms. The presentation
must be used as soon as menstruation resumes, the frequency or of GAD during postpartum is similar to GAD symptoms outside
duration of breastfeeds is reduced, bottle feeds are introduced, or of pregnancy.
the baby reaches 6 months of age [215].
WHO recommendations regarding hormonal contraception Epidemiology/Incidence
during breastfeeding are listed in Table 31.9. WHO guidelines The prevalence of PND is about 15%, affecting one in seven women
indicate that breastfeeding women can generally receive the [242, 243]. The prevalence of GAD during pregnancy is as high as
levonorgestrel intrauterine device (LNG-IUD) at <48 hours 29% and about 8%–16% in the postpartum period [244, 245]. It
postpartum [215]. In a small RCT [236], immediate postpartum should also be noted that much overlap exists between perinatal
placement of an LNG-IUD decreased exclusive breastfeeding anxiety and depression, and in many cases women have both.
Postpartum Care 369
Risk factors and associations Screening

Risk factors for PND and anxiety include past history of depres- Screening for PND should be performed using a validated
sion or anxiety, life stressors, lack of social support, unintended instrument, such as the EPDS. Despite the high prevalence and
pregnancy, lower income or education, domestic violence, and substantial morbidity associated with PND, this condition is
smoking. Additional risk factors for postpartum depression underrecognized. Major obstetric and pediatric medical organi-
include a traumatic birth experience, infant admission to neona- zations recommend routine screening. Although clinicians are
tal intensive care, and difficulties breastfeeding [246]. generally supportive of screening for PND, these attitudes do not
consistently translate into practice. In the United States, less than
Complications half of women are formally screened for PND [255]. Consistent
During the postpartum period, women with depression are at with such efforts, less than 50% of PND cases are detected in rou-
increased risk of maternal suicide, infanticide, and impaired tine clinical practice, with antenatal recognition rates reported
maternal sensitivity and attachment with the infant [247–250]. at 41% and postnatal rates ranging from 29% to 43% [256–258].
Women with depression are also less likely to engage in enrich- Screening alone does not ensure treatment: In a recent review, one
ing interactions with the child, such as reading or singing [251]. in five women who screened positive had at least one mental health
Anxiety symptoms have been associated with increased mater- visit [259]. Patient engagement strategies increased the chance that
nal health care utilization and reduced breastfeeding duration women with depression symptoms received mental health care.
[252, 253].
Treatment
Prevention Both psychotherapy and medications are effective for treat-
Psychosocial and psychological interventions are effective at ing PND. For further details on treatment of postpartum depres-
reducing postpartum depression. In a large meta-analysis, sion, see Chap. 21 in Maternal-Fetal Evidence Based Guidelines.
both lay and professional prevention interventions reduced As with any patient diagnosed with a health condition, women
postpartum depression symptoms (average RR 0.78, 95% CI with postpartum depression should be followed up to ensure
0.66–0.93). Effective strategies included postpartum home adequate engagement with treatment and response to therapy.
visits, telephone support, and interpersonal psychotherapy. Monitoring patient symptoms is essential, just as measurement
Another recent systematic review of mobile interventions (text of blood pressure is necessary to guide treatment of hyper-
messages, apps, etc.) in the prenatal and intraparutm peroid tension. A stepped care approach with serial measurement of
found an improvment in the Edinburgh Postnatal Depression symptoms with a tool such as the PHQ-9 to inform depression
Scale (EPDS), but no difference in anxiety or social support with management can increase the likelihood that patients receive
use of these interventions [254]. adequate therapy [260].
TABLE 31.11: Postpartum (Including Post-Cesarean) Advice Regarding Common Daily Life Activities
Advice Evidence Suggested Recommendations
Lifting Lifting increases intraabdominal pressure much less 1. Patients should continue lifting patterns as before pregnancy.
than Valsalva, forceful coughing, or rising from 2. Patients need an adequate postoperative analgesic regimen as
supine to erect position. necessary.
Climbing stairs Climbing stairs increases intraabdominal pressure 1. Patients should continue climbing stairs as before pregnancy.
much less than Valsalva, forceful coughing, or 2. Patients need an adequate postoperative analgesic regimen as
rising from supine to erect position. necessary.
Driving No consistent prospective or retrospective evidence. 1. Patients need an appropriate postoperative analgesic regimen that
does not cause a clouded sensorium when driving.
2. Patients may resume driving when comfortable with hand and foot
movements required for driving.
Exercise Limited retrospective and prospective evidence. 1. Patients need an appropriate postoperative analgesic regimen as
Forceful coughing increases intra-abdominal necessary.
pressure as much as jumping jacks. 2. Patients may resume pre-pregnancy exercise level.
3. Exercise program may need to be tailored for postpartum women.
4. Preprocedure and postprocedure recommendations should be
consistent.
Vaginal intercourse No retrospective or prospective evidence. 1. Women and their partners should make the decision to resume
intercourse mutually.
2. Women should use appropriate contraception after childbirth.
3. There is insufficient evidence as to when to resume vaginal intercourse.
Returning to work No consistent retrospective evidence; no prospective 1. Women should be encouraged to return to work relatively soon
evidence. postpregnancy; the usual times in the United States are 6 weeks after
vaginal and 8 weeks after cesarean delivery, but these are not based on
level 1 evidence.
2. Consider graded return to work, as tolerated.
Recommendation at discharge 8. Leeman L, Spearman M, Rogers R. Repair of obstetric perineal lacerations.

Am Fam Physician. 2003;68:1585–1590. [Guideline]
9. Kettle C, Dowswell T, Ismail KM. Continuous and interrupted sutur-
Women report receiving insufficient guidance from their provid-
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among black and Latina women. 1999;106:318–323. [II-1]
There is insufficient evidence for general postpartum advice 12. Fernando RJ, Sultan AH, Kettle C, et al. Methods of repair for obstetric anal
on common issues such as lifting, climbing stairs, driving, vagi- sphincter injury. Cochrane Database Syst Rev. 2013;8:CD002866. [Meta-
nal intercourse, and return to work. Suggestions based on this analysis: 6 RCTs, n = 588]
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ter injury after vaginal delivery: Results of a randomised controlled trial.
31.11 [264, 265]. The U.S. Department of Health and Human
BJOG. 2006;113(2):201–207. [RCT, n = 112]
Services physical activity guidelines for Americans recommends 14. Buppasiri P, Lumbiganon P, Thinkhamrop J, et al. Antibiotic prophylaxis
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surgery and in consultation with the obstetric provider [266, 267]. 15. American College of Obstetricians and Gynecologists’ Committee on
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weeks postpartum, but there are no data supporting this recom- [Guideline]
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confinement vs. laxative use after primary repair of a third-degree obstetric
weeks, and guidelines recommend that women resume inter-
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2005;18(2):CD00422. [Meta-analysis: 8 RCTs, n= 976]
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32
THE NEONATE
Laura De Angelis and Luca Ramenghi
Key points sexually transmitted infections. In the United States, the

benefits are not considered great enough for universal
• Necessary equipment for neonatal resuscitation must be male circumcision.
available at every delivery.
• Trained personnel in neonatal resuscitation should be Delivery room management
present at every delivery.
• An infant ≥37 weeks’ gestation, crying or breathing, For management of the normal neonate, see also Chap. 10. For
and with good muscle tone does not require resuscita- management specific to meconium, see Chap. 25. The perinatal
tion. Dry the baby, place the baby skin-to-skin with the period is the riskiest time in a child’s life [1–3]. Every newborn
mother, and cover the baby with dry linen to maintain infant has the right to receive a resuscitation performed at a
temperature. high level of competence. A competent resuscitation means that
• Provide routine care; provide warmth; assure open air- proper equipment and well-trained personnel must attend every
way; dry; and continuously evaluate color, activity and delivery. In addition, in case of prenatal and/or intrapartum con-
breathing. ditions which may impair neonatal transition, the presence of an
• Neonatal resuscitation must be started if the neo- experienced neonatal resuscitation team is required. Necessary
nate does not proceed through a successful transition, equipment is shown in Table 32.1.
regardless of the Apgar score at any time. Stimulate the
baby and open the airway. Routine suctioning is no lon- Initial steps of neonatal resuscitation
ger suggested. If further resuscitation is needed, it is fre- Due to the complex cardiorespiratory transition occurring at
quently due to poor respiratory transition and can usually birth, many newborn infants will experience apnea or bradycar-
be resolved with positive pressure ventilation. dia requiring stimulation, airway suctioning, and respiratory sup-
• Initial positive pressure ventilation should be per- port. The need for advanced resuscitation or medications is rare.
formed with room air. Oxygen should be titrated The first steps of neonatal resuscitation include the following:
according to pulse oximetry to achieve the target oxygen
saturations (Table 32.2). 1. Thermal management: Placing the infant under a pre-
• Low-risk infants are born ≥37 weeks’ gestation and have a heated radiant warmer, gently drying, and frequently
birth weight between 2500 and 4200 g, Apgar score of ≥7 replacing wet blankets with dry ones.
at 5 minutes, normal vital signs, and no signs of congenital 2. Opening the airway: Positioning the infant supine with
anomalies or respiratory distress. the head in midline position and a mild neck extension. As
• A difficult transition may be anticipated in infants who are nasopharyngeal suctioning may lead to vagal stimulation
at risk and may be due to hypothermia, hypoglycemia, or and subsequent bradycardia, airway suctioning should be
congenital anomalies. reserved for infants with airway obstruction or needing
• The preterm infant (especially <35 weeks) is at greater ventilatory support.
risk for complications in the delivery room and in the 3. Tactile stimulation: Gently rubbing the baby’s back,
nursery. With high-risk infants, there must be immediate trunk, or extremities may occasionally be necessary to
access to means of establishing intravenous (IV) access stimulate the baby to breathe, thus increasing heart rate.
and airway positive pressure support. In case of persistent apnea, positive pressure ventilation
• Late-preterm infants are those born at 34 0/7–366/7 weeks. should be promptly initiated.
While these infants are often the size and weight of term 4. Oxygen delivery: Newborn infants usually have low lev-
infants, they are physiologically more immature and at els of blood oxygen saturation during the first minutes of
higher risk for complications. life. Normal preductal oxygen saturations within the first
• Every nursery should have preexisting protocols to insti- 10 minutes after birth are shown in Table 32.2 (preductal
tute the best stabilization practices and should have clear pulse oximetry is measured at the upper right limb). As
statements of what conditions and degrees of illness are both insufficient and excessive oxygen may be harmful
appropriate to be admitted to the well-baby nursery. to the newborn infant, oxygen administration should be
• The majority of cases of cerebral palsy do not result carefully considered based on the infant’s condition and
from isolated intrapartum asphyxia with resultant oxygen saturation levels. Resuscitation of infants with a
hypoxemia and organ damage. gestational age ≥34 weeks should start using room air,
• The health benefits of circumcision include prevention of and oxygen concentration should be titrated according to
urinary tract infections, penile cancer, and transmission of infant response.
376 DOI: 10.1201/9781003102342-32

The Neonate 377
TABLE 32.1: Necessary Equipment for Neonatal Resuscitation TABLE 32.3: Apgar Score
in the Delivery Room
0 1 2
1. Suction equipment
Color Blue/pale Acrocyanosis Pink
a. Bulb syringe
Heart rate Absent <100 per minute >100 per minute
b. Mechanical suction and tubing
Reflex/irritability No response Grimace Cry/active withdrawal
c. Suction catheters of various sizes (recommended: 5 or 6, 8, 10, and
12 or 14 Fr) Tone Limp Some flexion Active motion
d. Feeding tubes (8 Fr with 20-mL syringe) Respirations Absent Weak cry/ Good/crying
e. Meconium aspirator hypoventilation
2. Bag mask equipment
a. Device for delivering PPV as neonatal resuscitation bag with adequately supported. Rarely, medications are necessary and
manometer or T-piece resuscitator should be readily available (refer to Table 32.4 for the full list).
b. Face masks in newborn and premature sizes The most commonly used are as follows:
c. Oxygen and compressed air sources
d. Oxygen blender with flow meter and tubing 1. Epinephrine 1:10,000: 0.1–0.3 mL/kg IV or via endotra-
3. Intubation equipment cheal tube given rapidly.
a. Laryngoscope with 00, 0, and 1 blades (for preterm and term infants) 2. Volume expanders: 0.9% saline, Ringer’s lactate, or whole
b. Endotracheal tubes (ETTs) (2.5–4.0 mm) blood. Dose is 10 mL/kg IV over 5–10 minutes.
c. Stylet 3. Sodium bicarbonate 0.5 mEq/mL: 2 mEq/kg IV given over
d. CO2 detector at least 2 minutes.
e. Laryngeal mask airway (for use in the case of a difficult intubation) 4. Naloxone hydrochloride 1.0 mg/mL: 0.1 mg/kg IV or IM
4. Other equipment given rapidly.
a. Clock (Apgar timer)
b. Alcohol Withholding or discontinuing neonatal resuscitation
c. Stethoscope Resuscitation should always be considered in cases with high rates
d. Gloves of survival and acceptable rates of morbidity. There are condi-
e. Scissors tions associated with high mortality and poor outcomes in which
f. Tape (for securing ETT and lines) withholding resuscitation may be appropriate, particularly when
g. Stopcocks there has been an opportunity for parental agreement. In cases of
h. Syringes (1–20 mL) uncertain prognosis, every single case should be addressed on an
i. Umbilical artery and vein tray with catheters (3.5 and 5 Fr) individual basis with a consistent and coordinated approach by
j. Warmer both the obstetric and neonatology teams according to the par-
k. Needles (25, 21, and 18 gauge) ents’ desire. Cases in which withholding of resuscitation should
l. Pulse oximeter be considered are the following:
m. Food-grade plastic wrap
n. Transporter • Gestational age ≤23 weeks
• Birth weight ≤400 g
Abbreviations: PPV, positive pressure ventilation; CO2, carbon dioxide.
• Anencephaly
• Some chromosomal abnormalities (e.g. trisomy 13)
Delivery room resuscitation
The need to start neonatal resuscitation is based on the evalua- It is appropriate to consider the interruption of resuscitation in
tion of breathing efforts, heart rate, and skin color. The algorithm infants who are born without a detectable heart rate, if the heart
in Figure 32.1 may be used as a guideline for the resuscitation rate remains undetectable at 10 minutes of life.
of a term or late preterm infant. The Apgar score (outlined
in Table 32.3) is a useful tool for communicating the infant’s Altered birth transition
adaptation but should not be used to guide resuscitation. The transition to extrauterine life generally occurs over the first
In case of persistent apnea and/or bradycardia after the first hours after birth. Delay in transition can occur for many rea-
steps of neonatal resuscitation, positive pressure ventilation sons—the most common are listed in Table 32.5.
should be promptly initiated. In infants with signs of poor transition (tachypnea, cyanosis,
Chest compressions may be necessary if bradycardia (heart mottled skin or pallor, tremors, and/or jitteriness), additional
rate less than 60 beats per minute) persists after breathing is measurements of the child’s vital signs should be considered.
These include temperature, blood glucose, and arterial blood sat-
uration (by pulse oximetry or blood gas analysis).
TABLE 32.2: Goal Preductal (Right-Hand)
Oxygen Saturations after Birth
TABLE 32.4: Medications Required for Resuscitation
1 minute 60%–65%
1. Epinephrine 1:10,000 (0.1 mg/mL)
2 minutes 65%–70% 2. Crystalloid fluids (normal saline or Ringer lactate)
3 minutes 70%–75% 3. Sodium bicarbonate 4.2% (5 mEq/10 mL)
4 minutes 75%–80% 4. Dextrose 10%
5 minutes 80%–85% 5. Normal saline flushes
10 minutes 85%–95% 6. Naloxone hydrochloride
Birth
Routine care
- Term gestation?
- Warmth
- Clear fluid? Yes
- Clear airway
- Breathing/crying?
- Dry and stimulate
- Good muscle tone?
(Routine suction is not indicated)
No
Yes No
Meconium present? Baby vigorous? Suction trachea
No Yes
Provide warmth
Position, clear airway
Dry, stimulate and reposition
Good respirations
Evaluate heart rate, Observational
Heart rate > 100
respirations, and color care
Pink
Apnea
Breathing
HR < 100
HR > 100
Central cyanosis Clear airway
PPV SpO2 monitoring
Consider CPAP
HR < 60
SpO2 out of target range
PPV
Chest compressions Good respirations
Heart rate > 100 Post-resuscitation care
Pink
HR < 60
If resuscitation efforts are not successful. Recheck:

- ventilation
Administer - chest compressions
epinephrine - intubation
- epinephrine delivery
Consider hypovolemia
FIGURE 32.1 Neonatal Resuscitation Program (NRP): guidelines for resuscitation. Abbreviations. PPV, positive pressure ventila-
tion; HR, heart rate.
Hypoglycemia All symptomatic and asymptomatic high-risk infants should be

Neonatal hypoglycemia is a common condition, often associated regularly checked for blood glucose levels in the first 24 hours of
with prenatal and perinatal risk factors (e.g. maternal diabetes, life. Routine screening of blood glucose is not needed in asymp-
large for gestational age [LGA], small for gestational age [SGA], tomatic term newborns who lack the risk factors for hypogly-
fetal growth restriction [FGR], prematurity), while rarely it may cemia. The diagnostic and treatment algorithm proposed by
be caused by congenital abnormalities of glucose metabolism. the AAP is presented in Table 32.6. In case of neonatal hypo-
The exact threshold to define hypoglycemia still remains unclear, glycemia, treatment should be promptly started. In case of pro-
but according to the 2011 report by the Committee of Fetus and longed (beyond the first 48–72 hours of life) and persistent low
Newborn of the American Academy of Pediatrics (AAP), hypo- blood glucose levels, a congenital hypoglycemia disorder must
glycemia is defined as a blood glucose <40 mg/dL in the first be suspected, and the neonate should be transferred to a third
4 hours of life and <45 mg/dL from 4 to 24 hours of life in high- level of care unit. Although persistent and prolonged neonatal
risk neonates [4]. hypoglycemia may result in brain injury and adverse long-term
The Neonate 379
TABLE 32.5: Factors Associated with Delayed Transition direct suction of the trachea are warranted. Intrapartum endo-
tracheal intubation and tracheal suction before the shoulder’s
Infant
delivery is no longer recommended in case of meconium-stained
Hypothermia
amniotic fluid (see Chap. 25) [6].
Hypoglycemia
Delayed pulmonary fluid absorption
Respiratory distress syndrome and other
Preterm birth (<37 weeks)
causes of respiratory insufficiency
Multiple births Respiratory distress syndrome is the most common respiratory
Small or large for gestational age (<2500 g or >4200 g) disorder in preterm infants, primarily caused by inadequate pul-
Postterm birth (≥42 weeks) monary surfactant production. Pulmonary surfactant is com-
Meconium-stained amniotic fluid posed of a mixture of phospholipids and specific proteins, and its
Low Apgar scores (<7 at 5 minutes) reduction/absence in the alveolar bed leads to compromised lung
Congenital problems (i.e. chromosomal abnormalities and compliance and a significant tendency to atelectasis with resul-
malformations) tant hypoxemia and hypercarbia.
Infection Signs of respiratory distress syndrome appear within the first
Mother hours from birth and include tachypnea (>60 breaths per minute),
Diabetes intercostal and subcostal retractions, nasal flaring, grunting, and
Hypertension or preeclampsia cyanosis. A progressive worsening for 48–72 hours is often fol-
lowed by a slow recovery. Other clinical features include hypoten-
Tocolysis
sion, acidosis, and hyperkalemia. Treatment consists of exogenous
Licit or illicit drug use
surfactant administration and respiratory support as needed. In
No prenatal care
the last three decades, introduction of antenatal steroids and exog-
Maternal age >35 years
enous surfactant has greatly improved neonatal outcomes [7].
In term neonates, signs of respiratory distress may be caused
neurodevelopmental outcomes, uncertainty exists about the glu- by a number of conditions, including congenital lung anoma-
cose threshold and the duration of hypoglycemia associated with lies, infections, pneumothorax, airway malformations (e.g. cho-
the risk of adverse neurologic consequences, especially in cases of anal atresia, tracheal-esophageal fistula), cardiovascular system
asymptomatic infants [5]. anomalies (e.g. congenital heart disease, congestive heart failure,
pulmonary hypertension), neurologic anomalies (e.g. central ner-
Meconium aspiration syndrome vous system infections, hypoxic injury, hydrocephalus), blood
Meconium is the first intestinal discharge of newborn infants, dyscrasia (anemia or polycythemia), or exposure to maternal
normally expelled within the first 24 hours from birth. It is a drugs. Specific diagnostic tests and treatments should address
thick, dark-greenish mass composed of substances ingested the underlying etiology.
during the intrauterine life, including intestinal epithelial cells,
lanugo, mucus, amniotic fluid, bile, and water. Intrauterine or Transient tachypnea of the newborn
intrapartum stress may cause the meconium to be expelled before Transient tachypnea of the newborn (TTN) is a benign, self-limit-
birth. Meconium-stained fluid is present in 8%–20% of deliveries, ing condition affecting term or near-term infants soon after birth,
and it is almost exclusively found in term or postterm infants. and it is characterized by the development of tachypnea (60–120
Meconium aspiration syndrome occurs intrapartum when a breaths per minute) associated with other signs of mild to mod-
newborn infant breathes a mixture of meconium or meconium- erate respiratory distress, including nasal flaring, grunting, and
stained amniotic fluid. The presence of meconium in the lungs retractions. Risk factors for TTN include cesarean delivery, pre-
may cause bronchial obstruction and lung inflammation, leading cipitous delivery, fetal polycythemia, and maternal diabetes. This
to a moderate to severe respiratory insufficiency. The treatment is condition is caused by a delayed resorption of fetal lung fluid.
based on the infant’s conditions at birth. If the baby is vigorous Oxygen administration and support therapy are usually enough
and cries immediately, routine neonatal care should be adminis- to resolve this condition, but severe cases may require continuous
tered. If the infant is floppy or lethargic, prompt intubation and positive airway pressure (CPAP). If the infant’s condition does not
TABLE 32.6: Hypoglycemia Management in Infants with Gestational Age ≥34 Weeks with Known Risk Factors for
Hypoglycemiaa According to the AAP
Symptomaticb Infant with BG <40 mg/dL Asymptomatic Infant (Birth to 4 hours of Age) Asymptomatic (4–24 hours of life)
Use IV glucose (2 mL/kg dextrose 10% IV and/ Initial feed within 1 hr after birth. BG screening Continue feeds every 2–3 hours. BG screening
or continuous infusion of dextrose 10% at 30 min after the first feed. before each feed. If BG <35 mg/dL, feed and
80–100 mL/kg per day). Maintain BG between If BG is <25 mg/dL, feed and recheck in 1 hr. recheck in 1 hr.
40 and 50 mg/dL. If BG persists <25 mg/dL, start IV dextrose, if If BG persists <35 mg/dL, start IV dextrose, if BG
BG is 25–40 mg/dL, refeed and use IV dextrose is 35–45 mg/dL, refeed and use IV dextrose as
as needed. needed.
TARGET GLUCOSE ≥45 mg/dL PRIOR TO ROUTINE FEEDINGS
a Risk factors for hypoglycemia: Maternal diabetes, large-for-gestational-age and small-for-gestational-age infants, prematurity.
b Symptomatic hypoglycemia: Irritability, tremors, jitteriness, exaggerated reflexes, high-pitched cry, seizures, lethargy, floppiness, cyanosis, apnea, and poor feeding.
Abbreviations: BG, blood glucose; IV, intravenously; hr, hour; min, minute.
quickly resolve, other diagnoses should be ruled out, including Care of the well newborn after L&D care
early-onset sepsis, pulmonary hypertension, congenital heart
disease, pneumonia, pneumothorax, central hyperventilation, All infants must be observed until they complete transition to
and congenital malformations. extrauterine life. A skilled staff member must assess vital signs
every 30 minutes for at least 2 hours from birth and observe
Common malformations affecting transition that the newborn is completely stable on its own. Completion of
Some congenital abnormalities may affect neonatal transition, transition includes thermostability, respiratory rate less than 60
thus requiring resuscitation maneuvers in the delivery room. breaths per minute, heart rate greater than 100 beats per minute,
Common malformations with stabilization procedures before and good muscle tone and sucking reflex.
transferring the infant to a tertiary care center are the following:
1. Choanal atresia (blockage of the nasal passageway): Secure

Newborn screening
an oral airway. Newborn screening identifies conditions that can affect a child’s
2. Pierre-Robin sequence (small mandible with relatively long-term health or survival. Early detection, diagnosis, and
large tongue): Secure an oral airway, consider intubation intervention can prevent death or disability and enable children
if inadequate. to reach their full potential. The newborn screening program var-
3. Congenital diaphragmatic hernia: Insertion of a nasogas- ies across countries and should be performed after 24 hours from
tric tube to decompress the stomach and intubation of the birth (a list of suggested tests is shown in Table 32.7) [8–10].
airway are required immediately after birth.
4. Abdominal wall defects (omphalocele and gastroschisis):
Cover the defect with a silo as soon as possible after birth.
Circumcision
Gastroschisis may require prompt surgical correction; Over 60% of the world male population is not circumcised, as
therefore, a surgical team should attend the delivery. this procedure is elective and tied in the past to religious prac-
5. Neural tube defects: The optimal management is contro- tices and not scientific benefit or considerations. The health
versial, but the goal is to keep the area moist and free of benefits to circumcision include prevention of urinary tract
contamination. The area may be covered with sterile plas- infection (from approximately 7–14/1000 to 1–2/1,000), penile
tic wrap, or the baby may be placed in a sterile plastic bag cancer (about 1000 circumcisions needed to prevent one penile
to just above the lesion. cancer), and transmission of sexually transmitted infections
(about 15% decrease in lifetime HIV risk). In the United States,
Type of nursery: Low- versus the benefits are not considered great enough to offer universal
elevated-risk neonates male circumcision. The AAP recommends that circumcision
be chosen by parents after having received all the informa-
Minimal intervention is needed for healthy infants following an tion about the risks and benefits associated with the procedure
uncomplicated delivery. Therefore, it is important to distinguish [11]. The World Health Organization suggests circumcision as
which infants are at low risk and can be admitted to the nursery a means to reduce the risk of acquiring HIV infection in high-
and which infants are at high risk and require further evaluation risk populations [12]. Complications of the procedure have been
and treatment. reported to range from 0.3% to 20% and include excessive bleed-
ing (1/100–1/1,000), infection (1–6/10,000), and penile injury
Low-risk infants (4/10,000).
These infants can be admitted without pediatric specialist con- Circumcision should be delayed in the following cases:
sultation. Low-risk infants are ≥37 weeks of gestation and have all
of the following characteristics: Birth weight between 2200 and • Suspected sepsis or bacteremia
4200 g, Apgar scores of ≥7 at 5 minutes, normal vital signs, and no • Family history of bleeding problems (until the child is fully
signs of congenital anomalies or respiratory distress. assessed by a hematologist)
• Genital abnormalities, including ambiguous genitalia, gen-
Elevated-risk infants ital tract anomalies (micropenis hypospadias, epispadias,
Elevated-risk infants require pediatric specialist consultation or chordae)
before being admitted to the nursery. The following conditions
should be evaluated: Infants at risk for neonatal abstinence syn- Performing a circumcision
drome, suspected sepsis, rupture of membranes longer than Prior to circumcision, infants should have completed transition,
16 hours, maternal vaginal/rectal swab positive for group B strep- voided at least once, and been fasting for 1 hour prior to the pro-
tococcus (GBS) inadequately treated with maternal prophylaxis cedure. Pain control should be utilized and can include dorsal
before birth, maternal temperature higher than 100.4°F (38°C) penile nerve block, topical analgesic, or subcutaneous ring block.
within 24 hours from delivery, infants of diabetic mothers, Sucrose solution and pacifier sucking may be used to reduce pain
infants born outside the hospital, infants of uncertain gestation, perception. Techniques for circumcision include the Mogen,
gestational age <37 weeks, and birth weight <2200 g or >4200 g. Plastibell, and Gomco. After the procedure, breastfeeding or bot-
Late-preterm infants (gestational age 34 +0 –36+6) weeks are tle feeding is an excellent pain control method. If needed, acet-
often the size of a term infant but have an increased risk of hypo- aminophen (12–15 mg/kg/dose) may be administered. A gauze
thermia, hypoglycemia, dehydration, and poor feeding. The AAP wrap is no longer recommended after the procedure. The area
recommends that late-preterm infants should receive special should be kept clean with plain water and covered with lubricant
attention prior to discharge and close outpatient follow-up in for up to 1 week until completely healed. The parents should be
order to prevent rehospitalization. told to expect a white-yellow discharge for 5–7 days.
The Neonate 381
TABLE 32.7: Disorders Recommended by the American TABLE 32.8: Survival to Discharge at Very Early (22–28
College of Medical Genetics Task Force for Inclusion Weeks) Gestational Ages
in Newborn Screeninga
Gestational Survival to Survival to Discharge without
Disorders of Organic Acid Metabolism Age (weeks) Discharge (all) Major Morbiditiesa
Isovaleric acidemia 22 9% 0%
Glutaric aciduria type 1 23 33% 0.75%
3-hydroxy-3-methylglutaric aciduria 24 65% 6%
Multiple carboxylase deficiency 25 81% 20%
Methylmalonic acidemia, mutase deficiency form 26 87% 26%
3-methylcrotonyl-CoA carboxylase deficiency 27 94% 47%
Methylmalonic acidemia, Cb1 A and Cb1 B forms 28 94% 56%
Propionic acidemia
Source: Data from Ref. 11.
Beta-ketothiolase deficiency a No necrotizing enterocolitis, sepsis, meningitis, bronchopulmonary dysplasia,
Disorders of Fatty Acid Metabolism severe intraventricular hemorrhage, periventricular leukomalacia, or retinopathy
Medium-chain acyl-CoA dehydrogenase deficiency of prematurity grade 3 or higher.
Very long-chain acyl-CoA dehydrogenase deficiency
Long-chain L-3-hydroxy acyl-CoA dehydrogenase deficiency
respiratory failure, facilitating lung recruitment. The presence of
Trifunctional protein deficiency
proper equipment and trained personnel for neonatal stabiliza-
Carnitine uptake defect tion and transport will optimize survival.
Disorders of Amino Acid Metabolism A detailed review of the topic of neonatal care of the preterm
Phenylketonuria infant is beyond the scope of this book. Table 32.8 shows recent
Maple syrup urine disease data on survival rates at early gestational ages (22–28 weeks) that
Homocystinuria may be considered for prenatal counseling [13].
Citrullinemia
Argininosuccinic acidemia Neonatal encephalopathy and cerebral palsy
Tyrosinemia type 1
Hemoglobinopathies Neonatal encephalopathy
Sickle cell anemia Neonatal encephalopathy is defined as a pathologic neurobehav-
Hemoglobin S-beta-thalassemia ioral state with altered level of consciousness and other signs of
Hemoglobin sickle cell disease neurologic and motor dysfunction. It is caused by many condi-
tions, both transitory (e.g. hypoglycemia, maternal drugs) and
Other Disorders
permanent (e.g. hypoxic-ischemic encephalopathy, neonatal
Congenital hypothyroidism
stroke), which may result in a permanent neurologic impairment
Biotinidase deficiency
[14, 15].
Congenital adrenal hyperplasia
Galactosemia Hypoxic-ischemic encephalopathy
Hearing deficiency Hypoxic-ischemic encephalopathy (HIE) is a neonatal enceph-
Cystic fibrosis alopathy caused by altered gas exchange with hypoxia and/or
a reduction in blood flow occurring in the perinatal period.
a The American College of Medical Genetics task force also recommends reporting
an additional 25 disorders (“secondary targets”) that can be detected through
A comprehensive assessment of neonatal status, maternal
screening but that do not meet the criteria for primary disorders [6]. At this time, history, obstetric antecedents, intrapartum factors, and pla-
there is state-to-state variation in newborn screening; a list of the disorders that cental pathology is required in order to determine if hypoxic-
are screened for by each state is available at http://genes-r-us.uthscsa.edu. ischemia occurred in close temporal proximity to labor and
Abbreviations: CoA, coenzyme A; Cb1 A, cobalamin A; Cb1 B, cobalamin B. delivery. The following conditions increase the likelihood that
hypoxia-ischemia played a role in causing neonatal encepha-
lopathy [16]:
Care of the preterm infant
• Apgar score ≤6 at 5 minutes (a 5 minute-Apgar score ≥7
Infants born at gestational age <36 weeks are at high risk of pre- renders HIE unlikely)
term-related complications. If a preterm delivery is anticipated, • Need for resuscitation with ventilatory support for longer
the delivery should be attended by a team of neonatal inten- than 10 minutes and/or fetal umbilical artery pH <7.0 or
sive care unit (NICU) personnel (physician, nurse, and respira- base deficit ≥12 mmol/L
tory therapist). Management of the infant includes accentuated • Magnetic resonance (MR) imaging or MR spectroscopy
attention to drying and maintaining thermal stability and close showing hypoxic-ischemic pattern of cerebral imaging
observation of blood glucose, fluid requirements, and respiratory (deep nuclear gray matter or watershed cortical injury)
function. Infants with a gestational <29 weeks should be wrapped • Multisystemic organ failure
in a polyethylene bag in order to prevent evaporative heat loss. • Sentinel hypoxic/ischemic event immediately before
In high-risk infants, the prophylactic placement of an umbilical or during labor and delivery (uterine rupture, umbili-
venous line should be considered. In addition, early institution cal cord prolapse, maternal cardiovascular collapse, fetal
of positive airway pressure support may be necessary to prevent exsanguination)
• Fetal heart rate pattern suggesting an acute peripartum or or posture, appearing early in life and not as a result of a recog-
intrapartum event nized progressive disease.
• Lack of other contributing factors such as infection, feto- Prevention is elusive. Most cases of cerebral palsy do not result
maternal hemorrhage, or chronic placental lesions from isolated intrapartum asphyxia with resultant hypoxemia
• Development of spastic quadriplegia or dyskinetic cerebral and organ damage [15]. Risk factors associated with cerebral
palsy (other types of cerebral palsy are less likely to be asso- palsy and/or neonatal encephalopathy are as follows:
ciated with acute intrapartum hypoxic-ischemic events)
• Increasing maternal age
Therapeutic hypothermia is recommended for infants ≥35 • Family history of seizures or neurologic disease
weeks’ gestation with evidence of moderate-to-severe HIE. • Maternal history of infertility treatment or previous neo-
Several randomized controlled trials have demonstrated lower natal death
mortality and an improved neurodevelopmental outcome at 18 • Severe preeclampsia
months. Therapeutic hypothermia should be performed in a • FGR
third-level neonatal care center [17]. • Congenital malformations or genetic abnormalities
It is important when considering fetal heart rate to distinguish • Autoimmune and coagulation disorders
between patients who present with an abnormal tracing and • Infections
those who develop an abnormal tracing during delivery. A heart
rate pattern that converts from a category I tracing to a category Apgar scores and cerebral palsy
III tracing is suggestive of a hypoxic-ischemic event. 0–3 at 5 minutes: 0.3–1.0% of babies with cerebral palsy
HIE can be a result of antenatal factors alone, intrapartum 0–3 at 10 minutes: 10% of babies with cerebral palsy (but rates drop to
factors alone, or both in combination. Around 25% of surviving 5% if scores improve at 15 and 20 minutes)
infants will have long-term neurologic sequelae [15]. <3 at 15 minutes: 53% mortality, 36% of survivors with cerebral palsy
The usual progression of events is as follows:
<3 at 20 minutes: 60% mortality, 57% of survivors with cerebral palsy
Seventy-five percent of children with cerebral palsy had normal

Antenatal Intrapartum Apgar scores at birth [12].
Factors/Injury hypoxia/ischemia
Criticism of the management of labor should not be confused
with cerebral palsy causation because the two often may not be
linked.
References
Neonatal
Encephalopathy 1. Gomella TL, Cunningham MD, Eyal FG, et al., eds. Neonatology:
Management, Procedures, On-Call Problems, Diseases, and Drugs. 7th ed.
New York, NY: McGraw-Hill; 2013. [Review]
2. Kattwinkel J, ed. Textbook of Neonatal Resuscitation. 6th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2011. [Review]
3. Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal resuscita-
tion: 2015 American Heart Association Guidelines Update for Cardiopul
monary Resuscitation and Emergency Cardiovascular Care. Circulation.
2015;132(18 Suppl 2):S543–560. [Review]
Neurodevelopmental 4. Adamkin DH, Committee on Fetus and Newborn. Clinical report—
Sequelae Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics.
+/– Cerebral Palsy 2011;127(3):575–579.
5. Thompson-Branch A, Havranek T. Neonatal hypoglycemia. Pediatr Rev.
2017;38(4):147–157. [Review]
6. Chabra S. Evolution of delivery room management for meconium-stained
Timing of neonatal encephalopathy
infants: Recent updates. Adv Neonatal Care. 2018;18(4):267–275. [Review]
Estimating the time when neonatal encephalopathy occurred is 7. Rubarth LB, Quinn J. Respiratory development and respiratory distress
extremely difficult. Some studies [12] reported the incidence of syndrome. Neonatal Netw. 2015;34(4):231–238. [Review]
risk factors related to this condition: 8. Natowicz M. Newborn screening—setting evidence-based policy for pro-
tection. N Engl J Med. 2005;353:867–870. [Review]
9. Watson MS, Mann MY, Lloyd-Puryear MA, et al.; American College of
• 69%: Only antepartum risk factors Medical Genetics Newborn Screening Expert Group. Newborn Screening:
• 25%: B
oth antepartum risk factors and evidence for intra- Toward a Uniform Screening Panel and System. Rockville, MD: Maternal
partum hypoxia and Child Health Bureau; 2005. [Review]
• 4%: Intrapartum hypoxia without antepartum risk factors 10. https://www.acmg.net/. Accessed October 1, 2020. [Review]
11. American Academy of Pediatrics, Task Force on Circumcision.
• 2%: No recognized risk factors
Circumcision policy statement. Pediatrics. 1999;103(3):686–693. [Review;
revised September 1, 2012]
Therefore, the incidence of neonatal encephalopathy attributed 12. Prabhakaran S, Ljuhar D, Coleman R, Nataraja RM. Circumcision in the
to intrapartum hypoxia in the absence of other preconception or paediatric patient: A review of indications, technique and complications. J
antepartum abnormalities is about 1.6/10,000 infants [14, 15]. Paediatr Child Health. 2018;54(12):1299–1307. [Review]
13. Stoll BJ, Hansen NI, Bell EF, et al. Eunice Kennedy Shriver National
Institute of Child Health and Human Development Neonatal Research
Cerebral palsy Network. Trends in care practices, morbidity, and mortality of
Cerebral palsy is a chronic neuromuscular disability affecting extremely preterm neonates, 1993-2012. JAMA. 2015;314(10):1039–1051.
2/1000 live births, characterized by aberrant control of movement [Epidemiologic data]
The Neonate 383
14. Hankins GD, Speer M. Defining the pathogenesis and pathophysiol- 16. American College of Obstetricians and Gynecologists Task Force on
ogy of neonatal encephalopathy and cerebral palsy. Obstet Gynecol. Neonatal Encephalopathy. Neonatal encephalopathy and neurologic out-
2003;102:628–636. [Review] come, second edition. Obstet Gynecol. 2014;123(4):896–901. [Guideline]
15. Clark SM, Basraon AK, Hankins GD. Intrapartum asphyxia, neonatal 17. Wassink G, Davidson JO, Dhillon SK, et al. Therapeutic hypothermia in
encephalopathy, cerebral palsy, and obstetric interventions in the term and neonatal hypoxic-ischemic encephalopathy. Curr Neurol Neurosci Rep.
near-term infant. Neoreviews. 2013;14(1):e13–e21. [Review] 2019;19(2):2. [Review]
33
THE ADNEXAL MASS
Connie D. Cao and Norman G. Rosenblum
Key points Definition/Diagnosis

• There are no randomized trials on interventions for An adnexal mass is any mass in the ovary or tube or attached to
adnexal masses in pregnancy. them (adnexa). There is an increase in the detection of asymptomatic
• Ultrasound, with transvaginal and Doppler capabilities, is adnexal masses in pregnancy due to the increase in prenatal ultra-
the mainstay of diagnosis and prognosis. sounds. The vast majority (>90%) of adnexal masses in pregnancy
• Most adnexal masses are simple cysts and will resolve. are ovarian. Most are benign simple cysts under 5 cm. The diagno-
The most common persistent adnexal mass in pregnancy sis is most accurately made by ultrasound, even if it is possible to
is a mature teratoma. diagnose an adnexal mass by bimanual physical exam. A persistent
• The risk of an adnexal mass representing malignancy adnexal mass is one that does not resolve by the second trimester.
is 0.93%–4.5%. Half of all ovarian cancers in pregnancy
are epithelial, and two-thirds of those are of low malignant Epidemiology/Incidence
potential.
• For a suspicious adnexal mass in pregnancy, early pre- In earlier studies, approximately 1%–4% of women were diag-
operative consultation with a gynecologic oncologist, nosed with an adnexal mass in pregnancy with persistence of only
anesthesiologist, and neonatologist is recommended. 1 in 200 to 1 in 600 into the second trimester [1, 2]. A recent study
• Complications related to the persistent adnexal mass looked at ultrasounds of asymptomatic women during nuchal
in gravid patients may include severe pain (5%–26%), translucency evaluation (11–14 weeks) and found an incidence of
ovarian torsion (7%–12%), cyst rupture (9%), pelvic 25%, with 85% of those resolving during the pregnancy with-
impaction and obstruction of labor (17%), and ovarian out intervention [3]. This dramatic increase in incidence is likely
cancer (<5%). secondary to the early prevalence of functional cysts that spon-
• CA-125 is nonspecific and can be elevated simply due to taneously resolve during the pregnancy. A separate study look-
pregnancy; however, between 15 weeks and delivery, levels ing at over 7.7 million deliveries from 2003 to 2011 showed the
between 1000 and 10,000 units/mL cannot be attributed to incidence of ovarian masses to be 0.25% at the time of delivery [4].
pregnancy alone. The majority of the adnexal masses are simple cysts such as
• Most adnexal masses can be safely followed with serial corpus luteal or other functional cysts. Most of them (up to 90%),
ultrasounds. Management in the first trimester is almost when identified during pregnancy, will spontaneously regress
uniformly expectant unless the clinical presentation is prior to the second trimester. Characteristics found to be pre-
acute or malignancy is suspected. Although there are dictive of persistence of adnexal mass in pregnancy include com-
no strict guidelines, surgery is appropriate for adnexal plex sonographic appearance and larger size of the mass [5]. Two
masses that persist in the second trimester and are ≥10 cm, adnexal conditions are specifically associated with pregnancy
symptomatic, or have sonographic features concerning and spontaneously regress in the postpartum period requiring no
for malignancy (i.e. complex masses consisting of both further treatment: Luteomas of pregnancy and theca lutein cysts.
solid and cystic components with nodularity, thick sep- About 0.93%–4.5% of adnexal masses found in pregnancy are
tations, irregular borders, irregular echoes, or papillary malignant ovarian tumors [6, 7]. The incidence of ovarian cancer
projections). in pregnancy is rare: ˜1 per 56,000 deliveries [6]. It is the fifth most
• When necessary and feasible, surgery should be sched- common cancer diagnosed in pregnancy and the second most
uled in the early second trimester (e.g. 14–18 weeks) common gynecologic cancer, following cervical cancer [4, 8].
when organogenesis is complete, most spontaneous
abortions have occurred, and the risk for preterm deliv-
ery is low.
Classification
• Intervention should be considered at any point in gesta- It is important to generate a differential diagnosis guided by
tion if a mass is complex or suspicious for malignancy ultrasound characteristics (Figure 33.1) of the mass and clini-
and increases in size. If a suspicious adnexal mass is cal presentation. The differential includes functional cysts, cyst-
identified incidentally at the time of cesarean section, it adenomas, corpus luteum, teratomas, endometriomas, theca
should be removed and not simply aspirated. lutein cysts, and malignant ovarian cancers (Table 33.1). Among
• If a malignant neoplasm of the ovary is found at the persistent adnexal masses diagnosed during pregnancy (age
time of exploration, the surgeon should consult a gyneco- group 18–35 years), mature teratomas are the most common
logic oncologist to properly stage the disease. For more (Table 33.2). Of note, ovarian malignancies are more commonly
advanced ovarian cancer, the degree of cytoreductive germ cell tumors among pregnant women (30%) compared to
surgery and the timing of initiation of chemotherapy will the general population (<5%), likely reflecting the younger age of
depend on fetal viability and maternal choice. women in the former group [6, 9].
384 DOI: 10.1201/9781003102342-33

The Adnexal Mass 385
B1 Unilocular cyst B2 Presence of solid components B3 Presence of acoustic B4 Smooth multilocular tumor B5 No blood flow (color score 1)
where the largest solid component shadows with largest diameter < 100 mm
has a largest diameter < 7 mm
M1 Irregular solid tumor M2 Presence of ascites M3 At least four papillary M4 Irregular multilocular-solid B5 Very strong blood flow
structures tumor with largest diameter ≥ (color score 4)
100 mm
FIGURE 33.1 Simple rules: Sonographic images for features of ovarian masses. (From Abramowicz JS, Timmerman D. Ovarian
mass-differentiating benign from malignant: The value of the International Ovarian Tumor Analysis ultrasound rules. Am J Obstet
Gynecol. 2017;217(6):652–660. [III] Ref. [19], with permission.)
Risk factors/Associations the incidence of enlarged ovaries and cysts, and therefore adnexal
masses.
Maternal age is a risk factor for malignancy, but ovarian malig-
nancies can occur at any reproductive age. Sonographic scoring Complications
systems have been proposed to optimize ultrasound examination
as a diagnostic test for ovarian malignancies, but these scoring Complications related to the persistent adnexal mass in gravid
systems require validation in pregnancy [10]. One study among patients include severe pain (26%), ovarian torsion (1%–22%),
nonpregnant women found several factors associated with an cyst rupture (0%–9%), pelvic impaction and obstruction of
increased risk of malignancy: Age >55, postmenopausal status, labor (2%–17%), and ovarian cancer (<5%) [13–16]. Ovarian tor-
weight ≤200 lb, complex or solid morphology (versus cystic), sion, the most common significant complication in pregnancy,
presence of ascites, tumor bilaterality, tumor diameter >10 cm, occurs usually in less than 15% of the cases and is most common
and CA-125 ≥35. None of the cystic tumors in that study were in adnexal masses with sizes between 6 and 8 cm. Approximately
malignant [11]. Furthermore, a large study in postmenopausal 60% of torsions occur between 10 and 17 weeks of gestation, and
women with unilocular cystic masses <10 cm found none to have less than 6% occur after 20 weeks of gestation [15]. Of the ovar-
malignancy [12]. Assisted reproductive technologies increase ian malignancies diagnosed in pregnancy, the majority represent
TABLE 33.2: Frequency of Adnexal Masses Diagnosed in

TABLE 33.1: Differential Diagnosis for Adnexal Masses in Pregnancy
Pregnancy Diagnosis Percentage
Benign Malignant
Benign Mass (95%)
Corpus luteum Germ cell tumor (e.g. Dermoid 37
Simple cyst dysgerminoma) Cystadenoma 24
Hemorrhagic cyst Cystadenocarcinoma Corpus luteum 17
Benign mature cystic teratoma (dermoid) Borderline tumors of low Endometrioma 5
Endometrioma malignant potential Leiomyoma 5
Myoma (pedunculated) Sex-cord stromal tumor (e.g.
Other (paraovarian, luteoma, theca-lutein) 12
Luteoma granulosa cell or Sertoli-
Malignant (5%)
Hyperstimulated ovary Leydig cell tumors)
Epithelial 50
Hydrosalpinx Metastatic cancer to ovary
Theca-lutein cyst/Hyperreactio luteinalis (Krukenberg) Low malignant potential 66
Ectopic/heterotopic pregnancy Invasive 33
Cystadenoma Germ cell tumor 30
Peritoneal cyst Sex-cord stromal tumor 20
Paraovarian/paratubal cyst Source: From Horowitz NS. Management of adnexal masses in pregnancy. Clin
Source: From McMinn E, Schwartz N. Adnexal masses in pregnancy. Clin Obstet Obstet Gynecol. 2011;54(4):519–527. [Review; III] Ref. [9], with
Gynecol. 2020;63(2):392–404. [Review; III] Ref. [36], with permission. permission.
epithelial tumors of low malignant potential, germ cell tumors, or management of adnexal masses in pregnancy, but a review of the
sex cord stromal tumors [9]. topic with respect to each type of adnexal mass and the useful-
ness of MRI has been published [20]. The conclusions are that
Management MRI can assist ultrasound in distinguishing exophytic leiomy-
oma, degenerating leiomyoma, endometrioma, dermoid cyst, and
Principles decidualized endometrioma from other masses. Furthermore, it
No randomized trials are available to guide the management supports the value of MRI to detect massive ovarian edema and
of adnexal masses in pregnancy. As about 90% of these masses distant findings such as widespread ascites, peritoneal implants,
resolve, expectant management with serial ultrasounds is and lymphadenopathy that can help distinguish benign from
usually appropriate in the vast majority of clinical situations malignant masses.
[17]. If malignancy is suspected, the best gestational age for sur-
gery is about 16–18 weeks, as the risk of loss is lowest [9]. Laboratory
Most tumor markers may be elevated in normal pregnancy and
Workup are generally not helpful in distinguishing between a benign or
Ultrasound malignant ovarian mass in pregnancy. For example, up to 16%
Highly skilled ultrasonographers may be able to accurately diag- of pregnant patients may have an elevated CA-125 [21]. Levels of
nose complications of adnexal masses in pregnancy (e.g. cancer CA-125 peak in the first trimester (range, 7–251 units/mL) and
and torsion) without surgical intervention. Suspicious character- decrease consistently thereafter. Low-level elevations in preg-
istics of an adnexal mass include complex masses consisting of nancy are typically not associated with malignancy [22]. However,
both solid and cystic components with nodularity, thick septa- CA-125 levels from 1000 to 10,000 units/mL after 15 weeks of
tions, irregular borders, irregular echoes, or papillary projections gestation are more likely to be cancer [9].
[10, 16]. In one study in pregnant women, ultrasound correctly
diagnosed 95% of dermoids, 80% of endometriomas, and 71% of Therapy
simple cysts. Of 14 masses with suspicious sonographic features, Treatment planning is dependent upon the timeliness of detection of
only 1 was a malignancy [16]. Even unilocular cysts <10 cm in post- an adnexal mass in pregnancy. When an adnexal mass is diagnosed
menopausal women can be safely followed by serial ultrasounds in the first trimester, the likelihood of a functional etiology is high,
until they resolve or develop solid and/or wall abnormalities as is the probability of spontaneous resolution. Two adnexal condi-
prompting surgical intervention secondary to a high suspicion tions are specifically associated with pregnancy and spontaneously
of malignancy [12]. In addition to routine ultrasonography, color regress in the postpartum period requiring no further treatment:
Doppler studies may be used to distinguish between malig- Luteomas of pregnancy and theca lutein cysts. In pregnant women,
nant and benign adnexal masses [18]. Low pulsatility index of most simple cysts <6 cm have been shown to spontaneously resolve
<1.0 and low impedance are associated with ovarian neoplasms. [5, 23–25]. Women who are identified via sonography as low risk for
Transvaginal ultrasound may also help to better visualize malignancy may be safely followed [14, 25].
the adnexal mass. Recently, the International Ovarian Tumor Although there are no strict guidelines, surgery is appropriate
Analysis (IOTA) group described the Simple Rules (Table 33.3 for adnexal masses that persist in the second trimester and
and Figure 33.1) that are based on a set of ultrasound features are ≥10 cm, or are symptomatic, or have sonographic features
indicative of benign tumors and malignant tumors (M-features), concerning for malignancy (i.e. mixed solid and cystic compo-
which has been shown to have an area under the curve (AUC) of nents) (Figure 33.2 and Table 33.4) [9]. When necessary and feasi-
0.917 [10, 19]. After 20 weeks, adnexal masses are more difficult to ble, surgery should be scheduled in the early second trimester
see by ultrasound, given the larger uterine size. However, defini- (e.g. 14–28 weeks) after most functional cysts have resolved,
tive diagnosis requires pathologic confirmation. organogenesis is complete, most spontaneous losses have
occurred, and the risk for preterm delivery is low. Additionally,
Magnetic resonance imaging surgical intervention at any point may be indicated if torsion,
Although ultrasound is the primary imaging modality, magnetic rupture, or hemorrhage is identified, or if an already suspicious
resonance imaging (MRI) has been used to characterize adnexal mass rapidly increases in size. Progesterone supplementation is
masses. There are insufficient data to assess the effect of MRI on necessary if the corpus luteum is removed prior to 8 weeks [9].
TABLE 33.3: Simple Rules TABLE 33.4: Sonographic Features That Have Been Associated
with an Increased Risk of Malignancy
Benign Features Malignant Features
Size >7 cm
Unilocular cyst Irregular solid tumor
Solid components or heterogeneous/complex appearance
Solid component <7 mm in Ascites
Excrescences/papillary structures
diameter
Internal septations (especially if thick or vascular)
Presence of acoustic shadows ≥4 papillary structures
Irregular borders
Smooth multilocular tumor with Irregular, multilocular mass>10 cm
largest diameter <10 cm in diameter Increased vascularity
No detectable color Doppler signal Strong color Doppler signal Low-resistance blood flow
Ascites
Source: From Abramowicz JS, Timmerman D. Ovarian mass-differentiating
Persistence or progression on follow-up imaging
benign from malignant: The value of the International Ovarian Tumor
Analysis ultrasound rules. Am J Obstet Gynecol. 2017;217(6):652–660. Source: From McMinn E, Schwartz N. Adnexal masses in pregnancy. Clin Obstet
[III] Ref. [19], with permission. Gynecol. 2020;63(2):392–404. [Review; III] Ref. [36], with permission.
Largest diameter ≥10 cm, Torsion/rupture/hemorrhage

Largest diameter <10 cm,
concerning ultrasound identified, or if suspicious
simple, and asymptomatic
features, and/or symptomatic mass grows rapidly
Follow with ultrasound Follow with ultrasound Surgical exploration
If persistent into 2nd trimester,

surgical exploration between
16 and 18 weeks gestation
FIGURE 33.2 Management of the ovarian mass in pregnancy.
For adnexal masses suspicious for malignancy in pregnancy, tumors in pregnancy, the available case series were too limited
the management is similar to that in premenopausal women. for conclusions to be drawn on risks and benefits of laparoscopy
Early preoperative consultation with a gynecologic oncolo- [30]. Nevertheless, laparoscopy has been demonstrated as safe
gist, anesthesiologist, and neonatologist is recommended [22]. in all trimesters of pregnancy, and adjustments should be made
Consultation at <15 weeks is recommended for better operative accordingly depending on the size of the gravid uterus (i.e. using
planning. nonintrauterine retractors), location of abdominal entry, and
patient positioning in the left lateral decubitus position [17].
Surgery Other intraoperative and postoperative considerations should
Many studies have shown that planned abdominal surgery in be kept in mind when performing laparoscopy on a preg-
pregnancy is safe [14, 15, 26]. Removal of adnexal masses can be nant patient (Table 33.5). Preoperative and postoperative fetal
accomplished via laparoscopy, laparotomy, or at the time of cesar- doptones are recommended if the fetus is considered previable,
ean section. When exploration is necessary, all efforts should and continuous electronic fetal heart monitoring can be consid-
be made to avoid unnecessary manipulation of the uterus to ered when the fetus is viable [31, 32], it is physically possible to
minimize premature uterine contractions. While traditionally a perform monitoring, and the nature of the planned surgery will
laparotomy was the standard recommendation used to explore allow for the interruption or alteration of the procedure to per-
the abdomen of a pregnant patient with an adnexal mass, lapa- form an emergent cesarean section if needed [9, 33].
roscopy is currently not only an acceptable alternative (in experi- If a suspicious adnexal mass is identified incidentally at the
enced hands) but also is preferred in cases with low suspicion of time of cesarean section, it should be removed and not simply
malignancy, as it offers the benefit of a more expeditious recov- aspirated [34]. With aspiration and cytologic evaluation, malig-
ery [27–29]. In a Cochrane review on laparoscopy for adnexal nancy could be missed [35].
TABLE 33.5: Guidelines for Laparoscopy in Pregnancy from SAGES June 2017
Patient Selection
Preoperative decision-making Laparoscopic treatment of acute abdominal disease offers similar benefits to pregnant and nonpregnant
patients compared to laparotomy
Laparoscopy and trimester of pregnancy Laparoscopy can be safely performed during any trimester of pregnancy when surgery is indicated
Treatment
Patient positioning Gravid patients beyond the first trimester should be placed in left lateral decubitus position or partial
left lateral decubitus position to minimize compression of the vena cava
Initial port placement Initial abdominal access can be safely performed with an open (Hasson), Veress needle, or optical trocar
technique if the location is adjusted for fundal height
Insufflation pressure CO2 insufflation of 10–15 mmHg can be safely used for laparoscopy in the pregnant patient
Intraoperative CO2 monitoring Intraoperative CO2 monitoring by capnography should be used during laparoscopy
Venous thromboembolic (VTE) prophylaxis Intraoperative and postoperative pneumatic compression devices and early postoperative ambulation
are recommended for prophylaxis
Adnexal masses Laparoscopy is a safe and effective treatment in gravid patients with symptomatic ovarian cystic masses
Adnexal torsion Laparoscopy is recommended for both diagnosis and treatment of adnexal torsion
Perioperative Care
Fetal heart monitoring Fetal heart monitoring of a viable fetus should occur preoperatively and postoperatively in the setting of
urgent abdominal surgery
Tocolytics Tocolytics should not be used prophylactically in pregnant women undergoing surgery, but should be
considered perioperatively when signs of preterm labor are present
TABLE 33.6: FIGO Staging for Cancer of the Ovary, Fallopian Tube, and Peritoneum (2014)
Stage I—Growth limited to the ovaries or fallopian tubes
Stage IA—Growth limited to one ovary or fallopian tube, no ascites, no tumor on external surface, and capsule intact
Stage IB—Growth limited to both ovaries or fallopian tubes, no ascites, no tumor on external surface, and capsule intact
Stage IC—Tumor limited to one or both ovaries or fallopian tubes with any of the following:
Stage IC1— Surgical spill intraoperatively
Stage IC2 —Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface
Stage IC3— malignant cells in the ascites or peritoneal washings
Stage II—Growth involving one or both ovaries, with pelvic extension (below pelvic brim) or peritoneal cancer
Stage IIA—Extension and/or implants to the uterus and/or fallopian tubes and/or ovaries
Stage IIB—Extension to other pelvic intraperitoneal tissues
Stage III—Tumor involving one or both ovaries, fallopian tubes, or peritoneal cancer, with cytologically or histologically confirmed peritoneal implants
outside the pelvis and/or metastasis to the retroperitoneal lymph nodes
Stage IIIA—Metastasis to the retroperitoneal lymph nodes with or without microscopic peritoneal involvement beyond the pelvis
Stage IIIA1— Positive retroperitoneal lymph nodes only (cytologically or histologically proven)
Stage IIIA1(i) — Metastasis ≤10 mm in greatest dimension
Stage IIIA1(ii) — Metastasis >10 mm in greatest dimension
Stage IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
Stage IIIB—Macroscopic peritoneal metastases beyond the pelvic brim ≤2 cm in greater dimension, with or without metastasis to the
retroperitoneal lymph nodes
Stage IIIC—Macroscopic peritoneal metastases beyond the pelvic brim >2 cm in greater dimension, with or without metastasis to the
retroperitoneal lymph nodes (Note 1)
Stage IV—Distant metastases excluding peritoneal metastases
Stage IVA—Pleural effusion with positive cytology
Stage IVB—Metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside the abdominal cavity) (Note 2)
Source: From Prat J. FIGO’s staging classification for cancer of the ovary, fallopian tube, and peritoneum: Abridged republication. J Gynecol Oncol. 2015;26(2):87–89, with
permission.
Note 1: Includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ.
Note 2: Parenchymal metastases are stage IVB.
Abbreviation: FIGO, Federation Internationale de Gynecologie et d’Obstetrique (International Federation of Gynecology and Obstetrics).
If a malignant neoplasm of the ovary is suspected prior to sur- 3. Yazbek J, Salim R, Woelfer B, et al. The value of ultrasound visualiza-
gery, a vertical incision is preferred, and a frozen section should tion of the ovaries during the routine 11-14 weeks nuchal translucency
scan. Eur J Obstet Gynecol Reprod Biol. 2007;132(2):154–158. [II-3,
be sent. The surgeon’s obligation is to consult a gynecologic n = 2925]
oncologist to properly stage the disease (Table 33.6). Since most 4. Nazer A, Czuzoj-Shulman N, Oddy L, Abenhaim HA. Incidence of mater-
present as stage I disease, a unilateral salpingo-oophorectomy, nal and neonatal outcomes in pregnancies complicated by ovarian masses.
omentectomy, and limited pelvic and paraaortic lymph node dis- Arch Gynecol Obstet. 2015;292(5):1069–1074. [II-3]
5. Bernhard LM, Klebba PK, Gray DL, Mutch DG. Predictors of persistence
section is the procedure of choice. All suspicious lesions should
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34
CERVICAL CANCER SCREENING AND MANAGEMENT IN PREGNANCY
Vaidehi Mujumdar and Scott D. Richard
Key points In response to the standardization of cytology results, the

American Society for Colposcopy and Cervical Pathology
• Cervical cancer screening guidelines for nonpregnant peo- (ASCCP) initiated a process that developed comprehensive,
ple with a cervix can be followed in pregnant people. The evidence-based consensus guidelines to assist clinicians in man-
American Cancer Society (ACS) published screening aging abnormal cervical cytology results. The ASCCP screen-
guidelines in 2020, which differ significantly from their ing guidelines were most recently updated in 2019 [3]. The 2019
2012 guidelines. The 2020 ACS guidelines recommend guidelines expand on the idea of having equal management for
that people with a cervix ages 25–65 get a primary equal risks that was a cornerstone of the 2012 guidelines [3].
human papillomavirus (HPV) test every 5 years as the
preferred screening method. They do not recommend
cervical cancer screening in patients less than 25 years
of age. Microinvasive cervical cancer is defined as cancer spread to no
• The only cervical diagnosis that is considered to alter more than 5 mm into the tissue of the cervix. Invasive cervical
management in pregnancy is invasive cancer. cancer is defined as cancer spread from the surface of the cervix
• A more conservative approach should be used to man- to deeper cervical tissue, possible spread to part of the vagina,
age cervical intraepithelial neoplasia (CIN) in pregnancy to the lymph nodes, to the other tissues surrounding the cervix,
compared to nonpregnancy. within the pelvis, or beyond the pelvic areas into nearby organs.
• Due to risks of bleeding and premature rupture of mem-
branes, endocervical curettage (ECC) is never recom-
mended in pregnancy. Epidemiology/Incidence
• Diagnostic conization during pregnancy should only be
According to the 2017 Cytopathology Checklist, the median
considered when either the biopsy or cytology is sugges-
reporting rate of atypical squamous cells– undetermined sig-
tive of invasive cancer and the diagnosis of invasion would
nificance (ASC-US) among laboratories in the United States was
result in a modification of treatment recommendations,
5.0% [4]. The incidence of biopsy-confirmed cervical intraepi-
timing, or mode of delivery.
thelial neoplasia (CIN) 1 was 1.6%, CIN 2 4.4%, and CIN 3+
• In the diagnosis of invasive cancer with a grossly visible
2.2% [4, 5]. In the United States, the incidence of cervical cancer
lesion, cesarean delivery is indicated and results in better
cases has dropped to 7.4 per 100,000, while deaths from inva-
survival outcomes, as well as a decreased risk of obstetric
sive cervical cancer have dropped to 2.8 per 100,000 women
bleeding in the intrapartum and postpartum periods.
[6, 7]. The peak age of incidence of cervical cancer is in the mid-
• If a nonvisible microinvasive lesion (stage IAI or IA2)
40s [6]. In low- and middle-income countries, cervical cancer is
is identified, either cesarean or vaginal delivery is
the second most common cancer among people with a cervix,
acceptable, depending on the obstetric and gynecologic
the third most common cause of cancer-related death, and the
circumstances.
most common cause of mortality from gynecologic malignancy.
• Once the diagnosis of cervical cancer is established, indi-
In contrast, in high-income countries, the success of Pap smear
vidualized recommendations for the management of the
screening has greatly reduced the incidence of disease by accu-
malignancy, as well as the pregnancy, are formulated with
rately detecting preinvasive and early-invasive cervical disease. In
consideration for the stage of disease, gestational age at
the United States, the incidence of cervical cancer ranges from
the time of diagnosis, and maternal desires regarding
1.5 to 12 cases in 100,000 pregnancies [8]. About 1% of people
the continuation of pregnancy.
who have cervical cancer are pregnant at the time of diagnosis.
• Fertility-sparing surgery and neoadjuvant chemotherapy
The likelihood that a pregnant person with ASC pathology has a
for earlier-stage cervical cancer found in pregnancy may be
detectable high-risk human papillomavirus (HR HPV) is 84% [9].
considered without worsening survival.
• Pregnancies exposed to the HPV vaccine are not associ-
ated with a higher risk of adverse pregnancy outcomes Classification
than pregnancies with no exposure.
The Pap smear report consists of the following [2]:
Historic notes Specimen type

• Conventional Pap smear: Cells from the transformation
The cytologic evaluation of the cervix, known as the Pap smear, zone are sampled and transferred directly onto a slide [10].
was developed in the 1940s by George Papanicolaou. The Bethesda • Liquid-based cytology: Cells from the transforma-
System standardized terminology for reporting Pap smear cytol- tion zone are placed in a prepared liquid preservative
ogy results in 1988 [1] and was subsequently updated in 2014 [2]. and processed by a laboratory. This is the method most
390 DOI: 10.1201/9781003102342-34

Cervical Cancer Screening and Management in Pregnancy 391
commonly used in clinical practice in the United States indicate if there are features suspicious for invasive
because of the added benefit of using a single sample for disease. When glandular cell abnormalities are pres-
HPV co-testing, using a combination of a Pap smear and ent, it should be noted whether there are changes
HPV test. The use of liquid-based media can also control favoring neoplasia.
for obscuring factors, including blood, inflammation, and • Carcinoma
other processes [10].
• There is no difference in unsatisfactory rates, cytology clas- Glandular cell abnormalities
sifications, and accuracy between conventional and liquid- • Atypical glandular cells (AGCs) may be of endocervical,
based cervical cytology [11]. endometrial, or other glandular origin
• Endocervical adenocarcinoma in situ (AIS)
Specimen adequacy • Adenocarcinoma
Satisfactory for evaluation
• Defined as a minimum of 5000 well-visualized squamous Human papillomavirus testing
cells on a liquid-based preparation or 8000–12,000 well- HPV testing is an integral part of cervical cancer screening.
visualized squamous cells on a conventional smear. Updated ASCCP Consensus guidelines that were most recently
• The presence of endocervical cells indicates that the area validated in 2019 state HPV co-testing is recommended for all
at risk for neoplasia—the transformation zone—has been female patients over the age of 30 and for all patients with
adequately sampled [12]. ASC-US cytology.
• Samples reported as negative but with absent or insuf-
ficient endocervical/transition zone components have • HPV infection is the leading etiologic agent in the devel-
raised concern about missed pathology. Prior guidelines opment of premalignant and malignant lower genital tract
have recommended repeat cytology. Recent meta-analysis disease [14].
studies reported that negative cytology (with or without • Co-testing should only detect for the presence of high-
sufficient sampling of the endocervical/transition zone) has risk HPV species. There is no role in testing for low-
both good negative predicative value and good specificity. risk genotypes. Detecting low-risk genotypes has been
Current guidelines do not recommend repeat follow-up proven to cause unnecessary procedures and testing,
Pap smears. People with a cervix age 25 or above are rec- therefore decreasing clinical specificity. It is recom-
ommended to undergo primary HPV testing, as well as mended to use only FDA-approved HPV DNA detection
co-testing or cytology alone when primary HPV testing kits [10].
is not available. This guideline is transitional, as full access • The most well-studied HPV test is the Hybrid Capture 2
to primary HPV testing is not available widely. Options for HPV DNA Assay (Digene Corporation, Beltsville, MD),
screening with co-testing every 5 years or cytology every which uses a probe mix for high-risk HPV types 16, 18, 31,
3 years are still secondary options. Pregnant individu- 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 [15].
als are recommended to follow the same age-dependent • A newer assay for detecting high-risk HPV was approved for
guidelines used for nonpregnant patients. Pregnant FDA use in 2009. Cervista HR HPV (Hologic Corporation,
individuals who screen positive for HPV and/or cytology Waltham, MA) includes the 13 HPV types noted and adds
should be managed in accordance with the 2019 ASCCP type 66 [8].
risk-based management consensus guidelines for abnor- • Cervista HPV 16/18 is another diagnostic test that speci-
mal cervical cancer screening tests (Figures 34.1–34.3) [3]. fies types 16 and 18. These two represent the most com-
mon types found in cervical squamous cell carcinomas and
Unsatisfactory for evaluation adenocarcinomas, respectively.
• Defined as more than 75% of the cells being uninterpre- • Ongoing research looks promising in improving specificity
table or an unlabeled specimen. and positive predictive value of screening for CIN 2+ by
• Since women with this result are more likely to have looking at mRNA instead of DNA for HR HPV [16].
intraepithelial lesions or cancer on follow-up than women
with satisfactory Pap smears [12], a repeated Pap smear in Management
2–4 months is recommended. If the subsequent Pap smear
is unsatisfactory, evaluation with colposcopy and/or biop- Pregnancy considerations
sies is appropriate [13]. Pregnancy-induced changes in the cervix include hyperemia,
eversion of columnar epithelium, more prominent glands,
Interpretation/Result and increased production and volume of mucus. The decidual
Squamous epithelial cell abnormalities changes may exaggerate the colposcopic appearance of CIN. A
• ASC of either of the following: biopsy during pregnancy may cause substantial bleeding [3]. In
• Undetermined significance (ASC-US) or pregnancy, the general philosophy for the treatment of intraepi-
• Suspicious for high-grade squamous intraepithelial thelial neoplasia of the cervix has become expectant management
lesions (HSIL or ASC-H) after careful diagnosis.
• Low-grade squamous intraepithelial lesions (LSIL)
• Changes consistent with HPV, mild dysplasia, or grade 1 Screening in pregnancy
CIN (CIN I) The Pap smear is used to screen for cellular abnormalities that are
• HSIL associated with an increased risk for the development of cervical
• HSIL includes moderate or severe dysplasia, CIN II, cancer. It selects those women who should have further evalua-
CIN III, and carcinoma in situ (CIS) and should tion, such as HPV DNA testing, colposcopy, and/or biopsy, which
(1) Recommendations are based on risk, not results.

• Recommendations of colposcopy, treatment, or surveillance will be based on a patient’s risk of CIN 3+ determined by a com-
bination of current results and history (including unknown history). The same current test results may yield different manage-
ment recommendations depending on the history of recent past test results.
(2) Colposcopy can be deferred for certain patients.
• Repeat HPV testing or co-testing at 1 year is recommended for patients with minor screening abnormalities indicating HPV
infection with a low risk of underlying CIN 3+ (e.g. low-grade cytologic abnormalities after a documented negative screening
HPV test or co-test).
(3) Guidance for expedited treatment is expanded (i.e. treatment without colposcopic biopsy).
• Expedited treatment was an option for patients with HSIL cytology in the 2012 guidelines; this guidance is now better defined.
• For nonpregnant patients 25 years or older, expedited treatment, defined as treatment without preceding colposcopic biopsy
demonstrating CIN 2+, is preferred when the immediate risk of CIN 3+ is ≥60%, and is acceptable for those with risks between
25% and 60%. Expedited treatment is preferred for nonpregnant patients 25 years or older with HSIL cytology and concurrent
positive testing for HPV genotype 16 (HPV 16) (i.e. HPV 16–positive HSIL cytology) and never or rarely screened patients with
HPV-positive HSIL regardless of HPV genotype.
• Shared decision-making should be used when considering expedited treatment, especially for patients with concerns about
the potential impact of treatment on pregnancy outcomes.
(4) Excisional treatment is preferred to ablative treatment for histologic HSIL (CIN 2 or CIN 3) in the United States. Excision is rec-
ommended for adenocarcinoma in situ (AIS).
(5) Observation is preferred to treatment for CIN 1.
(6) Histopathology reports based on Lower Anogenital Squamous Terminology (LAST)/World Health Organization (WHO) recom-
mendations for reporting histologic HSIL should include CIN 2 or CIN 3 qualifiers, i.e. HSIL (CIN 2) and HSIL (CIN 3).
(7) All positive HPV tests, regardless of genotype, should have additional reflex triage testing performed from the same laboratory
specimen (e.g. reflex cytology).
• Additional testing from the same laboratory specimen is recommended because the findings may inform colposcopy
practice. For example, those with HSIL cytology and concurrent positive testing for HPV genotype 16 qualify for expe-
dited treatment.
• HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional evaluation (e.g. colposcopy with
biopsy) is necessary even when cytology results are negative.
• If HPV 16 and 18 testing is positive and additional laboratory testing of the same sample is not feasible, the patient should
proceed directly to colposcopy.
(8) Continued surveillance with HPV testing or co-testing at 3-year intervals for at least 25 years is recommended after treatment
of histologic HSIL, CIN 2, CIN 3, or AIS. Continued surveillance at 3-year intervals beyond 25 years is acceptable for as long as the
patient’s life expectancy and ability to be screened are not significantly compromised by serious health issues.
• The 2012 guidelines recommended a return to 5-year screening intervals and did not specify when screening should cease.
New evidence indicates that risk remains elevated for at least 25 years, with no evidence that treated patients ever return to
risk levels compatible with 5-year intervals.
(9) Surveillance with cytology alone is acceptable only if testing with HPV or co-testing is not feasible. Cytology is less sensitive
than HPV testing for the detection of precancer and is therefore recommended more often. Cytology is recommended at 6-month
intervals when HPV testing or co-testing is recommended annually. Cytology is recommended annually when 3-year intervals are
recommended for HPV or co-testing.
(10) Human papillomavirus assays that are FDA-approved for screening should be used for management according to their regula-
tory approval in the United States. (Note: All HPV testing in this document refers to testing for high-risk HPV types only.)
• For all management indications, HPV mRNA and HPV DNA tests without FDA approval for primary screening alone should
only be used as a co-test with cytology, unless sufficient, exceptionally rigorous data are available to support primary HPV
testing in management.
FIGURE 34.1 Essential Changes from Prior ASCCP Management Guidelines. (From Perkins RB, Guido RS, Castle PE, et al. 2019
ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.
J Lower Genital Tract Dis. 2020;24(2): 102–131. [Review; III]. Ref. [3], with permission.)
then is used for treatment decisions. The National Comprehensive specifically identifying HPV 16 and 18. The rationale remains that
Cancer Network (NCCN) panel has adopted recommendations invasive cancer is rare in women under 21. Annual surveillance
set forth by the American Cancer Society on initiation and fre- is recommended for patients with known immunosuppres-
quency of Pap smear [17]. Of note, ACS has new 2020 recommen- sion from HIV or organ transplantation; individuals exposed
dations that include that people with a cervix ages 25–65 get to diethylstilbestrol in utero; or those who have been pre-
a primary HPV test every 5 years as the preferred screening viously treated for CIN 2, CIN 3, or cervical cancer [3]. Pap
method. They do not recommend cervical cancer screening in smears are often obtained at the first prenatal visit by many pro-
patients less than 25 years of age [3]. The primary HPV test, the viders, but the guidelines for nonpregnant patients (HPV test
cobas test, is manufactured by Roche and can be used alone for every 5 years for patients ≥25 years old) can be followed in
screening. This test detects 14 “high-risk” HPV types, while also pregnant patients [10].
Expedited Treatment
Preferred
60–100%
(immediate CIN3+ risk)
Expedited Treatment
Look at or Colposcopy
Immediate CIN3+ risk Acceptable
and find the correct 25–59%
(immediate CIN3+ risk)
Yes
Colposcopy
Recommended
4–24%
Is (immediate CIN3+ risk)
Immediate CIN3+
risk greater than or
equal to 4%?
Return in 1 year
No ≥0.55%
(5-year CIN3+ risk)
Look at Return in 3 years

5-year CIN3+ risk and 0.15–0.54%
find the surveillance (5-year CIN3+ risk)
interval.
Return in 5 years
<0.15%
(5-year CIN3+ risk)
FIGURE 34.2 Evaluation of patient risk for CIN3. For a given current results and history combination, the immediate CIN 3+ risk
is examined. If this risk is 4% or greater, immediate management via colposcopy or treatment is indicated. If the immediate risk is less
than 4%, the 5-year CIN 3+ risk is examined to determine whether patients should return in 1, 3, or 5 years. (From Perkins RB, Guido
RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and
Cancer Precursors. J Lower Genital Tract Dis. 2020;24(2): 102–131. [Review; III]. Ref. [3], with permission.)
Consultations required • Ages >25: In pregnant patients, colposcopy is recom-

Consultation with Gynecologic Oncology and Maternal-Fetal mended, but it is acceptable to defer colposcopy to 4–6
Medicine is recommended in cases of cervical cancer in preg- weeks postpartum.
nancy [18]. Consultation with gynecologic oncology should occur
as early as possible after the diagnosis of cervical cancer for better HSIL or more invasive cytology
therapeutic planning. Collaboration with a maternal-fetal medi- • In patients with higher-grade lesions noted on cervical
cine specialist is also recommended for management of obstetric screening exams, necessary colposcopically directed cer-
complications and delivery planning. vical biopsies can be safely performed at any time during
pregnancy. Many defer biopsy until the second trimester
Indications for colposcopy and cervical when the risk of incidental pregnancy loss is minimal.
biopsy during pregnancy (Figure 34.1) Due to risks of bleeding and premature rupture of mem-
As in nonpregnant women, women with abnormal Pap smears branes, endocervical curettage (ECC) is never recom-
during pregnancy should undergo colposcopy with directed mended in pregnancy. Cervical biopsies should only be
biopsies of suspicious areas to rule out invasive disease [3]. performed if CIN 2 or above is suspected on colposcopic
exam.
ASC-US, HPV negative
• No indication for colposcopy at any age. Pregnant patients
are to follow age-appropriate routine screening. CIN 1
• If adequate samples are obtained during colposcopy and
LSIL and ASC-US, HR HPV positive invasive disease is not suspected at any point during the
• Ages 21–25: Patients are to undergo repeat Pap smear and pregnancy, it is recommended to defer repeat colposcopy
co-testing in 12 months. Colposcopy is not recommended. to 6 weeks postpartum.
Initial Screening:
HPV-Positive ASC-US
Immediate CIN3+ Risk = 4.5%
Management: Colposcopy
Colposcopy Visit:
Colposcopic biopsy result is <CIN2
5-year CIN3+ risk is 2.9%
Management: 1-year follow-up
First Follow-up Surveillance:

HPV-positive ASC-US
Immediate CIN3+ Risk = 3.1%
Management: 1-year follow-up
Second Follow-up Surveillance Second Follow-up Surveillance

HPV-negative NILM HPV-positive ASC-US
5-year CIN3+ Risk = NA Risk = NA
Management: 3-year follow-up Management: Colposcopy
FIGURE 34.3 Management of common low-grade screening abnormality. An initial minimally abnormal screening test result
(HPV-positive ASC-US) would lead to colposcopy (immediate risk 4.45%). If colposcopy shows less than CIN 2, the 5-year risk is 2.9%
(1-year return). At the 1-year return visit, a second HPV-positive ASC-US result has an immediate risk of 3.1% (1-year return). Note
similar management would be recommended if the initial abnormality preceding colposcopy were any minimally abnormal test result
(i.e. less severe than ASC-H). If the HPV-based test performed for the second post-colposcopy surveillance test is negative, return in
3 years is recommended. If the second post-colposcopy surveillance test results are either a positive HPV test with any cytology result
or a negative HPV test result with a cytology result of ASC-H or higher, colposcopy is recommended. Return in 1 year is recommended
for HPV-negative ASC-US or LSIL results. NA, not applicable because stable risk estimates are not available. (From Perkins RB, Guido
RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and
Cancer Precursors. J Lower Genital Tract Dis. 2020;24(2): 102–131. [Review; III]. Ref. [3], with permission.)
CIN 2/3 and CIS The patient should seek consultation by both maternal-fetal
• In women with a histologic diagnosis of CIN 2/3 or CIS medicine and gynecologic oncology.
on initial colposcopy, it is recommended to perform
repeat colposcopy and cytology every 12 weeks for the Management of the abnormal Pap smear
duration of the pregnancy. Repeat biopsy is recom- There are no randomized controlled trials assessing any aspect
mended only if the appearance of the lesions worsens or of management of abnormal Pap smear in pregnancy. Most of the
if cytology is concerning for invasive cancer. It is accept- recommendations are based on expert opinion and anecdotal
able to defer tissue biopsy to 4–6 weeks postpartum if experience [18, 19]. The only diagnosis that is considered to
no progression of the lesion is noted on colposcopy and alter management in pregnancy is invasive cancer.
cytology [3]. Management of abnormal Pap smears in pregnancy should
follow the new recommendations delineated in Figure 34.1.
Diagnosis of invasive cancer Recommendations for colposcopy in pregnant patients are similar
Once the diagnosis of cervical cancer is established, individual- to those in the nongravid state, with certain exceptions, as listed
ized recommendations for the management of the malignancy, in Table 34.1. Newer guidelines for colposcopy in pregnancy state
as well as the pregnancy, are formulated with consideration for that colposcopy is preferred for ASC-US associated with positive
the stage of disease, gestational age at the time of diagnosis, and HR HPV type or LSIL Pap smears, but also that colposcopy can be
maternal desires regarding the continuation of her pregnancy deferred by the clinician until after pregnancy for these two cat-
(see Chap. 44 in Maternal-Fetal Evidence Based Guidelines). egories. Colposcopy during pregnancy has as its primary goal to
TABLE 34.1: Cervical Screening Considerations during TABLE 34.3: Staging and Management of Cervical Cancer in
Pregnancy Pregnancy
• Endocervical brush cytology is safe Stage I:
• Cervical biopsy is safe The carcinoma is strictly confined to the cervix uteri (extension to the
• Endocervical curettage (ECC) should be avoided corpus should be disregarded)
• For ASC and LSIL, HR HPV–positive, colposcopy is preferred but IA Invasive carcinoma that can be diagnosed only by microscopy, with
can be done postpartum maximum depth of invasion <5 mm
• For CIN 2 or CIN 3, Pap and colposcopy can be repeated • IA1 Measured stromal invasion <3 mm in depth
postpartum if cancer is not suspected • IA2 Measured stromal invasion ≥3 mm and <5 mm in depth
• Delay treatment of any level of CIN until postpartum period
• Cervical conization is recommended if invasion is suspected IB Invasive carcinoma with measured deepest invasion ≥5 mm (greater
than stage IA), lesion limited to the cervix uteri
Abbreviations: ASC, atypical squamous cells; LSIL, low-grade squamous intraepithe-
lial lesion; HR HPV, high risk human papillomavirus; CIN, cervical intraepithelial • IB1 Invasive carcinoma ≥5 mm depth of stromal invasion and <2 cm
neoplasia.
in greatest dimension
• IB2 Invasive carcinoma ≥2 cm and <4 cm in greatest dimension
assess for invasive cancer. Biopsies should only be performed for • IB3 Invasive carcinoma ≥4 cm in greatest dimension
women with colposcopic impression of CIN 3/CIS, AIS, or cancer,
with the purpose to exclude invasive cancer [20]. Stage II:
Repeat Pap and colposcopy is recommended if invasive cancer The carcinoma invades beyond the uterus, but has not extended onto the
is suspected but not yet proven, specifically with evidence of CIN lower third of the vagina or to the pelvic wall
2/3 or CIS on cytology or biopsy. Repeat biopsy during pregnancy IIA Involvement limited to the upper two-thirds of the vagina without
should only be performed if progression of the lesion is suspected. parametrial involvement
ECC is not performed in pregnancy [16, 20].
• IIA1 Invasive carcinoma <4 cm in greatest dimension
Conization performed during pregnancy is associated with
• IIA2 Invasive carcinoma ≥4 cm in greatest dimension
increased morbidity. The most common complications include
hemorrhage, abortion, premature delivery, and infection
IIB With parametrial involvement but not up to the pelvic wall
[20]. Therefore, cervical conization has limited indications in
Stage III:
pregnancy (Table 34.2). In general, diagnostic conization during
The carcinoma involves the lower third of the vagina and/or extends to
pregnancy should only be considered when either the biopsy or
the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney
cytology is suggestive of invasive cancer or AIS and the diagno-
and/or involves pelvic and/or paraaortic lymph nodes
sis of invasion would result in a modification of treatment recom-
IIIA Carcinoma involves the lower third of the vagina, with no extension
mendations, timing, or mode of delivery [20].
to the pelvic wall
Unlike standard recommendations for cervical conization in
IIIB Extension to the pelvic wall and/or hydronephrosis or
non-obstetric patients with inadequate colposcopy biopsies or
nonfunctioning kidney (unless known to be due to another cause)
discordance between Pap smears and colposcopic biopsies [15],
IIIC Involvement of pelvic and/or paraaortic lymph nodes, irrespective of
pregnant individuals with these findings can defer further exam-
tumor size and extent (with r and p notations)
ination until after pregnancy if invasive cancer has been ruled
out. If a cervical conization must be performed during pregnancy, • IIIC1 Pelvic lymph node metastasis only
this procedure should ideally be performed in the early second • IIIC2 Paraaortic lymph node metastasis
trimester.
Stage IV:
Management of cervical cancer (Table 34.1) The carcinoma has extended beyond the true pelvis or has involved
For staging and management, please refer to Table 34.3 [30] (biopsy proven) the mucosa of the bladder or rectum. A bullous edema,
and Chap. 44 in Maternal-Fetal Evidence Based Guidelines [1]. as such, does not permit a case to be allotted to stage IV
Microinvasive cervical cancer is defined as cancer spread to no
• IVA Spread of the growth to adjacent organs
more than 5 mm deep into the cervical stroma. Microinvasive
• IVB Spread to distant organs
disease includes stages IA1 and IA2. Invasive cervical cancer is
defined as cancer that has invaded deeper than 5 mm into the cer- Source: From Bhatla N, Berek JS, Cuello Fredes M, et al. Revised FIGO Staging for
vical stroma, is grossly visible, or involves additional structures. Carcinoma of the Cervix Uteri. Int J Gynaecol Obstet. 2019;145(1):129–
135, with permission.
Invasive disease includes stage IB1 or greater.
Stage IA1
• Conization is recommended for both treatment and diag- To minimize the risk of spontaneous abortion, is it optimal
nosis in patients with evidence of stage IA1 cancer [22]. to perform conization in the early second trimester [21].
• If conization margins are negative, patients can be man-
TABLE 34.2: Indications for Conization in Pregnancy aged expectantly for the duration of the pregnancy [21].
• Either abdominal or vaginal delivery routes are expected
• Histologic presence of microinvasive or invasive disease
with these patients. Mode of delivery should be discussed
• Persistent cytologic impression of invasive cancer (in the absence of
with a maternal-fetal medicine specialist with consider-
histologic confirmation)
ation of other gynecologic and obstetric circumstances.
• Histologic presence of adenocarcinoma in situ
This should be decided on an individual basis [22].
• If continued fertility is desired, patients can be followed up smear or colposcopic biopsies reveal CIN 2, CIN 3, or CIS and are
every 3 months for 2 years and every 6 months for the next the same as the nonpregnant guidelines [14].
3 years [21].
Prevention
Stage IA2 The HPV-16 vaccine reduces the incidence of both HPV-16 infec-
• Conization with the addition of pelvic lymphadenectomy tion and HPV-16–related CIN [25]. Currently, the three licensed
is recommended to rule out high-risk disease. Radical HPV vaccines include Cervarix (two-valent; types 16 and 18),
trachelectomy is not recommended, given the risk of sig- Gardasil (four-valent; types 6, 11, 16, and 18), and most recently,
nificant blood loss and obstetric complications resulting Gardasil-9 (nine-valent; types 6, 11, 18, 19, 31, 33, 45, 52, and 58).
from prolonged surgery [22]. The nine-valent vaccine is equivalent to the prior recommended
• Given the technical complications performing lymphade- vaccine and as of 2017, it is the only HPV vaccine available in the
nectomy after 25 weeks of gestation, in patients diagnosed United States [25–28]. Although the HPV vaccination is not rec-
after 25 weeks, it is recommended to delay treatment and ommended for pregnant women, studies have shown that HPV
full surgical staging until after delivery. If disease progres- vaccine–exposed pregnancies were not associated with a
sion is suspected, it is recommended to obtain an abdomi- higher risk of adverse pregnancy outcomes than pregnancies
nal and pelvic MRI [21]. with no such exposures [29, 30].
• As stated earlier, patients can undergo either abdominal or
vaginal delivery with consideration of other obstetric cir-
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n = 2392; I]
INDEX
Note: Locators in italics represent figures and bold indicate tables in the text.
A Amniotic fluid index (AFI), 91, 96 ATM gene, see Ataxia–telangiectasia

Amniotomy, 102, 278, see also Artificial mutated gene
Abdominal distension, 41 rupture of membranes Atosiban, 240
Abdominal surgery, in pregnancy, 387 AmniSure, 262 Atrial septal defect (ASD), 72
Abdominal trauma, 347 AMP, see Adenosine monophosphate Azithromycin, 251–252
Abdominal wall defects, 380 Ampicillin, 251–252, 264
Abnormal FHR in labor, algorithm for, 133 Ampicillin-sulbactam, 241 B
ABO/Rh (D) type screen test, 19–20 AMSTL, see Active management of the third
Abruptio placentae, 253 Baby friendly initiative (BFI), 364–365
stage of labor
Acetaminophen, 356 Back pain, 29
Analgesia/anesthesia, 119, 137, 208, 242,
aCGH, see Array comparative genomic Bacterial vaginosis (BV), 21, 224
253, 318
hybridization Balloon catheter, 276–277
emergency, 148–149
Acidemia, 122 Barusiban, 240
epidural, 139–144
FHR monitoring, 130 Baths, induction of labor, 282
neuraxial, 138
Acidosis, 122 Beta human chorionic gonadotropin, 196
for pain control, 118
Acid prophylaxis drugs, 100 Betamethasone, 162, 235, 250
spinal, 143
ACMG, see American College of Medical Betamimetics, 237–238, 240, 306
for vaginal breech delivery, 311
Genetics and Genomics Beta-thalassemia, 82
Anembryonic pregnancy, ultrasound diagnosis
ACOG, see American College of Obstetricians BFI, see Baby friendly initiative
of, 50–51
and Gynecologists Biofeedback, 139
Anemia, 43–44, 83
Active management of the third stage of labor Biophysical profile (BPP), 55, 270
Aneuploidy
(AMTSL), 117 Biophysical profile score (BPS), 55
diagnostic tests, 68–69
algorithm for, 114 Biparietal diameter (BPD), 49, 67
microdeletions and duplications, 75–76
oxytocin, 113–114 Birth, attendant at, 95
positive screening for, 67–68
Acupressure, 138 doulas, 95
pretest and posttest counseling, 61–63,
Acupuncture, 138, 282 62, 63 midwife-led care, 95
Adenosine monophosphate (AMP), 237 Birth, place of
Antenatal breast examination, 365
Adhering to the as low as reasonably freestanding birth center, 95
Antenatal class, 28
achievable (ALARA) principle, 48 planned home birth, 93–94
Antenatal corticosteroids, 256
Adhesion formation prevention, for cesarean planned hospital birth, 95
Antenatal education programs, 92
delivery, 167–168 Birth assistants, training of, 95
Antenatal noninvasive aneuploidy screening,
Adhesive drapes, for cesarean delivery, 163 Birth centers, 93
63–64
Adnexal mass, in pregnancy, 384–388 Birthing ball, 101
Antenatal perineal massage, 93
Advanced maternal age (AMA), 11 Bishop score, 275–276, 276
Antepartum, 316–317
AED, see Antiepileptic drug Bladder catheterization, 101
Antepartum hemorrhage, 348
Aerobic exercise, 23 Bladder flap, for cesarean delivery, 164
Antepartum testing, 208, 242, 334
AFI, see Amniotic fluid index Blighted ovum, definition of, 195
during cervical ripening, 282–283
Agonist/antagonists, 139 Blood pressure, 19
Antibiotic prophylaxis, 28, 99, 155
AIUM, see American Institute of Ultrasound Antibiotics, 200, 237, 251, 256, 265, 289 Blood product consent, for Jehovah’s Witness
in Medicine patients, 119, 119
Antibiotics and surfactant, 297
ALARA principle, see Adhering to the as low Bloom syndrome, 87
Antibody screen test, 19–20
as reasonably achievable principle Body mass index (BMI), 10, 12, 19
Anticoagulation, 144
Alcohol use, 23 BPD, see Biparietal diameter
Anti-D immune globulin, 334
Alpha-thalassemia, 83 BPP, see Biophysical profile
Antiepileptic drug (AED), 12
Altered birth transition, 377 BPS, see Biophysical profile score
Antigen avoidance diet, 24
AMA, see Advanced maternal age Breast engorgement, 365
Antiphospholipid syndrome, 206, 207
Ambroxol, 236 Breastfeeding, 29, 118, 364, 365
Antispasmodics, 101
Ambulation, 100–101 contraception during, 368
Appendectomy, for cesarean delivery, 168
Ambulation after cesarean delivery, 169 education, 364
Aromatherapy, 99–100, 138
American College of Medical Genetics and medications and complications, 365–366
Array comparative genomic hybridization
Genomics (ACMG) Breast stimulation, 282
(aCGH), 205
carrier screening, 86 Breech delivery, forceps for, 153
Artificial feeding, 363
American College of Obstetricians and Butorphanol, 132
ASD, see Atrial septal defect
Gynecologists (ACOG), 50, 53, 130, BV, see Bacterial vaginosis
Ashkenazi Jewish ancestry, 86–89
154, 181, 324 Asphyxia, 122
carrier screening, 82, 86 Aspirin, 356 C
Committee Opinion, 107 Aspirin, low-dose, 144, 215
premature rupture of membranes, 264–265 Caffeine, 25
Aspirin therapy, 145
American Institute of Ultrasound in Medicine Calcium channel blockers, 238, 241
Asthma exacerbation, 42
(AIUM), 50, 51 Calcium supplements, 27
Asymptomatic bacteriuria, 223–224
Amniocentesis, 59, 68, 222, 249 Calf stretching, 29
urine culture for, 20
Amnioinfusion, 133, 253, 296 Canavan disease, 87
Ataxia–telangiectasia mutated (ATM)
for prolonging latency, 250 Candida, 224
gene, 80
398
Index 399
Carbetocin, 115, 166 preoperative considerations, 159–162 Cord prolapse, 253

Carboprost, 115 rate, 255 Cord traction, 116–117
Carcinoma in situ (CIS), 391 retractors at, 164 Corticosteroids, 132, 235–236
Cardiopulmonary resuscitation, 149 short- and long-term outcomes, 171 for fetal/neonatal maturation, 250
Cardiotocography (CTG), 122 surgical site infection (SSI) after, 160 COVID-19 infection, 30
Cardiovascular changes, 34–41 surgical technique, 163–169 COX inhibitors, 238–240, 241
Carrier screening venous thromboembolism (VTE) CPCs, see Choroid plexus cysts
Ashkenazi Jewish population, 86–89 prophylaxis associated with, 161 Crown-rump length (CRL), 49
fragile X syndrome, 83–84, 84, 84 wound dressing at, 169 CRP, see C-reactive protein
genetic counseling, 79–81, 81 Cesarean delivery on maternal request Cryoprecipitate, 149
hemoglobinopathies, 82–86 (CDMR), 158 CSE, see Combined spinal epidural
spinal muscular atrophy, 84–86 CF, see Cystic fibrosis CTG, see Cardiotocography
Carrier screening approaches, 78 CFM, see Continuous fetal monitoring CVS, see Chorion villus sampling
ethnicity-based screening, 78–79 Chest compressions, 377 Cyclooxygenase inhibitors, 238–240
expanded carrier screening, 79 Childbirth, fear of, 91, 93 Cystic fibrosis (CF), 9, 81–82, 82, 83
pan-ethnic screening, 79 Child obesity, 364 Cytomegalovirus (CMV), 21
Castor oil, 282 Chlamydia, 249 Cytotec, see Misoprostol
Category I tracings, 122, 125 screening, 20
Category II tracings, 122, 126–128 Choanal atresia, 380
D
Category III tracings, 122, 129 Cholesterol-lowering diet, 24
CBC, see Complete blood count Chorioamnionitis, 253, 347 DCC, see Delayed cord clamping
CCT, see Controlled cord traction Chorion villus sampling (CVS), 68 Dehydroepiandrosterone sulfate
CD, see Cesarean delivery Choroid plexus cysts (CPCs), 67 (DHEAS), 282
CDMR, see Cesarean delivery on Chromosomal abnormalities, 67, 67 Delayed cord clamping (DCC), 116, 242
maternal request of early pregnancy loss, 196–197 Delivery mode, 307–309
Cell-free fetal DNA screening, 60, 64 Chromosomal microarray analysis Delivery room management, neonate
Cell salvage, 163 (CMA), 69 altered birth transition, 377
Cerclage removal, preterm premature rupture Chronic diseases, 11 initiation of resuscitation, 376–380
of membranes, 252–253 CI, see Cervical insufficiency resuscitation, 377, 377
Cerebral palsy, 382 Circumcision, 380–381 withholding or discontinuing
Cervical biopsy during pregnancy, 393 CIS, see Carcinoma in situ resuscitation, 377
Cervical cancer screening, 20, 390–396, 395 CL, see Cervical length Delivery room resuscitation, newborn, 377
Cervical dilation, for cesarean delivery, 167 Classical forceps, 153 Dental support device, during second stage of
Cervical examination, 21, 134 Clindamycin, 361, 362 labor, 107
frequency of, 101 Clinical pelvimetry, 21 DES, see Diethylstilbestrol
Cervical insufficiency (CI), 211 CMA, see Chromosomal microarray analysis Dexamethasone, 170
Cervical length (CL), 55 CMV, see Congenital cytomegalovirus; Dexamethasone sulfate, 282
screening, 225 Cytomegalovirus DHEAS, see Dehydroepiandrosterone sulfate
Cervical pessary, 237 Coached maternal pushing, 107 Diabetes, 11–12
Cervical ripening Coagulation system, 44 Diagnostic panty liner, 247
antepartum testing during, 282–283 Cocaine, 132 Diagnostic tests
definition of, 272 Colposcopy, indications for, 393–394 chorion villus sampling and
Cervidil, 279 Combined first- and second-trimester tests, amniocentesis, 68
Cervix, cytologic evaluation of, 390 65–69 Diastolic blood pressure, 19
Cesarean delivery (CD), 106–110, 288 Combined spinal epidural (CSE), 144 DIC, see Disseminated intravascular
adhesive drapes for, 163 Commercial infant feeding materials, 365 coagulopathy
ambulation after, 169 Complete abortion, 195 Diethylstilbestrol (DES), 208
anesthesia for, 146–148 Complete blood count (CBC), 20, 82 DiGeorge syndrome, 75–76
cell salvage techniques, 163 Computerized EFM analysis, 131 Digital scalp, see Vibroacoustic stimulation
delivery timing, 159 Congenital cytomegalovirus (CMV), 67 Dihydrolipoamide dehydrogenase (DLD)
extraperitoneal versus transperitoneal Congenital diaphragmatic hernia, 380 deficiency, 88
CD, 164 Congenital heart defects, 66 Dilapan, 276
Foley catheter, removal of, 170 Congenital heart disease, 146 Dinoprostone gel, 280
gum chewing after, 169 Conization, 395, 395 Disrupted laparotomy wound, 170, 361
history and epidemiology/incidence, 158 Constipation, 29 Disseminated intravascular coagulopathy
incision treatment, 169 Continuous fetal monitoring (CFM), 250 (DIC), 345, 348
indications for, 158, 184 Contraception, 366–368 DLD deficiency, see Dihydrolipoamide
labor induction, 273–275, 278 during breastfeeding, 368 dehydrogenase deficiency
magnesium sulfate during, 166 intrauterine devices (IUDs), 367, 367 DMD gene, see Duchene muscular
negative pressure wound therapy (NPWT), postpartum sterilization, 368 dystrophy gene
169 Contraceptive implant, 367–368 Doppler, 54–55
operative table, preparations on, 162–163 Controlled cord traction (CCT), Double-balloon Foley catheters, 278
optimal rate, 159 116–117 Doulas, 95
outcome in, 305 Conventional karyotype, 69 Down’s syndrome, genetic ultrasound
pain relief after, 170 Cord blood collection, 116 screening for, 69–70
planning of, 242 Cord drainage, 117 Duchene muscular dystrophy (DMD)
postoperative anxiety in, 170 Cord gases, 116 gene, 80
postoperative care, 169–170 Cord milking, 116 Ductus venosus (DV), 54
400 Index
Duodenal atresia, 66 Estriol, unconjugated, 65 Fetal surveillance, preterm premature rupture

Duplication, 75–76 Estrogen, 282 of membranes, 250
DV, see Ductus venosus Ethnicity-based screening, 78–79 FFN, see Fetal fibronectin
Dyspnea, 42 Etonogestrel (ENG), 368 FGR, see Fetal growth restriction
Euglycemia, 11 FHR, see Fetal heart rate
E Exclusive breastfeeding, 363 FHR monitoring, see Fetal heart rate monitoring
Exome sequencing (ES), 69 First stage of labor, 98, 99
Early cord clamping (ECC), 116 Expectant management, 265 acid prophylaxis drugs, 100
Early deceleration, of fetal heart rate, 125 of early pregnancy loss, 196, 198 active management of labor, 102
Early pregnancy loss (EPL), 196 vs. surgical management, 200 ambulation, 100–101
definition of, 195–196 External cephalic version (ECV), 191, 299, amniotomy, 102
diagnosis of, 196, 196 304–308 antibiotic prophylaxis, 99
management of, 198–200 External vs. internal FHR monitoring, 131 antispasmodics, 101
patient counseling of, 200, 206 Extra-amniotic prostaglandins, 280 aromatherapy, 99–100
risk factors of, 196 Extra-amniotic saline infusion (EASI), 278 birthing ball, 101
EASI, see Extra-amniotic saline infusion Extraperitoneal vs. transperitoneal cesarean bladder catheterization, 101
EBL, see Estimated blood loss delivery, 164 criteria for diagnosis of failure to progress
ECC, see Early cord clamping; Endocervical in, 103
curettage F frequency of cervical exams, 101
Echogenic intracardiac foci, 67 GBS prophylaxis, 98–99
ECV, see External cephalic version Failed intubation, 147 intrauterine pressure catheter (IUPC),
Edema, routine evaluation for, 22 False-positive rate, 130 102–103
Edinburgh Postnatal Depression Scale (EPDS), 369 Familial dysautonomia, 87 intravenous fluids, 100
EFM, see Electronic fetal monitoring Familial hyperinsulinism, 88 maternal position, 100
Elective forceps delivery, 152 Fanconi anemia, 87 membrane sweeping in labor, 101
Elective repeat cesarean delivery (ERCD), 188 Fascial closure techniques, 168 nutrition in labor, 100
Electronic fetal monitoring (EFM), 122, 130, Fascial incision, cesarean delivery, 164 oxytocin augmentation, 102
131, 133 Fentanyl, 140 partogram, use of, 101
Electronic FHR monitoring vs. intermittent Ferning test, 245, 247, 262 peanut ball, 101
auscultation, 130 Fetal anatomy, 51 vaginal chlorhexidine, 98
Elevated-risk infants, 380 Fetal assessment tests upon admission water, immersion in, 100
Embryonic demise amniotic fluid volume index, 96 First-trimester screening (FTS), 50, 50, 51
definition of, 196 enemas, 96 64–65
ultrasound diagnosis of, see Anembryonic fetal heart rate tracing, 96 “fetal dating” ultrasonography, 22
pregnancy, ultrasound diagnosis of perineal shaving, 96 FISH, see Fluorescent in situ hybridization
Empiric therapy, 361 Fetal bowel, echogenicity of, 67 Fish intake, preterm birth, 214
Endocervical curettage (ECC), 393, 395 Fetal cardiac activity, 51 5p-(Cri-Du-Chat Syndrome), 76
Endocrine, 206 Fetal compression syndrome, 254 FLM, see Fetal lung maturity
changes, 42–43 Fetal demise, 254 Fluorescent in situ hybridization (FISH), 69
evaluation, 206 Fetal echocardiography, 55, 56, 56 FMR-1 gene, see Fragile X mental retardation
Endometrial biopsy, 206 Fetal electrocardiogram, 132 1 gene
Endotracheal intubation, 147, 148, 296–297 Fetal fibronectin (FFN), 234, 247, 276 Foley bulbs, 264
Enemas, 91, 96 Fetal growth restriction (FGR), 52, 67, 125, Foley catheter, 276–277
induction of labor, 282 130, 223 removal of, 170
Energy (calorie)/protein supplementation, 24 Fetal heart rate (FHR), 132 Folic acid supplementation, 10, 25–26
ENG, see Etonogestrel disturbances, 191 Foodborne illnesses, prevention of, 21, 21
Enhanced recovery after surgery (ERAS) patterns, definitions of, 123 Food safety, in pregnancy, 24, 25
strategies, 357 Fetal heart rate (FHR) monitoring, 125, 159 Forceps vs. vacuum-assisted delivery, 131, 154
EPDS, see Edinburgh Postnatal Depression Scale amnioinfusion, 133 47, 75
Epidural anesthesia during cervical ripening, 282–283 FPO, see Fetal pulse oximetry
for cesarean delivery, 146 external vs. internal, 131 Fragile X mental retardation 1 (FMR-1) gene,
neuraxial labor analgesia, 139–144 vs. intermittent auscultation, 130 80, 84
Epidural blood patch, 143 intrauterine resuscitation, 134 Fragile X syndrome, 83–84, 84, 84
Epidural space, 141, 141 tocolysis, 133 Freestanding birth center, 95
Epinephrine, 377 Fetal heart rate tracing, 96 FSBS, see Fetal scalp blood sampling
Episiotomies, 355 Fetal heart tones, 21 FTS, see First-trimester screening
Episiotomy Fetal lung maturity (FLM), 249 Fundal pressure, during second stage of labor,
operative vaginal delivery, 155 Fetal macrosomia, 185 107–108
during second stage of labor, 108 Fetal maturity, steroids for, 162 Future fertility, on early pregnancy loss, 201
EPL, see Early pregnancy loss Fetal movement, 21
ERAS strategies, see Enhanced recovery after Fetal/neonatal benefit G
surgery strategies antibiotics for, 250–252
ERCD, see Elective repeat cesarean delivery corticosteroids for, 250 GA, see Gestational age
Ergometrine, 115 tocolysis for, 252 Gabapentin, 358
Ergot alkaloids, 115 Fetal neuroprotection, magnesium sulfate for, 252 Galactagogues, 366
Erythromycin/erythromycin alone, 251 Fetal pulse oximetry, 132 GAP, see Gentle assisted pushing
ES, see Exome sequencing Fetal pulse oximetry (FPO), 132 Gastrointestinal changes, 44–45
Estimated blood loss (EBL), 325 Fetal scalp blood sampling (FSBS), 131 Gastrointestinal infection, infants, 363
Index 401
Gaucher disease, 87–88 Hospitalization, preterm premature rupture of Intrauterine resuscitation, 134
GBA gene, see Glucocerebrosidase gene membranes, 249–250 Intravenous fluids, 100
GBS, see Group B streptococcus HPV testing, see Human papillomavirus testing Intravenous hydration, 134
General anesthesia, for cesarean delivery, HSV, see Herpes simplex virus Intravenous (IV)
146–147 HUAM, see Home uterine activity monitoring administration, 139
Genetic amniocentesis, 295 Human chorionic gonadotropin (hCG), 207 prostaglandins, 280
Genetic counseling, 79–81 Human immunodeficiency virus (HIV), 249, 366 Invasive cancer, diagnosis of, 394
Genetic evaluation, 204–205 serology screening, 20 Iodine supplements, 27
Genetic testing, 69 Human milk production, 365 iPPROM, see Iatrogenic PPROM
“Genetic” ultrasound screening for trisomy Human papillomavirus (HPV) testing, 391 Iron-deficiency anemia, 43–44
21, 66 Hyaluronidase, 282 Iron supplements, 27
Genital herpes, 21 Hydration, 134, 237 Itching, 29
Gentamicin, 361, 362 Hygroscopic dilators, 276 IUDs, see Intrauterine devices
Gentle assisted pushing (GAP), 108 Hyperemesis gravidarum, 43 IUFD, see Intrauterine fetal demise
Gestational age (GA), 49–50, 49, 50, 64, 210, Hypertension, 12 IUPC, see Intrauterine pressure catheter
247–248 Hypertensive disorders, 145
and labor induction, 274 Hypnosis, 139 J
Gestational sac, 51 Hypnotherapy, 139
Ginger capsules, 170 Hypoglycemia, 378, 378–379, 379 Jehovah’s Witness pregnant woman care,
Glandular cell, 391 Hypotension, 142, 146, 148 118–119
Glucocerebrosidase (GBA) gene, 80 Hypoxemia, 122 Joubert syndrome, 88
Glucose, urine dipstick for, 20 Hypoxia, 122
Glyceryl trinitrate (GTN), 238 Hypoxic–ischemic encephalopathy (HIE), 131, K
Glycogen storage disease, 88 190, 381
Glycosuria, urine dipstick for, 20 Karyotype, 204–205
Glycosylated hemoglobin (HgB A1c), 11–12 I Karyotype abnormalities
Gonorrhea, 249 future pregnancy preconception
screening, 20 IAI, see Intra-amniotic infection counseling, 70–71
Group B streptococcus (GBS) Iatrogenic PPROM (iPPROM), 256–257 Klinefelter syndrome, 74–75
colonization, 224 IDM, see Infant/diabetic mother neonatology management, 69–75
culture and prophylaxis, 256 IGFBP-1, see Insulin-like growth factor– trisomy 13, 72
premature rupture of membranes, 264 binding protein 1 trisomy 21 (Down’s syndrome), 69–70
prophylaxis, 98–99 IM administration, see Intramuscularly Turner syndrome, 73–74
Group prenatal care, 16–17 administration Klinefelter syndrome, 74–75
GTN, see Glyceryl trinitrate Immunologic evaluation, 206
Gum chewing after cesarean delivery, 169 Incision treatment, 169 L
Incomplete abortion, 195
Indomethacin, 217, 222, 240 Labor
H
Induction of labor, see Labor induction active management of, 102
Hair removal, for cesarean delivery, 162 Indwelling bladder catheterization, 162 membrane sweeping in, 101
Hands-on vs. hands-poised method delivery, 109 Infant/diabetic mother (IDM), 380 nutrition in, 100
HBsAg screening, 20 Infant feeding Labor, preparation before, 91
hCG, see Human chorionic gonadotropin health effects of, 363–364 antenatal classes and education, 92–93
Health care provider, 16 recommendations for, 364 antenatal perineal massage, 93
Heartburn, 30 Infection precautions, preterm premature birth, attendant at, 95
Heart disease, 146 rupture of membranes, 249 birth, place of, 93–95
HELLP syndrome, 145 Influenza vaccination, 10 birth assistants, training of, 95
Hemabate, 115 Informed consent, 138 delayed vs. early hospital admission, 96
Hematologic changes, 43–44 Inhibin, 65 fetal assessment tests upon admission, 96
Hematoma, 143 Insulin-like growth factor–binding protein 1 pelvic floor muscle training (PFMT), 93
Hemodynamic changes, in pregnancy, 34–41 (IGFBP-1), 247, 262 pelvimetry, 93
Hemoglobinopathies, 82–86 Integrated screening, 60 spontaneous labor, prediction of the onset
Hemorrhoids, 30 Interobserver variability, fetal heart rate of, 91–92
Hepatitis B vaccination, 10–11 monitoring, 130 sweeping of membranes, 93
Hepatitis C serology screening, 20 Intraabdominal drain, for cesarean delivery, 168 teamwork training, 95–96
Heritable genetic disorders, 9 Intraabdominal irrigation, for cesarean Labor and delivery (L&D) care, 381
Herpes simplex virus (HSV), 249 delivery, 167 Laboratory screening, follow-up, 22
screening for, 21 Intraamniotic infection (IAI), 233, 234, Laboratory tests, 9
HgB A1c, see Glycosylated hemoglobin 287–288 Labor induction, 274, 317
HIE, see Hypoxic–ischemic encephalopathy Intramuscularly (IM) administration, 139 amniotomy, 278
HIV, see Human immunodeficiency virus Intraobserver variability, fetal heart rate antepartum testing, 282
Homeopathy, 282 monitoring, 130 balloon catheter, 276–277
Homeostasis changes, 45–46 Intrapartum, 317 breast stimulation, 282
Home uterine activity monitoring (HUAM), Intrapartum ultrasound, 55–56 cervical assessment, 272
222, 242 Intrauterine devices (IUDs), 367, 367 double-balloon Foley catheters, 278
Home vs. in-hospital care, preterm labor, 242 Intrauterine fetal demise (IUFD), 130 extra-amniotic saline infusion, 278
Hormonal contraception, 367 Intrauterine pressure catheter (IUPC), hygroscopic dilators, 276
Hospital admission, delayed vs. early, 96 102–103, 191 indications for, 273–275
402 Index
management, 283 Maternal demographics, 184 Multidisciplinary care, 2

maternal characteristics, 274 Maternal diet, during lactation, 366 Multifetal reduction, 224–225
membrane stripping, 278 Maternal-Fetal Medicine Units Network Multiple gestations, 224–225
outpatient vs. inpatient, 283 (MFMU Network), 187 Multivitamin supplements, 25
pharmacologic methods, 279–282 Maternal hemorrhage, 149
premature rupture of membrane, 277 Maternal infection prevention, 10–11 N
sequential ripening, 277–278 Maternal medications, 365–366
Labor management during induction, 283 Maternal obesity, 146 Nalbuphine, 132
Labor pain, 138 Maternal oxygen, 105 Naloxone, 140
Labor stimulant, 133 Maternal position, 100 hydrochloride, 377
augmentation, 102 during cesarean delivery, 162 Nasal bone, 65
prophylaxis, 115 during second stage of labor, 106–107 NASG, see Nonpneumatic antishock garment
receptor antagonists, 240 Maternal position change, 133–134 Nasopharyngeal suctioning, 296
Lamicel, 276 Maternal serum alpha-fetoprotein (MS-AFP), Nausea, 45
Laminaria, 276 63, 347 NE, see Neonatal encephalopathy
Large for gestational age (LGA), 52–53, 378 Maternal surveillance, preterm premature Negative pressure wound therapy
LAST, see Local anesthetic systemic toxicity rupture of membranes, 250 (NPWT), 169
Last menstrual period (LMP), 49 Mature teratomas, 384 Nemaline myopathy, 88
Late deceleration, of fetal heart rate, 123 MCA, see Middle cerebral artery Neoadjuvant chemotherapy, 396
Late-preterm infants, 380 MDD, see Major depressive disorder Neonatal
L&D care, see Labor and delivery care Mean sac diameter (MSD), 196 consultation, 72
Left uterine displacement, 138, 149 Meconium, 249, 293–297, 294, 379 echocardiogram, 70
Leg cramps, 29 Meconium and drug screening, 297 Neonatal death rates, 190
Leg edema, 30 Meconium aspiration syndrome (MAS), 293, 379 Neonatal encephalopathy (NE), 381, 382
Leiomyomas, 347 Meconium at genetic amniocentesis, 295 Neonatal intensive care unit (NICU), 381
Leopold’s maneuvers, 21 Meconium peritonitis, prenatal diagnosis of, 294 Neonatal management, 290
LGA, see Large for gestational age Meconium-stained amniotic fluid (MSAF), Neonatal morbidity/mortality, prophylaxis to
Liquid-based cytology, 390 293, 295 prevent, 235–236
LMP, see Last menstrual period Medical management of early pregnancy loss, Neonatal resuscitation, initiation of, 376, 378
LMWH, see Low-molecular-weight heparin 198, 198 Neonatal seizures, 130
Local anesthetic, 142 patient acceptability, preference, Neonate
Local anesthetic systemic toxicity (LAST), 148 counseling, 200–201 care of preterm infant, 381
Local cooling techniques, 118 Medical vs. expectant management, 200 cerebral palsy, 382
Long-term morbidities, 255 Medical vs. surgical management, 198–199 delivery room management, 376–380
Low-dose aspirin, 207 Medications/teratogens, 12 labor and delivery care, 380
Low-dose low-molecular-weight heparin Medium-chain acyl-CoA dehydrogenase low- vs. elevated-risk, 380
(LMWH), 161, 207, 359 deficiency, 86 neonatal encephalopathy, 381
thromboprophylaxis, 144–145 Megaloblastic macrocytic anemia, 44 Neonatology management, karyotype
Lower uterine segment, ultrasound of, 191 Meiotic nondisjunction, 71 abnormalities, 70
Low-glycemic index diet, 24 Membrane stripping, 278 Neural tube defects (NTDs), 10, 63, 380
Low- vs. elevated-risk neonates, 380 Membrane sweeping in labor, 101 maternal serum alpha-fetoprotein
Lumbosacral sterile water injection, 140 Meperidine, 132, 139 screening for, 68
Lung development, phases of, 254, 255 Methergine, 115 Neuraxial labor analgesia, 138, 141
Methotrexate, 198 combined spinal epidural, 146
M Metoclopramide, 170 contraindications to regional
MFMU Network, see Maternal-Fetal Medicine anesthesia, 144
Magnesium sulfate (MgSO4), 132, 166, 240, 350 Units Network epidural analgesia, 141–143
for neuroprotection, 236, 256 Microdeletion, 75–76 Newborn neonatal screening, 380
Magnesium supplements, 26–27 Microinvasive cervical cancer, 390 Nicardipine, 238
Magnesium vs. magnesium alone, 241 Middle cerebral artery (MCA), 54 Nicotine replacement therapy (NRT), 215
Major depressive disorder (MDD), 368 Midwife-led care, 95 NICU, see Neonatal intensive care unit
Malposition, 303, 309–311 Mifepristone, 198, 281 Niemann–Pick disease, 88
Malpresentation, 303 Milk expression, 366 Nifedipine, 238, 306
external cephalic version, 304–307 Milking of cord, 242 Nifedipine and sildenafil citrate versus
mode of delivery, 307–308 Minute ventilation, 41 nifedipine alone, 241
moxibustion, 307 Misoprostol, 115, 166, 200, 264, 277–278 Nitrazine test, 245, 247, 262
Manual rotation, in second stage of labor, Mixed feeding, 363 Nitric oxide (NO) donors, 240–241, 282
108–109 Mode of delivery, 307–309 Nitroglycerine, 240–241
Maple syrup urine disease, 88 Monotherapy, 12 NO donors, see Nitric oxide donors
Markers, 66 Morphine, 132 Nonmegaloblastic macrocytic anemia, 44
MAS, see Meconium aspiration syndrome Morphology ultrasound, 51 Nonpneumatic antishock garment
Massage therapy, 139 Mosaicism, 71, 72 (NASG), 327
Massive transfusion, 149 Moxibustion, 307 Nonreassuring fetal heart rate tracing
Mastitis, 365 MSAF, see Meconium-stained amniotic fluid (NRFHT), 70, 106, 125, 130,
Maternal age, 385 MS-AFP, see Maternal serum 131–134, 158, 299
Maternal analyte screening, 65 alpha-fetoprotein Nonsteroidal antiinflammatory drugs
Maternal blood pressure, 134 MSD, see Mean sac diameter (NSAIDs), 170, 238, 356, 357
Maternal cardiac disease, 145 Mucolipidosis, 88 for perineal pain control, 118
Index 403
Nontocolytic interventions, for preterm Parietal peritoneum, for cesarean risk factors, 336
labor, 237 delivery, 164 symptoms and complications, 337–338
bed rest, 237 Partogram, use of, 101 time of delivery, 338
hydration, 237 PAS, see Placenta accreta spectrum Placenta accreta spectrum (PAS), 56–57, 57
NPWT, see Negative pressure wound therapy Patient acceptability of early pregnancy loss, Placental abruption, 345, 346, 247, see also
NRFHT, see Nonreassuring fetal heart 200–201 Abruptio placentae
rate tracing Patient-controlled epidural analgesia (PCEA), anesthesia, 351
NRT, see Nicotine replacement therapy 141, 142, 143 classification, 346–347
NSAIDs, see Nonsteroidal antiinflammatory Patient counseling, of early pregnancy complications, 348
drugs loss, 200 definition/diagnosis, 345
NT, see Nuchal translucency PCEA, see Patient-controlled epidural analgesia epidemiology/incidence, 345
NTDs, see Neural tube defects PDPH, see Postdural puncture headache etiology/basic pathophysiology, 346
Nuchal fold, 67 Peanut ball, 101 general principles, 350
Nuchal translucency (NT), 50, 63, 64–65, 67 PEIC, see Physical exam-indicated cerclage genetics, 345
Nursery management, karyotype Pelvic examination, 19 late preterm placental abruption, 351
abnormalities, 70 Pelvic floor disorders (PFDs), 355–356 management, 348–351, 349
Nusinersen, 86 Pelvic floor muscle training (PFMT), maternal, 348
Nutrition in labor, 100 93, 355, 356 mode of delivery, 351
Pelvic lymphadenectomy, 396 perinatal, 348
O Pelvic pain, 29 postpartum, 351
Pelvimetry, 93 preconception counseling, 349
Obesity, 12, 25 Penicillin, 361, 362 preterm abruption, 351
Obstetric interventions for periviable Perinatal death rates, 130, 190 prevention, 348–349
birth, 234 Perinatal depression (PND), 368 risk factors/associations, 347
Obstetric lacerations, repair of, 354–355 Perinatal mortality signs and symptoms, 345
Oligohydramnios, 54, 255–256 incidence of, 16 term placental abruption, 350
Omega-3 fatty acids, 214, 218 Perineal gel, 108 timing of delivery, 350
Omega-3 supplements, 27 Perineal hyaluronidase injections, 108 workup, 349–350
Onasemnogene abeparvovec, 86 Perineal lacerations, 117, 117, 355 Placental alpha-microglobulin test, 245, 247
Ondansetron, 170 Perineal massage, 28 Placenta previa, 330
Opening the airway, 376 during second stage of labor, 108 antepartum testing, 334
Operative vaginal birth, 130 Perineal pain control, 118 anti-D immune globulin, 334
Operative vaginal delivery (OVD), 152–156, Perineal protection device, 108 cervical cerclage, 334
153, 154, 155 Perineal shaving, 96 cervical pessary, 334
Optimal duration of breastfeeding, 364 Perineal warm packs, during second stage of definition, 330
Oral dexamethasone, 235 labor, 108 delivery, 334–335
Oral health care, 27 Periodontal disease, 223 diagnosis, 330–331
Oral misoprostol, 280 Peripheral nerve blocks, 140 epidemiology/incidence, 330
Oral prostaglandins, 280 Peritoneal nonclosure, 168 examination, 332
Oropharyngeal and nasopharyngeal Pessary, 217, 224–225 management, 331–335
suctioning, 296 PFDs, see Pelvic floor disorders management at home versus
Oropharyngeal suctioning, 296 PFMT, see Pelvic floor muscle training hospitalization, 333–334
Otitis media, 363 PGE2, see Prostaglandin E2 prenatal care, 333
Ovarian cancer, Federation Internationale PGF2α see Prostaglandin F2α principles, 331–332
de Gynecologie et d’Obstetrique PH, see Pulmonary hypoplasia risk factors, 330
staging for, 388 Pharmacokinetics, 46 steroids, 334
Ovarian cyst rupture, 384, 385 Pharmacologic agents, 328 symptoms and complications, 331
OVD, see Operative vaginal delivery pH definitions, 122 tocolysis, 334
Oxygen administration, for cesarean Phenobarbital, 236 ultrasound, 332–333
delivery, 163 Phenylketonuria, 86 Placentophagy, 117
Oxygenation, 133–134 Physical exam-indicated cerclage (PEIC), 223 Planned home birth, 93–94
Oxygen supplementation, 134 Pierre Robin sequence, 380 Planned hospital birth, 95
Oxytocin, 95, 113–115, 165, 263–264, Piracetam, 134 Planned repeat cesarean delivery (PRCD),
281, 363 Pitfalls, 51–54 189–192
labor stimulation with, 280–281 PL, see Pregnancy loss PND, see Perinatal depression
Placenta POC, see Products of conception
P third stage of labor, 116–117 Poliglecaprone, 169
Placenta accreta spectrum disorders, 332, Polyhydramnios, 54, 54, 347
Pain, 137 335, 337 Post-CD analgesia, 148
labor, 138 classification, 335 Postdural puncture headache (PDPH), 141,
Pain control, 356–357, 357–358 definition, 335 143, 147
Pain relief after cesarean delivery, 170 diagnosis, 336–337 Postmaturity syndrome, 269
Pan-ethnic screening, 79 epidemiology/incidence, 335–336 Postoperative anxiety in cesarean delivery, 170
PAPP-A, see Pregnancy-associated plasma etiopathology, 335 Postoperative counseling, after cesarean
protein-A interventional radiology, 340 delivery, 171
Pap smear, 390–396 management, 338 Postpartum/breastfeeding, 208, 290
Paracervical block, 140 mode of delivery, 338–340 preterm birth, 242
Parenteral opioids, 139 preparation and place of delivery, 338 Postpartum care
404 Index
breastfeeding, 363–366 organizational issues, 16–17 Proteinuria, screening for, 20

contraception, 366–368 preterm labor, 242 PTB, see Preterm birth
endometritis, 361–362 Prenatal counseling, 248 PTL, see Preterm labor
mood and anxiety disorders, 368–369 Prenatal diagnosis, definition of, 60 Pudendal block, 140
wound complications, 360–362 Prenatal education, 23, 28, 191 Pulmonary hypoplasia (PH), 254
Postpartum endometritis, 255, 361–362, 362 Prenatal record, 17 Pushing method, second stage of labor, 107
Postpartum hemorrhage (PPH), 114–115, Prepidil, 280 Pyelectasis, 67
324–329, 325 Preterm birth (PTB), 1, 211, 212, 219, 232–237
prevention of, 165 infections, 224–225 R
Postpartum mood disorders, 368–369 multiple gestations, 224–225
Postpartum period depression, 28–29 prevention, 210–212, 213 Randomized controlled trials (RCTs), 1, 11, 16,
Postpartum sterilization, 368 primary prevention strategies for, 213–215 68, 113–114, 131–134, 311
Postpartum thromboprophylaxis, 359–360 secondary prevention of, 215–221 RCTs, see Randomized controlled trials
Postpartum ultrasound, 362–363 Preterm infant care, 381 Rectus muscle cutting, for cesarean delivery, 164
Postpartum wound complications, 360–361, Preterm labor (PTL), 210, 212, 233, 247 Rectus muscles, 168
360–362 calcium channel blockers, 238 Recurrent pregnancy loss (RPL), 203–204, 204
Postterm pregnancy, 253 fetal fibronectin, 234 anesthesia, 208
Posture, maternal change in, 307 magnesium sulfate, 240 antepartum testing, 208
Post–vaginal delivery analgesia, 148 neonatal morbidity/mortality, 235–236 counseling, 203–204
PPH, see Postpartum hemorrhage nitric oxide donors, 240–241 preconception care, 206
PPROM, see Preterm premature rupture nontocolytic interventions for, 237 screening tests, 204–206
of membranes postpartum/breastfeeding/counseling, 242 Regional anesthesia, 141, 144
PRCD, see Planned repeat cesarean delivery preconception counseling, 242 Relaxation techniques, 139
Precautions, 51–54 primary tocolysis, 237–238 Relaxin, 281–282
Preconception care, 2, 206, 316 tocolysis, 237 Remifentanil, 140
folic acid supplementation, 10 transvaginal ultrasound cervical length, Renal system changes, 45–46
for maternal medical disorders, 6–9 232–233 Reproductive health plan, 9–10
nutrition, weight, and exercise, 10 Preterm prelabor rupture of membranes Resealing techniques, preterm premature
opportunities for, 1–3 (PPROM), 212, 245–247, 246, 248, rupture of membranes, 255
recommendations, 11 265, 290 Residual risk, 82
reproductive health plan, 9–10 amniocentesis, 249 Respiratory changes, 41–42
substance use disorder/environmental anesthesia, 253 Respiratory complications rates, 190
hazards/toxins, 12 antibiotics for prolongation of latency, Respiratory depression/arrest, 143
vaccinations, 10–11 250–252 Respiratory distress, 379
Preconception counseling, 119 cerclage removal, 252–253 Retained placenta, 113, 255, 328
preterm birth, 242 corticosteroids for fetal/neonatal Retinal hemorrhages, 154
preterm premature rupture of maturation, 250 Retractors, 164
membranes, 248 iatrogenic, 256–257 Risdiplam, 86
Predominant breastfeeding, 363 infection precautions, 249 Ritgen’s maneuver, 109
Preeclampsia, 223 postpartum, 253 ROM, see Rupture of membranes
Pregnancy preconception counseling, 248–249 Rotational forceps, 153
cervical biopsy during, 393 prenatal counseling, 248 Routine platelet count, 144
depression, 28–29 previable, 253–256 Routine vs. selective ultrasound
dyspnea of, 42 in twin gestations, 257–258 examination, 49
induction of labor, 274 ultrasound, 249 RPL, see Recurrent pregnancy loss
iodine requirements, 43 vitamin C and E, 252 Rubella antibody, 20
and periviable PTB, 235 Preterm twins, 309 Rupture of membranes (ROM), 131
physiologic adaptations during, 35–37 Preterm uterine contractions, women with, 234
physiologic changes in, 34 Previous lumbar surgery, 146 S
preconception counseling for, 73 Primary tocolysis, 237–238, 241
screening in, 391 Probiotics, 24 Screening tests
Pregnancy-associated plasma protein-A Products of conception (POC), 206 anatomic evaluation, 205–206
(PAPP-A), 347 karyotype, 204–205 vs. diagnostic tests, 60–61, 61
Pregnancy loss (PL), 211 Progesterone, 206, 207–208, 223, endocrine evaluation, 206
threatened, 196 241, 252 genetic evaluation, 204–205
Pregnancy-related endocrine alterations, 42 Prolactin, 363 immunologic evaluation, 206
Pregnancy-related hemodynamic Prolongation of latency for infections, 237
changes, 34 antibiotics for, 250–252 Second stage of labor, 106
Pregnancy-specific hormones, 42 tocolysis for, 252 cesarean delivery in, 110
Pregnant women, normal reference ranges in, Prolonged second stage of labour, management, 106–109
38–40 109–110, 109 prolonged second stage, 109–110
Prelabor rupture of membranes (PROM), 99, PROM, see Prelabor rupture of membranes prophylactic interventions, 106
247, 262–265, 263, 277, 287 Prophylactic antibiotics, 160, 355, 361 Second-trimester “fetal anatomy”
diagnostic tests, 247 cesarean delivery, 160–161 ultrasound, 22
labor induction for, 278 Prophylactic tocolysis, 106 Second-trimester screening (STS), 51, 52, 65
Prenatal care, 119, 206 Prostaglandin E2 (PGE2), 280 Seizure disorders, 12
interventions for common pregnancy Prostaglandin F2α (PGF2α), 115, 281 Sensitivity of screening test, 60
complaints, 29–30 Prostaglandins, 115, 280 Sepsis calculator, 290
Index 405
Sequential ripening, 277–278 SVR, see Systemic vascular resistance Training of providers, breastfeeding, 364
17 α-hydroxyprogesterone caproate (17P), 225 Sweeping of membranes, 93 Tranexamic acid (TA), 115–116, 166, 326
vs. cerclage, 221 Symphyseal-fundal height measurement, 21 Transabdominal amnioinfusion,
Sexual intercourse, 282 Syncope, 41 133, 247, 256
SGA, see Small for gestational age Syntocinon, 113–114 Transabdominal and transperineal
Short humerus, 67 Syntometrine, 115 ultrasound, 109
Shoulder dystocia, 314–316. 315, 315, 318 Syphilis screening, 20 Transabdominal (TA) cerclage, 220
anesthesia, 318 Systemic vascular resistance (SVR), 34 Trans-cerebellar diameter (TCD), 50
antepartum, 316–317 Transcervical amnioinfusion, 133
intrapartum, 317 T Transcutaneous electrical nerve stimulation
neonatal/infant follow-up, 320 (TENS), 139
preconception, 316 TA, see Tranexamic acid Transient tachypnea of the newborn (TTN),
therapy, 317–318 TA cerclage, see Transabdominal cerclage 379–380
training/simulation, 320–322 Tachysystole, 122 Translocations, 72, 73
Sickle cell disease, 82 Tactile stimulation, 376 Transperitoneal cesarean delivery,
SIDS, see Sudden infant death syndrome TAP block, see Transversus abdominis extraperitoneal vs., 164
Skin cleansing, for cesarean delivery, 162 plane block Transvaginal cervical length, 276, 331
Skin incision techniques, for cesarean Targeted gene sequencing, 69 Transvaginal scanning, 50
delivery, 163 Tay-Sachs disease, 87 Transvaginal ultrasound (TVU), 50, 196,
Skin-to-skin contact, 365 TCD, see Trans-cerebellar diameter 331, 334, 336, 386
Slow-release pessary (vaginal insert), 280 Teamwork training, 95–96 Transvaginal ultrasound cervical length
SMA, see Spinal muscular atrophy TENS, see Transcutneous electrical nerve (TVU CL), 55, 92, 216, 218,
Small for gestational age (SGA), 378 stimulation 232–233
SMFM, see Society for Maternal-Fetal Teratogens, 9, 12 screening, 55
Medicine Terbutaline, 132 Transversus abdominis plane (TAP) block,
Smith-Lemli-Opitz syndrome, 86 pump, 241 148, 356, 358
Smoking cessation programs, 12–13, 215 Termination of pregnancy (TOP), 214, 254 TRH, see Thyrotropin-releasing hormone
Society for Maternal-Fetal Medicine Term Prelabor Rupture of Membranes Study Trial of labor after cesarean (TOLAC),
(SMFM), 55 (Term PROM), 288, 290 180, 182
Sodium bicarbonate, 377 Tetanus vaccination, 11 benefits and least morbidity of, 186–188
Specificity of screening test, 60 Therapeutic hypothermia, 382 candidates for, 183–184
Specimen adequacy, 391 Therapeutic ultrasound, for perineal definitions, 182
Spinal anesthesia pain, 118 historical perspectives, 180–182
for cesarean delivery, 147 Therapy of an adnexal mass, in pregnancy, labor factors, 184–185
neuraxial labor analgesia, 144 386–387 management of, 190–192
Spinal muscular atrophy (SMA), 84–86, 85 Thermal management, 376 maternal demographics, 184
Spontaneous abortion, 195 Third stage of labor obstetric history, 184
Spontaneous labor, prediction of the onset active management of, 117 uterine rupture, 185–189, 181, 190
of, 91 definition of, 113 Trichomonas vaginalis, 224
time of day, 92 perineal pain control and breast- Trimester, ultrasound examinations by, 50
transvaginal ultrasound cervical length feeding, 118 Triple screen, 65
(TVU CL), 92 umbilical cord and placenta, 116 Triplets, 309
weather effects, 91 uterotonics, 113–116, 114 Trisomy 13, 72
Spontaneous PPROM, 248 Third trimester, 52–54 Trisomy 18 (Edward syndrome), 71
Squamous epithelial cell, 391 Third-trimester “fetal growth” ultrasound, 22 Trisomy 21 (Down’s syndrome), 69–70
SSI, see Surgical site infection Three-dimensional ultrasound, 55 “genetic” ultrasound screening for, 66
Standard ultrasound, 51 Three-tier FHR interpretation system, TSH level, see Thyroid-stimulating
Sterile water, injections of, 140 122, 124 hormone level
Steroids, 334 Thrombocytopenia, 44 TTN, see Transient tachypnea of the newborn
for fetal maturity, 162, 265 Thrombophilia, 206 Tuberculosis, 21
Stillbirth rates, 190 Thyroglobulin antibodies, 347 breastfeeding, 366
Stress urinary incontinence (SUI), 356 Thyroid-binding globulin, 43 Turner syndrome, 73–74
Stretch marks, 29 Thyroid gland, functions of, 43 TVU, see Transvaginal ultrasound
STS, see Second-trimester screening Thyroid homeostasis, 43 TVU CL, see Transvaginal ultrasound
Subclinical hypothyroidism, 347 Thyroid-stimulating hormone (TSH) cervical length
Subcutaneous tissue, for cesarean delivery, level, 11 Twin pregnancies, with PPROM, 257–258
163–164, 168–169 Thyroperoxidase antibodies, 347 Twins, 308–309
Sublingual misoprostol, 280 Thyrotropin-releasing hormone (TRH), 236 screening for aneuploidies in, 68
Sudden infant death syndrome (SIDS), Tocolysis, 133, 252, 256, 334, see also Type 2 diabetes, 364
68, 364 Tocolytic therapy
SUI, see Stress urinary incontinence Tocolytic therapy, 237–238, 238, 239 U
Surgical intervention, 329 TOLAC, see Trial of labor after cesarean
Surgical management of early pregnancy TOP, see Termination of pregnancy UFH, see Unfractionated heparin
loss, 198 Topical anesthetics, 118 UIC, see Ultrasound-indicated cerclage
Surgical site infection (SSI), 160, 358 Total spinal, 148 Ultrasound, 249
Suture care Toxins, 12 biophysical profile score, 55
dressing removal, 358 Toxoplasmosis, 21 cervical length, 55
staple removal, 358–359 Tractocile, see Atosiban Doppler, 54–55
406 Index
gestational age dating, in pregnancy, Uterine cooling, 167 risk factors, 340
49–50 Uterine enlargement, 41 screening and diagnosis, 340
informed consent, 49 Uterine exteriorization, 167 symptoms and complications, 342
of lower uterine segment, 191 Uterine incision, 164 therapy, 342
routine vs. selective use of, 49 Uterine inversion, 113, 328–329 VBAC, see Vaginal birth after cesarean
safety of, 48 Uterine massage, 117, 167 Venous thromboembolism, prophylactic
three-dimensional, 55 Uterine relaxation, 133 agents to prevent, 161
by trimester, 50 Uterine rupture, 182, 185–189, 190 Venous thromboembolism (VTE), 161, 359
Ultrasound-detected subchorionic Uterine stapling, 164 Ventricular septal defect (VSD), 71
hemorrhage, 347 Uterotonics, 113–116 Vibroacoustic stimulation, 131
Ultrasound examination UTI, see Urinary tract infections Visual analog scale (VAS), 139
induction of labor, 274 UUI, see Urgency urinary incontinence Vitamin A supplements, 26
Ultrasound-indicated cerclage (UIC), 217 Vitamin B6 (pyridoxine) supplements, 26
Umbilical artery, 54, 316 V Vitamin C, 252
Umbilical cord, third stage of labor, 116 Vitamin C supplements, 26
Umbilical cord drainage, 117 Vaccinations, 10–11, 27–28 Vitamin D supplements, 26
Uncomplicated term pregnancy, management Vacuum application, 155 Vitamin E, 252
of, 268 Vacuum-assisted delivery, forceps vs., 154 Vitamin E supplements, 26
antepartum testing, 269–270 Vacuum extractors, 153–154 Vitamin K, 236
breast and nipple stimulation, 269 Vaginal birth after cesarean (VBAC), 130, 181, Vomiting, 45
complications, 268–269 182, 183 VSD, see Ventricular septal defect
diagnosis/definition, 268 Vaginal chlorhexidine, 98 VTE, see Venous thromboembolism
epidemiology/incidence, 268 Vaginal delivery, 183, 187, 356
etiology/basic pathophysiology, 268 Vaginal insert W
interventions, 270 misoprostol, 277–278
management, 269–270 PGE2 (Cervidil), 280 Walker-Warburg syndrome, 89
preconception counseling, 269 Vaginal irrigation, 162–163 Water, immersion in, 100
pregnancy considerations, 269 Vaginal misoprostol, 277–278 Water immersion, 138
risk factors/associations, 268 Vaginal prostaglandins, 263 Withholding/discontinuing neonatal
routine early ultrasound, 269 Valsalva maneuver, 107 resuscitation, 377
stripping/sweeping of membranes, 269 Valsalva vs. spontaneous pushing Withholding or discontinuing
Unfractionated heparin (UFH), 144, 161, 207 method, 107 resuscitation, 377
Ureoplasma urealyticum colonization, 224 Valvular heart disease, 145–146 Wound dressing at cesarean
Urgency urinary incontinence (UUI), 356 Vancomycin, 264 delivery, 169
Urgent cesarean delivery (CD), 299 Variable deceleration, of fetal heart rate, 123
Urinary tract infections (UTI), 160 Varicella, 21 X
Urine culture, for asymptomatic bacteriuria, 20 Varicosities, 30
Urine dipstick for protein, 20 VAS, see Visual analog scale X-inactive specific transcript (XIST), 74
Usher syndrome, 88–89 Vasa previa, 340, 341 XIST, see X-inactive specific transcript
Uterine artery, 54–55 classification, 340
Uterine atony, prevention of, 165–166 definition, 340 Z
Uterine balloon tamponade, 327 epidemiology/incidence, 340
Uterine cavity, 207 management, 342 Zidovudine, 132
Uterine cleaning, 167 principles, 342 Zinc supplements, 27

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OBSTETRIC EVIDENCE

About the Series

Maternal-Fetal Evidence Based Guidelines, Fourth Edition

Obstetric Evidence Based Guidelines, Fourth Edition

Operative Obstetrics, Fourth Edition

Placenta Accreta Syndrome

Neurology and Pregnancy: Clinical Management

Problem-Based Obstetric Ultrasound, Second Edition

Recurrent Pregnancy Loss: Causes, Controversies and Treatment, Third Edition

For more information about this series please visit: https://www.routledge.com/Series-in-Maternal-Fetal-Medicine/book-series/

Vincenzo Berghella, MD, FACOG

and by CRC Press

© 2022 Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, LLC

ISBN: 978-0-367-60877-4 (hbk)

Typeset in Warnock Pro

5. Prenatal Diagnosis and Screening for Aneuploidy.........................................................................................................................60

6. Carrier Screening for Inherited Genetic Conditions...................................................................................................................... 78

7. Preparation before Labor................................................................................................................................................................... 91

8. First Stage of Labor.............................................................................................................................................................................98

9. Second Stage of Labor.......................................................................................................................................................................105

10. Third Stage of Labor..........................................................................................................................................................................113

11. Intrapartum Fetal Monitoring........................................................................................................................................................122

12. Analgesia and Anesthesia.................................................................................................................................................................137

13. Operative Vaginal Delivery..............................................................................................................................................................152

14. Cesarean Delivery..............................................................................................................................................................................157

15. Trial of Labor after Cesarean...........................................................................................................................................................180

16. Early Pregnancy Loss........................................................................................................................................................................195

17. Recurrent Pregnancy Loss................................................................................................................................................................203

18. Preterm Birth Prevention in Asymptomatic Women................................................................................................................... 210

19. Preterm Labor....................................................................................................................................................................................232

20. Preterm Prelabor Rupture of Membranes......................................................................................................................................245

21. Prelabor Rupture of Membranes at or Near Term........................................................................................................................262

22. Management of the Uncomplicated Term Pregnancy..................................................................................................................268

23. Induction of Labor.............................................................................................................................................................................272

24. Intraamniotic Infection and Inflammation (Triple I)..................................................................................................................287

26. Malpresentation and Malposition...................................................................................................................................................299

27. Shoulder Dystocia............................................................................................................................................................................. 314

28. Postpartum Hemorrhage, Retained Placenta, and Uterine Inversion........................................................................................324

29. Placental Disorders...........................................................................................................................................................................330

30. Placental Abruption..........................................................................................................................................................................345

31. Postpartum Care...............................................................................................................................................................................354

32. The Neonate........................................................................................................................................................................................ 376

33. The Adnexal Mass..............................................................................................................................................................................384

34. Cervical Cancer Screening and Management in Pregnancy.......................................................................................................390

Alfred Abuhamad Alison G. Cahill Lorraine Dugoff

Rebecca Jackson Giovanni Morganelli Norman G. Rosenblum

B. Anthony Armson Colleen Horan Jennifer Salati

Sean C. Blackwell Kyle Jespersen Sally Segel

Sara Campbell Christine H. Kim Moeun Son

Eileen M. Gariepy Dawnette Lewis Alison M. Stuebe

Alessandro Ghidini Talia M. Maas Michela Villani

William Grobman Swati Murthy Serena Xodo

Lauren Cooper Hand George Patounakis Amanda Yeaton-Massey

Ab antibody EKG (synonym of EDC) electrocardiogram

NRFHT nonreassuring fetal heart testing RCT randomized controlled study

Key points to incorporate change in modifiable health behaviors in

TABLE 1.4: Preconception Laboratory Screening Depending on Risk Factors

TABLE 1.4 (Continued): Preconception Laboratory Screening Depending on Risk Factors

reatment: Treatment options include enzyme replacement