Esteroides Canada 2019

SOGC CLINICAL PRACTICE GUIDELINE
It is SOGC policy to review the content 5 years after publication, at which time the document may be re-affirmed or revised to
reflect emergent new evidence and changes in practice.
No. 364, September 2018, (Replaces No. 122, January 2003)
No. 364-Antenatal Corticosteroid Therapy for

Improving Neonatal Outcomes
This Clinical Practice Guideline has been prepared by Antenatal Verdun, QC; Lynne McLeod, MD, Halifax, NS; Savas Menticoglou,
Corticosteroid Therapy Working Group and reviewed and MD, Winnipeg, MB; William Mundle, MD, Windsor, ON; Anne
approved by the Maternal-Fetal Medicine and Guideline Roggensack, MD, Calgary, AB; Frank Sanderson, MD, Saint
Management and Oversight Committee; and approved by the John, NB; Jennifer Walsh, MD, Rothesay, NB.
Board of the Society of Obstetricians and Gynaecologists of Special Contributor: Sarah McDonald, MD, MSc, provided a
Canada. figure that was adapted and added to the guidelines.
Amanda Skoll, MD*, Vancouver, BC Disclosure Statement: Disclosure statements have been received
Amélie Boutin, PhD*, Québec City, QC from all authors, and none declared any conflicts of interest.
Emmanuel Bujold, MD, MSc, Québec City, QC Key Words: Antenatal corticosteroid therapy, fetal maturation,
prematurity, late preterm, pre-labour Caesarean section
Jason Burrows, MD, Vancouver, BC
Joan Crane, MD, MSc, St.-John’s, NL
Michael Geary, MD, Ireland
Venu Jain, MD, PhD, Edmonton, AB WHAT IS NEW/CHANGED
Thierry Lacaze-Masmonteil, MD, PhD, Calgary, AB
1. ACS should be routinely administered from 24 + 0 and 34 + 6
Jessica Liauw, MD, Vancouver, BC weeks gestation when delivery is expected within 7 days.
William Mundle, MD, Windsor, ON 2. ACS should be administered to women at risk of delivery prior
to 24 weeks when delivery is expected within 7 days and in-
Kellie Murphy, MD, MSc, Toronto, ON tensive care is planned for the baby.
Suzanne Wong, MD, Toronto, ON 3. Routine use of rescue or repeat courses of ACS is not
recommended.
K.S. Joseph, MD, PhD, Vancouver, BC 4. Routine use of ACS is not recommended prior to pre-labour
Caesarean section at term.
Maternal Fetal Medicine Committee : Melanie Basso, RN,

Vancouver, BC; Hayley Bos, MD, Victoria, BC; Richard Brown,
MD, Beaconsfield, QC; Emmanuel Bujold, MD, Québec, KEY MESSAGES
QC;Stephanie Cooper, MD, Calgary, AB; Robert Gagnon, MD,
1. ACS improved neonatal outcomes when administered to
*Shared co-first authorship. women at risk of preterm birth between 24 + 0 and 34 + 6
weeks gestation.
J Obstet Gynaecol Can 2018;40(9):1219–1239 2. ACS should be administered only when preterm delivery is
anticipated within 7 days.
https://doi.org/10.1016/j.jogc.2018.04.018 3. Possible neonatal benefit should be weighed against pos-
Copyright © 2018 The Society of Obstetricians and Gynaecologists of sible long-term harm when considering ACS at 35 or 36 weeks
Canada/La Société des obstétriciens et gynécologues du Canada. Pub- gestation.
lished by Elsevier Inc. All rights reserved.
Disclaimer: This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information
should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments
to these opinions. They should be well-documented if modified at the local level. None of these contents may be reproduced in any form without
prior written permission of the publisher.
Patients have the right and responsibility to make informed decisions about their care in partnership with their health care providers. In order
to facilitate informed choice women should be provided with information and support that is evidence based, culturally appropriate, and tai-
lored to their needs. The values, beliefs, and individual needs of each patient and their family should be sought, and the final decision about
the care and treatment options chosen by the patient should be respected.
SEPTEMBER JOGC SEPTEMBRE 2018 • 1219

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Abstract 2. Evidence from cohort studies shows a significant reduction in peri-

natal mortality among infants exposed to antenatal corticosteroid
Objective: To assess the benefits and risks of antenatal therapy at less than 24 weeks gestation (Low).
corticosteroid therapy for women at risk of preterm birth or 3. Antenatal corticosteroid therapy administered to women at risk of
undergoing pre-labour Caesarean section at term and to make preterm delivery between 34 + 0 and 36 + 5 weeks gestation de-
recommendations for improving neonatal and long-term creases neonatal respiratory morbidity (Moderate).
outcomes. 4. There is an increased risk of neonatal hypoglycemia among infants
exposed to antenatal corticosteroid therapy at 34 + 0 to 36 + 5 weeks
Options: To administer or withhold antenatal corticosteroid therapy gestation (Moderate).
for women at high risk of preterm birth or women undergoing pre- 5. Administration of antenatal corticosteroid therapy decreases re-
labour Caesarean section at term. spiratory distress syndrome and need for mechanical ventilation
Outcomes: Perinatal morbidity, including respiratory distress in infants of women undergoing elective pre-labour Caesarean de-
syndrome, intraventricular hemorrhage, bronchopulmonary livery at term (Moderate).
dysplasia, infection, hypoglycemia, somatic and brain growth, and 6. Limited evidence is available on long-term outcomes following an-
neurodevelopment; perinatal mortality; and maternal morbidity, tenatal corticosteroid therapy in cases of elective pre-labour
including infection and adrenal suppression. Caesarean delivery at term gestation. However, there are con-
cerns regarding the cognitive functioning of children exposed to
Intended Users: Maternity care providers including midwives, family antenatal corticosteroid therapy prior to elective Caesarean section
physicians, and obstetricians. at term gestation (Low).
7. Betamethasone has been more commonly used in studies evalu-
Target Population: Pregnant women.
ating the effect of antenatal corticosteroid therapy. In indirect
Evidence: Medline, PubMed, Embase, and the Cochrane Library comparisons, betamethasone shows greater reductions in
were searched from inception to September 2017. Medical chorioamnionitis, respiratory distress syndrome, and chronic lung
Subject Heading (MeSH) terms and key words related to disease compared with dexamethasone. In direct comparisons, dexa-
pregnancy, prematurity, corticosteroids, and perinatal and methasone is associated with a greater reduction in intraventricular
neonatal mortality and morbidity were used. Statements from hemorrhage and lower length of neonatal intensive care unit stay
professional organizations including that of the National Institutes compared with betamethasone. Effects on other outcomes are gen-
of Health, the American College of Obstetricians and erally similar (Low).
Gynecologists, the Society for Maternal Fetal Medicine, the Royal 8. The likelihood of preterm delivery and also the gestational age
College of Obstetricians and Gynaecologists, and the Canadian need to be carefully considered when contemplating the use of
Pediatric Society were reviewed for additional references. antenatal corticosteroid therapy among pregnant women. The ef-
Randomized controlled trials conducted in pregnant women ficacy of such therapy is highest when the course is given 24 hours
evaluating antenatal corticosteroid therapy and previous to 7 days prior to delivery. Administration more than 7 days before
systematic reviews on the topic were eligible. Evidence from delivery leads to reduced benefit and potentially unnecessary adverse
systematic reviews of non-experimental (cohort) studies was also effects (Low).
eligible. 9. Repeated courses of antenatal corticosteroid therapy are associ-
ated with a reduction in respiratory distress syndrome, mechanical
Validation Methods: This Committee Opinion has been reviewed ventilation, and use of surfactant (Moderate).
and approved by the Maternal-Fetal Medicine Committee of the 10. Birth weights and head circumferences are decreased in infants
SOGC and approved by SOGC Council. exposed to multiple courses compared with those exposed to a single
Benefits, Harms, and/or Costs: A course of antenatal corticosteroid course of antenatal corticosteroid therapy (High).
therapy administered within 7 days of delivery significantly 11. There is limited evidence on the long-term effects of
reduces perinatal morbidity/mortality associated with preterm birth repeated courses of antenatal corticosteroid therapy. Follow-up from
between 24 + 0 and 34 + 6 weeks gestation. When antenatal a large trial indicated higher risks of neurosensory disability and
corticosteroid therapy is given more than 7 days prior to delivery of a composite of death or severe disability (neuromotor,
or after 34 + 6 weeks gestation, the adverse effects may outweigh neurosensitive, neurocognitive) in children exposed to multiple
the benefits. Evidence on long-term effects is scarce, and courses of antenatal corticosteroid therapy and born at term
potential neurodevelopment harms are unquantified in cases of (Moderate).
late preterm, term, and repeated exposure to antenatal 12. Few trials of antenatal corticosteroid therapy in multifetal pregnan-
corticosteroid therapy. cies are available. Subgroup analyses show that effects of antenatal
corticosteroid therapy are not different between multifetal preg-
Guideline Update: Evidence will be reviewed 5 years after nancies and singleton pregnancies (Low).
publication to evaluate the need for a complete or partial update of 13. Evidence from cohort studies shows benefits of antenatal cortico-
the guideline. If important evidence is published prior to the 5-year steroid therapy are greater in multifetal pregnancies when antenatal
time point, an update will be issued to reflect new knowledge and corticosteroid therapy is administered within 7 days prior to deliv-
recommendations. ery (Low).
14. Evidence on the effects of antenatal corticosteroid therapy in dia-
Sponsors: The guideline was developed with resources provided by
betic women is scarce, and no comparative study has been
the Society of Obstetricians and Gynaecologists of Canada with
conducted in this subpopulation (Low).
support from the Canadian Institutes of Health Research
15. Antenatal corticosteroid therapy leads to an increase in maternal
(APR-126338).
blood glucose levels up to 1 week after the initiation of the first dose
Summary Statements: (Low).
16. There is an absence of evidence on the effects of antenatal cor-
1. Trials enrolling pregnant women from 24 + 0 to 34 + 6 weeks
ticosteroid therapy among women with obesity, and no comparative
gestation at high risk of preterm birth show that antenatal
study has been conducted in this subpopulation (Low).
corticosteroid therapy significantly reduces perinatal death, respi-
17. Responsiveness of growth-restricted fetuses to antenatal cortico-
ratory distress syndrome, and intraventricular hemorrhage
steroid therapy remains largely unknown (Low).
(Moderate).
1220 • SEPTEMBER JOGC SEPTEMBRE 2018

No. 364-Antenatal Corticosteroid Therapy for Improving Neonatal Outcomes
18. A lower frequency of major brain lesions, but a higher frequency 13. Antenatal corticosteroid therapy should be administered to asymp-
of body size below the 10th centile at school age is observed in tomatic patients with vasa previa or placenta previa when the risk
cohort studies of small for gestational age infants exposed to an- of delivery within 7 days is high and the gestational age criteria are
tenatal corticosteroid therapy (Low). met (Strong, Low).
19. Antenatal corticosteroid therapy may induce transient variations in 14. In cases where the diagnosis of preterm labour has not been firmly
fetal body movements including a potential reduction in fetal move- established (i.e., no documented cervical change and dilatation
ments in the first 3 days following therapy initiation (Low). <3 cm), and the woman is being transferred to a higher level of care
for further assessment, antenatal corticosteroid therapy should not
Recommendations: Gestational Age Considerations be administered prior to transfer (Strong, Low).
1. One course of antenatal corticosteroid therapy should be routinely 15. If the risk of preterm delivery decreases significantly following ad-
administered to women at 24 + 0 to 34 + 6 weeks gestation who are ministration of the first dose of antenatal corticosteroid therapy,
at high risk for preterm delivery within the next 7 days (Strong, cancellation of the second dose of corticosteroids should be con-
Moderate). sidered. If the second dose is cancelled and a high risk of preterm
2. Women between 22 + 0 weeks and 23 + 6 weeks gestation birth arises subsequently at less than 34 + 6 weeks gestation, 1
at high risk of preterm birth within the next 7 days should be pro- dose or 1 course of antenatal corticosteroid therapy should be con-
vided with a multidisciplinary consultation regarding the high likelihood sidered, depending on gestational age and the duration since the
for severe perinatal morbidity and mortality and associated mater- first dose (Strong, Low).
nal morbidity. Antenatal corticosteroid therapy may be considered 16. If the woman remains undelivered beyond 7 days after the first an-
if early intensive care is requested and planned (Conditional, tenatal corticosteroids course, the balance of risks and benefits does
Low). not support further routine administration of antenatal corticoste-
3. The balance of risks and benefits does not support routine admin- roid therapy even if the risk of preterm delivery increases
istration of antenatal corticosteroid therapy for women at 35 + 0 to subsequently. The gestational age and the time interval since the
35 + 6 weeks gestation who are at high risk for preterm birth in the first course of antenatal corticosteroid therapy (at least 14 days)
next 7 days (Conditional, Moderate). should be taken into account when considering a rescue course.
4. Antenatal corticosteroid therapy should not be routinely adminis- A single rescue course of antenatal corticosteroid therapy may be
tered to women at 36 + 0 to 36 + 6 weeks gestation who are at risk administered after risks and benefits are discussed with the woman
for preterm delivery (Conditional, Moderate). (Conditional, Moderate).
5. Antenatal corticosteroid therapy may be administered between 35 + 0 Subpopulations and Special Consideration
and 36 + 6 weeks gestation in select clinical situations after
risks and benefits are discussed with the woman and the pediatric 17. Antenatal corticosteroid therapy should be administered accord-
care provider(s) (Conditional, Moderate). ing to the same indications and in the same gestational age range
6. Elective pre-labour Caesarean section should be performed at or to women with twin or higher-order multifetal pregnancies as for
after 39 + 0 weeks gestation to minimize respiratory morbidity (Strong, singleton pregnancies (Conditional, Low).
Low). 18. Antenatal corticosteroid therapy should not be administered to
7. Antenatal corticosteroid therapy should not be routinely adminis- women with multifetal pregnancies in the absence of a high risk
tered to women undergoing pre-labour Caesarean section at term of preterm birth within the next 7 days (Conditional, Low).
gestation (including at 37 and 38 weeks gestation) (Strong, 19. Antenatal corticosteroid therapy should be administered to dia-
Low). betic women at the same dosage, according to the same indications,
and in the same gestational age range as that recommended for
Agents, Dosage, Regimen, and Target Timing non-diabetic women (Conditional, Low).
8. When antenatal corticosteroid therapy is indicated, women should 20. Close attention should be paid to control of maternal blood glucose
receive a course of antenatal corticosteroid therapy (i.e., either 2 among women with diabetes in the days following antenatal cor-
doses of betamethasone 12 mg given by intramuscular injection ticosteroid therapy because of anticipated elevations in maternal
24 hours apart or 4 doses of dexamethasone 6 mg given by in- blood glucose levels (Strong, Low).
tramuscular injection 12 hours apart) (Strong, Moderate). 21. Because of the transient elevation of blood glucose levels induced
9. Antenatal corticosteroid therapy should be administered to women by corticosteroids, gestational diabetes screening should be delayed
requiring medically indicated delivery only when the plan to proceed for a minimum of 1 week following antenatal corticosteroid therapy
with delivery within 7 days has been finalized and gestational age (Strong, Low).
criteria for antenatal corticosteroid therapy are met (Strong, 22. Antenatal corticosteroid therapy should be administered to women
Low). with obesity at the same dosage as that recommended for women
10. Antenatal corticosteroid therapy should be routinely administered without obesity (according to the same indications and in the same
to women in spontaneous preterm labour characterized by regular gestational age range) because there is insufficient evidence to guide
uterine contractions associated with significant cervical dila- dosage adjustments by maternal weight (Conditional, Low).
tion or significant cervical change on repeated examination 23. There is insufficient evidence to withhold routine antenatal corti-
when gestational age criteria for antenatal corticosteroid therapy costeroid therapy in cases of suspected fetal growth restriction with
are met. a high risk of preterm birth. Antenatal corticosteroid therapy should
Regular contractions in the absence of cervical dilation/change, or be administered according to the same indications and in the same
a short cervical length in the absence of regular contractions, are gestational age range as in normal pregnancies after risks and ben-
not indications for antenatal corticosteroid therapy (Strong, Low). efits are discussed with the woman (Conditional, Low).
11. Antenatal corticosteroid therapy should be routinely administered 24. Antenatal corticosteroid therapy should not be administered to
at the time of diagnosis to women with preterm premature rupture women with suspected fetal growth restriction at the time of diag-
of membranes, when gestational age criteria are met (Strong, Low). nosis unless there is a high risk of preterm birth within the next 7
12. Antenatal corticosteroid therapy should be administered to women days (Conditional, Low).
with significant antepartum hemorrhage when the risk of delivery 25. Women should be informed of the potential for a transient reduc-
within 7 days is high and the gestational age criteria for such therapy tion in fetal movements and advised to consult with their health care
are met (Strong, Low). professional if this occurs (Strong, Low).

INTRODUCTION suspected fetal growth restriction. In Canada, antenatal cor-

ticosteroid therapy is frequently administered to women who
T he rate of preterm birth has remained stable over the
last decade in Canada, with 7.3% of live births in 2001
and 7.9% of live births in 2015–2016 delivered at <37 weeks
will ultimately deliver at term or more than 2 weeks after
treatment,31 both of which are associated with decreased
benefit and potential harms.32,33 These observations high-
gestation.1,2 Preterm birth remains a significant cause of
light the need for a more rigorous assessment of the risk
perinatal morbidity and mortality,3–6 with higher risks of of preterm delivery before exposing fetuses to antenatal cor-
RDS, intraventricular hemorrhage, and long-term ticosteroid therapy.
neurodevelopmental deficits observed in infants born prior
to term.7–9 Such complications have significant long-term This new guideline on antenatal corticosteroid prophy-
health implications and lead to a substantial social and eco- laxis incorporates recent evidence and updates the 2003
nomic burden.10–14 SOGC guideline on the topic. As with any intervention, ad-
ministration of antenatal corticosteroid therapy should always
Since the first trial of betamethasone for lung maturation
be preceded by a full discussion of benefits and risks with
in 1972,15 numerous trials have explored the effect of an-
the woman meeting criteria for such treatment.
tenatal corticosteroid therapy for preventing adverse
outcomes among infants of women at high risk of preterm
birth. These studies showed that antenatal corticosteroid
GESTATIONAL AGE
therapy results in a reduction in neonatal mortality and in
complications such as intraventricular hemorrhage, necro- Gestational Age Notation
tizing enterocolitis, and severe RDS.15–27 The previous This guideline follows the World Health Organization’s no-
guideline by the SOGC on antenatal corticosteroid therapy tation on gestational age,34 under which the first day of the
for women at risk of preterm birth was published in 2003,28 last menstrual period is labelled day 0 (of week 0) and days
and currently such treatment is routinely used in women at 7 to 13 involve week 1 (or week 1 + 0 to week 1 + 6). A
high risk of birth between 24 and 34 weeks gestation. recommendation to administer antenatal corticosteroid
However, variations in practice are common as uncertain- therapy to women at high risk of preterm birth between 24
ties persist with regard to the benefits and risks of antenatal and 34 weeks gestation refers to women at 24 + 0 to 34 + 6
corticosteroid therapy in specific clinical situations and weeks gestation.
subpopulations.29,30 Clinical scenarios where there is uncer-
tainty with regard to the benefits and risks of antenatal
corticosteroid therapy include women at high risk of preterm Gestational Age: 24 + 0 to 34 + 6 Weeks
birth at periviable or late preterm gestations, women re- of Gestation
quiring elective pre-labour Caesarean delivery at term The 2017 Cochrane review27 summarized the results of 30
gestations, and women at high risk of preterm birth who randomized controlled trials that enrolled women from
have received a first course of antenatal corticosteroid therapy 24 + 0 to 37 + 0 weeks gestation. A majority of studies
more than 7 days previously. Other areas of uncertainty enrolled women up to a maximum of 34 + 6 weeks
include the use of antenatal corticosteroid therapy and dose- (n = 11 studies) or to a lower maximal gestational age
related issues among women with multifetal pregnancies, (n = 6 studies). The subgroup analyses of studies that
women with diabetes, women with obesity, and women with recruited women up to 35 + 0 weeks gestation showed a
significantly reduced risk of RDS (RR 0.65; 95% CI
0.58–0.73), perinatal death (RR 0.71; 95% CI 0.58–0.87),
neonatal death RR 0.67; 95% CI 0.57–0.79), and intraven-
tricular hemorrhage (RR 0.54; 95% CI 0.42–0.68) in the
ABBREVIATIONS
antenatal corticosteroid therapy group compared with the
ACS Antenatal corticosteroid therapy
control group. The previous 2006 Cochrane review32 had
ALPS Antenatal Late Preterm Steroids
shown that RDS was significantly reduced in those who
ASTECS Antenatal Steroids for Term Caesarean Section received their first dose of antenatal corticosteroid therapy
CI confidence interval at 26 + 0 to 29 + 6 weeks gestation, 30 + 0 to 32 + 6 weeks
MACS Multiple Courses of Antenatal Corticosteroids for gestation, and 33 + 0 to 34 + 6 weeks gestation compared
Preterm Birth Study
with the control group.
OR odds ratio
RDS respiratory distress syndrome The evidence presented in the 2017 Cochrane review on
RR risk ratio the long-term impact of antenatal corticosteroid therapy

Table 1. Summary of studies regarding antenatal corticosteroid therapy administered to women prior to 24 weeks of
gestation
Studies No of patients Effect
Adjusted OR
No. of studies Study design ACS No treatment (95% CI) Certainty Importance
Mortality before hospital discharge
4 Observational studies 946/1628 (58.1%) 1423/1982 (71.8%) OR 0.48 ⨁⨁ Critical
(0.38–0.61) Low
Respiratory distress syndrome
2 Observational studies NA NA OR 1.09 ⨁ Important
(n = 262) (n = 599) (0.69–1.73) Very low
Severe intraventricular hemorrhage
2 Observational studies NA NA OR 0.82 ⨁ Important
(n = 261) (n = 598) (0.55–1.21) Very low
N/A: not available.
Adapted from Park et al.36
is limited and shows no significant effects of 1 course of Periviable Fetuses: < 24 + 0 Weeks of Gestation
antenatal corticosteroid therapy on childhood developmen- There are limited data on the efficacy of antenatal cortico-
tal delay or cerebral palsy.27 A review of long-term steroid therapy in the periviable period, specifically
neurodevelopmental outcomes by Sotiriadis et al. (which from 22 + 0 weeks to 23 + 6 weeks gestation, and no
included additional observational studies) reported less randomized trials have been carried out in women at this
cerebral palsy and severe disability, and greater intact gestational age (Table 1).27,36,37 However, a meta-analysis of
survival in children whose mothers had received 1 course cohort studies evaluating antenatal corticosteroid therapy
of antenatal corticosteroid therapy.35 However, this review in infants delivered before 24 weeks gestation suggests
documented several limitations with regard to long-term potential benefit.36 Such cohort studies show a reduction
follow-up, and the certainty regarding the long-term effects in perinatal mortality when antenatal corticosteroid therapy
of antenatal corticosteroid therapy is low. These limita- is given to women who deliver between 23 + 0 weeks and
tions do not negate the reductions in perinatal mortality 23 + 6 weeks gestation, and a possible mortality reduction
and severe neonatal morbidity associated with antenatal between 22 + 0 weeks and 22 + 6 weeks. Several national
corticosteroid therapy, and overall, the available evidence and international groups recommend considering such
shows significant benefits and limited risks when antenatal corticosteroid therapy at a periviable gestation of 23
corticosteroid therapy is administered between 24 + 0 and weeks.38–42 The recommendation to offer such therapy at
34 + 6 weeks gestation among women at high risk of 22 + 0 weeks to 22 + 6 weeks is also consistent with
preterm birth. Canadian Pediatric Society guidelines.43 However, the ex-
tremely high risk of serious neonatal long-term morbidity
Summary Statement and neonatal death associated with delivery before 24 weeks
1. Trials enrolling pregnant women from 24 + 0 to gestation requires that use of antenatal corticosteroid
34 + 6 weeks gestation at high risk of preterm birth therapy be preceded by an in-depth discussion on progno-
show that antenatal corticosteroid therapy signifi- sis for the infant as well as the mother. Ideally, this should
cantly reduces perinatal death, respiratory distress be done in consultation with neonatal care providers. Use
syndrome, and intraventricular hemorrhage (Moderate). of a self-fulfilling line of questioning such as “Do you
want everything done for the baby?” should be avoided,
Recommendation as such statements may lead to unintentional moral or
emotional coercion. Instead, after the woman (and her
1. One course of antenatal corticosteroid therapy should
partner) has obtained a realistic understanding of prognos-
be routinely administered to women at 24 + 0 to
tic issues, the options of non-intervention versus early
34 + 6 weeks gestation who are at high risk for preterm
intensive care (i.e., active resuscitation) should be pro-
delivery within the next 7 days (Strong recommenda-
vided from a neutral standpoint. Antenatal corticosteroid
tion, Moderate certainty of evidence).
therapy should only be administered if early intensive care

is requested and planned. If the non-intervention option therapy. There was no significant difference in the rate of
is chosen, the woman should be reassured that the plan RDS in those who received betamethasone versus placebo
will be revisited and revised with advancing gestation in (RR 0.87; 95% CI 0.65–1.17). However, neonatal hypogly-
accordance with the woman’s wishes. cemia occurred more frequently following antenatal
corticosteroid therapy (24% vs. 15%; RR 1.60; 95% CI 1.37–
Summary Statement 1.87). The study report did not include stratified analyses
2. Evidence from cohort studies shows a significant re- by gestational week, but a subgroup analysis of women re-
duction in perinatal mortality among infants exposed cruited at or after 36 + 0 weeks gestation showed no
to antenatal corticosteroid therapy at less than 24 weeks significant difference in primary outcome (RR 1.00; 95% CI
gestation (Low). 0.64–1.6) or in the rate of severe respiratory complica-
tions (RR 1.28; 95% CI 0.65–2.52). Furthermore, the
Recommendation frequency of the primary outcome and severe respiratory
2. Women between 22 + 0 weeks and 23 + 6 weeks ges- complications was significantly lower among women who
tation at high risk of preterm birth within the next 7 delivered at 36 + 0 to 36 + 6 weeks compared with those
days should be provided with a multidisciplinary con- who delivered at 34 + 0 to 35 + 6 weeks gestation.
sultation regarding the high likelihood for severe A recent meta-analysis summarizing data from the ALPS
perinatal morbidity and mortality, and associated ma- trial and 5 other randomized controlled trials examining an-
ternal morbidity. Antenatal corticosteroid therapy may tenatal corticosteroid therapy in women at risk for preterm
be considered if early intensive care is requested and delivery from 34 + 0 to 36 + 6 weeks gestation showed a
planned (Conditional recommendation, Low cer- significant decrease in severe RDS among those who re-
tainty of evidence). ceived antenatal corticosteroid therapy (Table 2).27 Although
these studies demonstrated a reduction in respiratory mor-
bidity with administration of antenatal corticosteroid therapy
Late Preterm: 35 + 0 to 35 + 6 and 36 + 0 to 36 + 6
throughout the late preterm period, the balance of risks and
Weeks of Gestation
benefits at each gestational week remains unclear.26,27,44 Pre-
Recent studies have provided evidence regarding the routine
vious publications have cautioned against routine use of
administration of antenatal corticosteroid therapy to women
antenatal corticosteroid therapy at late preterm gestation
at risk of late preterm delivery (34 + 0 to 36 + 6 weeks
because of the relatively low baseline rates of respiratory
gestation).27 In 2016, Gyamfi-Bannerman et al. published
morbidity and concerns regarding an increased risk of hy-
the ALPS study,26 a randomized, blinded, controlled trial ex-
poglycemia and possible neurodevelopmental morbidity.45
amining 1 course of antenatal betamethasone versus placebo
A meta-analysis of 3 trials of women at risk of late preterm
in women with a singleton pregnancy at 34 + 0 to 36 + 5
delivery showed that neonatal hypoglycemia occurs signifi-
weeks gestation who were at high risk for delivery during
cantly more frequently following antenatal corticosteroid
the late preterm period (defined as up to 36 + 6 weeks ges-
therapy.26,46,47 A recent cohort study documented that neo-
tation; N = 2831). According to the ALPS study, a significant
natal hypoglycemia (i.e., glucose <2.5 mmol/L) in infants
reduction in respiratory morbidity (a composite outcome
between 32 + 0 and 35 + 6 weeks gestation was associated
including receipt of continuous positive airway pressure or
with developmental delay at approximately 4 years of age.48
high-flow nasal cannula for at least 2 consecutive hours,
However, there is no consensus on the critical threshold
supplemental oxygen of at least 30% for at least 4 continu-
of blood glucose level and the period of time the infant is
ous hours, extracorporeal membrane oxygenation, mechanical
exposed to hypoglycemia for the risk of neurodevelopmental
ventilation, or stillbirth or neonatal death within 72 hours
morbidity to increase.45,49 Previous research has shown an
after delivery) was observed in the women who received an-
increased risk of neurodevelopmental deficits in children
tenatal corticosteroid therapy. Several secondary outcomes
exposed to multiple courses of antenatal corticosteroid
including severe respiratory complications (a composite
therapy prior to term and then subsequently delivered at
outcome of continuous positive airway pressure or high-
term.33 On the other hand, as noted in 2 reviews, follow-
flow nasal cannula for at least 12 continuous hours,
up studies have not found an increased risk of
supplemental oxygen of at least 30% for at least 24 con-
neurodevelopmental morbidity in children who were exposed
tinuous hours, extracorporeal membrane oxygenation or
to antenatal corticosteroid therapy and delivered at preterm
mechanical ventilation, stillbirth, or neonatal death within
gestation.27,35
72 hours after delivery), transient tachypnea of the newborn,
surfactant use, and bronchopulmonary dysplasia were also The balance of short-term benefits and risks (caused by re-
significantly less frequent following antenatal corticosteroid ductions in respiratory morbidity and increases in

Table 2. Summary of studies regarding antenatal corticosteroid therapy administered to women between 34 + 0 and
36 + 6 weeks of gestation
Studies No. of patients Effect
Study No treatment RR Absolute
No. of studies design ACS (or placebo) (95% CI) (95% CI) Certainty Importance
Perinatal death
3 RCT 6/1658 (0.4%) 6/1638 (0.4%) RR 1.03 0 fewer per 1000 ⨁ Critical
(0.29–3.67) (from 3 fewer to 10 more) Very low
6 RCT 102/1901 (5.4%) 202/1882 (10.7%) RR 0.71 31 fewer per 1000 ⨁⨁⨁ Important
(0.56–0.91) (from 10 fewer to 47 fewer) Moderate
Chorioamnionitis
3 RCT 20/1604 (1.2%) 35/1598 (2.2%) RR 0.57 9 fewer per 1000 ⨁⨁ Important
(0.33–0.99) (from 0 fewer to 15 fewer) Low
Hypoglycemia
3 RCT 367/1666 (22.0%) 222/1628 (13.6%) RR 1.62 85 more per 1000 ⨁⨁⨁ Important
(1.39–1.88) (from 53 more to 120 more) Moderate
RCT: randomized controlled trial.
Based on data from Roberts et al.27 and additional information from original studies.
hypoglycemia) and the absence of evidence regarding the 7 days (Conditional recommendations, Moderate cer-
long-term neurodevelopmental effects of antenatal corti- tainty of evidence).
costeroid therapy suggest the need for a nuanced approach 4. Antenatal corticosteroid therapy should not be rou-
to antenatal corticosteroid therapy at late preterm gesta- tinely administered to women at 36 + 0 to 36 + 6 weeks
tion. The balance of benefits and risks supports routine gestation who are at risk for preterm delivery (Con-
antenatal corticosteroid at 34 + 0 to 34 + 6 weeks gesta- ditional recommendations, Moderate certainty of
tion (when respiratory morbidity is relatively high) but does evidence).
not support routine antenatal corticosteroid therapy at 35 + 0 5. Antenatal corticosteroid therapy may be adminis-
to 35 + 6 and especially at 36 + 0 to 36 + 6 weeks gesta- tered between 35 + 0 and 36 + 6 weeks gestation in
tion (when risks of respiratory morbidity are relatively low). select clinical situations after risks and benefits are dis-
If the anticipated benefit with regard to respiratory mor- cussed with the woman and the pediatric care
bidity is expected to outweigh potential harms, antenatal provider(s) (Conditional recommendations, Moder-
corticosteroid therapy may be considered for women at risk ate certainty of evidence).
of preterm delivery from 35 + 0 to 35 + 6 weeks gesta-
tion with close monitoring of the infant’s blood glucose
levels. Term Gestation: Pre-Labour Caesarean Section at
37 + 0 Weeks or Later
Summary Statements A number of studies have shown that delivery by elective
pre-labour Caesarean section at less than 39 + 0 weeks
3. Antenatal corticosteroid therapy administered to
gestation can lead to respiratory morbidity in infants,
women at risk of preterm delivery between 34 + 0 and
requiring admission to the neonatal intensive care unit.50–53
36 + 5 weeks gestation decreases neonatal respira-
This has led to recommendations regarding the use of
tory morbidity (Moderate).
antenatal corticosteroid therapy to reduce the risk of
4. There is an increased risk of neonatal hypoglycemia
respiratory morbidity in babies delivered by elective pre-
among infants exposed to antenatal corticosteroid
labour Caesarean section prior to 39 + 0 weeks gestation.42
therapy at 34 + 0 to 36 + 5 weeks gestation (Moderate).
A meta-analysis of 4 randomized controlled trials of
Recommendations antenatal corticosteroid therapy prior to elective Caesar-
ean delivery54–57 shows some benefits related to respiratory
3. The balance of risks and benefits does not support morbidity in infants (Table 3). A decrease in RDS (from
routine administration of antenatal corticosteroid 6.7% to 2.7%), transient tachypnea (from 7.0% to 3.0%),
therapy for women at 35 + 0 to 35 + 6 weeks gesta- and mechanical ventilation (from 3.6% to 0.7%) was
tion who are at high risk for preterm birth in the next observed after antenatal corticosteroid therapy in infants

Table 3. Summary of studies regarding antenatal corticosteroid therapy administered to women prior to elective Cae-
sarean section at term
Study No treatment RR Absolute
No. of studies design ACS (or placebo) (95% CI) (95% CI) Certainty Importance
Neonatal death
4 RCT 2/1853 (0.1%) 3/1917 (0.2%) RR 0.67 0 fewer per 1000 ⨁ Critical
RDS
Severe RDS
2 RCT 1/601 (0.2%) 7/670 (1.0%) RR 0.22 8 fewer per 1000 ⨁ Important
(0.02–1.31) (from 3 more to 10 fewer) Very low
Mechanical ventilation
3 RCT 14/1625 (0.9%) 51/1693 (3.0%) RR 0.30 21 fewer per 1000 ⨁⨁ Important
(0.14–0.63) (from 11 fewer to 26 fewer) Low
Admission to NICU
4 RCT 51/1853 (2.8%) 89/1917 (4.6%) RR 0.55 21 fewer per 1000 ⨁ Important
(0.31–1.00) (from 0 fewer to 32 fewer) Very low
RCT: randomized controlled trial; NICU: neonatal intensive care unit.
Based on data from Saccone et al.44 and Nooh et al.57
of women undergoing elective Caesarean section at term. respiratory morbidity do not justify the risk of antenatal cor-
However, some of these studies were affected by a high ticosteroid therapy in such cases.59
risk of bias caused by a lack of blinding and other
considerations.44 Only 1 study55 included a large number Summary Statements
of women with medically indicated Caesarean sections 5. Administration of antenatal corticosteroid therapy de-
and showed improvements in respiratory morbidity, al- creases respiratory distress syndrome and need for
though these benefits were minimal with increasing mechanical ventilation in infants of women undergo-
gestational age. Furthermore, evidence regarding the safety ing elective pre-labour Caesarean section at term
of antenatal corticosteroid therapy in infants born after (Moderate).
36 + 0 weeks gestation is limited.44,54 The follow-up study 6. Limited evidence is available on long-term outcomes
of the ASTECS trial raised concerns regarding the aca- following antenatal corticosteroid therapy in cases of
demic ability of children exposed to antenatal corticosteroid elective pre-labour Caesarean delivery at term gesta-
therapy at term gestation.58 The authors concluded that tions. However, there are concerns regarding the
there were no significant behavioural or general health cognitive functioning of children exposed to antena-
differences at 8 to 15 years between children who received tal corticosteroid therapy prior to elective Caesarean
antenatal corticosteroids prior to term elective Caesarean section at term gestations (Low).
section and those who received a placebo. However, the
school assessments of academic ability were significantly Recommendations
lower in children exposed to betamethasone. Importantly, 6. Elective pre-labour Caesarean section should be per-
losses to follow-up diminished the validity of this formed at or after 39 + 0 weeks gestation to minimize
finding. respiratory morbidity (Strong recommendation, Low
Elective pre-labour Caesarean section should not be per- certainty of evidence).
formed until 39 + 0 weeks gestation. Caesarean delivery at 7. Antenatal corticosteroid therapy should not be rou-
or after 39 + 0 weeks gestation is associated with lower rates tinely administered to women undergoing pre-labour
of respiratory morbidity, and there are limited benefits as- Caesarean section at term gestation (including at 37
sociated with antenatal corticosteroid therapy at this and 38 weeks gestation) (Strong recommendation, Low
gestation.54-57 The benefits of reductions in short-term certainty of evidence).

Table 4. Summary table of recommendations according to gestational age

Recommendation in case of high risk of delivery Strength of
Gestational age within 7 days Level of evidence recommendation
<24 + 0 weeks Administration based on desire for early intensive care by Low Conditional
woman in consultation with health care providers
24 + 0 to 34 + 6 weeks Routine administration Moderate Strong
35 + 0 to 35 + 6 weeks Administration based on discussion of risk and benefits with Moderate Conditional
patients
36 + 0 to 36 + 6 weeks Administration restricted to specific clinical situations Moderate Conditional
Elective Caesarean delivery at term Not recommended Low Strong
Summary of the Evidence by Gestational Age betamethasone involved different populations and was po-
Category tentially confounded.
Gestational age and the associated risk of morbidity need
to be carefully considered when contemplating antenatal cor- A recent Cochrane review by Brownfoot et al. examined 12
ticosteroid therapy (Table 4, Figure 1). randomized trials directly comparing different types of cor-
ticosteroids and regimens used for accelerating fetal lung
AGENTS, DOSAGE, REGIMEN maturation.60 Dexamethasone and betamethasone showed
similar effects (Table 5). However, the risk of intraventricu-
Agents and Dosage lar hemorrhage was lower among infants whose mothers
In the recent Cochrane review of 30 trials by Roberts et al.,27 were treated with dexamethasone compared with infants
no significant difference was observed between whose mothers were treated with betamethasone. Length
betamethasone and dexamethasone, except for a signifi- of neonatal intensive care unit stay was also decreased fol-
cantly larger beneficial effect on chorioamnionitis, RDS, and lowing dexamethasone prophylaxis compared with
chronic lung disease following betamethasone administra- betamethasone prophylaxis. There was no other signifi-
tion (vs. placebo) compared with studies evaluating cant difference for comparisons involving perinatal death,
dexamethasone administration (vs. placebo). However, this RDS and other perinatal outcomes. The upcoming results
indirect comparison between dexamethasone and from the Australian Antenatal Study To Evaluate the Role Of
Figure 1. Summary of the evidence.
IVH: intraventricular hemorrhage; Mech Vent: mechanical ventilation; NEC: necrotizing enterocolitis; OR: odds
ratio; RR: risk ratio; RDS: respiratory distress syndrome; green arrow: benefit; red arrow: harm. (From S. Mc-
Donald, personal communication).

Table 5. Summary of studies comparing dexamethasone and betamethasone

Study Relative Absolute
No. of studies design Dexamethasone Betamethasone (95% CI) (95% CI) Certainty Importance
Neonatal death
4 RCT 8/278 (2.9%) 6/318 (1.9%) RR 1.41 8 more per 1000 ⨁ Critical
(0.88–1.27) (from 36 fewer to 82 more) Moderate
Intraventricular hemorrhage
4 RCT 9/257 (3.5%) 21/292 (7.2%) RR 0.44 40 fewer per 1000 ⨁⨁⨁⨁ Important
(0.21–0.92) (from 6 fewer to 57 fewer) High
Birth weight (kg)
5 RCT N/A N/A N/A Mean difference ⨁⨁⨁ Important
0.01 Moderate
(−0.11 to 0.12)
RCT: randomized controlled trial; N/A: not applicable.
Based on data from Brownfoot et al.60
Intramuscular Dexamethasone (A*STEROID) comparing 2 in- compared with dexamethasone. In direct compari-
tramuscular 12-mg doses of dexamethasone and 2 doses of sons, dexamethasone is associated with a greater
11.4 mg betamethasone both 24 hours apart may shed light reduction in intraventricular hemorrhage and lower
on some of the differences observed between the 2 agents.61 length of neonatal intensive care unit stay compared
with betamethasone. Effects on other outcomes are
Only 1 study of 228 women (260 fetuses) compared 12- generally similar (Low).
hourly to 24-hourly dosing of betamethasone.62 Respiratory
distress syndrome was reduced (RR 0.83 [0.69, 0.99]) with Recommendation
the administration of betamethasone 12 hourly compared
8. When antenatal corticosteroid therapy is indicated,
with 24 hourly when women were enrolled between 23 + 1
women should receive a course of antenatal cortico-
and 26 + 0 weeks gestation. Postpartum maternal length of
steroid therapy (i.e., either 2 doses of betamethasone
stay was also lower (mean difference −0.73 days [−1.28,
12 mg given by intramuscular injection 24 hours apart
−0.18]) in women who received betamethasone every 12
or 4 doses of dexamethasone 6 mg given by intra-
hours. The results of this study have to be interpreted cau-
muscular injection 12 hours apart) (Strong
tiously, considering personnel and participants were not
recommendation, Moderate certainty of evidence).
blinded to intervention allocation and no long-term studies
have been conducted to evaluate the impact of shorter delays
between doses. Target Timing
The benefits of antenatal corticosteroid therapy are thought
Most studies conducted on the use of antenatal cortico- to be most pronounced in babies born between 1 and 7 days
steroids have used either 2 doses of betamethasone 12 mg after the first dose of antenatal corticosteroid therapy.63–65
24 hourly or 4 doses of dexamethasone 6 mg 12 hourly.27,60 However, the majority of patients who receive antenatal cor-
ticosteroid therapy remain undelivered beyond this
Summary Statements window.31,66–70 A recent Canadian study shows that 52% of
women who receive antenatal corticosteroid therapy deliver
7. Betamethasone has been more commonly used in
at 35 weeks gestation or later.31 The potential benefits of
studies evaluating the effect of antenatal corticoste-
antenatal steroids as well as their risks are gestational age
roid therapy. In indirect comparisons, betamethasone
dependent, with the risks potentially increasing and ben-
shows greater reductions of chorioamnionitis, respi-
efits decreasing with advancing gestational age. Both the
ratory distress syndrome, and chronic lung diseases
likelihood of preterm delivery and the gestational age need

to be considered when contemplating necessity for ante- change and/or a dilatation ≥3 cm (see earlier text for detail
natal corticosteroid therapy.71 on the diagnosis of preterm labour) and the woman is being
transferred for further assessment or observation, initia-
Antenatal corticosteroid therapy, when not clearly indi- tion of antenatal corticosteroid therapy should be withheld
cated, can lead to at least 2 potential problems. First, the until a reassessment regarding the risk of preterm labour
adverse effects of steroids will likely outweigh any poten- is carried out in the receiving centre. In cases where the first
tial benefits when the risk of preterm delivery is low. The dose of antenatal corticosteroid therapy has been admin-
2006 Cochrane review did not show benefit of antenatal cor- istered and then reassessment suggests that delivery within
ticosteroid therapy when the first dose was administered more the next 7 days is unlikely, cancellation of the second dose
than 7 days prior to delivery.32 Second, if the woman remains should be considered.
undelivered beyond the 1-week window of benefit, subse-
quent preterm labour or other indications may prompt In cases with “imminent” preterm delivery such as iatro-
consideration of a rescue course. Administration of mul- genic delivery for maternal or fetal indications, or preterm
tiple courses of antenatal corticosteroids has the potential labour with advanced cervical dilation, a dose of cortico-
for adversely affecting neurodevelopment, as seen in the steroids can still be given with the understanding that even
5-year follow-up of the MACS-5 study.33 This study re- an interval of a few hours between antenatal corticoste-
ported a higher risk of a composit of death and severe roid therapy administration and delivery could yield some
disability in babies exposed to repeated courses of antena- fetal benefit.32,72 However, depending on the maternal/
tal corticosteroid therapy and delivered at term. In patients fetal condition, delivery should not be delayed to allow for
with a planned, medically indicated preterm delivery, the de- this benefit.
cision regarding when to administer antenatal corticosteroid
therapy is usually straightforward.69,70 However, among Summary Statement
women at risk of spontaneous preterm delivery or un- 8. The likelihood of preterm delivery and also the
planned medically-indicated delivery, the decision and timing gestational age need to be carefully considered
of antenatal corticosteroid therapy administration may be when contemplating the use of antenatal corticoste-
more difficult. roid therapy among pregnant women. The efficacy
of such therapy is highest when the course is given
The diagnosis of preterm labour is challenging. Antenatal 24 hours to 7 days prior to delivery. Administration
corticosteroid therapy should be considered at the rel- more than 7 days before delivery leads to reduced
evant preterm gestation in the presence of regular uterine benefit and potentially unnecessary adverse effects
contractions associated with significant cervical dila- (Low).
tion or significant cervical change on repeated
examination. Women with uterine contractions at preterm Recommendations
gestation who do not have other features supporting a di- 9. Antenatal corticosteroid therapy should be admin-
agnosis of preterm labour (sometimes labelled as having istered to women requiring medically indicated delivery,
“threatened preterm labour”) should be provided clinical only when the plan to proceed with delivery within
oversight, but such a scenario does not warrant antenatal 7 days has been finalized and gestational age criteria
corticosteroid therapy. Incidental findings of a short cervix for antenatal corticosteroid therapy are met (Strong
or a positive fetal fibronectin test result in the absence of recommendations, Low certainty of evidence).
uterine contractions are other clinical scenarios that do not 10. Antenatal corticosteroid therapy should be rou-
warrant administration of antenatal corticosteroid therapy tinely administered to women in spontaneous preterm
per se. It is a clinically prudent policy to repeat the assess- labour characterized by regular uterine contrac-
ment and ensure that women are in active preterm labour tions associated with significant cervical dilation
before initiating the administration of antenatal corticoste- or significant cervical change on repeated ex-
roid therapy unless the cervix is already dilated to 3 cm or amination when gestational age criteria for antenatal
more on first examination. corticosteroid therapy are met.
Regular contractions in the absence of cervical
Women being transferred to a higher level of care need to dilation/change, or a short cervical length in the
be assessed on a case-by-case basis to determine whether absence of regular contractions, are not indications
antenatal corticosteroid therapy should be initiated prior to for antenatal corticosteroid therapy (Strong recom-
transfer. If the diagnosis of preterm labour has not been mendations, Low certainty of evidence).
clearly established on the basis of documented cervical

11. Antenatal corticosteroid therapy should be rou- antenatal corticosteroid therapy compared with a single
tinely administered at the time of diagnosis to women course (Table 6).73 However, the largest study of repeated
with preterm premature rupture of membranes, when courses (MACS), which reported similar risks of severe RDS
gestational age criteria are met (Strong recommen- in repeated courses and single-course groups, was not in-
dations, Low certainty of evidence). cluded in the meta-analysis of RDS.74 The systematic review
12. Antenatal corticosteroid therapy should be admin- showed significantly lower birth weights and head circum-
istered to women with significant antepartum ferences in neonates exposed to repeated courses of antenatal
hemorrhage when the risk of delivery within 7 days corticosteroid therapy (Table 6). No benefits of repeated
is high and the gestational age criteria for such therapy courses of antenatal corticosteroid therapy on fetal and neo-
are met (Strong recommendations, Low certainty of natal mortality were observed.
evidence).
13. Antenatal corticosteroid therapy should be admin- The 1- to 2-year follow-up of 1 randomized trial reported
istered to asymptomatic women with vasa previa or in 2017 showed no difference following a rescue course of
placenta previa when the risk of delivery within 7 days antenatal corticosteroid therapy versus placebo in pulmo-
is high and the gestational age criteria are met (Strong nary function tests, asthma, respiratory syncytial virus
recommendations, Low certainty of evidence). infection, hospital admission for respiratory illness, weight,
14. In cases where the diagnosis of preterm labour has length, or head circumference.75 Similarly, the 6- to 8-year
not been firmly established (i.e., no documented cer- follow-up of the Australasian Collaborative Trial Of Repeat
vical change and dilatation <3 cm), and the woman Doses Of Prenatal Steroids (ACTORDS) showed no sig-
is being transferred to a higher level of care for further nificant differences in rates of survival free of disability,
assessment, antenatal corticosteroid therapy should intellectual quotient, neurosensory disability, cerebral palsy,
not be administered prior to transfer (Strong recom- lung function, use of health services, bone status, or risk
mendations, Low certainty of evidence). factors for cardiovascular and metabolic diseases in those
who received weekly repeat doses versus those who re-
ceived a single course of antenatal corticosteroid therapy.76–78
Rescue Course and Repeated Doses
However, higher frequency of attention deficit (lower
NB. In this section “rescue course” refers specifically to 1
memory and learning score in the Rey Auditory Verbal Learn-
course of antenatal corticosteroid therapy, administered to
ing Test) and a borderline significant increase in behavioural
women who have previously received 1 full course of an-
dysfunction (lower Behavioural Regulation Index scores;
tenatal corticosteroids but have remained undelivered
P = 0.05) were observed in the multiple-courses group.76 Fur-
following completion of this initial course. “Repeat doses”
thermore, the MACS-5 follow-up study showed that 5-year-
refers to any administration of antenatal corticosteroids at
old children born at term who were exposed to multiple
regular intervals after 1 full course of antenatal corticoste-
courses of antenatal corticosteroid therapy were at higher
roid therapy has been previously administered.
risk of neurosensory disability (adjusted OR 3.70; 95% CI
The recent Cochrane review by Roberts et al.27 showed that 1.57–8.75), and a composite of severe (neuromotor, neu-
weekly administration (n = 9 studies) of antenatal cortico- rosensory, or neurocognitive) disability or death (adjusted
steroid therapy results in a reduction of neonatal and perinatal OR 1.69; 95% CI 1.04–2.77).33
deaths, RDS, and intraventricular hemorrhage when com-
pared with placebo or no intervention. However, pooled Use of a single rescue dose or course of antenatal corti-
effects from studies evaluating weekly repeats are not sig- costeroid therapy is currently supported by American, British,
nificantly different from those of studies evaluating single and Australian guidelines.79–81 However, evidence support-
courses. Weekly repeats of antenatal corticosteroid therapy ing such use of a single rescue dose or course is limited.
were not significantly associated with other outcomes in this Most studies included in the Cochrane review compared
review. weekly repeated courses to a single course of antenatal cor-
ticosteroid therapy, with less than 50% of participants in
Another recent Cochrane review of randomized con- the weekly repeated courses group receiving a single rescue
trolled trials evaluating repeated doses (n = 2 studies) or course.74,82–85 Most of the studies on multiple doses tested
courses (n = 8 studies) of antenatal corticosteroid therapy weekly repeats.82–87
up until women reached 32 to 34 weeks gestation re-
ported lower risks of RDS, and neonatal interventions such Three studies compared a single rescue course88,89 or
as mechanical ventilation, oxygen supplementation, surfac- dose90 to 1 course of antenatal corticosteroid therapy.
tant, and inotropic support following repeated exposure to Two trials evaluated a single rescue course at least 14 days

Table 6. Summary of studies regarding repeated courses of antenatal corticosteroid therapy

Study Relative Absolute
No. of studies design Repeated courses single (95% CI) (95% CI) Certainty Importance
Fetal and neonatal mortality
9 RCT 96/2791 (3.4%) 102/2763 (3.7%) RR 0.94 2 fewer per 1000 ⨁⨁⨁⨁ Critical
(0.71–1.23) (from 8 more to 11 fewer) High
Birth weight (g)
9 RCT NA NA NA Mean difference ⨁⨁⨁⨁ Important
−75.8 g High
(−117.6 to −34.0)
Small for gestational age at birth
Head circumference at birth (cm)
9 RCT N/A N/A N/A Mean difference ⨁⨁⨁⨁ Important
−0.32 cm High
(−0.49 to −0.15)
Mechanical ventilation
Use of surfactant
Total mortality up to early childhood follow-up
RCT: randomized controlled trial; N/A: not applicable.
Based on data from Roberts et al.27 and Crowther et al.73
after the first course;88,89 and 1 trial evaluated a rescue Overall, the evidence of benefits of rescue or repeated
dose at least 7 days after the first course of antenatal courses of antenatal corticosteroid therapy are limited, no
corticosteroid therapy.90 All administered repeated antena- long-term benefit has been shown compared with single
tal corticosteroids before 34 weeks gestation. One trial course therapy, and concerns regarding potential long-
showed benefits on respiratory morbidity (reduced RDS, term harms are supported by data from the largest
surfactant use and composite morbidity)88; 1 small trial trial.33
showed no effect except on respiratory compliance (al-
though the 1- to 2-year follow-up study showed no long- Summary Statements
term differences in pulmonary outcomes),75,89 and another
9. Repeated courses of antenatal corticosteroid therapy
was stopped early because of a significant reduction in
are associated with a reduction in respiratory dis-
intact survival (survival until hospital discharge without
tress syndrome, mechanical ventilation, and use of
RDS or grade III–IV intraventricular hemorrhage) follow-
surfactant (Moderate).
ing exposure to a rescue dose of antenatal corticosteroid
10. Birth weights and head circumferences are de-
therapy and delivery within 24 hours.90 In addition,
creased in infants exposed to multiple courses
the largest trial of a single rescue course of antenatal
compared with those exposed to a single course of
corticosteroid therapy, by Garite et al.,88 showed that a
antenatal corticosteroid therapy (High).
delay greater than 7 days between rescue course and
11. There is limited evidence on the long-term effects of
delivery was associated with no significant short-term
repeated courses of antenatal corticosteroid therapy.
benefits.

Follow-up from a large trial indicated higher risks of studies were low, leading to limited statistical power. More
neurosensory disability and of a composite of death importantly, there was no significant difference between the
or severe disability (neuromotor, neurosensitive, effects of antenatal corticosteroid therapy among single-
neurocognitive) in children exposed to multiple ton pregnancies and multifetal pregnancies.
courses of antenatal corticosteroid therapy and born
Recent cohort studies show benefits of antenatal cortico-
at term (Moderate).
steroid therapy in multifetal pregnancies,91–93 and effects
Recommendations among twins and singletons are similar.94–96 Palas et al. also
report the largest benefits among multifetal pregnancies when
15. If the risk of preterm delivery decreases signifi- antenatal corticosteroid therapy are administered a maximum
cantly following administration of the first dose of of 7 days prior to delivery.93 Furthermore, a study of
antenatal corticosteroid therapy, cancellation of the betamethasone concentration in maternal serum and cord
second dose of corticosteroids should be consid- blood shows no significant difference between multifetal and
ered. If the second dose is cancelled and a high risk singleton pregnancies after adjustment for gestational age
of preterm birth arises subsequently at less than 34 + 6 at delivery, number of antenatal corticosteroids courses, days
weeks gestation, 1 dose or 1 course of antenatal cor- from last course to delivery, and body mass index.97
ticosteroid therapy should be considered, depending
on gestational age and the duration since the first dose Summary Statements
(Strong recommendations, Low certainty of
evidence). 12. Few trials of antenatal corticosteroid therapy in
16. If the woman remains undelivered beyond 7 days after multifetal pregnancies are available. Subgroup analy-
the first antenatal corticosteroids course, the balance ses show that effects of antenatal corticosteroid
of risks and benefits does not support further routine therapy are not different between multifetal preg-
administration of antenatal corticosteroid therapy even nancies and singleton pregnancies (Low).
if the risk of preterm delivery increases subse- 13. Evidence from cohort studies shows benefits of an-
quently. The gestational age and the time interval since tenatal corticosteroid therapy are greater in multifetal
the first course of antenatal corticosteroid therapy pregnancies when antenatal corticosteroid therapy is
(at least 14 days) should be taken into account when administered within 7 days prior to delivery (Low).
considering a rescue course. A single rescue course
Recommendations
of antenatal corticosteroid therapy may be admin-
istered after risks and benefits are discussed with the 17. Antenatal corticosteroid therapy should be admin-
woman (Conditional recommendation, Moderate cer- istered according to the same indications and in the
tainty of evidence). same gestational age range to women with twin or
higher-order multifetal pregnancies as for singleton
Summary of the Evidence regarding the timing of expo- pregnancies (Conditional recommendation, Low cer-
sure to antenatal corticosteroid therapy. The risk of delivery tainty of evidence).
within 7 days needs to be carefully assessed when contem- 18. Antenatal corticosteroid therapy should not be ad-
plating antenatal corticosteroid therapy (Table 7, Figure 2). ministered to women with multifetal pregnancies in
the absence of a high risk of preterm birth within
the next 7 days (Conditional recommendation, Low
SUBPOPULATIONS AND SPECIAL certainty of evidence).
CONSIDERATION
Multifetal Gestation Women with Pre-Gestational or Gestational

The recent review by Roberts et al. 2017 included 11 trials Diabetes Mellitus
of antenatal corticosteroid therapy in which women with No randomized controlled trial has been conducted to evalu-
multifetal pregnancies were included, and 4r of these re- ate the effect of antenatal corticosteroid therapy in diabetic
ported RDS rates specifically among the subgroup of women women. In the recent Cochrane review, 10 studies explic-
with multifetal pregnancies.27 There was no significant effect itly excluded women with insulin-treated diabetes or other
of antenatal corticosteroid therapy observed on RDS, peri- cases of diabetes.27 Another recent systematic review con-
natal death, intraventricular hemorrhage, chorioamnionitis, ducted in 2014 also failed to identify any comparative studies
or birth weight in multifetal pregnancies. However, the of antenatal corticosteroid therapy in women with pre-
number of studies and the number of women in these existing diabetes or gestational diabetes.98

Table 7. Summary table of recommendations for agents, dosage and regimens

Recommendation when gestational age criteria for antenatal corticosteroid Level of Strength of
Agents, dosage, and regimens therapy are met evidence recommendation
Agents and dosage 2 × 12 mg doses of betamethasone IM, 24 hours apart Moderate Strong
or
4 × 6 mg doses of dexamethasone IM, 12 hours apart
Timing of antenatal Administer if medically indicated delivery planned within 7 days Low Strong
corticosteroid initiation Administer if woman is in spontaneous preterm labour (ie, regular uterine Low Strong
contractions associated with significant cervical dilation or significant
cervical change on repeated examination)
Do not administer in absence of cervical dilation/change or in the absence Low Strong
of regular contractions
Administer at the time of diagnosis of preterm premature rupture of Low Strong
membranes
Administer in cases of significant antepartum hemorrhage with a high risk Low Strong
of delivery within 7 days
Administer in cases of asymptomatic vasa previa or placenta previa with a Low Strong
high risk of delivery within 7 days
Do not administer prior to transfer unless a diagnosis of preterm labour Low Strong
has been firmly established
Repeated dose or course Consider cancellation of a second dose if the risk of preterm delivery Low Strong
decreases significantly following administration of the first dose
After cancellation, consider administration of 1 dose or 1 course if a high
risk of preterm birth arises, taking into account gestational age and time
interval since the first course
Do not administer rescue dose or course routinely Moderate Conditional
Gestational age and time interval since the first course of antenatal
corticosteroid therapy (at least 14 days) should be taken into account
A single rescue course may be administered after risks and benefits are
discussed with the woman
IM: intramuscularly.
A study of 22 women without diabetes and 11 women with dia- Summary Statements
betes showed an increase of glucose levels following antenatal
corticosteroid therapy administration in both groups, with 97% 14. Evidence on the effects of antenatal corticosteroid
reaching a blood glucose level of 140 mg/dL or higher at least therapy in diabetic women is scarce, and no com-
once over a 48-hour period following the first dose parative study has been conducted in this
administration.99 Similar results were obtained in a retrospec- subpopulation (Low).
tive study of 55 women with gestational or pre-gestational 15. Antenatal corticosteroid therapy leads to an in-
diabetes, showing an increase in fasting or post-prandial glucose crease in maternal blood glucose levels up to 1 week
level in the 3 days following administration of a first dose of an- after the initiation of the first dose (Low).
tenatal corticosteroids.100 Another smaller prospective cohort study
Recommendations
of 9 women showed similar increases in blood glucose among
women with and without insulin-requiring diabetes, and the 19. Antenatal corticosteroid therapy should be admin-
changes lasted up to 72 hours after the first dose of antenatal istered to diabetic women at the same dosage,
corticosteroid therapy.101 In a prospective cohort of 11 non- according to the same indications, and in the same
diabetic women and 4 women with diabetes, blood glucose levels gestational age range as that recommended for non-
over 110 mg/dL were observed up to 156 hours after initiation diabetic women (Conditional recommendation, Low
of antenatal corticosteroid therapy.102 Therefore, gestational dia- certainty of evidence).
betes screening should not be undertaken until at least 1 week 20. Close attention should be paid to control maternal
after antenatal corticosteroid therapy administration. However, blood glucose among women with diabetes in the days
there is insufficient evidence in the literature to provide guid- following antenatal corticosteroid therapy because of
ance on glucose monitoring or insulin dosage following antenatal anticipated elevations in maternal blood glucose levels
corticosteroid therapy. (Strong recommendation, Low certainty of evidence).

Figure 2. Summary of the evidence (agents, dosage, and target timing). Note: the same
recommendation applies to women with multifetal pregnancies, pre-gestational or ges-
tational diabetes, obesity, or growth-restricted fetuses. See the text for further details.
BET: betamethasone: DEX: dexamethasone.
21. Because of the transient elevation of blood glucose Summary Statement

levels induced by corticosteroids, gestational diabe- 16. There is an absence of evidence on the effects of an-
tes screening should be delayed for a minimum of tenatal corticosteroid therapy among women with
1 week following antenatal corticosteroid therapy obesity, and no comparative study has been con-
(Strong recommendation, Low certainty of evidence). ducted in this subpopulation (Low).
Women with Obesity Recommendation

We did not identify any trials evaluating the effect of an- 22. Antenatal corticosteroid therapy should be admin-
tenatal corticosteroid therapy on obese women or trials istered to women with obesity at the same dosage as
examining the effects of antenatal corticosteroid therapy by that recommended for women without obesity
obesity status, body mass index, or weight. Current recom- because there is insufficient evidence to guide dosage
mendations use a 1-size-fits-all approach in terms of dosage adjustments by maternal weight (Conditional recom-
and regimens, although no data are available to evaluate mendation, Low certainty of evidence).
whether such approach is optimal for the subpopulation of
women with obesity. Intrauterine Growth Restriction
Responsiveness of growth-restricted fetuses to antenatal
A post hoc analysis97 of women delivering within 1 week corticosteroid therapy remains largely unknown.103–106 Cor-
of antenatal corticosteroid therapy in a randomized con- tisol levels and risks of hypoglycemia are increased in
trolled trial of weekly courses of antenatal corticosteroid fetuses displaying growth restriction, and administration
therapy85 showed no significant association between body of additional exogenous steroids might not lead to the
mass index and cord blood or maternal serum concentra- same benefits and harms as expected in normally grown
tions of betamethasone after adjustment for gestational age fetuses. Furthermore, a trend towards reduction in birth
at delivery, number of courses, days from last course to de- weight27 among infants exposed to antenatal corticoste-
livery, and twin pregnancy. However, the study was based roid therapy has raised concerns regarding their use in
on a small number of participants (n = 55). growth-restricted foetuses.

Table 8. Summary table of recommendations according to subpopulation

Recommendation given high risk of delivery within 7 days and if gestational age Level of Strength of
Subpopulation criteria are met evidence recommendation
Multifetal gestation Administer according to the same indications and in the same gestational age Low Conditional
range as for singleton pregnancies
Do not administer in the absence of a high risk for preterm birth within the next 7 Low Conditional
days
Pre-gestational or Administer at the same dosage, according to the same indications and in the Low Conditional
gestational diabetes same gestational age range as that recommended for non-diabetic women
Pay close attention to control of maternal blood glucose in the days following Low Strong
antenatal corticosteroid therapy
Gestational diabetes screening should be delayed for a minimum of 1 week Low Strong
following antenatal corticosteroid therapy
Obesity Administer at the same dosage as that recommended for women without obesity Low Conditional
Intrauterine growth Administer according to the same indications and in the same gestational age Low Conditional
restriction range as in normal pregnancies after risks and benefits are discussed with the
woman
Do not administer to women with suspected fetal growth restriction at the time of Low Conditional
diagnosis unless there is a high risk of preterm birth within the next 7 days
Among the trials included in the recent Cochrane review, is administered to fetuses with suspected growth
3 studies explicitly excluded women with fetuses sus- restriction.
pected of intrauterine growth restriction, and no trial
evaluated the effect of antenatal corticosteroid therapy in Summary Statements
growth-restricted fetuses specifically.27 A systematic review 17. Responsiveness of growth-restricted fetuses to an-
of comparative studies conducted by Amiya et al. identi- tenatal corticosteroid therapy remains largely unknown
fied 6 retrospective cohort studies, 1 prospective cohort study, (Low).
and 1 case-control study evaluating the effect of antenatal 18. A lower frequency of major brain lesions, but a higher
corticosteroid therapy in women with growth restricted frequency of body size below the 10th centile at
fetuses or who delivered small for gestational age infants.98 school age is observed in cohort studies of small for
Although intrauterine growth restriction and small for ges- gestational age infants exposed to antenatal cortico-
tational age are not synonymous, the latter population was steroid therapy (Low).
considered to provide valuable information on the poten-
tial impact of antenatal corticosteroid therapy on growth- Recommendations
restricted fetuses. Antenatal corticosteroid therapy in small 23. There is insufficient evidence to withhold routine an-
for gestational age births was associated with a lower fre- tenatal corticosteroid therapy in cases of suspected
quency of major brain lesions (5 studies; n = 762; OR 0.57; fetal growth restriction with a high risk of preterm
95% CI 0.41–0.78) but a higher frequency of body size below birth. Antenatal corticosteroid therapy should be ad-
the 10th centile at school age (1 study; n = 91; OR 5.50; 95% ministered according to the same indications and in
CI 1.38–19.6). No benefit was observed following antena- the same gestational age range as in normal preg-
tal corticosteroid therapy exposure on perinatal mortality, nancies after risks and benefits are discussed with the
respiratory morbidity, neonatal sepsis, or chorioamnionitis woman (Conditional recommendation, Low cer-
in this population. The lack of adjustment for potential con- tainty of evidence).
founders limits the validity of these results, thus leaving little 24. Antenatal corticosteroid therapy should not be ad-
evidence to guide the use of antenatal corticosteroid therapy ministered to women with suspected fetal growth
in this population. restriction at the time of diagnosis unless there is a
high risk of preterm birth within the next 7 days (Con-
Considering the potentially higher risks of harm caused
ditional recommendation, Low certainty of evidence).
by excess exposure to glucocorticoids, high vigilance is
needed regarding the timing (within 7 days of delivery) Table 8 summarizes the evidence and recommendations re-
and gestational age at which antenatal corticosteroid therapy garding specific subpopulations.

Fetal Movements 7 days are paramount when contemplating antenatal cor-

Antenatal corticosteroid therapy has been shown to induce ticosteroid therapy.
a temporary disruption of the diurnal rhythm and tran-
sient variations in fetal body movements, breathing
SUMMARY
movements, and heart rate, including a reduction in fetal
movements in the first 3 days following antenatal cortico- A single course of antenatal corticosteroid therapy at 24 + 0
steroid therapy initiation.107-109 Women should be informed to 34 + 6 weeks gestation among women at high risk for
of this potential transient side effect and advised to consult preterm birth reduces perinatal mortality and morbidity. The
with their health care professional if they notice a reduc- benefits are maximised by administration within 7 days of
tion of fetal movements. delivery. In cases of deliveries beyond this time window,
adverse effects may outweigh the expected benefits. A careful
Summary Statement assessment of the risk of preterm delivery within 7 days is
19. Antenatal corticosteroid therapy may induce tran- therefore required prior to administration of antenatal cor-
sient variations in fetal body movements including ticosteroid therapy to avoid unnecessary use. There is limited
a potential reduction in fetal movements in the first evidence to suggest differential efficacy of antenatal corti-
3 days following therapy initiation (Low). costeroid therapy in subpopulations such as multifetal
pregnancies, diabetic women, women with obesity, and preg-
Recommendation nancies with suspected fetal growth restriction. Dosage
25. Women should be informed of the potential for a regimens that account for maternal weight have also not been
transient reduction in fetal movements and advised evaluated. All such women should be treated with single-
to consult with their health care professional if this course antenatal corticosteroid therapy if indications and
occurs (Strong recommendation, Low certainty of gestational age criteria are met. Although many trials have
evidence). evaluated antenatal corticosteroid therapy, some areas of
clinical equipoise persist. For example, studies of the long-
term impact of late preterm exposure to antenatal
LONG-TERM CONSIDERATIONS corticosteroid therapy are needed. In situations where the
risk of preterm birth is judged to be high, health care pro-
Although evidence supports benefits of antenatal cortico- viders should discuss the benefits and risks of antenatal
steroid therapy in terms of perinatal mortality and morbidity, corticosteroid therapy with the woman.
few long-term follow-up studies are available to assess po-
tential long-term effects, especially on neurodevelopment.
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SOGC CLINICAL PRACTICE GUIDELINE

No. 364, September 2018, (Replaces No. 122, January 2003)

No. 364-Antenatal Corticosteroid Therapy for

Maternal Fetal Medicine Committee : Melanie Basso, RN,

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Abstract 2. Evidence from cohort studies shows a significant reduction in peri-

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INTRODUCTION suspected fetal growth restriction. In Canada, antenatal cor-

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Table 4. Summary table of recommendations according to gestational age

Figure 1. Summary of the evidence.

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Table 5. Summary of studies comparing dexamethasone and betamethasone

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Table 6. Summary of studies regarding repeated courses of antenatal corticosteroid therapy

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Multifetal Gestation Women with Pre-Gestational or Gestational

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Table 7. Summary table of recommendations for agents, dosage and regimens

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BET: betamethasone: DEX: dexamethasone.

21. Because of the transient elevation of blood glucose Summary Statement

Women with Obesity Recommendation

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Table 8. Summary table of recommendations according to subpopulation

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Fetal Movements 7 days are paramount when contemplating antenatal cor-

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