dr abdul qadeer

khan
pgr
gestroenterology
1) EVALUATION OF THE PREGNANT PATIENT WITH ABNORMAL

LIVER ENZYME

2) IMAGING

3) SAFETY OF ENDOSCOPY IN PREGNANCY

4) MANAGEMENT OF BILIARY DISEASE IN PREGNANCY

5) LIVER MASSES IN PREGNANCY

6) LIVER DISEASES UNIQUE TO PREGNANCY

7) COINCIDENT LIVER DISEASE (HAV, HEV, HSV)

8) CHRONIC LIVER DISEASES, CIRRHOSIS, AND

LIVERTRANSPLANTATION
EVALUATION OF THE PREGNANT
PATIENT WITH ABNORMAL LIVER ENZYMES
The basis for the workup of abnormal
liver tests in a pregnant woman should be
predicated on understanding the normal
physiological changes observed during
pregnancy. The incidence of abnormal
liver tests in pregnant women is ~3–5%,
even in this relatively young and healthy
population. Some liver test results, which
would otherwise suggest liver or biliary
dysfunction in the non-pregnant
individual may in fact be “normal” in the
pregnant woman.
B Generally, the majority of liver tests remain in
the normal range in pregnancy except those
produced by the placenta (alkaline phosphatase,
alphafetoprotein) or impacted as a result of
hemodilution (albumin, hemoglobin).
Conversely, abnormal test results should be
appropriately evaluated as some diseases
newly diagnosed in pregnancy may require
more immediate intervention for the mother or
the neonate (e.g., herpes hepatitis, hepatitis
Of note, during pregnancy, cardiac output is
increased by 40–45% with substantive increases
to the renal, uterine, and skin systems. However,
the liver blood flow shows little change during
pregnancy
The first step in assessing a woman
presenting at any stage of pregnancy with
abnormal liver tests should be the same as
with any non-pregnant patient. A complete
history, physical exam, and standard
serological workup should be performed
as indicated by the clinical presentation.
Initial evaluation of these patients can be
cate gorized into two general groups: (i)
pre-existing and coincidental, not related
to pregnancy, or (ii)related to the
pregnancy itself.
IMAGING
It may be clinically appropriate and necessary
during pregnancy to image the liver, hepatic
vasculature, or biliary system. Any pregnant
woman presenting with abnormal
aminotransferases or jaundice should first
undergo an abdominal ultrasound. Ultrasound,
with or without Doppler imaging, as it uses
sound waves and not ionizing radiation, has
never been shown to have any adverse fetal
effects . Therefore, there are no
contraindications to ultrasound in pregnancy and
it should be used as the imaging modality of
choice.
Teratogenicity has been clearly established,
with large doses of radiation >100 rad,
linked in humans to growth restriction and
microcephaly, among other adverse effects.
The greatest exposure risk is at 8–15
weeks of gestation. Fetal risks of
anomalies and growth restriction appear
not to be increased if the exposure is <5
rad. Fetal exposure for commonly used
gastroenterology imaging ranges from 100
mrad, for a single abdominal fi lm, to 2–4
rad, for a barium enema or small bowel
series, to 3.5 rad for a CT scan of the
abdomen.
If ultrasonography is indeterminate and further
imaging is necessary, judicious use of CT or MRI
without gadolinium may be considered for the
expeditious diagnosis of an acute presentation.
Oral and intravascular contrast agents used for
CT contain derivatives of iodine which do not
appear teratogenic in animal studies. However,

neonatal hypothyroidism has been

associated with iodinated contrast agent exposure
during pregnancy.
Gadolinium is not recommended as it
crosses the placenta and is excreted
by the fetal kidneys into the amniotic
fluid where it can remain for long
periods, exposing the fetal pulmonary
and gastrointestinal systems to
potential injury. Animal studies have
also reported spontaneous abortion,
skeletal abnormalities, and visceral
abnormalities with high doses of
gadolinium.
Fortunately, the necessity of liver
biopsy for diagnosis of disease in
pregnancy is uncommon as most
etiologies can be determined in this
population by biochemical, serological,
and clinical parameters. However, if
required, percutaneous liver biopsy
can be performed safely. Transjugular
liver biopsy can also be performed but
carries some limited radiation
exposure of 0.05–0.1 rad .
SAFETY OF ENDOSCOPY IN PREGNANCY
Although clinical studies on the safety and

effectiveness of endoscopy for the pregnant

patient have been limited, endoscopy can be safe

and effective if careful assessment of the risks,

benefits, and clinical rationale is performed. One

of the most important clinical issues in

endoscopy of the pregnant patient is to ensure

Oversedation, resulting in hypotension
or hypoxia, or positioning that
compresses the inferior vena cava can
lead to decreased uterine blood flow and
fetal hypoxia. Thus, the patient should
be positioned in the left lateral position
to avoid vascular compression and
aggressively managed with respect to
intravenous hydration. Other concerns
include teratogenicity of medications
and radiation exposure.
There are currently no FDA pregnancy category A
medications available for the management of sedation
during endoscopy. The benzodiazepine class of sedatives
(FDA category D) should be avoided in pregnancy owing
to known congenital malformations. One of the most
commonly used sedation medications during pregnancy
is meperidine, an opiate analgesic, which has more
recently been replaced by shorter acting agents, such as
propofol, with lower risk for respiratory depression and
seizures. Meperidine crosses the placenta and is
converted to a long-lasting normeperidine, so repeated
or prolonged meperidine administration should be
avoided late in pregnancy or at term, as meperidine is an
FDA pregnancy category C
Propofol is an FDA pregnancy
category B anesthetic which is very
short acting with a rapid recovery
period, which is of signifi cant benefi
t in the case of a pregnant patient. If
propofol is used, an anesthesiologist
should monitor respiratory function
closely.
MANAGEMENT OF BILIARY DISEASE IN
PREGNANCY
Cholelithiasis is common in pregnancy owing
to the increased estrogen levels, causing
cholesterol supersaturation and
increased gallstone formation. Cholecystitis is
the second most common surgical condition in
pregnancy and occurs in ~1
in 1,600 to
1 in 10,000 pregnancies. The
incidence of cholelithiasis in pregnant women
is 3.5% ( 10 ).
In the setting of laboratory testing indicating a
possible biliary etiology, the first step in
diagnosis should be an abdominal ultrasound,
which has 95% sensitivity for the diagnosis of
gallstones. Biliary pancreatitis, symptomatic
choledocholithiasis, and cholangitis may have
poor fetal outcomes without intervention. ERCP
safety has been reported in multiple series, with
some reports of increased pancreatitis risk
(16%). Reducing fetal exposure to radiation
should be attempted by limiting fluoroscopy
time, external fetal shielding, and adjusting the
patient position
Symptomatic cholecystitis had been
previously managed conservatively, but
more recent data suggests high rates of
recurrent symptoms (40–90%), increased
rates of hospitalizations, preterm labor
and deliveries, and spontaneous
abortions when intervention is deferred.
The development of gallstone
pancreatitis portends a high rate
(10 60%) of fetal demise. Thus, early
surgical intervention with laparoscopic
cholecystectomy after ERCP is preferred
 LIVER MASSES IN PREGNANCY
Fortunately, liver masses discovered during
pregnancy are rare and most commonly are
benign. Hemangiomas, focal nodular hyperplasia,
and hepatic adenoma may be discovered on
routine imaging with ultrasound. Further
characterization with MRI or tagged RBC scan
may be needed. Patients presenting with large
hemangiomas can present asymptomatically or
with pain and abdo minal distension. Spontaneous
rupture of hemangiomas is exceedingly rare, even
with large lesions, thus routine symptomatic
follow-up and standard vaginal delivery is safe.
Focal nodular hyperplasia is found in 3%
of the population, and multiple case series
in pregnant women reported routine
pregnancies with good clinical outcomes
. Hepatic adenomas have a higher risk of
growth during pregnancy owing to hormonal
stimulation, and ultrasound monitoring
should be done during pregnancy. If a
diagnosis of large hepatic adenoma is made
in a young woman of child-bearing age,
appropriate consultation and follow-up
should be performed. If a hepatic adenoma
is larger than 5 cm or rapid growth is noted,
surgical or radiological intervention should
be recommended before pregnancy.
LIVER DISEASES UNIQUE TO PREGNANCY
Several liver injuries are unique to
pregnancy and typically resolve with
delivery. Accurate identification of the
insult and the potential impact on both
maternal and fetal health is imperative.
The gestational age of the pregnancy is
an important diagnostic clue and can help
tailor the diagnostic evaluation, as these
insults typically occur only at certain
stages of development A thorough history,
including prior pregnancies, high-risk
behaviors and medications, and careful
physical examination is essential.
First trimester
HG is defined by persistent vomiting,
associated with loss of 5% or more of
pre-pregnancy body weight,
dehydration, and ketosis. HG is
uncommon (0.3–2% of pregnancies),
occurs early in the first trimester, and
typically resolves by 20 weeks
gestation. Risk factors for HG include
molar pregnancy, multiple
pregnancies, trophoblastic disease,
prior HG, and fetal abnormalities
(triploidy, trisomy 21, and
hydropsfetalis)
Liver test abnormalities are
common in HG and resolve when
the vomiting stops. In all, 50–60%
of hospitalized women with HG
will have a mild elevation in
aminotransferase levels, although
AST and ALT levels more than 20
times the upper limit of normal
rarely have been reported
Jaundice and hepatic synthetic
dysfunction are uncommon. Although
women with HG have increased rates of
low birth weight (LBW) babies, small
for gestational age babies, preterm
birth, and poor 5-min Apgar scores,
outcomes are generally favorable.
Management of HG is supportive,
however, given the risk for electrolyte
abnormalities and dehydration,
hospitalization is not infrequent
Intrahepatic cholestasis of
pregnancy
IHCP is the most common liver disease in
pregnancy with prevalence ranging between
0.3 and 5.6% ( 36–38 ). IHCP presents in the
second and third trimesters as persistent
pruritus, typically involving the palms and
soles as well as the rest of the body, with
elevated bile acid levels, andresolves with
delivery. Jaundice occurs in <25% of IHCP
patients, always aft er the onset of pruritus.
If jaundice is the presenting symptom,
further evaluation for alternative
explanations is necessary. Fat malabsorption
can result in fat-soluble vitamin defi ciencies
requiring supplementation
Risk factors for IHCP include
advanced maternal age, a history of
cholestasis secondary to oral
contraceptives, and a personal or
family history of IHCP. Some studies
suggest a higher prevalence in
patients with hepatitis C,
cholelithiasis, and nonalcoholic fatty
liver disease. Evaluation for
alternative etiologies should be
pursued if cholestasis fails to resolve
after delivery.
In IHCP, bile acid concentrations are typically >10 μ
mol/l with increased cholic acid levels and decreased
chenodeoxycholic acid levels. Increased bile acid
concentration (>40 μ mol/l) is one factor that can
identify higher risk, and may be the only biochemical
abnormality present. Bile acid levels also correlate
with fetal distress. Most complications occur when
bile acid levels exceed 40 μ mol/l . Aminotransferase
levels may also be elevated, reaching values >1,000
U/l. Ultrasonography should be performed to exclude
cholelithiasis.
Maternal outcomes are excellent,
however, there is a risk of fetal distress,
preterm labor, prematurity, and
intrauterine death. Early delivery at 37
weeks is encouraged, because
intrauterine death is more common in the
last month of pregnancy and few deaths
occur before 37 weeks.
First-line therapy for IHCP is UDCA at 10–15 mg/kg maternal
body weight. It is well-tolerated and safe for both the mother and
fetus. UDCA increases expression of bile salt export pumps and
increases placental bile transporters. UDCA therapy normalized
serum bile acid patterns in babies with minimal accumulation in
amniotic fluid and cord blood . A recent meta-analysis also found
that women who received UDCA had better outcomes with less
pruritus, improved liver enzymes, and possibly improved fetal
outcomes. UCDA is more effective than cholestyramine or
dexamethasone in controlling pruritus. Dexamethasone may be
used, if needed, to promote fetal lung maturity before delivery, as
there is a higher rate of prematurity in IHCP.
Preeclampsia and eclampsia
 Preeclampsia is characterized by new
onset hypertension (systolic blood pressure
≥140 mm Hg or dystolic blood pressure
≥90 mm Hg) and proteinuria (≥300 mg/24
h) after 20 weeks of gestation. Organ
dysfunction defines severe preeclampsia
and can include hepatomegaly and
hepatocellular injury. Up to 7.5% of all
pregnancies are affected, but only 25% of
preeclampsia cases are severe. Liver
involvement is not a common expression
and when it does occur symptoms are
generally non specific. Eclampsia is
present when grand mal seizures occur.
Hepatic involvement can present
with epigastric or right upper
quadrant pain, likely from
hepatomegaly stretching Glisson’s
capsule. Liver injury results as a
consequence of vasoconstriction
and fibrin precipitation in the
liver. AST and ALT elevations can be
striking. Complications can include
hematoma below Glisson’s capsule
and hepatic rupture.
Th e magnitude of the liver chemistry
abnormalities parallels the risk of
adverse maternal but not fetal
outcomes. Liver tests cannot
exclusively be used to gauge clinical
decisions, as the presence of normal
liver enzymes does not exclude disease.
An expectant approach is advised until
after 34 weeks gestation to limit fetal
morbidity. However, delivery is the
only curative treatment and after 36–37
weeks there is no advantage in
continuing the pregnancy.
The HELLP syndrome is characterized
by hemolytic anemia, increased liver
enzymes, and low platelets. HELLP
affects a minority of pregnancies but
complicates up to 20% of cases of
severe preeclampsia/eclampsia.
Although HELLP typically presents
between 28 and 36 weeks of
gestation, 30% manifest symptoms in
the first week postpartum. Risk factors
include advanced maternal age,
nulliparous, and multiparity.
The hypertension-related liver diseases share similar
clinical presentations. Differentiation is difficult as
there is overlap in their features. The diagnosis of
HELLP is most oft en made through recognition of
typical laboratory results. Signs of hemolytic anemia
and thrombocytopenia with platelets <100,000
cells/μ l, elevations in AST, ALT, serum bilirubin, and
lactate dehydrogenase are expected. There are no
pathognomonic clinical signs and some women with
HELLP may be asymptomatic. Right upper quadrant
and epigastric pain, nausea, vomiting, malaise,
headache, edema, and weight gain are common
complaints. Hypertension and proteinuria should be
expected, occurring in up to 80% of cases. Jaundice
is rare, occurring in only 5% of patients.
HELLP syndrome
Maternal consequences can be severe with
mortality rates of 1–3% . Progression can
also be rapid but laboratory values typically
begin to normalize 48 h postpartum. Fetal
prognosis is most strongly linked to
gestational age at delivery and birth
weight.
Hepatic consequences include hepatic
infarction, subcapsular hematomas, and
intraparenchymal hemorrhage. When the
ALT or AST is >1,000 U/l or abdominal pain
radiates into the right shoulder, cross-
sectional imaging can assist in excluding
hepatic complications with more accuracy
Hepatic infarction should be suspected with
right upper quadrant pain with fever,
whereas abdominal swelling or shock
presentation can occur with hepatic
rupture. Supportive management is
appropriate for most contained hematomas.
Surgery is indicated for those with
enlarging hematomas or evidence of rupture
with hemodynamic instability. Alternatively,
successful percutaneous embolization of the
hepatic arteries in stable women has been
reported. Liver transplantation has also
been an effective salvage in patients with
continued decompensation despite standard
interventions
Glucocorticoids are oft en part of the
therapeutic protocol in HELLP,
especially in pregnancies <34 weeks
where theyaccele rate pulmonary
maturity during expectant management.
The University of Mississippi developed a
treatment protocol that is oft en applied
as standard of care in the management
of women with HELLP. Known as “The
Mississippi Protocol”, it includes
corticosteroids, magnesium sulfate, and
systolic blood pressure control .
However, a recent Cochrane review
found that although dexamethasone
resulted in a greater improvement
in platelet count, there was no
difference in the risk of maternal
morbidity and mortality, or
perinatal/ infant death.
Thrombocytopenia can be marked.
There is no contraindication to
platelet transfusion, and transfusion
to >40,000 cells/μ l is advised when
invasive procedures are anticipated.
Acute fatty liver disease of
pregnancy
AFLP is a rare, life-threatening
condition characterized by
microvesicular fatty infiltration
of the liver leading to hepatic
failure. The median gestation
age at the time of identification
is 36 weeks. Risk factors
include twin pregnancies and
low body mass index .
Early recognition, prompt delivery, and
supportive care are essential to optimize
maternal and fetal prognosis, as the
postpartum clinical course is dependent on
the interval between symptoms and
termination of the pregnancy. If hepatic
function does not rapidly improve,
evaluation for liver transplantation offers
the patient the best chance for survival.
Presenting symptoms are non-specific:
nausea, vomiting, and abdominal pain.
Concomitant preeclampsia is present in
roughly one half of the affected women.
Striking aminotransferase elevations
and hyperbilirubinemia are typical.
Hepatic failure can manifest with signs
of hepatic dysfunction such as
encephalopathy, coagulopathy, and
hypoglycemia. Renal dysfunction and
pancreatitis are common.
The diagnosis of AFLP is usually
made clinically based on
compatible presentation,
laboratory, and imaging results.
The “Swansea Criteria” combine
symptoms and laboratory
derangements. These criteria
have been validated in a large
cohort in the United Kingdom,
where the incidence of AFLP was
5.0 casesper 100,000 maternities.
The “Swansea Criteria” had
substantial agreement with
the clinical diagnosis of
AFLP. Although there was
only 1 death in this series,
65% were admitted to an
intensive care or specialty
liver unit.
When the Swansea Criteria were
applied to a large group of women
with suspected pregnancyrelated liver
disease who underwent liver biopsy,
the screening tool offered an 85%
positive predictive value and 100%
negative predictive value for hepatic
microvesicular steatosis. The authors
felt confident that the Swansea
Criteria could obviate the need for
liver biopsy in clinical management.
The LCHAD enzyme catalyzes the
step in beta-oxidation of
mitochondrial fatty acid that forms
3-ketoacyl-CoA from 3-hydroxyacyl-
CoA. There is a pathophysiologic
pathway between fetal deficiency
of LCHAD and AFLP. Homozygous-
deficient off spring spill
unmetabolized long-chain fatty
acids into the maternal circulation.
Accumulation of fetal or placental
metabolites can lead to hepatoxicity.
Some women with AFLP are
heterozygous for LCHAD and carry
heterozygous or homozygous infants.
In addition, not all genetic defects that
lead to LCHAD confer a risk for AFLP.
COINCIDENT LIVER
DISEASE (HAV, HEV, HSV)
There are no published
systematic reviews or
meta-analysis on the
evaluation and
management of hepatitis A,
hepatitis E, or HSV
hepatitis during pregnancy.
Although acute infection with
HAV has been associated with
preterm labor and premature
rupture of membranes, this has
been reported to have no
significant impact on maternal or
fetal outcomes.
The pregnant state does not
appear to alter the course of
acute HAV infection.
Nevertheless, pregnant women
presenting with acute hepatitis
should be tested for HAV-IgM as
vertical transmission of HAV has
been reported, even leading to
outbreaks within neonatal care
units.
In addition to careful
infection control precautions,
the CDC recommends HAV
immunoglobulin treatment
for the neonate if the
maternal HAV infection
occurs within 2 weeks of
delivery. Treatment is
otherwise supportive.
HEV infection has achieved notoriety with
its association with pregnancy and reports
of increased risk of acute liver failure
leading to high maternal and infant
mortality in Southeast Asia.
Reports of acute HEV are rare in the
United States and Europe although it may
be under-diagnosed owing to limited
awareness regarding HEV.
However, pregnant women
presenting with acute hepatitis
should be tested for HEV with
HEV-IgM to make the diagnosis
and to increase anticipation and
preparation for possible
progression to acute liver failure
and need for liver transplantation
evaluation. Treatment is
otherwise supportive
Although hepatitis from HSV is very rare,
HSV seroprevalence is common in
women of child-bearing age in the
United States at ~20% for HSV-2 and
60% for HSV-1 ( 87 ). Clinical clues to
HSV hepatitis are the presence of fever,
upper respiratory infection symptoms,
or an anicteric, severe hepatitis
presentation on laboratory testing.
The pathognomonic mucocutaneous
lesions are present in <50% of cases,
requiring a high index of suspicion for
HSV in the pregnant patient with an
acute hepatitis presentation. The
challenge of HSV hepatitis is that the
diagnosis is difficult to make and has
extremely high mortality rates reported
up to 74%
This diagnostic difficulty is
compounded by limitedspecifi
city and sensitivity of routine
HSV-IgM testing. HSV PCR
should be performed when HSV
hepatitis is suspected .
Empiric acyclovir is recommended if HSV
hepatitis is suspected in a pregnant
patient. Acyclovir is already recommended
by the American College of Obstetrics and
Gynecology as prophylaxis at 36 weeks of
pregnancy to prevent HSV recurrence and
vertical transmission in women with
previous infection with HSV .
Acyclovir should be started once HSV
hepatitis is suspected, as the diagnosis
is difficult to make and oft en delayed
and as acyclovir has been shown to be
safe and well-tolerated in pregnancy. As
HSV hepatitis is associated with poor
outcomes, even with appropriate
acyclovir treatment initiation and
availability of liver transplantation,
there is little to lose in initiating
acyclovir once HSV hepatitis is
suspected as early treatment is
associated with improvement in
is not recommended in all pregnant
patients with hepatitis when HSV
infection is not suspected . The key is
to have a low threshold to suspect
HSV hepatitis, especially if the
pregnant patient has a fever,
anicteric severe hepatitis on
laboratory testing, and a rash.
Acyclovir can then be discontinued if
the HSV PCR is negative.
HBV can present during pregnancy
and it may be difficult to differentiate
reactivation from acute HBV
infection. Nevertheless, HBV testing
with HBs Ag and hepatitis B core IgM
is recommended in pregnant patients
presenting with acute hepatitis.
Management of HBV during
pregnancy is covered elsewhere in
this guideline.
CHRONIC LIVER DISEASES,
CIRRHOSIS, AND LIVER
TRANSPLANTATION

Hepatitis B
Chronic HBV infection is estimated to
affect >350 million people worldwide and
represents a significant source of
morbidity and mortality related to cirrhosis
and hepatocellular carcinoma. Mother-to-
child transmission (MTCT) of HBV remains
an important source of incident cases of
HBV.
Current barriers to eradication
of incident HBV infections via
MTCT include underutilization of
immunoprophylaxis with
hepatitis B vaccination and
hepatitis B immunoglobulin in
certain endemic regions as well
as failure of immunoprophylaxis.
The risk for development of chronic HBV
infection is strongly linked to the age of
exposure. Risk for chronic infection after
exposure varies from ~90% in infants, 50% in
toddlers and young children, and 5% in
adults. MTCT rates also vary significantly
according to the mother’s HBeAg status (70–
90% transmission rate for HBeAg+ mothers
vs. 10–40% for HBeAg-mothers).
Standard active–passive
immunoprophylaxis with HBIG and
hepatitis B vaccination administered
immediately after birth (within 12 h)
to infants of HBsAg-positive mothers,
followed by 2 additional doses of
vaccine within 6–12 months, prevents
transmission in ~95%. However,
recent review of published literature
from 1975 to 2011 demonstrated that
active–passive immunoprophylaxis
fails to prevent HBVtransmission in 8–
30% of children born to highly
viremicmothers
Postulated causes of immunoprophylaxis
failure include high levels of maternal
viremia, intrauterine infection, or
mutations of the HBV surface protein.
Thus a clinical need remains to identify all
causes of immunoprophylaxis failure and
to determine safe and effective means of
reducing MTCT rates.
High maternal viremia is correlated with
the highest risk for the transmission of
HBV in pregnancy. In a large, nested
casecontrol study of 773 HBsAg-positive
women in Taiwan, high levels of HBV
DNA (≥1.4 ng/ml or ~3.8×10 8
copies/ml) in
HBeAg-positive women was associated
with an odds ratio of 147 for chronic
infection in infants.
Even in the era of
immunoprophylaxis, viremia
remains a strong predictor of MTCT.
In a study of 138 babies born to
HBsAg-positive women, Wiseman et
al. found the immunoprophylaxis
failure rate to be 9%, all occurring
with mothers who were HBeAg-
positive with HBV DNA ≥8 log 10
copies/ml (2×10 7 U/ml).
Older data assessing MTCT rate in infants
born via cesarean section vs. vaginal
delivery failed to conclusively show a
significant difference in neonatal HBV
infection. Expert opinion has suggested
that there were insufficient data to
recommend changes in the mode of
delivery for HBV-infected women.
Some more recent data support
reconsideration of elective cesarean section
to reduce MTCT including a metaanalysis
that suggested a 17.5% absolute risk
reduction compared with
immunoprophylaxis alone. However, other
studies report no benefi t to elective
cesarean section. Data from Beijing of 1,409
infants born to HBsAg-positive mothers
from 2007 to 2011, all of whom received
appropriate immunoprophylaxis at birth,
reported MTCT rates of 1.4% with elective
cesarean section compared with 3.4% with
vaginal delivery and 4.2% with urgent
cesarean section
(P <0.05).
When mothers in this study were stratified
according to HBV DNA, in those with low HBV
DNA (<1,000,000 copies/ml or 2×10 5 IU/ml),
delivery modality did not impact MTCT. This
suggests a potential role for elective cesarean
section among women with HBV DNA
>1,000,000 copies/ml (2×10 5 IU/ml).
However, before definitive recommendations can
be made, validation studies are needed to
determine the relative safety and efficacy of
elective cesarean section and immunoprophylaxis
vs. immunoprophylaxis alone in reducing MTCT
without compromising fetal outcomes.
There is a growing body of literature to
support both the safety and efficacy of
antiviral therapy initiated in late pregnancy
for reduction of MTCT among women in the
highest risk for immunoprophylaxis failure
(those with HBV DNA levels in the range of
10 7 log copies/ml and higher). Han
conducted a prospective, open-label trial of
women aged 20–40 years who were HBeAg +
with HBV DNA>7 log 10 copies/ml (2×10 6
IU/ml) between gestation week 20–32.
All women were offered antiviral
therapy and 135 who accepted received
telbivudine 600 mg daily. The comparison
arm consisted of 94 women who
consented to participate in the trial but
declined antiviral therapy. All infants
were administered appropriate
immunoprophylaxis. Mean viral load at
enrollment was ~8 log 10 copies/ml
(2×10 7 IU/ml) in both arms and was
reduced to 2.44 log 10 copies/ml in the
telbivudinetreatedarm before delivery
The reported MTCT rate was 0% with
telbivudine therapy compared with 8%
without antiviral therapy. One infant in
each group had LBW and there were 6
infants in the telbivudine group
compared with 5 infants in the control
group with pneumonia by age 7
months. No congenital abnormalities
were identified.
In a similar study, Pan et al. compared
53 women with HBeAg+ HBV with
viral loads >6 log 10 copies/ml and
elevated ALT treated with telbivudine
initiated in the second or third
trimester with 35 similar women who
declined therapy. Immunoprophylaxis
failure rate in this study was 0% with
telbivudine therapy compared with
8.6% in controls with no significant
difference in adverse event rates out
to 28 weeks postpartum.
In one multicenter, prospective study from
Australia, 58 women with HBV DNA >7 log 10
IU/ml (2×10 6 IU/ml) commencing therapy with
tenofovir dipivoxil at 32 weeks gestation were
compared with women (n =52) treated with
lamivudine and untreated historical controls (n
=20). Perinatal transmission was reduced to 0
and 2% in the lamivudine and tenofovir cohorts,
respectively, compared with 20% in the
untreated groups. No differences were noted in
obstetric or infant safety outcomes.
Although some studies have suggested a
favorable safety profile for antiviral
therapy even in the first and second
trimesters of pregnancy, when utilized
purely for purposes of reducing MTCT,
antiviral therapy should be initiated in the
third trimester (thus minimizing the risk
associated with fetal exposure to these
medications). Treatment at levels lower
than 10 6 log copies/ml (2×10 5
IU/ml) does not appear to be indicated
unless the pregnant woman has liver
disease for which viral suppression is
indicated.
The end point of antiviral therapy
administered to reduce risk of MTCT
typically is immediately in the
postpartum period for mothers who
plan to breastfeed their infants, unless
treatment continuation is indicated for
the clinical benefit of the mother.
Discontinuation of therapy at any point
during or after pregnancy requires
careful monitoring because of the
potential for HBV flares upon antiviral
therapy withdrawal.
Transmission of HBV with breastfeeding
is low risk in infants who receive
appropriate immunoprophylaxis.
Current WHO recommendations are to
allow breastfeeding as there is no
evidence for additional risk, even
without immunization.
 Breastfeeding should beavoided in
the presence of breast pathology
such as cracked or bleeding nipples.
Oral nucleos(t)ide analogs have
been shown to be excreted in breast
milk, albeit at low levels, and there
is limited data on the effect of these
medications on infants.
Hepatitis C (HCV)
Chronic infection with the HCV can lead to
significant liverrelated morbidity and
increases in all-cause mortality.
HCV has little impact during pregnancy
with minimal risk to either the mother or
infant. However, there may be a higher
risk for premature rupture of
membranes and gestational diabetes in
women with HCV. ALT and viral loads
fluctuate but these changes lack clinical
significance. Pregnancy induces a state of
relative immune suppression followed by
immune reconstitution postpartum. The
changes in liver enzymes and viral kinetics
mirror a response to this immune
modulation.
During the second and third
trimester aminotransferase levels
decline, only to rebound
postpartum. Viral load also
fluctuates, peaking during the
third trimester then returning to
prepregnancy levels after
delivery. Unlike HBV,
postpartum flares of HCV
havenot been described.
Although HCV is transmitted through
percutaneous exposure of infected blood or
body fluids, screening for HCV is not part of
routine perinatal testing owing to a
combination of low rates of perinatal
transmission and low prevalence of HCV in
pregnant women. Cross-sectional studies
estimate that only 0.5–8% of pregnant
women have anti-HCV.
As in the general population,
the prevalence of anti-HCV is
higher in those who engage
in risk factors that increase
potential exposure. Pregnant
women should be screened
using the same guidelines as
the general population.
Although there is only a 3–10% risk of
transmitting HCV at the time of birth,
vertical transmission remains
responsible for the majority of
childhood HCV infection. This risk is
highest in pregnant women co-infected
with HIV.
Unfortunately, there is no
perinatal management
strategy that can clearly
decrease this risk. Although
studies have reported
conflicting findings, it is
generally recommended that
invasive procedures, such as
internal fetal monitoring
devices, should be avoided.
Although prolonged (>6 h) rupture of
membranes may increase the risk of
transmission, vaginal delivery itself does not
appear to increase the risk of vertical
transmission of HCV transmission compared
with cesarean delivery.
There is no evidence of an
association between breast
feeding and risk for vertical
transmission. Still,
breastfeeding should be avoided
when the potential risk for
exposure is higher, such as
when there are cracked nipples
or skin breakdown.
HCV can be eradicated effectively with either
all-oral treatments. HCV rarely requires urgent
therapy, making it easier to defer treatment
decisions until after delivery. In addition, both
interferon and ribavirin are strictly
contraindicated during pregnancy. There is no
data at this time to guide or support the use of
all-oral combination therapy during
pregnancy.
Autoimmune
hepatitis
AIH is associated with an increased risk of
fetal prematurity and loss, with worse
outcomes with inadequate AIH activity control,
especially in the absence of or discontinuation
of AIH treatment before or during pregnancy.
Although AIH was historically thought
to be quiescent during pregnancy,
more recent data suggest that AIH
may have an initial presentation
during pregnancy, an intrapartum
flare risk of >20% and postpartum
flare risk of up to 30–50% .
Treatment for AIH is based on
immunosuppression with corticosteroids and/or
AZA, with recent practice guidelines for AIH
recommending prednisone monotherapy for
pregnant individuals .
A systematic review of AIH treatment
concluded that corticosteroids ±AZA
was appropriate for induction
whereas corticosteroids +AZA or AZA
monotherapy was superior to
corticosteroid monotherapy for
maintenance management of AIH.
However, there are no systematic
reviews or meta-analysis on the
treatment of AIH during pregnancy.

In the absence of such data, it

is important to consider that
flares of AIH during pregnancy
may be potentially more
detrimental to neonatal
outcomes than the potential risk
of medical therapy needed to
Corticosteroids, pregnancy category C
drugs, have been studied in a population-
based study of >51,000 corticosteroid-
exposed pregnancies, with no increase in
orofacial cleft defects or other signifi cant
adverse events .

Corticosteroid monotherapy has

traditionally been used for the
management of AIH flares during
pregnancy because AZA is a
pregnancy category D drug, which
Concerns regarding AZA arose from animal
studies using suprapharmacologic doses and
non oral delivery routes such as
intraperitoneal or subcutaneous dosing,
associated with limbic malformations, cleft
palate, skeletal anomalies, and hematopoietic
suppression.

However, utilization of AZA during

pregnancy for treatment of AIH has
been reported to be safe in a limited
number of case reports and series.
AZA treatment in AIH during
pregnancy has not been studied
systematically. However, utilization
of AZA during pregnancy has been
studied systematically in
inflammatory bowel disease with
3,000 AZA-exposed pregnancies
showing an association with
preterm births but no increase in
congenital abnormalities or LBWs.
Studies of AZA in other autoimmune
diseases and inflammatory bowel
disease have found scattered reports
of preterm births but no increased
risk of congenital abnormalities,
spontaneous abortions, or infections
supporting the growing evidence
regarding the acceptability of AZA
The mounting evidence of AZA’s safety during
pregnancy coupled with the importance of
achieving and maintaining AIH disease control
during pregnancy supports the mandate that
treatment continuation for AIH is critical in
optimizing maternal and fetal outcomes.

The potential benefi t of treatment

with corticosteroids and AZA to keep
the mother’s AIH in control appears to
be signifi cantly greater than the
potentially small risk of treatment-
Primary biliary cirrhosis
Older literature suggested poor
outcomes of pregnancy in patients with
PBC . As patients with PBC tend to
present at an older age after the usual
child-bearing age, and as women with
PBC were discouraged in the past from
pursuing pregnancy, there is an
extremely limited number of studies on
PBC and pregnancy.
Studies on the use of UDCA treatment
for PBC during pregnancy have been
limited, especially in the first
trimester. Similar to the situation
with AIH, the potential risks of UDCA
during pregnancy appear small
compared with the potential positive
effect of treatment on maternal and
fetal outcomes. With growing
evidence that udca is safe during
pregnancy in other diseases such as
intrahepatic cholestasis of pregnancy.
However, more recent studies have
reported good maternal and fetal
outcomes. PBC has been associated
with disease flare after delivery. UDCA
is a pregnancy category B drug that is
generally recommended for PBC.
Wilson’s
disease
WD is postulated to lead to reduced
fertility as copper deposition in the
uterus may interfere with embryo
implantation leading to an increase in
miscarriages and spontaneous
abortions.
WD and the complex nature of its
benefit from referral to high-risk
pregnancy multidisciplinary specialists
in maternal–fetal medicine and liver
disease. Pregnancy in general does not
appear to change the course of WD
progression.
However, treatment discontinuation or a lack
of treatment has been reported to lead to
disease flares with attendant risk of hepatic
decompensation or liver failure . There is one
recent systematic review on the treatment of
WD in general, but no reports specific to
treatment for WD during pregnancy .
Similar to AIH and PBC, the decision
regarding treatment for WD must weigh
the potential risks and adverse effects of
treatment vs. not only the benefits of
treatment but the risks of not treating the
WD during pregnancy.
There is inadequate data to make
recommendations on a preferred treatment for
WD during pregnancy, between penicillamine,
trientine, or zinc. Some data on conversion to zinc
therapy during pregnancy has also been reported.

There are also multiple case reports of fetal

myelosuppression or embryopathy
associated with penicillamine treatment
during pregnancy for WD . On the other
hand, treatment discontinuation or lack of
treatment for WD can not only lead to
maternal hepatic decompensation but can
also lead to copper deposition in the
placenta and fetal liver, damaging the fetus
The risks of treatment
discontinuation or lack of
treatment for WD during
pregnancy appears to outweigh
the potential risks of treatment.
The data to recommend dose
reduction of penicillamine in
anticipation of possible cesarean
section appears to be very limited.
Cirrhosis and portal
hypertension
There are no published systematic reviews or meta-
analyses on the management of cirrhosis or portal
hypertension during pregnancy, likely because of the
low prevalence of cirrhosis in women of reproductive
age and reduced fertility of women with cirrhosis.

Appropriate discussion regarding

pregnancy and counseling regarding the
management of cirrhosis during
pregnancy is critical for optimizing
outcomes. Pregnant women with cirrhosis
should ideally be managed in a
multidisciplinary setting with maternal–
Similar to the management of chronic
liver disease in pregnancy, the principle
of optimizing the management of
cirrhosis and portal hypertension
appears prudent to enhance maternal
and fetal outcomes.
Pregnancy in women with underlying cirrhosis
has been associated with an increase in
prematurity, spontaneous abortions, and
maternal–fetal mortality .

Non-cirrhotic portal hypertension

has been reported to have better
outcomes than cirrhotics with
portal hypertension.
Varibceal leeding is the most frequent and
feared complication of portal hypertension
during pregnancy, with an increased risk at
delivery and the second trimester,
potentiated by an increase in intravascular
volume, compression from the gravid uterus,
and repeated Valsalva maneuvers .

Up to 30% of cirrhotic pregnant

women bleed from esophageal varices
during pregnancy, and the risk of variceal
bleeding increases up to 50–78% if
there are pre-existing varices.
Each episode of variceal bleeding leads to
maternal mortality rates as high as 20–
50%, with an even higher risk of fetal loss.

Variceal bleeding during pregnancy is

managed very similarly to variceal
bleeding in general given the acute and
life-threatening nature of the event, with
a focus on endoscopic hemostasis and
supportive care for the mother and
fetus.
 Octreotide is a pregnancy category B drug
and appears to be safe as an adjunct
treatment in acute variceal bleeding along
with antibiotics. Salvage therapy with
transjugular intrahepatic systemic shunts and
liver transplantation has also been described,
but are not routinely advocated .
As outlined in the general endoscopy
section above, endoscopy during
pregnancy appears safe, but must be
considered carefully in terms of the
indication for endoscopy, the risks vs.
benefit evaluation and whether it will lead
Given the risks of variceal bleeding in
cirrhotic women during pregnancy, the
significantly increased mortality
associated with such bleeding, and the
opportunity to intervene if varices are
identified preemptively, the indications
for screening for esophageal varices
appears to have at least a moderate
indication.
Despite acceptance of band ligation and
beta-blockers as first line management of
esophageal varices for non-pregnant
patients, there are limited data on their
efficacy and safety in pregnancy .
Propranolol is a pregnancy category C
drug, but has been used to treat fetal
arrhythmias as well as maternal
conditions such as thyrotoxicosis,
arrhythmias, or hypertension.
There are risks of intra uterine growth
retardation, neonatal bradycardia,
and hypoglycemia, but propranolol
appears overall to be safe in
pregnant patients. Nadololis also a
category C drug, but has a long half-
life owing to low protein-binding and
low rate of excretion, so is not
preferred.there is no data comparing
the benefits of vaginal delivery
Liver transplantation
Fertility is rapidly restored after successful
liver transplantation, with reports of 80%
normalization of the menstrual cycle within
1 year and as early as a few months after
liver transplantation.

Most experts advocate waiting at least 1

year, and some up to 2 years after liver
transplantation before planning a
pregnancy, citing the lower doses of
immunosuppression use, lower risk of
acute cellular rejection, and lower risk of
opportunistic infections after the
There is one published systematic review
on pregnancy outcomes in liver transplant
recipients. Higher rates of preterm births
and cesarean sections compared with the
general population were reported.

The National Transplantation Pregnancy

Registry, a questionnaire-based registry,
has reported a higher risk of
prematurity, LBW, maternal
hypertension and preeclampsia, and
cesarean sections compared with the
Higher risk of acute cellular
rejection and graft loss were noted
if pregnancy occurred within 6
months of liver transplantation.
Overall, the literature suggests that
pregnancy in liver transplant
recipients is safe and not
uncommon, with good outcomes
given careful management and
monitoring.
There is one meta-analysis on
pregnancy and cyclosporine in
transplant recipients. There are no
other meta-analyses or systematic
reviews on pregnancy and use of
tacrolimus, AZA, mycophenolic
acid, sirolimus, everolimus, or
corticosteroids in the setting of
liver transplantation.
It is clear that mycophenolic acid should
not be used during pregnancy owing to
risk of congenital malformations and
embryo-fetal toxicity .
Expert and society recommendations
have traditionally opposed
breastfeeding in the setting of
immunosuppression medications and
transplantation, given the potential for
harm of these medications and a lack of
safety data.
More recently, small series have
reported safety with minimal to no
adverse events for babies who are
breastfed while mothers are on
immunosuppression medications after
liver transplantation .