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LIVER TRANSPLANTATION 14:1081-1091, 2008

REVIEW

Pregnancy and Cirrhosis


Jennifer Tan,1 Bijal Surti,1 and Sammy Saab1,2
Departments of 1Medicine and 2Surgery, David Geffen School of Medicine, University of California–
Los Angeles, Los Angeles, CA

As the treatment of cirrhosis improves, pregnancy in patients with cirrhosis is likely to become more common. Although
maternal and fetal mortality is expected to similarly improve, pregnant patients with cirrhosis face unique risks. These include
higher rates of spontaneous abortion and prematurity and a potential for life-threatening variceal hemorrhage, hepatic
decompensation, splenic artery aneurysm rupture, and postpartum hemorrhage. Pregnancy outcome may be influenced by the
underlying etiology of liver disease, as in viral and autoimmune hepatitis. Medications also impact the course of pregnancy, and
must be tailored appropriately during this time.Liver Transpl 14:1081-1091, 2008. © 2008 AASLD.

Received March 28, 2008; accepted May 28, 2008.

INTRODUCTION AND EPIDEMIOLOGY complications have been described in nearly half of


pregnancies affected by cirrhosis and portal hyperten-
Pregnancy is a rare event in patients with cirrhosis. The
sion, largely as a result of variceal hemorrhage and liver
exact incidence is unknown, but it has traditionally
failure.3
been low for 2 reasons. First, advanced liver disease
does not typically occur until well after most patients Esophageal Varices
have completed their reproductive years, with only 45 Esophageal variceal bleeding has been reported in 18%
cases of cirrhosis occurring in every 100,000 women of to 32% of pregnant women with cirrhosis and in up to
reproductive age. Second, cirrhosis results in metabolic 50% of those with known portal hypertension.4,5
and hormonal derangements that lead to anovulation Among those with preexisting varices, up to 78% will
and amenorrhea.1
have gastrointestinal bleeding during pregnancy, with a
Increasing numbers of case reports and case series of
mortality rate of 18% to 50%.1 In contrast, pregnant
pregnancy in this population, however, indicate that
patients with noncirrhotic portal hypertension fare
improvements in the treatment of chronic liver disease
much better. Their mortality rate from variceal bleeding
have resulted in higher conception rates and more suc-
is between 2% to 6%.1 This disparity may be related to
cessful pregnancy outcomes.1 Although previously re-
the severity of their underlying liver disease, with pa-
ported to be as high as 10.5%,2 maternal mortality has
tients with cirrhosis more likely to be coagulopathic.
likely improved along with better management of
Variceal bleeding most commonly occurs during the
variceal hemorrhage and liver failure.
second and third trimesters when maternal blood vol-
Nevertheless, morbidity and mortality likely remains
ume is maximally expanded and the larger fetus causes
higher than that of the general pregnant population. It
increased compression of the inferior vena cava and
is therefore important for physicians caring for preg-
collateral vasculature.6
nant patients with cirrhosis to understand how to ap-
proach potential complications and tailor medication As in nonpregnant patients with cirrhosis, endo-
regimens appropriately. scopic band ligation remains the mainstay of therapy
for acute episodes of hemorrhage. The first case of suc-
cessful band ligation in a pregnant patient with acute
EFFECTS OF CIRRHOSIS AND PORTAL
bleeding was reported in 1998 by Starkel et al.,7 but no
HYPERTENSION prospective randomized trials for this treatment cur-
Although it is difficult to distinguish the effects of preg- rently exist. As in the nongravid population, sclerother-
nancy from the natural history of cirrhosis, maternal apy was previously looked to as a potential alternative,8

Abbreviations: AIH, autoimmune hepatitis; ALD, alcoholic liver disease; FDA, Food and Drug Administration; PBC, primary biliary
cirrhosis; TIPS, transjugular intrahepatic portosystemic shunt; UDCA, ursodeoxycholic acid.
Address reprint requests to Sammy Saab, M.D., M.P.H., Pfleger Liver Institute, UCLA Medical Center, 200 Medical Plaza, Suite 214, Los Angeles,
CA 90095. Telephone: 310-206-6705; FAX: 310-206-4197; E-mail: ssaab@mednet.ucla.edu
DOI 10.1002/lt.21572
Published online in Wiley InterScience (www.interscience.wiley.com).

© 2008 American Association for the Study of Liver Diseases.


1082 TAN, SURTI, AND SAAB

but it has largely been replaced by band ligation. Ex- have a lower risk of spontaneous abortion compared to
perts argue that band ligation should be preferred dur- women without shunts17 and a 7-fold lower risk of
ing pregnancy because it avoids any potential risk from severe gastrointestinal hemorrhage.18 However, surgi-
chemical instillation.7 cal shunt procedures are generally performed only in
Upper endoscopy in general appears to be safe during the setting of a life-threatening hemorrhage that is re-
pregnancy, with the main risk being fetal hypoxia from fractory to medical and endoscopic treatments.1
sedative drugs or positioning. No cases of premature Another area of controversy in pregnant patients with
labor or fetal malformations have been reported in pa- portal hypertension is how to approach delivery. The
tients who have undergone endoscopy during preg- risk of variceal bleeding is thought to be particularly
nancy.9 increased at the time of labor because of the need for
Octreotide, designated as pregnancy category B by repetitive Valsalva maneuver. The resultant increased
the Food and Drug Administration, is often used to intra-abdominal pressure is postulated to lead to in-
treat acute variceal bleeding, although its safety has not creased portal hypertension and thus a higher risk of
been well studied in pregnant patients.10 Given its sim- variceal rupture. As a result, many experts advocate
ilarity to vasopressin, however, possible concerns in- using elective caesarian section or forceps delivery un-
clude arteriolar vasospasm, which can result in de- der extradural analgesia in order to decrease this
creased placental perfusion and an increased risk of risk.3,19 Although this seems reasonable, no random-
placental abruption, myocardial infarction, peripheral ized controlled trials have been performed to support
ischemia, and hypertension.1,3 this recommendation. If a prophylactic caesarian sec-
Although transjugular intrahepatic portosystemic tion is performed, a vascular surgeon should be avail-
shunt (TIPS) placement is generally contraindicated able in the event that bleeding from pelvic or abdominal
during pregnancy because of the risk of radiation expo- wall collaterals is encountered.6
sure to the fetus, it may be an appropriate rescue ther-
apy for failed attempts to control variceal bleeding with
band ligation or sclerotherapy.11 The risk of fetal mal-
Hepatic Decompensation
formations from radiation is thought to be increased at Up to 24% of pregnant patients with cirrhosis will also
doses above 150 mGy and is considered negligible if experience hepatic decompensation, which can lead to
doses are below 50 mGy.12 Only 3 cases of TIPS place- rapid clinical deterioration.3 This has been described in
ment in pregnant patients with cirrhosis have been all stages of pregnancy, but often occurs after episodes
reported thus far, with radiation dosages of 0.1, 5.2, of variceal bleeding.20
and 5.49 mGy used. In all 3 cases, the mothers survived When fulminant hepatic failure occurs, the only
the episode of acute variceal bleeding.11,13,14 In 1 case, treatment available may be emergent liver transplanta-
the fetus ultimately died as a result of premature deliv- tion. This has been performed during pregnancy in a
ery and infant respiratory distress syndrome, but this small number of cases, with successful outcomes for
was not thought to be related to the TIPS procedure.11 both mother and fetus.21,22 Reported complications re-
The prophylactic treatment of varices in pregnant main high, however, and have included an increased
women remains controversial. A case report by Zeeman risk of fetal ischemia, pregnancy-induced hyperten-
and Moise15 in 1999 reported a successful outcome for sion, anemia, caesarian section, and preterm deliv-
prophylactic banding in a pregnant patient with cryp- ery.23,24 Moreover, these case reports largely involved
togenic cirrhosis and portal hypertension, but no pro- women without underlying cirrhosis, and it is unclear
spective, randomized trials have been performed. Ac- how underlying liver disease would change the out-
cording to the American Association for the Study of come.
Liver Diseases practice guidelines, all patients diag-
nosed with cirrhosis should undergo screening endos-
copy for the diagnosis of gastric and esophageal vari-
Ascites and Spontaneous Bacterial Peritonitis
ces.16 Although there are no formal guidelines for Ascites rarely occurs during pregnancy because of in-
pregnant women, most experts recommend that a creased intra-abdominal pressure, which acts to resist
screening endoscopy be done in women with cirrhosis the extravasation of fluid from splanchnic vessels and
either before pregnancy or in the early second trimes- organs. If therapy is required, however, sodium restric-
ter. tion and diuretics can be used, as in nonpregnant pa-
In women at high risk for bleeding, the potential ben- tients with cirrhosis. Although cases of spontaneous
efits of primary prophylaxis with nonselective beta bacterial peritonitis have not been reported, other
blockers such as propranolol and nadolol, designated causes of peritonitis have been known to increase the
by the Food and Drug Administration as pregnancy risk of premature delivery and placental abruption. If
category C, may outweigh the risks of potential fetal spontaneous bacterial peritonitis does occur, treatment
harm. The most commonly reported morbidities from should consist of a third-generation cephalosporin.1
these drugs include fetal growth retardation, neonatal
hypoglycemia, and neonatal bradycardia.16
Hepatic Encephalopathy
Surgical creation of splenorenal or portacaval shunts
has also been advocated on the basis of observational Like nonpregnant patients with cirrhosis, pregnant pa-
studies showing that women with cirrhosis with shunts tients with cirrhosis can develop encephalopathy if they
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
PREGNANCY AND CIRRHOSIS 1083

TABLE 1. The Food and Drug Administration Pregnancy Categories

Pregnancy
Category Definition
A Controlled studies indicate no risk.
B Animal studies show no risk, and there are no human controlled studies, or animal studies
may show an adverse effect that was not reproduced in human controlled studies.
C Risk cannot be ruled out; animal studies show an adverse effect, and there are no human
controlled studies, or there are no studies available.
D Risk is evident in human studies; use may be considered if the benefit outweighs the risk.
X Risk is evident in animal and human studies and outweighs any benefit; use is
contraindicated in women who are or may be pregnant.

are given predisposing medications or experience hypo- population, with a rate of 30% to 40%27 versus 15%
tension, hypoxia, infection, hypoglycemia, or gastroin- to 20%.28 This is not true for patients with extrahe-
testinal hemorrhage. Of note, spinal and general anes- patic portal obstruction unrelated to cirrhosis, in
thesia should be avoided during delivery because of the whom the rate of spontaneous abortion is 3% to 6%.29
potential for hypotension and the risk of precipitating Moreover, patients with cirrhosis who have under-
encephalopathy. The mainstay of treatment remains gone portal decompressive procedures prior to con-
lactulose and/or antibiotic therapy.1 ception have spontaneous abortion rates comparable
to patients with extrahepatic obstruction.30 Termina-
Splenic Artery Aneurysm Rupture tion of pregnancy most often occurs as a result of
maternal death, variceal hemorrhage, stillbirth, in-
Pregnant patients with cirrhosis also have an increased
trauterine growth retardation, and maternal compli-
risk of splenic artery aneurysm rupture, which occurs
in 2.6%. In fact, 20% of all splenic artery aneurysm cations during delivery.6
ruptures occur during pregnancy, with 70% occurring In those pregnancies that do result in live births,
during the third trimester. Rapid intra-abdominal the risk of prematurity is significantly increased, with
bleeding and hypovolemic shock often ensue, resulting a rate of up to 25%.30 In contrast, the general popu-
in substantial maternal and fetal mortality rates of 70% lation, as of 2006, had a preterm birth rate of
and 80%, respectively.3 The mechanism for the devel- 12.8%.31 The perinatal death rate is likewise elevated
opment of these aneurysms is unclear but may be re- and may be as high as 18%30 versus 1.08% in the
lated to increased splenic blood flow from both preg- noncirrhotic population.32 The majority of these data
nancy and portal hypertension. High estrogen levels are from older literature, however, and may reflect
during pregnancy may also have effects on the elastic complications of prematurity at a time when routine
tissue of the tunica media. Management options consist measures such as corticosteroids, surfactants, and
of emergency splenectomy, transcatheter embolization modern neonatal intensive care management were
of the aneurysm, or stent-graft placement. The latter 2 unavailable.1
options are usually preferred in cases of portal hyper-
tension, as an extensive collateral circulation in these
patients makes surgery more difficult.25
MEDICATIONS USED IN PATIENTS WITH
Postpartum Uterine Hemorrhage LIVER DISEASE
Postpartum uterine hemorrhage is another potential Data regarding the use of medications commonly pre-
source of maternal morbidity and mortality, occur- scribed for patients with cirrhosis during pregnancy
ring in 7% to 10% of pregnancies in patients with are scarce, with the majority of medications falling
cirrhosis. This is likely related to a higher incidence of into pregnancy category C (Tables 1 and 2). Notable
coagulopathy and thrombocytopenia.9 Treatment is exceptions are neomycin, azathioprine, and penicil-
similar to that in patients without cirrhosis. Blood lamine, which have been designated pregnancy cate-
and coagulation factors should be transfused and
gory D because of animal studies showing a possible
administered oxytocin or other uterine contractile
risk of fetal harm (Tables 1 and 2). Octreotide, cefo-
agents. Surgical therapy to ligate the bleeding vessels
taxime, lactulose, telbivudine, prednisone, and ur-
or hysterectomy is indicated when these measures
sodeoxycholic acid (UDCA) have been deemed preg-
fail.26
nancy category B, as animal studies have shown no
harmful effects (Tables 1 and 2). Ribavirin is preg-
Fetal Outcomes nancy category X, with significant teratogenic effects
The spontaneous abortion rate in patients with cir- in all animal studies at 0.01 times the maximum
rhosis is significantly higher than that of the general human dose (Tables 1 and 2).

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
1084 TAN, SURTI, AND SAAB

TABLE 2. Medications Used for Liver Disease

FDA
Pregnancy Effect on Breast-Feeding
Drug Category Conception Effect on Mother Effect on Fetus Safe? References
Furosemide C None Electrolyte Decreased uteroplacental Unknown; no 76-78
disturbances, perfusion and reports available
decreased hepatic hypovolemia, electrolyte
perfusion disturbances
Spironolactone C None Electrolyte Decreased uteroplacental Probably; 76,79
disturbances perfusion and negligible
hypovolemia, amount in
feminization of males in breast milk
rat studies
Propranolol C None Bradycardia, Intrauterine growth Probably; 80-87
bronchospasm, retardation, bradycardia, negligible
hypotension, hypoglycemia, neonatal amount in
fatigue respiratory depression breast milk
during labor
Nadolol C None Bradycardia, Unknown Possibly unsafe; 88-90
bronchospasm, concentrations
hypotension, in breast milk
fatigue can be
significant if
high doses are
used or in
younger infants
Octreotide B Unknown Gastrointestinal No teratogenic effects in Unknown 14
side effects animal models
Lactulose B None Diarrhea, No adverse effects in Unknown; no 91
electrolyte animal models reports available
disturbances,
abdominal cramps
Rifaximin C None Nausea, Teratogenic in high doses Unknown; no 92
abdominal pain in animals; no human reports available
studies
Neomycin D None Nephrotoxicity, Like other Unknown; no 93-96
ototoxicity aminoglycosides, may reports,
cause fetal ototoxicity although other
aminoglycosides
are considered
safe
Cefotaxime B None Diarrhea, No fetal harm in animal Probably; 97-101
abdominal pain studies negligible
amount in
breast milk
Ciprofloxacin C None Nausea, dyspepsia Teratogenic in animal Probably; 102-109
studies; congenital arthropathy in
anomalies reported in 1 juvenile
human study, but none animals; 1 case
in 3 other studies report of
pseudomembranous
colitis
Norfloxacin C None Nausea, dyspepsia Teratogenic in animal Probably; no 102-103,
studies; no harm in reports, 107
human observational although other
study quinolones are
considered safe
Lamivudine C Unknown Lactic acidosis, No increases in birth Unsafe; possible 110-113
pancreatitis, defects overall; reports of severe adverse
peripheral mitochondrial reactions in
neuropathy, dysfunction infant
anemia

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PREGNANCY AND CIRRHOSIS 1085

TABLE 2. (CONTINUED)

FDA
Pregnancy Effect on Breast-Feeding
Drug Category Conception Effect on Mother Effect on Fetus Safe? References
Interferon alfa C Unknown Fatigue, mood Abortifacient in monkeys Unknown but 114, 115
2a and 2b changes, at 90 times human dose; not
pancytopenia, case reports of transient recommended;
myalgias thrombocytopenia, excretion into
intrauterine growth milk reported in
restriction, and neonatal mice
lupus
Adefovir C Unknown Nephrotoxicity, Unknown; no studies or Unknown but 116
lactic acidosis case reports in either not
women or animals recommended
Entecavir C Unknown Lactic acidosis No studies in humans; in Unsafe; secreted 117
rats, lower body weights, into milk of
tail and vertebral lactating rats
malformations, and
reduced ossification were
seen at 3100 times
human dose
Telbivudine B Unknown Lactic acidosis, No adverse effects in Possibly unsafe; 118
neutropenia, animals at doses as high found to be
thrombocytopenia as 37 times human dose excreted into the
milk of lactating
rats
Ribavirin X Unknown Pancytopenia, Embryocidal and Possibly unsafe; 119
nephrotoxicity, teratogenic in all animals unknown
myalgias studied; should also be whether it is
avoided in men whose excreted into
female partners are or milk
may become pregnant
Azathioprine D Unknown Leukopenia, 22% malformations, 45% Unsafe 120
gastrointestinal first trimester abortion
side effects
Prednisone B None Hypertension, 4% malformation rate, Safe 121
gestational adrenal insufficiency,
diabetes, premature rupture of
cushingoid membranes
appearance,
osteonecrosis,
weight gain,
dyslipidemia,
infection
Penicillamine D Unknown Anemia, Possible cutaneous Unknown 122, 123
agranulocytosis, defects
proteinuria
Trientine C Unknown Anemia, Chromosomal defects Unknown 124
neurologic
worsening,
iatrogenic copper
deficiency
Ursodeoxycholic B Unknown Headache, Effects during first Unknown 64, 66
acid dizziness, trimester unclear;
constipation presumed safe during
third trimester
Cholestyramine C None in rat Vitamin No studies in pregnant Not excreted 125
models malabsorption, humans, possible into breast milk
particularly K vitamin deficiencies
Hydroxyzine C Unknown Central nervous Neonatal withdrawal Unknown 67
system depression syndrome

Abbreviation: FDA, Food and Drug Administration.

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
1086 TAN, SURTI, AND SAAB

EFFECT OF PREGNANCY ON SPECIFIC LIVER vaccine series must then be completed according to the
DISEASES standard schedule.47,48
Caesarian delivery remains controversial for mothers
Chronic Viral Hepatitis B and C with hepatitis C, with 1 multicenter European study
The chief potential risk posed by viral hepatitis during demonstrating no protective effect of Caesarean deliv-
pregnancy is transmission of the virus from mother to ery49 and another demonstrating a significantly higher
child. In areas endemic for hepatitis B, vertical trans- rate of vertical transmission in vaginally delivered in-
mission of the virus is responsible for the vast majority fants.50 There are no vaccines or immunoglobulins
of infections. When a mother is a hepatitis B surface available at this time for hepatitis C.
antigen carrier with viral DNA present in her serum, the According to guidelines published by the American
neonate has an 80% to 90% risk of also becoming a College of Obstetricians and Gynecologists, breastfeed-
chronic carrier.33 High levels of viremia are the most ing is considered safe for mothers with hepatitis C.51 In
important risk factor for infection of the infant, with mothers with hepatitis B, breastfeeding is also encour-
transmission rates decreasing to as low as 10% to 30% aged, although mothers are advised to hold off until the
when viral DNA is absent from the mother’s serum.34 neonate receives hepatitis B immunoglobulin.52
Intraplacental transmission is the most common Antiviral treatment of hepatitis B during pregnancy is
means of vertical spread, although infection can also controversial. Because the rate of mother-to-child
transmission of hepatitis B is dependent on the level of
occur during delivery and breastfeeding.35
viral DNA in the mother’s serum, it has been argued
In contrast, rates of transmission of hepatitis C from
that treating mothers with lamivudine, or more re-
mother to infant are typically low, ranging from 4% to
cently, telbivudine results in decreased rates of neona-
10%.35 Risk is increased by high levels of viral RNA in
tal infection.53,54 Lamivudine is designated pregnancy
the mother and by prolonged time from rupture of
category C. However, extensive experience in pregnant
membranes to delivery. Most children who acquire hep-
women with human immunodeficiency virus, as re-
atitis C from their mothers do so during delivery, when
ported in a national antiviral pregnancy registry, shows
they are exposed to a high volume of their mother’s
the drug to be well tolerated and safe in both mothers
blood and vaginal fluids. Additional risk factors for the
and infants.55 Telbivudine has been deemed category B
vertical spread of hepatitis C are genotypes 1 and 3,
because animal studies have shown no increase in fetal
elevated alanine aminotransferase levels, and coinfec-
harm (Table 1). With no long-term studies as of yet,
tion with human immunodeficiency virus.35
however, antiviral treatment during pregnancy remains
Laboratory parameters, are expected to fluctuate
a subjective decision between mothers and physicians.
during pregnancy, although the clinical significance is Antiviral treatment of hepatitis C is contraindicated
unknown. Because of the expansion of extracellular during pregnancy. Although case reports of patients
fluid, all markers of liver function except for alkaline who became pregnant while on interferon showed rela-
phosphatase, which is produced by the placenta, tend tive safety of the medication,56 ribavirin is considered
to decrease. This is particularly true during the second pregnancy category X. Animal studies of ribavirin have
and third trimesters.3 Hepatitis B virus DNA levels typ- shown a high incidence of birth defects and spontane-
ically increase late in pregnancy or in the early postpar- ous abortion (Table 1).
tum period, with 1 retrospective study showing a mean
increase of 0.4 log.36 Several studies have likewise
shown hepatitis C RNA levels to increase during the Autoimmune Hepatitis (AIH)
second and third trimesters.37-39 Although earlier studies of pregnancy in patients with
Hepatitis B viral infection itself does not appear to AIH showed an increased risk of prematurity, low birth
alter fertility, conception, or pregnancy beyond the ef- weight, and fetal loss,57 recent advances in therapy
fects of cirrhosis or liver failure.40 Case reports have have modified the prognosis of pregnancy in these pa-
reported delivery before 34 weeks, antepartum hemor- tients.
rhage,41 fetal distress, and meconium peritonitis,42 but Theoretically, AIH should improve during pregnancy
these have been isolated experiences. because of changes in female sex hormones and cyto-
In mothers affected by hepatitis C, 1 study demon- kine profiles, resulting in a shift from T helper 1 cells to
strated an increased incidence of intrahepatic cholesta- T helper 2 cells. Indeed, there are multiple reported
sis of pregnancy.43 Another suggested that pregnant cases of improvement of AIH during pregnancy.58 How-
women with hepatitis C may experience worsening ever, in a significant number of patients, AIH may by
necroinflammatory and fibrotic changes on liver biopsy exacerbated by pregnancy, with a rate of intrapartum
after pregnancy.44 Other studies, however, have shown flare of 12.5% to 21%.59,60 Postpartum flares of AIH
no adverse effects on pregnancy or neonatal outcome.45 also occur, with exacerbation rates ranging widely, any-
Caesarean delivery is not advocated in order to re- where from 12.5% to 86%.58-61 This discrepancy in
duce transmission of hepatitis B, as studies have not data may be due to inconsistent alteration of therapy
shown it to significantly decrease infection rates.46 during pregnancy, with dosing being maintained, re-
Rather, prevention of transmission is accomplished duced, or even discontinued.
through administration of hepatitis B vaccine and hep- Maternal and fetal complications do appear to be
atitis B immunoglobulin within 12 hours of birth. The slightly increased, although evidence is limited. Pa-
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
PREGNANCY AND CIRRHOSIS 1087

tients with AIH have been shown to undergo caesarian animal studies showing increased fetal abnormalities
section at higher rates than the general population, at high doses. Human studies also show an increased
ranging from 16.1% to 43%.60,61 The rate of serious risk of neonatal withdrawal symptoms.
maternal complications was as high as 9% in 1 study, On the other hand, continuation of therapy is advo-
but this may have been biased by 1 mother who died of cated in pregnant patients with Wilson’s disease. Ces-
multiorgan failure from a septic abortion and another sation of therapy can lead to hemolytic crisis, with pos-
who developed fulminant hepatic failure requiring sible hepatic failure and maternal death.68 Although
emergent liver transplantation and hysterectomy.58 Fe- penicillamine is pregnancy category D, successful out-
tal loss was reported to be as high as 33% in earlier comes have been reported in patients treated through-
studies,57 but more recent studies have shown rates out their pregnancies.69 Current guidelines recom-
between 14% and 24%.59,60 mend that pregnant women be continued on
A recent review of pregnancy in AIH, published by penicillamine at a reduced dose of 25% to 50% their
Schramm et al.60 in 2006, examined 42 pregnancies in prepregnancy dose.70 The safety of trientine during
22 women with AIH. The spontaneous abortion rate in pregnancy is less clear, but it can also be considered at
this population was 17%, and the rate of preterm deliv- reduced doses.
ery was 17%. Twenty-one percent of patients had AIH Pregnancy data in women with hemochromatosis are
flares during pregnancy, and 52% suffered postpartum exceedingly rare, given that women are generally diag-
AIH flares. Interestingly, the presence of anti-Ro/SSA nosed during their postmenopausal years and that
and anti-soluble liver antigen/liver-pancreas antibod- those in their reproductive years often present with
ies was associated with adverse pregnancy outcomes. secondary amenorrhea.
Because of the risk of intrapartum and postpartum Pregnancy data are also rare in women with alcoholic
flares, it is generally recommended that immunosuppres- liver disease (ALD), as women with ALD are often infertile.
sive therapy be continued during pregnancy. A modest Infants born to mothers with ALD who continue to drink
decrease in immunosuppression can often be performed are at high risk for fetal-alcohol syndrome, which consists
after the third month of pregnancy, when liver test typi- of several abnormalities, including poor growth, central
cally improve. However, this is usually followed by a need nervous system defects, dysmorphic facial features, and
for increased doses just before delivery and in the post- cognitive and behavioral impairments.71
partum period. Azathioprine has been used successfully
during pregnancy in patients with inflammatory bowel PREGNANCY AFTER LIVER
disease and rheumatoid arthritis, with benefits that far
outweighing its teratogenic potential.62,63
TRANSPLANTATION
Although successful pregnancy is possible in patients The advent of liver transplantation has further changed
with AIH, careful monitoring is required because of the the course of pregnancy in patients with liver disease.
higher rate of maternal and fetal complications the un- Although rare, like pregnancy in the context of cirrho-
predictable course of disease during pregnancy. sis, successful pregnancy after liver transplantation is
achievable. As of January 2006, 202 pregnancies and
205 outcomes have been reported in 121 female liver
Other Liver Diseases transplant recipients in the National Transplantation
Reports of pregnancy outcomes in patients with pri- Pregnancy Registry.72 Although children born to female
mary biliary cirrhosis (PBC) are rare, largely because of liver transplant recipients have a greater risk of prema-
the negative effect of PBC on fertility.64 It is thought turity (35% versus 11.0%-12.7%) and low birth weight
that high levels of estrogen during pregnancy may re- (34% versus 8.2%) compared to the general population,
sult in impaired biliary function and altered amino- overall outcome is similar, with no associated malfor-
transferase levels, but the impact of these changes on mation patterns reported thus far.72 Recent data, how-
maternal and fetal outcomes is unknown. ever, indicate that mycophenolate may be associated
The safety of medications commonly used to treat with first trimester pregnancy loss and an increased
PBC is also a matter of debate. Although UDCA is risk of congenital malformations.73
thought to be safe during the third trimester, it is un- Maternal complications have been shown to be in-
clear whether use in the first trimester can result in creased in liver transplant recipients, particularly preg-
fetal harm. The American Association for the Study of nancy-induced hypertension (34% versus 4%-10%),
Liver Diseases recommends avoiding UDCA in women preeclampsia (22% versus 6%-8%), and caesarian sec-
considering pregnancy.65 Furthermore, breastfeeding tion (35% versus 20%-25%).72 The incidence of preg-
is not advised, as it is unknown whether UDCA is ex- nancy-induced or exacerbated hypertension may relate
creted into breast milk.66 to the type of immunosuppressive regimen used, with
No well-controlled studies exist on the effects of bile the highest risk posed by cyclosporine, followed by ta-
acid sequestrants such as cholestyramine, and caution crolimus and then corticosteroids.74
is advised regarding their use. Cholestyramine is par- The rate of acute rejection in pregnant liver recipients
ticularly known to interfere with the absorption of fat- is not substantially different, from that of their non-
soluble vitamins. pregnant counterparts. In a 2005 National Transplan-
Hydroxyzine, often used to treat pruritus in PBC pa- tation Pregnancy Registry report evaluating 121 liver
tients, is contraindicated in early pregnancy because of recipients, 7% developed acute rejection during preg-
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
1088 TAN, SURTI, AND SAAB

nancy, and 8% suffered graft loss within 2 years of 12. Parry RA, Glaze SA, Archer BR. The AAPM/RSNA physics
delivery. This risk was highest in women who conceived tutorial for residents. Typical patient radiation doses in
diagnostic radiology. Radiographics 1999;19:1289-1302.
within 6 months of their transplant.72
13. Wildberger JE, Vorwerk D, Winograd R, Stargardt A,
Experts recommend that pregnancy be postponed for
Busch N, Günther RW. New TIPS placement in pregnancy
at least 1 year post-transplant, when graft function is in recurrent esophageal varices hemorrhage-assessment
optimal on lower doses of immunosuppression and the of fetal radiation exposure [in German]. Rofo 1998;169:
risks of acute rejection and opportunistic infection are 429-431.
lower.75 Until then, contraception is advised, preferably 14. Savage C, Patel J, Lepe MR, Lazarre CH, Rees CR. Tran-
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