C H A P T E R

21

The liver in pregnancy

Michelle Lai, MD, MPH n Jacqueline L. Wolf, MD

KEY POINTS
1 Liver diseases in pregnancy include those that occur exclusively in pregnancy and those that
occur coincidentally in pregnancy or are present at the time of pregnancy.
2 Normal physiologic changes in pregnancy may alter the normal range for liver biochemical tests
(Table 21.1).
3 Important clues to the diagnosis are found in the history and physical examination.
4 Laboratory findings with particular importance to diagnosing liver disease in pregnancy are
proteinuria, hyperuricemia, elevated serum bile acid levels, thrombocytopenia, and anemia.
5 Abdominal ultrasonography may be helpful. Liver biopsy is rarely necessary, but it may be
diagnostic for acute fatty liver of pregnancy.
6 Timely diagnosis and hence appropriate treatment are critical to outcome. Delivery of the infant
is indicated for severe pre-eclampsia, eclampsia, acute fatty liver of pregnancy, and HELLP
(hemolysis, elevated liver tests, low platelets) syndrome, and immunization is indicated in infants
born to mothers with hepatitis B.
7 Although women with chronic liver disease may have more trouble conceiving, pregnancy has
no adverse effect on the progression of liver disease.

Overview
1. L
 iver diseases in pregnancy consist of the following:
n Those that occur exclusively during pregnancy
n T
 hose that occur coincidentally in pregnancy or are present at the time of pregnancy
2. The approach to the pregnant patient with abnormal liver biochemical test levels should
include thorough history taking and physical examination.
3. Liver disorders unique to pregnancy include the following:
n Hyperemesis gravidarum
n Intrahepatic cholestasis of pregnancy (IHCP)
n Acute fatty liver of pregnancy (AFLP)
n Pre-eclampsia/eclampsia
n HELLP (hemolysis, elevated liver tests, low platelets) syndrome
n Hepatic rupture
4. Liver disorders that occur coincidentally with pregnancy include viral hepatitis, BuddChiari
syndrome, cholelithiasis, and cholecystitis, Wilson disease, and autoimmune hepatitis
(AIH).
282

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TABLE 21.1 n Changes in liver biochemical test levels in normal pregnancy

Test

Change

Trimester of maximum change

Albumin

10%60%

Second

Gamma globulins

None to slight

Third

Fibrinogen

50%

Second

Transferrin

Third

Bilirubin

None

Alkaline phosphatase

Two- to fourfold

Third

AST

None

ALT

None

Cholesterol

Twofold

Third

, increase; , decrease; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

From Olans LB, Wolf JL. Liver disease in pregnancy. In: Carlson KJ, Eisenstat SA, eds. The Primary Care of Women,
2nd edn. St. Louis: MosbyYear Book; 2003:531539.

Approach to the Pregnant Patient

HISTORY
1. R
 elation to time of gestation (Table 21.2)
2. Pruritus
n Characteristic of IHCP
n Affects palms of hands and soles of feet initially, then elsewhere
3. Nausea and vomiting
n Occurs in 50% to 90% of all pregnancies
n Key feature of hyperemesis gravidarum
n W hen associated with headache and peripheral edema may indicate pre-eclampsia
n W hen associated in late pregnancy with abdominal pain, with or without hypotension, may
indicate hepatic rupture
4. Abdominal pain
n The location, character, duration, and factors that induce or relieve pain should be noted
n Right upper quadrant or midabdominal pain in late pregnancy may have ominous implications. Consider cholelithiasis, AFLP, hepatic rupture, and pre-eclampsia
5. Jaundice
n Note the relation of jaundice to the onset of other symptoms
n Jaundice follows pruritus in IHCP
6. Systemic symptoms
n Headache, peripheral edema, foamy urine, oliguria, and neurologic symptoms may occur in
pre-eclampsia
n Fever, malaise, and a change in stools may indicate infection such as hepatitis
n Easy bruisability may occur in HELLP syndrome
n Weight loss or gain or dizziness may occur with liver disease in pregnancy
7. History of past pregnancy and birth control use
n Note the time of onset of symptoms in previous pregnancies

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TABLE 21.2 n Differential diagnosis of elevated serum aminotransferase levels

and/or jaundice according to trimester of pregnancy
Trimester

Differential diagnosis

First

Hyperemesis gravidarum
Gallstones
Viral hepatitis
Drug-induced hepatitis
Intrahepatic cholestasis of pregnancy*

Second

Intrahepatic cholestasis of pregnancy

Gallstones
Viral hepatitis
Drug-induced hepatitis
Pre-eclampsia/eclampsia*
HELLP syndrome*

Third

Intrahepatic cholestasis of pregnancy

Pre-eclampsia/eclampsia
HELLP syndrome
Acute fatty liver of pregnancy
Hepatic rupture
Gallstones
Viral hepatitis
Drug-induced hepatitis

*Uncommon in this trimester.

HELLP, hemolysis, elevated liver tests, low platelets.
From Olans LB, Wolf J. Liver disease in pregnancy. In: Carlson KJ, Eisenstat SA, eds. The Primary Care of Women, 2nd
edn. St. Louis: MosbyYear Book; 2003:531539.

n Note the outcome of previous pregnancies

n A history of jaundice with previous birth control use is a risk factor for IHCP
8. R
 elevant pregnancy-related factors
n Multiple versus single gestation (Table 21.3)
n P
 rimiparous versus multiparous
n Medications

PHYSICAL EXAMINATION

 ormal findings that occur in pregnancy include spider telangiectasias and palmar erythema
N
Abnormal findings that occur with liver disease in pregnancy are jaundice, hepatomegaly, hepatic tenderness, friction rub or bruit, splenomegaly, Murphys sign, and diffuse
excoriations
n Systemic findings that may occur with liver disease in pregnancy are hypertension, orthostatic hypotension, peripheral edema, asterixis, hyperreflexia or other neurologic findings,
ecchymoses, and petechiae
n

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TABLE 21.3 n Rates of recurrence of pregnancy-associated liver disease in subsequent

pregnancies
Disease

Rate of recurrence

Intrahepatic cholestasis of pregnancy

40%70%

HELLP syndrome

4%27%

Acute fatty liver of pregnancy

20%70% in carriers of LCHAD mutation

Pre-eclampsia

2%43%

HELLP, hemolysis, elevated liver tests, low platelets; LCHAD, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase.

DIAGNOSTIC TESTS

The only major restrictions compared with the nongravid state are radiation and gadolinium
exposures
n Routine blood chemistry tests and a blood count are helpful. Uric acid levels are often
elevated in AFLP and may be elevated in pre-eclampsia
n Hemolysis and a low platelet count occur in HELLP syndrome. Disseminated intravascular coagulation (DIC) with a low fibrinogen level, increased fibrin split products, and an
elevated partial thromboplastin time may also occur in HELLP syndrome
n Elevations in the serum bile acid level occur before or are concurrent with the onset of IHCP
n Amylase and lipase levels should be checked in a patient with abdominal pain
n If viral hepatitis is suspected, serologic tests should be checked for the following: hepatitis A
(immunoglobulin M [IgM] and IgG antibody to hepatitis A virus [anti-HAV]); hepatitis B
(surface antigen [HBsAg] and antibody, core antibody, and, if HBsAg is positive, e antigen and
antibody); hepatitis C (antibody to hepatitis C virus [anti-HCV] and possibly HCV RNA). If
the patient has traveled to an endemic area, consider testing for hepatitis E (see Chapter 3)
n The benefits of endoscopy, including endoscopic retrograde cholangiopancreatography (ERCP),
should be weighed against the risks in pregnancy. Risks include fetal hypoxia from sedative
drugs or positioning. Sedative medications and radiation exposure should be minimized
n Abdominal ultrasonography is safe and useful
n Although abdominal computed tomography (CT) is more sensitive than abdominal ultrasonography for hepatic rupture and may yield more information, radiation exposure and the
stability of the patient should be considered in decisions about the choice of imaging test
n Angiography is rarely needed for hepatic rupture
n Magnetic resonance imaging (MRI) is probably safe, although this is not conclusively
proven. Gadolinium should not be used in pregnancy

Liver Disorders Unique to Pregnancy

See Table 21.4 for the laboratory findings associated with these disorders.

HYPEREMESIS GRAVIDARUM
1. Definition: Intractable vomiting in pregnancy that leads to dehydration, electrolyte disturbances, weight loss of 5% or more, and nutritional deficiencies.

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TABLE 21.4 n Results of laboratory tests in pregnancy-associated liver disease

Aminotrans- Bile
ferases*
acids*

Bilirubin

Alkaline
Uric
phosphatase* acid

PT/
Platelets PTT

Urine
protein

Hyperemesis 12
gravidarum

Normal

<5 mg/dL

12

Normal Normal

Normal Normal

Intrahepatic 14
cholestasis
of pregnancy

30100

<5 mg/dL

12

Normal Normal

Normal Normal

Acute fatty
liver of
pregnancy

15

Normal

<10 mg/
dL

12

Preeclampsia/
eclampsia

1100

Normal

<5 mg/dL

12

HELLP
syndrome

1100

Normal

<5 mg/dL

12

Hepatic
rupture

2100

Normal

Normal

Normal

*Results

are indicated as times the upper limit of normal.

PT, prothrombin time; PTT, partial thromboplastin time.

2. Epidemiology
n Most common in first trimester
n I ncidence: 0.3% to 2%
n Risk factors: age less than 25 years, preexisting diabetes mellitus, hyperthyroidism, overweight, primiparity, multiple gestations, prior history of hyperemesis gravidarum, and
molar pregnancy
3. Etiology: Thought to be multifactorial involving immunologic, hormonal, and psychological
factors.
4. Clinical and laboratory features
n Liver biochemical test abnormalities in 50% of patients
n Serum alanine aminotransferase (ALT) elevations generally 1- to 3-fold but may reach
20 times the upper limit of normal
n Occasional serum alkaline phosphatase and bilirubin elevations
n Concomitant hyperthyroidism in 50%
5. Diagnosis: clinical.
6. Treatment: Supportive with rehydration, vitamin supplementation, small and frequent
low-fat meals, and antiemetics (e.g., metoclopramide 10 to 30 mg orally four times daily or
10mg intramuscularly or intravenously every 4 to 6 hours or ondansetron 4 to 8 mg orally
every 8hours or 8 mg intravenously every 4 to 8 hours); total parenteral nutrition possibly
needed in severe cases.
7. Outcome: Observed lower rate of spontaneous abortion, but also lower birth weights and
increased incidence of congenital hip dysplasia in infants.

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INTRAHEPATIC CHOLESTASIS OF PREGNANCY

1. Definition: Reversible form of cholestasis characterized by intense pruritus in pregnancy,
elevated serum ALT and fasting serum bile acid levels, and spontaneous relief of symptoms
and signs within 4 to 6 weeks after delivery.
2. Epidemiology
n More common in late second or third trimester, but can occur in any trimester
n Incidence: 0.01% to 2%, with higher incidence in South Asian, South American, and Scandinavian populations; highest incidence (up to 27%) in Chilean Araucanian Indians
n Risk factors: progesterone use in pregnancy, past medical or family history of IHCP, and
personal history of intrahepatic cholestasis resulting from oral contraceptive or estrogen
ingestion
3. Etiology: Multifactorial, including genetic, hormonal, and environmental factors. Theories
include the following:
n Gene variants of hepatocanalicular transport proteins (ATP-binding cassette [ABC] transporter B4 = phosphatidylcholine floppase, ABC transporter B11 = bile salt export pump,
ABC transporter C2 = conjugated organic anion transporter, ATP8B1 = FIC1) and their
regulators (e.g., the bile acid sensor farnesoid X receptor, FXR) found in some patients;
incidence of IHCP increased in mothers of children with progressive familial intrahepatic
cholestasis (PFIC) type 3
n Inherited sensitivity to estrogens
n Association with low serum selenium levels; decreasing incidence in Chilean population
linked to increases in serum selenium levels
4. Clinical and laboratory features
n Jaundice in 25% of patients and following the onset of pruritus
n Elevated serum aminotransferase levels (up to four-fold), serum bile acid levels (30100x),
mono- or disulfated progesterone metabolites (particularly 3- and 5-alpha isomers), and
occasionally serum cholesterol and triglyceride levels
n Liver biopsy (not usually indicated) specimens reveal cholestasis with minimal hepatocellular necrosis
5. Diagnosis: clinical.
6. Treatment
n Symptom management: sleeping in a cold room, topical alcohol and camphor menthol
lotion, cholestyramine, and ursodeoxycholic acid (UDCA) 10 to 15 mg/kg body weight
n Close monitoring and early delivery of fetus
7. Outcome
n Mothers do well
n Increased risk of preterm delivery (19% to 60%); meconium staining of amniotic fluid
(24%); fetal bradycardia (14%); fetal distress (22% to 41%); fetal loss (0.4% on average; 4.1%
in severe cases), particularly when fasting serum bile acid levels are greater than 40 mol/L

ACUTE FATTY LIVER OF PREGNANCY

1. Definition: A rare life-threatening complication of pregnancy manifested by microvesicular
fatty infiltration of the liver and progressive liver failure
2. Epidemiology
n Onset in third trimester (usually after 35th week, but as early as 26 weeks; can occur in the
immediate postpartum period)

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n Incidence: 1 in 10,000 to 15,000 deliveries

n Risk factors: primiparity, multiple gestations, and male fetuses
3. Etiology
n Defects in mitochondrial fatty acid beta-oxidation in the mother, caused by fetal deficiency in the long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) enzyme.
LCHAD is part of mitochondrial trifunctional protein (MTP) and catalyzes the third step
in -oxidation of long-chain fatty acids. Up to 70% of cases result from homozygous longchain LCHAD deficiency in the fetus, with a heterozygous mother
n Abnormal concentrations of fetal long-chain fatty acids enter the maternal circulation and
have toxic effects in the mother
n G1528C (E474Q mutation) in the MTP causes LCHAD deficiency
n A second fatty-acid oxidation defecthepatic carnitine palmitoyl transferase I deficiencyis also associated with maternal AFLP
n Nutritional factors, alterations in lipoprotein synthesis, and enzyme deficiencies in the
mitochondrial urea cycle are other proposed pathogenic factors
4. Clinical and laboratory features
n Symptoms include headache, fatigue, malaise, nausea, vomiting, and abdominal pain
n Jaundice may follow a prodrome
n Progressive liver failure may occur, with coagulopathy, encephalopathy, or renal failure
n 50% of patients have signs of pre-eclampsia
n Serum aminotransferase levels are elevated (usually less than 500 U/L)
n Serum alkaline phosphatase and bilirubin levels are mildly to moderately elevated
n Hyperuricemia occurs in 80%
5. Diagnosis
n Abdominal ultrasonography and CT are inconsistent in detecting fatty infiltration
n If the disorder and a risk to delivering a premature infant are clinically suspected, then
emergency liver biopsy should be done. The frozen liver biopsy specimen shows a micro
vesicular fatty infiltrate of liver detectable by Oil-Red-O stain
6. Treatment
n Rapid delivery of the infant is critical. Most women improve, but fulminant hepatic failure
may occur, and treatment with liver transplantation has been reported
n Screening for a fatty acid oxidation defect is indicated in affected patients
7. Outcome
n Maternal mortality rate of 8% to 18%
n Fetal mortality rate of 18% to 23%

PRE-ECLAMPSIA/ECLAMPSIA
1. Definition: The triad of hypertension, proteinuria, and edema. Pre-eclampsia is a multisystem disease with renal, hematologic, hepatic, central nervous system, and fetal-placental
involvement. Eclampsia is the presence of convulsions or coma in addition to the symptoms
and signs of pre-eclampsia.
2. Epidemiology
n More common in late second or third trimester, but may occur postpartum
n Incidence: pre-eclampsia in 5% to 7% of pregnancies, eclampsia in 0.1% to 0.2%
n Risk factors: insulin resistance, obesity, extremes of maternal age (age less than 20 or
more than 45 years), primiparity, infection, family history of pre-eclampsia/eclampsia,
multiple gestations, hydatidiform mole, fetal hydrops, polyhydramnios, and inadequate
prenatal care

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289

3. Etiology: Unknown. Proposed mechanisms include vasospasm, abnormal placental development, abnormal endothelial reactivity, activation of coagulation, and decreased nitric oxide
synthesis. Levels of fms-like tyrosine kinase 1 (sFlt1; also known as soluble vascular endothelial growth factor) are high, and up-regulation of placental endoglin occurs. A mutation in
the gene encoding STOX1 transcription factor has been proposed to cause susceptibility, but
data are still not clear.
4. Clinical and laboratory features
a. Hypertension

n Mild pre-eclampsia: blood pressure 140/90 mm Hg or higher but lower than 160/
110 mm Hg

n Severe pre-eclampsia: blood pressure 160/110 mm Hg or higher
b. Convulsions or coma in eclampsia
c. Headaches, visual changes, abdominal pain, heart failure, respiratory distress, and oliguria
are possible in severe disease
5. Diagnosis
n Clinical features suggest the diagnosis
n Serum aminotransferase levels are elevated in 90% of patients with eclampsia, 50% with
severe pre-eclampsia, and 24% with mild pre-eclampsia
n Serum aminotransferase levels are elevated 5 to 100 times, with modest increases in serum
bilirubin levels (up to 5 mg/dL)
n Thrombocytopenia and microangiopathic hemolytic anemia may occur
n Liver biopsy specimens, if available, may demonstrate periportal deposition of fibrin and
fibrinogen associated with hemorrhage, with or without necrosis. In some cases, micro
vesicular fatty infiltration is seen, suggesting overlap with AFLP
6. Treatment
n Delivery of the infant is the preferred treatment of eclampsia and near-term pre-eclampsia.
Management remote from term is controversial but may include bed rest, antihypertensive
therapy, and magnesium sulfate
n The incidence of pre-eclampsia is not reduced with nutritional supplementation, including
calcium, or with low-dose aspirin
7. Outcome
n Morbidity and mortality rates correlate with severity
n The most common cause of death is cerebral involvement
n The risk of hepatic rupture and HELLP syndrome is increased
n Risks to the fetus include prematurity, fetal growth retardation, abruptio placentae, and low
birth weight
n Increased perinatal morbidity and mortality in the mother and fetus correlate with the
severity of pre-eclampsia, preterm delivery, multiple gestations, and preexisting maternal
medical conditions
n Postdelivery liver biochemical test abnormalities generally resolve

HELLP SYNDROME
1. Definition: Hemolysis, elevated liver tests, and low platelets
2. Epidemiology
n More common in the third trimester (usually at or after 32 weeks but as early as 25 weeks);
15% to 25% of cases occur postpartum (most within 2 days of delivery but can be later)
n Incidence: 0.2% to 0.6% of all pregnancies; 4% to 12% in women with pre-eclampsia/
eclampsia

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HANDBOOK OF LIVER DISEASE

n May occur in patients with AFLP or de novo

n Risk factors: white race, multiparity, age greater than 25 years
3. Etiology: Unknown. Pathogenic factors may include abnormal vascular tone, vasospasm,
coagulation, and LCHAD deficiency in the infant.
4. Clinical and laboratory features
a. Epigastric pain (65%), nausea or vomiting (30%), headache (31%), hypertension (85%),
visual changes, weight gain, edema
b. Microangiopathic hemolytic anemia with increased serum lactate dehydrogenase and
indirect bilirubin levels and decreased haptoglobin levels
c. Elevated serum aminotransferase levels (from mild to 10 to 100 times)
d. Decreased platelet count (may be lower than 10,000/mm3)
e. Proteinuria
f. Positive D-dimer test is possibly predictive of HELLP syndrome in pre-eclamptic
patients
g. Postpartum resolution of the following:

n Abnormal platelets, usually within the first 5 days

n Hypertension or proteinuria, if present, up to 3 months
5. Diagnosis: Presence of hemolytic anemia, elevated serum aminotransferase levels, and low
platelets
6. Treatment
n Delivery of the infant is indicated in the presence of maternal or fetal distress or a rapidly
dropping platelet count. Coexisting pre-eclampsia or AFLP may dictate early delivery
n Hospitalization is indicated for treatment of hypertension, stabilization of DIC, seizure
prophylaxis, and fetal monitoring
n Corticosteroids are recommended if gestation is less than 34 weeks, to improve fetal lung
maturity, but the use of corticosteroids to improve postpartum maternal outcome remains
experimental
7. Outcome
n Maternal mortality rate of 1%
n Perinatal infant mortality rate of 7% to 22%
n Complications: maternal DIC, abruptio placentae, eclampsia, ascites, subcapsular hematoma, hepatic rupture, wound hematoma, and renal, cardiopulmonary, or hepatic failure
n Increased risk of infant prematurity, intrauterine growth retardation, DIC, and
thrombocytopenia

HEPATIC RUPTURE
1. Definition: Rupture of the hepatic capsule
2. Epidemiology
n Occurs in 1 in 45,000 to 1 in 250,0000 deliveries
n Incidence: 0.9% to 2% in patients with HELLP syndrome
n Most cases are associated with pre-eclampsia, eclampsia, AFLP, or HELLP
n Also occurs with hepatocellular carcinoma, adenoma, hemangioma, and hepatic
abscess
n Recurrence is rare
3. Etiology: In HELLP and pre-eclampsia/eclampsia, hepatic rupture is usually preceded by
severe intraparenchymal hepatic hemorrhage that progresses to subcapsular hematoma in
patients with severe thrombocytopenia

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291

4. Clinical and laboratory features

n Usually occurs in last trimester or occasionally within 24 hours of delivery
n T
 ypical symptoms: sudden onset of abdominal pain, nausea, and vomiting followed by
abdominal distention and hypovolemic shock
n Usually involves the right lobe of liver but may occur in either or both lobes
n Serum aminotransferase levels are increased 2 to 100 times and associated with anemia and
consumptive thrombocytopenia, with or without DIC
5. Diagnosis: Abdominal ultrasonography, CT, MRI, and angiography are useful.
6. Treatment
n Early recognition leads to prompt delivery and surgical or radiologic intervention
n Surgical therapies include application of direct pressure, evacuation, packing or hemostatic
wrapping, topical hemostatic agents, oversewing lacerations, hepatic artery ligation, partial
hepatectomy, and liver transplantation
n Angiographic embolization is an alternative option
7. Outcome
n Maternal mortality rate of 50% (caused by hemorrhagic shock, hepatic failure, cerebral
hemorrhage)
n Fetal mortality rate of 10% to 60% (caused by placental rupture, prematurity, intrauterine
asphyxia)

Pregnancy in Patients with Chronic Liver Disease

OVERVIEW

n
n

 atients have more difficulty conceiving

P
Pregnancy has no adverse effect on the progression of liver disease

CIRRHOSIS (see also Chapters 9 and 10)

1. The risk of bleeding esophageal varices is increased (more commonly in the second and
third trimesters).
a. Etiology: expanded maternal blood volume and fetal compression of maternal inferior
vena cava and collateral vasculature
b. Risk of esophageal bleeding

n Cirrhosis: 18% to 32%

n Known portal hypertension: 50%

n Preexisting varices: 78%
c. Treatment

n Treatment of variceal bleeding is the same as in a nongravid patient and includes band
ligation or sclerotherapy and, if necessary, transjugular intrahepatic portosystemic shunt
placement or portosystemic shunt surgery

n Screening endoscopy is recommended in patients with cirrhosis before pregnancy or
early in the second trimester

n Areas of controversy include the delivery method (elective caesarian section to avoid
Valsalva maneuver during vaginal birth?) and primary prophylaxis of variceal bleeding
with banding or beta blockers
d. Outcome: maternal mortality rate of 18% to 50%

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2. O
 ther complications that occur in pregnant patients with cirrhosis are hepatic decompensation (24%), splenic artery aneurysm rupture (2.6%), postpartum uterine hemorrhage
(7%to10%), spontaneous abortion (30% to 40%), prematurity (25%), fetal stillbirth (13%),
and neonatal mortality (4.8%).
3. Medications prescribed to manage the complications of cirrhosis should be reviewed carefully
for safety in pregnancy (e.g., furosemide, spironolactone, beta blockers, fluoroquinolones, and
rifaximin are pregnancy category C drugs according to the US Food and Drug Administration [FDA]; octreotide and lactulose are FDA category B drugs).

WILSON DISEASE (see also Chapter 17)

1. Impact on pregnancy: The disease may decrease fertility and increases the rate of recurrent
spontaneous abortions.
2. Treatment: Pregnant patients should continue anticopper therapy (penicillamine, trientine,
zinc) during pregnancy because serious adverse maternal outcomes, including death, can
result if anticopper therapy is stopped.
n Data in pregnancy are limited for all three anticopper drugs
n Penicillamine is potentially teratogenic in animals and humans. Trientine is teratogenic in
animals
n Penicillamine is considered safe during pregnancy at relatively low doses (0.25 to 0.5 g/day).
Trientine has appeared safe and effective based on limited data. Because of the potential
teratogenic effects of penicillamine and trientine, zinc is recommended during pregnancy
by some authorities
3. Special considerations: Genetic counseling should be offered.

AUTOIMMUNE HEPATITIS (see also Chapter 5)

1. I mpact on pregnancy
n The natural history of AIH is variable during pregnancy
n S
 uccessful pregnancies can occur in women with well-controlled AIH
n The rate of fetal loss is 19% to 24% (no different from that for other chronic diseases)
2. Treatment
n Cessation of therapy during pregnancy is associated with relapse of disease
n The use of azathioprine is controversial, but reports of experience in patients taking azathioprine following organ transplants or for inflammatory bowel disease have described
good outcomes for mothers and infants
n Patients should be monitored closely for flare-ups of AIH during pregnancy and in the
early postpartum period
3. Special considerations: Women of childbearing age with AIH should be counseled to consider pregnancy only if the disease is well-controlled.

PRIMARY BILIARY CIRRHOSIS (see also Chapter 14)

1. I mpact on pregnancy
n Some data suggest that women with primary biliary cirrhosis may be able to have normal
pregnancies
n Antimitochondrial antibody titers and serum alkaline phosphatase, ALT, bile acid, bilirubin, and IgG and IgM levels improve during pregnancy
n The risk of postpartum flare-up exists
2. Treatment: Continue UDCA, which is safe in pregnancy.

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PRIMARY SCLEROSING CHOLANGITIS (see also Chapter 33)

1. Impact on pregnancy: The natural history in pregnancy is unknown.
2. Treatment: Continue UDCA, which is safe in pregnancy, improves maternal symptoms, and
decreases the risk of fetal complications.

Viral Hepatitis and Herpes Simplex Virus Infections

inPregnant Women (see also Chapters 3 and 4)
OVERVIEW

n
n

 f all the viral hepatitides, only the course of hepatitis E is affected by pregnancy
O
V iral hepatitis may occur throughout pregnancy

HEPATITIS A
1. E
 pidemiology
n This occurs in as many as 1 in 1000 pregnancies in the United States
n P
 erinatal transmission is rare
n Acute infection only occurs (no chronic disease)
2. Treatment
n The course and management are unaffected by pregnancy
n Prevention with immune globulin in an exposed mother is safe for mother and fetus
n For infants of mothers infectious at or soon after delivery, the dose of immune globulin is
0.02 mL/kg intramuscularly (vaccination against HAV can be considered at age 2 years)

HEPATITIS B
1. E
 pidemiology
n Acute disease occurs in 2 of 1000 pregnancies
n C
 hronic disease occurs in 5 to 15 per 1000 pregnancies in the United States
2. Transmission to the infant may occur without immunoprophylaxis
n When the mother is HBsAg positive and HBeAg negative, the chronic infection rate is 40%
n W hen the mother is HBsAg and HBeAg positive, the chronic infection rate is 90%
n The risk of transmission to the infant correlates with the mothers serum HBV DNA level
n Following infection of the mother in the first trimester, 10% of neonates become HBsAg
positive
n Following infection of the mother in the third trimester, 80% to 90% of neonates become
HBsAg positive
n Transmission to the neonate is usually perinatal
3. Treatment: A combination of active (HBV vaccine) and passive (hepatitis B immune globulin) immunotherapy of the newborn is 85% to 95% effective in decreasing perinatal transmission to less than 10% (Table 21.5).

HEPATITIS C
1. E
 pidemiology
n The overall rate of mother-to-infant transmission is generally low (4% to 10%). Higher
rates of vertical transmission are reported when maternal viral titers are high (36% when

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HANDBOOK OF LIVER DISEASE

TABLE 21.5 n Treatment of neonates born to mothers with hepatitis B

Treatment

Age of administration to infant based on hepatitis B surface

antigen status of mother
+

Unknown

Hepatitis B immune globulin

100 IU
(0.5 mL IM)

12 hr

12 hr

Not administered

Hepatitis B vaccine, first

dose 5.0 g
(0.5 mL IM)

12 hr

12 hr

1 wk

Recombivax HB 5 g
(0.5 mL)

1 mo

12 mo

12 mo

Engerix-B 10 g (0.5 mL)

6 mo

6 mo

618 mo

Subsequent hepatitis
B vaccine doses:

IM, intramuscularly.
Adapted from American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 86: viral hepatitis in
pregnancy. Obstet Gynecol 2007; 110:941956.

the maternal serum HCV RNA level is higher than 1010 copies/mL) and with human
immunodeficiency virus coinfection
n HCV infection does not adversely affect pregnancy
n The course of HCV infection is not affected by pregnancy
2. Treatment
n No effective prevention is available for infants
n Treatment of chronic hepatitis C with pegylated interferon and ribavirin is contraindicated in pregnancy because ribavirin is teratogenic

HEPATITIS D

n
n

 are instances of vertical transmission have been reported

R
Hepatitis B infection should be controlled to prevent the spread of hepatitis D virus

HEPATITIS E

J aundice is nine times more common in pregnant than nonpregnant women with hepatitis E
Hepatitis E is the leading cause of fulminant hepatic failure in pregnancy
n The disease is more severe in the third trimester than at other times, with a maternal mortality rate of up to 27%, compared with 0.5% to 4% in nonpregnant patients. In patients
with fulminant hepatic failure, the mortality rate is 65% in pregnant women compared with
23% in nonpregnant women
n The risk of abortion and intrauterine death is 12%
n Vertical transmission occurs in up to 33%
n No specific therapy during pregnancy exists
n

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HERPES SIMPLEX VIRUS INFECTIONS

Disseminated herpes simplex virus (HSV) infection during pregnancy is rare, but it has
been reported, usually in the late second or third trimester
n The clinical presentation can include fulminant hepatitis (see Chapter 2)
n Fever, nausea, vomiting, abdominal pain, leukopenia, thrombocytopenia, coagulopathy, and
markedly elevated serum aminotransferase levels are often present
n Liver biopsy specimens show extensive necrosis, often hemorrhagic, with typical intranuclear viral inclusion particles
n Hepatic necrosis, DIC, hypotension, and death can occur rapidly if antiviral therapy is not
initiated promptly

BuddChiari Syndrome (see also Chapter 19)

1. Definition: Thrombosis of one or more of the three hepatic veins
2. Epidemiology
n 20% of cases are associated with pregnancy and oral contraceptive use
n Postpartum onset is rare and is associated with a poor prognosis
3. Etiology
n A hypercoagulable state (e.g., factor V Leiden mutation) may play a role
n It may be associated with antiphospholipid antibodies, pre-eclampsia, and ingestion of
herbal teas
4. Clinical features
n Symptoms are usually acute in pregnancy
n Features include abdominal pain, hepatomegaly, and ascites
5. Diagnosis
n MRI, ultrasonography, and liver biopsy are used
n If possible, venography or angiography should be avoided until after pregnancy
6. Treatment: Same as in nonpregnant patients
7. Outcome: With acute onset in pregnancy, the maternal mortality rate is as high as 70%.

Cholelithiasis and Cholecystitis in Pregnant Women

(see also Chapter 32)
1. E
 pidemiology
n Symptomatic onset is most common in the second and third trimesters
n T
 he frequency in pregnancy is 18% to 19% in multiparous women and 7% to 8% in primiparous women. Symptomatic gallstones occur only in 0.1% to 0.3% of pregnancies
n Risk factors include increasing age, increasing frequency and number of pregnancies, obesity, high serum leptin levels, insulin resistance, and low high-density lipoprotein levels
n Frequency rates of new biliary sludge and gallstones in pregnancy are 14% and 2%, respectively,
at the end of the second trimester and 31% and 2%, respectively, 2 to 4 weeks postpartum
n Sludge disappears in 61% of patients at 3 months and in 96% at 12 months after delivery;
gallbladder stones disappear in 13% to 28% of women by 1 year
2. Etiology
n Increased estrogen levels lead to increased lithogenicity of bile in the second and third
trimesters (increased cholesterol secretion and supersaturation of bile)

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HANDBOOK OF LIVER DISEASE

Increased progesterone levels lead to larger gallbladder volume and decreased emptying
time
3. Clinical features
n Vomiting occurs in 32%, dyspepsia in 28%, and pruritus in 10%
n Biliary pain occurs in 29% with preexisting stones and in 4.7% with sludge but generally
does not occur in patients with new sludge or stones
4. Treatment
a. Conservative medical management with intravenous fluids, correction of electrolytes,
bowel rest, and broad-spectrum antibiotics is considered safe in pregnancy.
b. Laparoscopic cholecystectomy should be performed in the second trimester if medical
management fails or the patient has a relapse. Surgery should be avoided in the first trimester if possible.

n A questionable increase in spontaneous abortions occurs when surgery is performed in
the first trimester

n Surgery in the third trimester is associated with premature labor in 40% of cases
c. ERCP should be done for choledocholithiasis; it can be performed safely by shielding the
fetus from radiation exposure and minimizing fluoroscopy time.
FURTHER READING
Aggarwal R, Naik S. Epidemiology of hepatitis E: current status. J Gastroenterol Hepatol 2009; 24:14841493.
American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 86: viral hepatitis in
pregnancy. Obstet Gynecol 2007; 110:941956.
Badizadegan K, Wolf JL. Liver pathology in pregnancy. In: Odze RD, Goldblum JR, eds. Surgical Pathology of
the GI Tract, Liver, Biliary Tract, and Pancreas. Philadelphia: Saunders Elsevier; 2009:12311243.
Brewer GJ, Johnson VD, Dick RD, et al. Treatment of Wilsons disease with zinc XVII: treatment during
pregnancy. Hepatology 2000; 31:364370.
Date RS, Kaushal M, Ramesh A. A review of the management of gallstone disease and its complications in
pregnancy. Am J Surg 2008; 196:599608.
Fang CJ, Richards A, Liszewski MK, et al. Advances in understanding of pathogenesis of aHUS and HELLP.
Br J Haematol 2008; 143:336348.
Glantz A, Marschall H-U, Mattsson L-. Intrahepatic cholestasis of pregnancy: relationships between bile
acid levels and fetal complication rates. Hepatology 2004; 40:467474.
Indolfi G, Resti M. Perinatal transmission of hepatitis C virus infection. J Med Virol 2009; 81:836843.
Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in
intrahepatic cholestasis of pregnancy. Gastroenterology 2005; 129:894901.
Reck T, Bussenius-Kammerer M, Ott R, et al. Surgical treatment of HELLP syndromeassociated liver
rupture: an update. Eur J Obstet Gynecol Reprod Biol 2001; 99:5765.
Schramm C, Herkel J, Beuers U, et al. Pregnancy in autoimmune hepatitis: outcome and risk factors. Am J
Gastroenterol 2006; 101:556560.
Tan J, Surti B, Saab S. Pregnancy and cirrhosis. Liver Transpl 2008; 14:10811091.
Terrabuio DR, Abrantes-Lemos CP, Carrilho FJ, Canado EL. Follow-up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes. J Clin Gastroenterol 2009;
43:350356.
United States Preventive Services Task Force: Screening for hepatitis B virus infection in pregnancy: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med 2009; 150:869873.
Urato AC. Maternal and neonatal herpes simplex virus infections. N Engl J Med 2009; 361:2678;author reply
2679.