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Chapter 29
Liver Diseases in Pregnancy Search
Christian G. Stevoff and Andres T. Blei
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Christian G. Stevoff, MD
Postdoctoral Fellow, Department of Gastroenterology, Northwestern University Medical School, Chicago, Illinois (Vol 3, Chap 29)
Andres T. Blei, MD
Professor Medicine and Surgery, Northwestern University Medical School, Chicago, Illinois (Vol 3, Chap 29)
INTRODUCTION
THE LIVER DURING NORMAL PREGNANCY
PREEXISTENT LIVER DISEASES IN PREGNANCY
LIVER DISEASES DEVELOPING DURING PREGNANCY
PROBLEM-ORIENTED APPROACH
REFERENCES
INTRODUCTION
Liver diseases in pregnancy encompass a diverse range of problems. Some of these disorders are
unique to the gestational state, whereas others may reflect a preexisting condition that has been
unmasked or exacerbated by pregnancy. Knowledge of the spectrum of disease is important because
some of these entities require specific or urgent management. Because not all changes to the liver
during pregnancy are pathologic, familiarity with interpretation of liver function tests is necessary to
direct a proper workup of abnormalities, especially those found incidentally on automated biochemical
screening. The goals of this chapter thus encompass discussion of physiologic hepatic changes
associated with the pregnant state, preexistent liver disease in pregnancy, liver diseases arising during
pregnancy, and a problem-oriented approach to diagnosis and treatment. Several reviews have been
published recently.1,2
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There is a 40% increase in blood volume in pregnancy, which is maximal in the third trimester. Cardiac
output increases until the second trimester and then may decrease or plateau during the third
trimester. Despite these systemic hemodynamic changes in pregnancy, absolute hepatic blood flow is
unchanged. This relative decrease in hepatic blood flow is an intriguing observation in view of the
generalized hyperdynamic state of pregnancy.11 This relative reduction may impair the clearance of
substances requiring adequate hepatic perfusion.
Most liver “function” tests detected on automated panels do not truly evaluate a specific hepatic
function. Even those that qualify as such do so partially, since other factors may influence their serum
concentrations. Bilirubin levels may reflect liver uptake and metabolic transformation. Serum albumin
may reflect its synthetic function but also may be related to nutrition. Serum transaminases, alkaline
phosphatase (AP), and γ-glutamyl transferase (GGT) are markers of hepatic injury. Furthermore, the
source for an elevated aspartate transaminase or lactate dehydrogenase may reside in other tissues,
such as skeletal muscle.
A recent series comparing liver test results of 103 pregnant patients with 103 control subjects12
showed differences in liver chemistries during pregnancy. AP was significantly higher and also above the
normal range in the third trimester. This represents AP of placental, not canalicular, origin. Similarly,
alanine transaminase and 5%-nucleotidase were mildly elevated but still within the normal range
compared with that of control subjects. Aspartate transaminase and total bile acids were not
significantly different from those of control subjects. Conversely, total and indirect bilirubin were lower
in all trimesters, and direct bilirubin and GGT were lower in the second and third trimesters (Table 1).
Test Comment
Hepatic function
Bilirubin Normal; urine bilirubin may be positivie in the absence of jaundice
Albumin Decreased because of hemodilution
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Test Comment
Serum bile acids Cholylglycine may rise, but not above upper limits of normal
Hepatocellular injury
Transaminases Unchanged
Cholestasis
Alkaline phosphatase Elevated in third trimester; placental origin
Leucine aminopeptidase Elevated in third trimester; placental origin
5'-nucleotidase Normal
γ-Glutamyl transferase May not rise with hepatic injury
A marked increase in serum triglycerides and, to a lesser extent, cholesterol also may be seen. This
effect is due in part to increased production of very low-density liproprotein in pregnancy.
Physical examination of the liver does not show major changes. The enlarging uterus often causes the
liver to shift upward under the rib cage, relatively hidden from examination. The liver is impalpable
during a normal pregnancy, and its detection should raise the possibility of underlying disease. Spider
angiomas and palmar erythema, classic cutaneous signs of liver disease, may be features of an
uncomplicated pregnancy and usually disappear after delivery.
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Cholestasis can be defined physiologically as a decrease in bile flow. The differential diagnosis of biliary
stasis, schematically divided into intrahepatic and extrahepatic types, progresses from biliary structures
within the liver (bile canaliculi, ductules, and ducts) to the extrahepatic tree. Both share symptoms,
such as jaundice and generalized pruritus. Right upper quadrant pain is more suggestive of
extrahepatic biliary obstruction. Elevations of AP, 5%-nucleotidase, or GGT are common. Bilirubin rises
according to the extent of impairment of bile flow. For the differential diagnosis of cholestasis in
pregnancy, ultrasonography is the test of choice. It should be remembered that dilation of the common
bile duct or intrahepatic ducts may be intermittent in the presence of an intraluminal stone.
Factors that favor the genesis of cholelithiasis in pregnancy have already been discussed. A review of
the literature suggests surgical management of cholecystitis should be reserved only for complicated or
unremitting cases, since more than 90% of acute cholecystitis in pregnancy resolves spontaneously.13
Opposite views have been expressed.14 Laparoscopic cholecystectomy is considered a safe option,
especially in the second trimester after organogenesis and before uterine enlargement, causing
difficulties with laparoscopic technique.15
Pregnancy may worsen features of underlying intrahepatic cholestatic disorders, a reflection of the
underlying hormonal changes discussed previously. Jaundice may worsen in primary biliary cirrhosis,
but this does not necessarily reflect a worsening of the overall disease process. The Dubin-Johnson
syndrome, one of the familial conjugated hyperbilirubinemia, may show exacerbation during the second
or third trimester.16 In one case of Alagille's syndrome, a familiar disorder of intrahepatic cholestasis,
worsening of pruritus, was noted in the third trimester.17 A common theme in all these disorders is
their clinical expression in the latter part of pregnancy, when the hormonal change that affects biliary
function is at its peak.
Chronic Hepatitis
The clinical course of chronic viral hepatitis usually remains stable in the pregnant state; however,
changes in viral replication occur. In the case of hepatitis C, recent studies document a decrease in
serum alanine transaminase and an increase in serum hepatitis C virus (HCV)-RNA during pregnancy,21
with a postpartum return to prepregnancy values. In the case of hepatitis B, changes in the immune
status after delivery could account for the subsidence of viral replication.22 Treatment with interferon is
contraindicated during pregnancy.
There is no consensus regarding the course of autoimmune hepatitis in pregnancy. Although some
reports have described a worsening of liver disease, others have described no change or even
improvement in histology and biochemistry.23 Steroid therapy may be continued safely. Azathioprine,
used at the low doses required for autoimmune hepatitis, can be continued. The risk of azathioprine-
induced teratogenesis is quite low at these doses, but a higher than normal fetal loss can be expected
in this disease.24
Wilson's disease is a rare genetic disorder of copper accumulation and toxicity, caused by a defect in an
enzyme that is part of the pathway of biliary copper excretion.25 In the absence of specific therapy,
patients have a relentless, deteriorating course. Copper accumulation in specific tissues such as liver,
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brain, cornea, and kidney is the basis for its symptomatology. The disease may first manifest during
pregnancy.26 A positive diagnosis may be difficult during this stage, since serum ceruloplasmin levels
(traditionally below normal in this disease) may rise as a nonspecific effect of pregnancy on plasma
proteins.27 Every effort should be made to exclude such a treatable disease, preferably with serum-free
copper or hepatic copper determination.25 Patients treated with D-penicillamine or trientene (copper
chelators) have carried their pregnancy to term successfully, although some evidence of prematurity
with penicillamine has been reported.26,28 Although it generally is recommended that these drugs be
discontinued when pregnancy is discovered in many other diseases, doing so in Wilson's disease may
lead to fulminant hepatic failure and death.25,29 Therefore, patients with Wilson's disease discovered to
be pregnant should continue therapy.
Although little is known about the course of α1-AT deficiency-related liver disease in pregnancy, there
are several cases of healthy offspring being carried to term. Occasionally, it is the lung disease that is
the limiting factor for healthy pregnancy.30,31
Another rare cause of chronic hepatitis is erythropoietic protoporphyria, a disorder that may cause
photosensitive cutaneous reactions and hepatic dysfunction. There have been reports of a lessening of
the severity of cutaneous reactions to light, possibly secondary to lower circulating erythrocyte
protoporphyrin burden in pregnancy.32,33 Little is known of the hepatic aspects of this disease in
pregnancy.
Cirrhosis/Portal Hypertension
In the United States, alcoholic cirrhosis is the most common type of cirrhosis encountered in general
practice. Women may have this disease develop after substantially less alcohol intake than men.34 It is
uncommon to encounter patients with decompensated cirrhosis who become pregnant, since
amenorrhea is a common occurrence. Alcohol itself disrupts reproductive function, as seen in
experimental animals.35 Women found to have alcoholic cirrhosis should be counseled as to the
dangers of fetal alcohol syndrome if they continue to consume alcohol through pregnancy.
Prenatal care is very important for the cirrhotic patient, as potential problems may be averted. The
frequency and severity of complications during pregnancy are related to the severity of the cirrhosis.36
Early termination of pregnancy should be considered if severe hepatic decompensation exists.37
However, pregnancy generally is considered safe in patients with well-compensated cirrhosis.36 If portal
hypertension is suspected clinically, upper endoscopy should be part of routine prenatal workup to
assess for the presence of esophageal varices. The absence of varices does not preclude development
later in pregnancy but makes their occurrence less likely. The role of prophylactic beta-adrenergic
blockers or endoscopic band ligation has not been studied systematically, although band ligation has
been used safely in bleeding pregnant patients.38 The patient should be aware that in the absence of
liver transplantation, a mother with severe cirrhosis has a very poor chance of raising the child to
adulthood.39 If transplantation is to be undertaken, pregnancy should be delayed until after transplant.
The medication regimen used for the complications of cirrhosis should be tailored according to the
patient. Spironolactone, shown to be associated with fetal genital malformations, should be
discontinued. Beta-adrenergic blockers have been associated with fetal growth restriction40 but may be
worth the risks in women with large esophageal varices with red wales, findings that increase the
likelihood of hemorrhage.
Splenic artery rupture occurs in 2.6% of pregnant patients with cirrhosis, with up to 69% occurring in
the third trimester.48,49 Left upper quadrant pain or syncope may precede hemorrhagic shock. Because
fetal and maternal mortalities are 80% and 70%, respectively, a high index of suspicion and rapid
intervention are essential.
Miscellaneous Conditions
Hepatic adenomas are observed most often in women taking oral contraceptives.50 The tumors may
grow during pregnancy and rupture, endangering the life of the mother and fetus.51 The mechanism of
growth is related to the effects of sex hormones. Similarly, focal nodular hyperplasia and hepatic
hemangiomas may grow during pregnancy, a mechanism likely related to the increase in blood volume.
In patients with known histories of these tumors, a baseline ultrasound examination early in pregnancy
is prudent. Adenomas should be resected before pregnancy.
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Acute hepatic vein thrombosis (Budd-Chiari syndrome) can be a life-threatening condition and has been
reported in both pregnancy52 and the postpartum state.53 There are many known causes, but the
hypercoagulable state of pregnancy may be a contributing factor. However, an additional underlying
hypercoagulable state should always be investigated. Budd-Chiari syndrome has been reported with the
hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome54 and with factor V Leiden
mutation.55 Right upper quadrant pain, hepatomegaly, and hepatic dysfunction are hallmarks of this
disease. Urgent consultation with a hepatologist should always be obtained as soon as this life-
threatening condition is diagnosed.
Hepatocellular carcinoma occurs very rarely in pregnancy.56 Typically, patients have been treated by
termination of pregnancy, followed by appropriate surgical treatment, chemotherapy, or ablative
therapy. There has been a report of a healthy pregnancy taken to term after resection of hepatocellular
carcinoma without chemotherapy.57
A single case of pregnancy complicated by symptomatic adult polycystic liver disease has been
reported.58 Multiple transcutaneous cyst aspirations were performed to alleviate pain. The mother and
fetus did well, with labor induced at 35 weeks' gestation.
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Intrahepatic cholestasis of pregnancy (ICP) predominantly affects women in the third trimester,
although symptoms also may become manifest in the second trimester. In general, ICP is a rare
disorder, affecting 1 in 1000 to 10,000 pregnancies worldwide.59 However, there is a much higher
incidence in Scandinavia (1% to 2%) and Chile (14%); in the latter, native Araucanians (24%) are
preferentially affected.59,60 This finding, along with the observation that women with ICP are more
likely to have a sister or mother with a history of the disorder, suggests a genetic predisposition for the
disease.61 Studies of high-prevalence populations have suggested an autosomal-dominant pattern of
inheritance.62 The condition recurs in 60% to 70% of subsequent pregnancies63 and is more common
in multiple gestation pregnancies. Environmental factors also seem to play a role, with a decreased
incidence in Scandinavia in winter months.64
The exact cause of ICP is unknown. Increased levels of estrogen may play a role via altered bile
excretion. Estrogen can alter bile excretion in normal subjects, and patients with a history of ICP show
an exaggerated response.65 However, because subsequent pregnancies do not necessarily lead to
repeat episodes of ICP, there are likely additional factors that play a role in the development of the
disease. Some theories include defects in enzymes used for bile acid detoxification in the liver66 and
estrogen-induced changes in actin microfilaments necessary for bile acid excretion by the
hepatocytes.67
Clinical expression varies from pregnancy to pregnancy, but the main complaint is pruritus typically
affecting palms and soles extending to legs and abdomen. There are no skin rashes. Jaundice affects
20% of patients and typically is mild.63 Abdominal pain is unusual, and most patients appear clinically
well; however, nocturnal pruritus and insomnia may cause increasing distress to the expectant mother.
Anorexia, nausea, and vomiting also may be reported by some patients. Pruritus should resolve within
days of delivery and laboratory abnormalities within 2 to 4 weeks.63
Diagnosis is that of exclusion and cannot be made without first ruling out viral hepatitis, drug reaction,
or, in severe cases, HELLP syndrome. Pruritus, a primary feature of ICP, is unlikely in these other
conditions but also can suggest the possibility of exacerbation of primary biliary cirrhosis. Right upper
quadrant ultrasound examination should show no evidence of biliary tract dilation. If present, further
investigation is warranted to rule out other structural causes of cholestasis. A potentially complicating
factor is the finding that cholelithiasis may occur more frequently in patients with ICP.68 Urinary tract
infections also are more likely in cases of ICP, with treatment of urinary tract infection in some patients
improving pruritus and biochemical markers.69,70
Bile acid levels are elevated, often to levels 100 times greater than normal.71 The AP levels also may be
increased, but the difficulty in evaluating elevated AP levels in pregnancy has already been discussed.
Although some patients show significant elevations in GGT and 5%-nucleotidase, levels usually are
normal to only mildly elevated.64 Jaundice often is mild, with serum bilirubin levels rarely greater than
10 mg/dL.63 There may be mild transaminase elevations. Liver biopsy, only rarely needed for diagnosis,
shows evidence of “bland” cholestasis, with canalicular bile plugs, intracellular bile pigment, and scant
evidence of inflammatory reaction. Electron microscopy shows dilated canaliculi, loss of microvilli, and
thickening of the pericanalicular filamentous network.73
Several agents such as antihistamines, phenobarbital, and benzodiazepines have been used to control
pruritus, but none have shown success in improving the laboratory abnormalities.63 Cholestyramine, 8
to 16 g/day in divided doses, is a commonly used treatment of ICP-related pruritus and has been
shown to improve symptoms.74 Care must be taken when using cholestyramine, as adsorption of other
medications or fat-soluble vitamin malabsorption is common. Both ICP and cholestyramine can lead to
vitamin K deficiency and coagulopathy in both mother and fetus.72 Therefore, parenteral vitamin K
administration should accompany cholestyramine therapy. Cholestyramine also may worsen
constipation, a common problem in pregnancy.
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S-adenosyl- L -methionine (SAMe) has been proposed as a treatment of cholestasis of pregnancy. In
one study, it was shown to improve not only pruritus but the biochemical abnormalities of ICP.75 SAMe
prevents estrogen-related effects on bile flow and increases detoxification of bile acids by increasing the
bioavailability of glutathione.80–83 However, a double-masked evaluation of a 3-week course failed to
show benefits.84 Conversely, the use of ursodeoxycholic acid (UDCA) has been evaluated more
thoroughly.76–79 UDCA is a hydrophilic bile acid that induces changes in the bile acid pool, substituting
for more hepatotoxic hydrophobic compounds. It should be noted that although no adverse fetal effects
have been reported in humans receiving UDCA therapy, animal studies have suggested possible
cytotoxic and embryotoxic effects.86,87 Further investigation is necessary to determine the risk to the
human fetus, since initiation of therapy often occurs after organogenesis has been completed. A recent
randomly assigned double-masked evaluation of 1 g UDCA versus placebo showed effectiveness in the
control of symptoms as well as improvement in fetal outcome.94 An open comparison between UDCA
and SAMe showed benefits of the former.85
Dexamethasone has been shown to improve both pruritus scores and bile acid levels88; however, there
has been a report of dramatic worsening of a patient's condition after beginning therapy.89 More
investigation into the safety of dexamethasone is necessary before its acceptance for widespread use.
Contrary to earlier beliefs, ICP conveys higher rates of fetal distress, spontaneous preterm delivery,
thick meconium, and perinatal morbidity and mortality.90–92 The exact mechanism is not known but
likely relates to increased levels of maternal and fetal bile acid levels.93 Reliable predictors of fetal
outcome are lacking in ICP. UDCA has been shown to improve bile acid transport across the placenta
and decrease endogenous bile acid levels in colostrum, while not adversely affecting bile acid
concentrations in meconium.94–97 Larger studies are necessary to determine whether the changes in
bile acid concentrations translate into positive effects on fetal morbidity and mortality. Early delivery
has been shown to decrease fetal morbidity and mortality and is used frequently once fetal lung
maturity has been ensured. Fetal deaths were not predicted by antepartum fetal nonstress testing,
suggesting a more acute cause of fetal loss.92,98,99
In general, maternal outcome is good. However, care must be given to minimize the morbidity
associated with nocturnal pruritus, nausea, and vomiting in the expectant mother so that excessive
malabsorption and subsequent malnutrition are avoided. In addition, the physician should be aware of
possible vitamin K deficiency and coagulopathy, especially at the time of delivery.
A range of hepatic abnormalities have been reported in pre-eclampsia/eclampsia and one of its more
severe forms, the syndrome of HELLP.100 It has been estimated that HELLP develops in 20% of cases of
severe pre-eclampsia.101 There is a significant degree of overlap in the presentations of HELLP
syndrome, hemolytic uremic syndrome, thrombotic thrombocytic purpura, and acute fatty liver of
pregnancy (AFLP). Ninety percent of patients experienced fatigue or malaise preceding their seeking
medical attention. Half to two thirds report epigastric or right upper quadrant pain. Half report nausea,
vomiting, or headache.102–104 The degree of elevation of transaminases reported has been
variable.105–107 Jaundice usually is mild, but higher values of bilirubin may be observed.105 In 30% of
cases, the full manifestation of HELLP is expressed postpartum.101
In severe pre-eclampsia/eclampsia, vascular endothelial injury promotes the deposition of fibrin in the
vessel lumen. Liver biopsy shows periportal fibrin deposits.108 Even in asymptomatic cases,
perisinusoidal deposits of fibrinogen may be observed. Fatty infiltration occasionally may be seen in the
periportal region.109 In more dramatic cases, the periportal fibrin deposits may extend and result in
either subcapsular hematomas or overt hepatic rupture.110 In the latter, abdominal pain and shock
quickly ensue, and emergent laparotomy with packing of the affected area is mandatory. Both maternal
and fetal survival are endangered. In the case of the mother, disseminated intravascular coagulation,
abruptio placentae, and acute renal failure may develop. In a group of 152 women with HELLP
syndrome, the risk of obstetric complications in subsequent pregnancies was high, but recurrence of
HELLP was low.111
Acute fatty liver of pregnancy (AFLP) is a unique disease of the pregnant state. Although it typically
manifests in the third trimester, its appearance in the late second trimester has been reported. It never
develops after delivery, although some patients may go undiagnosed until after childbirth. Its
presentation may range from mild biochemical abnormalities to fulminant hepatic failure. It is an
important diagnosis to establish in view of urgent therapeutic decisions that may be indicated.
The incidence of AFLP has been estimated to range from approximately 1 per 7000 deliveries to 1 per
16,000.112,113 AFLP is more likely to occur with twin gestations.114,115 Although once believed to not
recur in subsequent pregnancies, there have been several reports of recurrence of the condition in
some women.114,116,117 Women in whom AFLPs have developed should be monitored closely for
recurrence in the third trimester of subsequent pregnancies.
Advances in both adult and neonatal intensive care as well as earlier recognition have allowed a great
reduction in the mortality once associated with AFLP. The maternal mortality rate, greater than 90% in
1970,114 has been decreased to less than 10% with prompt intervention and delivery. Similarly, fetal
mortality has been reduced significantly from approximately 50% before 1985.114,118
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Presenting symptoms include nausea or vomiting, epigastric pain, anorexia, or jaundice. Jaundice
typically is mild and may be absent completely with early diagnosis. Headaches are common, and
altered sensorium may be noted on presentation as well. Approximately half of the patients with AFLP
show clinical signs of pre-eclampsia, namely hypertension, proteinuria, and peripheral edema.114
Pruritus usually is not a feature of AFLP and may suggest another cholestatic process such as
ICP.113,114
Laboratory test results show mild hyperbilirubinemia without gross evidence of hemolysis. Serum
transaminases rarely are elevated above 300 IU/mL. A marked prolongation of the prothrombin time,
unresponsive to vitamin K, signals hepatic insufficiency and the severity of the case. Leukocytosis and
thrombocytopenia may be present. Any patient in whom thrombocytopenia develops in the third
trimester should be evaluated closely for AFLP. A decrease in the serum fibrinogen and a rise in fibrin
split products may signal the presence of disseminated intravascular coagulation. Hyperuricemia, rarely
present, may be caused by tissue destruction and a decrease in renal function. Hyperammonemia may
be detected on arterial blood specimens.
Histologically, there is little evidence for widespread necrosis, although scattered areas of necrosis may
be present.119 On hematoxylin-eosin stain, the hepatic cells are enlarged and contain clear vacuoles
that do not displace the nucleus and give the cytoplasm a foamy appearance. This characterized the
disorder within the microvesicular fat disorders, together with such entities as Reye's syndrome,
carnitine deficiency, Jamaican vomiting sickness, and certain drug toxicities.120 These pathologic
abnormalities resolve rapidly after delivery.115
Although the exact mechanism of liver injury still is unknown, great advances have been made in
understanding the pathophysiology of AFLP. It has been observed that impairment of mitochondrial β-
oxidation may lead to microvesicular steatosis.124 Furthermore, it has been shown that mothers giving
birth to children with a deficiency of a specific mitochondrial oxidative enzyme, long-chain 3-
hydroxyacyl-coenzyme A dehydrogenase (LCHAD), have a higher incidence of AFLP, pre-eclampsia, and
HELLP syndrome.125 This enzyme is part of the mitochondrial trifunctional protein, which comprises
LCHAD, long-chain 2,3-enoyl-CoA hydratase, and long-chain 3-ketoacyl-CoA thiolase. Several
mutations of this enzyme have been associated with AFLP and HELLP syndrome, the most common of
which is substitution of glutamine for glutamate at residue 474 (Glu474Gln).126 It is inherited in an
autosomal-recessive fashion. Heterozygous mothers with homozygous fetuses appear to be at
significantly increased risk for AFLP and HELLP. It is hypothesized that excessive concentrations of a
toxic fetal metabolite cross the placental barrier and cause maternal hepatic injury. Additionally,
maternal mitochondrial oxidation of fatty acids is decreased during late pregnancy, likely secondary to
ultrastructural changes in the mitochondria induced by elevated levels of sex hormones.124 This may
further predispose the pregnant patient to this condition.
AFLP is an obstetric emergency. It does not resolve spontaneously, and delayed delivery exposes the
mother and fetus to increased risk of death. Early delivery is therefore crucial in the management of
AFLP. If no fetal or maternal distress exists, vaginal delivery may be attempted; however, cesarean
delivery is warranted in the acute setting.127 Other treatment is mainly supportive, with the level of
care being set by the degree of hepatic dysfunction. Differential diagnosis of fulminant hepatic failure in
pregnancy includes herpetic hepatitis and, in endemic areas, hepatitis E infection. Fulminant hepatic
failure requires intensive care monitoring before and after delivery, with special attention being paid to
respiratory status, prevention of infection and gastrointestinal tract hemorrhage, and, in advanced
coma, management of intracranial hypertension. In extreme cases, liver transplantation has been
performed.128,129 For the surviving mother, complete recovery is expected. However, because of the
associated fatty acid oxidation defect in the child, closer monitoring is warranted. Confirmation of fatty
acid β oxidation defects in the child may be obtained by cultured skin fibroblasts.130 Without dietary
management, mortality of children with fatty acid oxidation disorders is very high.131
In the future, the spectrum of fatty oxidation-related disorders will expand. Another fetal deficiency,
hepatic carnitine palmitoyltranferase I, may be present with AFLP in the mother.132
Viral hepatitis acquired during pregnancy is a common cause of altered liver biochemistry and jaundice
in pregnancy. This section addresses the risk to the mother. Risk of hepatitis to the offspring is
addressed in the section on problem-oriented approaches.
Hepatitis A
Hepatitis A virus infection leads to an acute and self-limited hepatitis. Very rarely, fulminant hepatitis
may develop secondary to hepatitis A and often is related to a poor nutritional state, advanced
maternal age, or coexistent hepatitis B infection.34 Chronic carrier state of hepatitis A is not known to
occur. Management in pregnancy is supportive and not different from management of hepatitis A
infection in the nonpregnant patient. Serum hepatitis A virus immunoglobulin M should be checked in
all patients suspected of having hepatitis A infection and may persist for up to 6 months after acute
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infection. Travelers to endemic areas should be immunized for hepatitis A. The vaccine appears to be
safe in pregnancy.134
Hepatitis B
Hepatitis B virus (HBV) infection in adults leads to chronic hepatitis in approximately 5% of those
exposed.135 Pregnancy neither conveys a higher risk of chronic infection nor a worse clinical course of
hepatitis.136 Conversely, pregnancy course and outcome are not adversely affected by the presence of
active HBV infection, except in cases of fulminant hepatitis.137 Cessation of viral replication has been
observed after delivery.22 Hepatitis B testing may yield evidence of infection through “classic” antibody
patterns and should be confirmed by checking for the presence of HBV DNA in serum. Hepatitis D (delta
hepatitis), an RNA virus that requires hepatitis B surface antigen (HBsAg) to replicate, may coinfect or
superinfect persons with acute hepatitis B or hepatitis B carriers. This signals an unfavorable prognosis
for the patient but is no worse in pregnancy than in the nongravid patient. Fulminant hepatitis occurs in
fewer than 1% of patients with hepatitis B. Vaccination of patients is associated with a weak antibody
response, especially in obese mothers with advanced age.138
Hepatitis C
Hepatitis C is an RNA virus that causes chronic infection in 75% to 85% of those exposed. The clinical
course is not affected by pregnancy nor is the course of pregnancy affected by the presence of the
virus.139 However, viral replication appears to increase with a lowering of serum aminotransferases.222
Postpartum, values return to prepregnancy levels. Unlike hepatitis B, there have been few reports of
HCV causing fulminant hepatitis. When suspected, anti-HCV antibody should be measured and
confirmed with serum HCV-RNA if positive. No vaccination currently is available for hepatitis C
prophylaxis.
Hepatitis E
Hepatitis E virus, unlike hepatitis A, B, or C, does convey an acute risk to both mother and fetus.140
There is a high probability of patients having fulminant hepatitis develop when the virus is acquired in
the third trimester, and 20% mortality rate of the mother has been described. Even in noncomplicated
cases, there is a higher rate of abortion and intrauterine death reported.141 The route of spread is
fecal-oral, and epidemics have occurred in India, Pakistan, southeast Asia, Africa, Mexico, and China.
Sporadic cases are rare in women who have not traveled to these areas. Chronic carrier state does not
exist. Confirmation of infection may be obtained by stool or serum. A vaccine currently is undergoing
clinical testing.
Clinically, acute viral hepatitis may mimic other acute hepatitides, such as drug-induced hepatitis and
hepatic ishemia, which may occur in the event of left ventricular failure. A careful history should be
obtained. The most important differential diagnosis is that of AFLP, which, in cases of fulminant hepatic
failure, ultimately may require a liver biopsy. Distinction is important because management of the two
entities is entirely different. An aggressive strategy with early delivery is warranted for AFLP, and an
expectant attitude should be the initial approach in acute viral hepatitis. AFLP is a disease of the third
trimester not associated with conspicuous jaundice; rarely are transaminase levels above 300 IU/mL.
Conversely, lack of serologic viral markers does not exclude the diagnosis of viral hepatitis. Tests for
cytomegalovirus, Epstein-Barr virus, and rubella should be ordered to further clarify the diagnosis.
Prompt interaction between obstetrician and hepatologist clearly is warranted.
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PROBLEM-ORIENTED APPROACH
Abnormal Transaminases in Normal Women
Despite cost-containing efforts used broadly in today's medical environment, many asymptomatic
patients still consult with unsuspected abnormalities of serum transaminases. In nonpregnant subjects,
this is most likely because of hepatic fatty infiltration or hepatitis C. A systematic series screening
pregnant women for asymptomatic elevations of transaminases has not been reported.
Patients should be questioned about alcohol intake and use of medications. Aspartate aminotransferase
(AST) and γ-glutamyl transferase (GGT) are nonspecific markers and should not be used to assess
alcohol intake. Muscle source of transaminases needs to be considered as well. Physical examination
should be complete to avoid misdiagnosis of pre-eclampsia. If this is noncontributory, the initial
laboratory workup during pregnancy should be limited to repeat tests to confirm the abnormality.
Hepatitis A, B, and C serologies should be checked, as well as antinuclear antibody (ANA), anti-smooth
muscle antibody (ASMA), and anti-liver-kidney-microsomal antibody if necessary to evaluate for
autoimmune hepatitis. Hepatic ultrasound examination with Doppler flows can be obtained to
investigate the possibility of chronic parenchymal disease or portal hypertension.
Liver diseases in pregnancy are more conspicuous in the second and third trimesters. Even if clinically
stable, a complete liver panel should be repeated periodically. It is important to be aware of clinical
changes suggestive of a more serious picture such as AFLP or overt pre-eclampsia, since prompt
intervention is imperative in either of these conditions. Liver tests should be followed after delivery with
a wide differential diagnosis if abnormalities persist.
Sudden onset of right upper quadrant abdominal pain should alert the clinician to several important
diagnoses, the most important of which is cholelithiasis. The pregnant state results in the production of
lithogenic bile, and it is not uncommon for the patient, especially the multipara, to develop her first
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symptoms during pregnancy. A patient with choledocholithiasis or gallstone pancreatitis may exhibit
more severe symptoms, and physical findings or biochemical tests may be diagnostic.
Pain associated with biliary colic typically is intermittent and builds to a crescendo. Severe unremitting
pain suggests the possibility of a subcapsular hematoma or a ruptured liver, either spontaneous (as
seen in HELLP) or complicating a hepatic adenoma. An abdominal CT scan is preferable to ultrasound
for diagnostic purposes; however, CT may be relatively contraindicated depending on the stage of
pregnancy. If blood is found on peritoneal aspiration, a ruptured splenic artery aneurysm should be
considered. Emergency laparotomy may be necessary for such patients.
Parenchymal liver disease also may present as right upper quadrant or epigastric pain, generally
because of stretching of the hepatic capsule. The pain is dull, and the liver edge may be tender on
examination. Patients with viral hepatitis, AFLP, or pre-eclampsia may present with such symptoms.
HEPATITIS A.
Hepatitis A infection is transmitted via the fecal-oral route and is only rarely passed vertically. However,
there have been isolated reports of perinatal transmission.142 Horizontal transmission from an acutely
infected mother who is caring for her newborn is, of course, possible. Therefore, an infant born to a
woman who is acutely infected with hepatitis A virus should receive immune globulin.
HEPATITIS B.
Hepatitis B virus carries a significant risk of vertical transmission, with most affected infants becoming
chronic carriers. Transmission is not affected by route of delivery, and breastfeeding is thought to play a
minimal role in transmission, since 95% of cases are acquired intrapartum.143 The likelihood of
transmission is related to the timing of onset of acute hepatitis or active viral replication in the mother.
Acute hepatitis B infection in the first two trimesters carries a low risk of transmission to the fetus
versus acute infection in the third trimester, which carries a 70% risk of transmission.137 In chronic
hepatitis, mothers who are hepatitis B e antigen-positive (HBeAg+ ) have 80% to 90% chance of
vertical transmission, with 85% of these becoming chronic carriers.144,145 The high rate of carriage
may be because of tolerance induced by HBeAg, which, unlike HBsAg, can cross the placental barrier.
The transmission rate in chronic hepatitis also is related to levels of HBV-DNA present in maternal
serum. In mothers who are HBeAg- and HBsAg+ , the rate of transmission is 2% to 15% and only 10%
to 15% of these infants become carriers.145,146 There have been cases of infected newborns showing
fulminant hepatitis from mothers who are HBeAg-, and these likely are caused by a mutant strain of
HBV.147
All women should have screening for hepatitis B at the first antenatal care visit.148 If positive, further
workup to assess extent of liver disease should be undertaken. In addition, women testing positive for
HBV should have serologies and, if appropriate, HBV-DNA levels repeated in the third trimester.
Because 95% of transmission is thought to occur at or near the time of birth, postexposure prophylaxis
at birth is a reasonable strategy. Indications include acute infection in the third trimester or chronic
infection with positive serology for HBeAg or HBV-DNA.148 Hepatitis B immune globulin (HBIg) should
be given within 2 days of birth, preferably within 12 hours.149–151 Recombinant vaccine also should be
given at birth, followed by repeat injections at 1 and 6 months after the initial dose.149,150,152 This
strategy has been shown to be 85% to 95% effective in preventing neonatal transmission.149,150 If the
recombinant vaccine is not given, repeat doses of HBIg at 3 and 6 months have been shown to have
further protective effects than a single dose.153,154 In patients who are delivering without knowledge of
hepatitis B status and in whom the results will not be known for more than 12 hours postpartum,
consideration should be given to empiric coverage of the newborn with HBIg as efficacy falls rapidly
after 12 hours.155 Delta superinfection rarely is transmitted vertically and is equally protected by
postexposure prophylaxis as is HBV.
HEPATITIS C.
Unlike HBV, vertical transmission plays a small role in the transmission of HCV. A large study
investigating vertical transmission of HCV has shown a 5.1% rate of HCV-RNA viremia at 1 year in
newborns whose mothers were known to have HCV viremia.156 The transmission rate appears to be
related to maternal viremia levels. HIV coinfection also confers higher rates of transmission and may do
so via immunosuppression on the mother with subsequent increased viremic titers.157,158 Further
investigation is necessary to determine whether HCV genotype plays a role in transmission rate.
Breastfeeding is not contraindicated, as only very low levels of HCV-RNA are detected in breast milk.159
The administration immune globulin to newborns has not been examined in controlled clinical trials.
HEPATITIS E.
A series of eight mothers with hepatitis E virus infection showed that six of their newborns had
evidence for clinical hepatitis E infection, two of whom died within 24 hours after delivery.160 Hepatitis
E virus is likely transmitted from mother to child commonly, intrauterine, and with increased fetal and
neonatal risks.161 Children born to women with known hepatitis E virus infection should be monitored
closely after birth for signs of infection. Table 2 summarizes the strategies currently used in neonatal
prophylaxis.
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Disease Prophylaxis
Hepatitis 0.5 mL ISG IM at birth
A
Hepatitis Hepatitis B recombinant vaccine (Recombivax 5 μg IM or Energix-B 10 μg IM) at birth and
B at 1 and 6 months
Hepatitis No proven therapy
C
Hepatitis Undergoing clinical trials
E
Viral hepatitis is the most common cause of jaundice during pregnancy in most populations. The next
most frequent is cholestasis of pregnancy, but this may vary with geographic location. An approach to
the differential diagnosis of jaundice during pregnancy is offered in Table 3.
Associated
Disease Symptoms Laboratory Tests Prognosis
HAV, hepatitis A virus; IgM, immunoglobulin M; HBV, hepatitis B virus; HCV, hepatitis C virus; AFLP,
acute fatty liver of pregnancy.
Indirect hyperbilirubinemia may be seen in cases of hemolytic anemia, such as pre-eclampsia. In the
absence of renal insufficiency, hemolysis rarely produces bilirubin levels greater than 5 mg/dL. Urinary
dipstick test results should be negative in the case of indirect bilirubinemia, as only conjugated bilirubin
is excreted into the urine.
Orthotopic liver transplant is being performed at an increasing number of medical centers, many on
women of childbearing age. Conception occurring during the first 6 months posttransplant carries a
higher risk of allograft rejection.162 All women of childbearing age undergoing liver transplantation
should be counseled on the need for contraception several months posttransplant. Pregnant women
after transplantation are at higher risk of having pre-eclampsia, hypertension, premature rupture of
membranes, preterm delivery, and cesarean delivery than are normal obstetric patients.162 Women
who enter pregnancy with renal insufficiency appear to be at particular risk.162 Offspring of such
mothers are reported to have normal development.163 Pregnancies have been described in women
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using various immunosuppressive regimens and generally are thought to carry an acceptable risk if the
patient is under the care of experienced transplant physicians to minimize the necessary dose of
immunosuppressives.164
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