Hepatology

Liver Disease in Pregnancy

Jamilé Wakim-Fleming

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Definition and Causes

Liver disease in pregnancy encompasses a spectrum of diseases encountered during gestation and the postpartum period that result in abnormal liver function tests, hepatobiliary dysfunction, or both. It occurs in 3% to 10% of all pregnancies.

Several disorders contribute to liver disease in pregnancy (Box 1). These include diseases induced by the pregnancy such as acute fatty liver of pregnancy (AFLP) and intrahepatic cholestasis of pregnancy (IHCP), diseases that existed before pregnancy that could potentially flare during pregnancy such as autoimmune hepatitis and Wilson’s disease, and diseases not related to the pregnancy but that could affect the pregnant woman at any time during gestation such as viral hepatitis.

Box 1 Physiologic Changes During Pregnancy
Increases
Blood volume, heart rate, and cardiac output rise by 35% to 50%, peak at 32 weeks' gestation; further increase by 20% in twin pregnancies
Alkaline phosphatase levels rise three- to fourfold because of placental production
Clotting factors I, II, V, VII, VIII, X, and XII
Ceruloplasmin level
Transferrin level
Decreases
Gallbladder contractility
Hemoglobin level (because of volume expansion)
Uric acid level
Albumin and total protein levels
Antithrombin III and protein S level
Systemic vascular resistance
Modest decline in blood pressure
No Changes
Liver transaminase levels (aspartate aminotransferase, alanine aminotransferase)
γ-Glutamyl transferase (GGT) level
Bilirubin level
Prothrombin time
Platelet count (or slight decline)

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Diagnosis and Outcomes

The diagnosis of liver disease in pregnancy is challenging and relies on laboratory investigations. Signs and symptoms are often not specific and consist of jaundice, nausea, vomiting, and abdominal pain. The underlying disorder can have a significant effect on morbidity and mortality in both mother and fetus, and a diagnostic workup should be initiated promptly.

The physical examination of a pregnant woman can show skin changes suggesting chronic liver disease, such as palmar erythema and spider angiomas. These changes are the result of hyperesterogenemia of pregnancy and occur in up to 60% of healthy pregnancies.

Alterations of laboratory test results can represent physiologic changes of pregnancy an example of this is a decreased level of serum albumin and increased level of alkaline phosphatase whereas. Elevations of transaminase, bilirubin, and prothrombin time (PT) indicate a pathologic state. The unconjugated hyperbilirubinemia of Gilbert’s syndrome is not affected by the pregnancy. Clotting factors are affected by normal pregnancy and favor a hypercoagulable state. Women with inherited thrombophilia, such as factor V Leiden or antithrombin III deficiency, are at increased risk for hepatic vein and portal vein thrombosis during pregnancy.

When diagnostic imaging is needed during the workup of liver test abnormalities in a pregnant woman, ultrasonography becomes the modality of choice because of its safety for the fetus. Magnetic resonance imaging (MRI) may be used as a second line test if additional information is still necessary. Computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP) involve radiation to the fetus and require shielding of the uterus.

Outcome depends on the causative factors. Newly acquired primary herpes simplex hepatitis can cause fulminant liver failure, premature delivery, and stillbirths. On the other hand, pregnancy can induce eclampsia and AFLP with a potential for liver failure and death.

Extreme vigilance in recognizing physical and laboratory abnormalities in pregnancy is a prerequisite for an accurate diagnosis. This could lead to a timely intervention and successful outcome.

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Physiologic Changes During Pregnancy

Pregnancy induces hemodynamic changes that involve several organ systems throughout gestation, the postpartum period, and lactation. The major physiologic changes in pregnancy (Box 2) include an increase in cardiac output, sodium and water retention, blood volume expansion, and a reduction in systemic vascular resistance and systemic blood pressure. These changes peak in the second trimester and then plateau until the time of delivery. Total blood flow to the liver increases after 28th week driven by the increased flow to the portal vein. Histology of the liver remains essentially normal during pregnancy.

Box 2 Causes of Liver Disease in Pregnancy
Preexisting Liver Disease
Cirrhosis and portal hypertension
Autoimmune hepatitis
Primary biliary cirrhosis, primary sclerosing cholangitis
Wilson's disease
Chronic viral hepatitis B and C
Liver Disease Coincidental with Pregnancy
Budd-Chiari syndrome
Hepatitis
     Viral hepatitis E
     Herpes simplex virus hepatitis
     Acute hepatitis A, B, and C
     Cytomegalovirus hepatitis
Alcohol and pregnancy
Gallstone disease
Liver Disease Unique to Pregnancy
Acute fatty liver of pregnancy
Preeclampsia, eclampsia
HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count)
Intrahepatic cholestasis of pregnancy
Hyperemesis gravidarum

Physiologic changes during pregnancy could be misinterpreted as pathologic. Lack of understanding of these changes can appreciably alter the criteria for diagnosis and therapy and can contribute to the morbidity and mortality associated with the pregnancy.

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Factors to Consider During Pregnancy

Safety of Drugs

Treatment of liver disease in pregnancy may involve prompt delivery, supportive management, or drug therapy. The choice of drugs in pregnancy should be based on the U.S. Food and Drug Administration (FDA) classification for drugs and fetal risk (Box 3). Although not all drugs have been tested in pregnant women, the FDA has classified them into five categories based on the level of teratogenicity determined from animal and human studies.

Box 3 U.S. Food and Drug Administration (FDA) Classification of Drugs and Fetal Risk
Category A: Controlled studies show no risk
Category B: No evidence of risk in humans
Category C: Risk cannot be ruled out
Category D: Positive evidence of risk
Category X: Contraindicated in pregnancy

Pregnancy after Liver Transplantation

Women with a liver transplant may increasing in number, and many of them are of reproductive age and attempting pregnancy. Menstrual function, libido, and fertility are usually restored within 6 months after transplantation, and pregnant women can have excellent outcome and deliver healthy babies, especially when pregnancy is planned 2 years after the transplant.

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Preexisting Liver Disease and Pregnancy

The outcome of a pregnancy is greatly affected by the medical condition of the liver before conception. Diagnosis and treatment of a liver disorder before conception will minimize potential exacerbations that could lead to liver failure and fetal loss.

Cirrhosis and Portal Hypertension

The prevalence of cirrhosis in reproductive-age women approximates 0.45 cases per 1000. Etiology of cirrhosis in pregnancy is similar to that in the nonpregnant state and commonly includes alcohol and viral hepatitis C and B. Cirrhosis can affect ovulation and cause infertility. However, women might still become pregnant and should expect a good outcome if their liver function is well compensated (as in noncirrhotic portal hypertension) and if their liver disease is treated before conception and treatment is maintained during pregnancy. Patients with cirrhosis and noncirrhotic portal hypertension are at high risk for premature deliveries. Hepatic decompensation with jaundice, bleeding from esophageal varices, ascites, and fulminant liver failure can occur. In general, diuretics and spironolactone, which are in FDA category D, are not advisable during pregnancy or lactation because of the potential for teratogenicity. Banding of bleeding esophageal varices and octreotide (FDA category B) are safe during pregnancy. Meperidine (Demerol) and midazolam (Versed) are both in FDA category C and safe to use during endoscopy.

Autoimmune Hepatitis

Autoimmune hepatitis (see the chapter “Chronic Autoimmune Hepatitis”) is a progressive liver disease that predominantly affects women of all ages and can manifest at any time during gestation and the postpartum period.

The disease activity of autoimmune hepatitis is usually attenuated during pregnancy, and dosages of medication can be decreased because of the state of immune tolerance induced by the pregnancy. Nonetheless, flares have occurred in 11% of patients during gestation and up to 25% in the postpartum period. There is an increased risk of prematurity, low-birth-weight infants, and fetal loss. Pregnancy does not contraindicate immunosuppressive therapy. Both prednisone and azathioprine (FDA category D at dosages <100 mg/day) are considered safe during pregnancy and lactation. In one meta-analysis, prednisone given during the first trimester was linked to a marginal risk of oral cleft defect in the newborn.

Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Primary biliary cirrhosis and primary sclerosing cholangitis (see the chapter “Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, and Other Cholestatic Liver Diseases”) are autoimmune diseases that can overlap with autoimmune hepatitis. Pregnancy is rare in these conditions and carries a high risk of prematurity, stillbirths, and liver failure.

In patients with primary biliary cirrhosis, pregnancy can induce a new-onset pruritus or worsen a preexisting pruritus. Diagnosis is not different from that in the nonpregnant woman. Ursodeoxycholic acid is considered FDA category B and can be continued safely in pregnancy. However, no large studies have demonstrated its safety during the first trimester and lactation.

Primary sclerosing cholangitis is rarely described in pregnancy; pruritus and abdominal pain seem to be the major symptoms. Alkaline phosphatase and γ-glutamyl transferase levels are elevated. Diagnosis relies on clinical and ultrasound findings. No specific treatment exists for primary sclerosing cholangitis, but ursodeoxycholic acid and stabilization of cirrhosis, when present, have been associated with good outcome.

Wilson’s Disease

Wilson’s disease (see the chapter “Wilson’s Disease”) is an inherited autosomal recessive defect of copper transport. Fertility in Wilson’s disease is decreased but can improve with therapy. Treatment should be initiated before conception and should not be interrupted during pregnancy, because of the risk of fulminant liver failure. The treatment of choice in pregnancy is zinc sulfate 50 mg three times daily (FDA category C), because of its efficacy and safety for the fetus. Patients who are treated with d-penicillamine (FDA category D) or trientine (FDA category C) before pregnancy require a dose reduction by 25% to 50% of that in the pre-pregnancy state especially during the last trimester, to promote better wound healing if a cesarean section is to be performed.

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Liver Diseases Coincidental with Pregnancy

Budd-Chiari Syndrome

Budd-Chiari syndrome is an occlusive syndrome of the hepatic veins that leads to sinusoidal congestion and necrosis of hepatocytes around the central vein. Most cases occur during the postpartum period. Of pregnant women who develop Budd-Chiari syndrome, 25% have an underlying predisposing condition, such as factor V Leiden, antithrombin III, protein C or S deficiency, or the presence of antiphospholipid antibodies. Clinical manifestations include hepatomegaly, ascites, and abdominal pain. On physical examination, the liver is palpable and hepatojugular reflux is absent. Doppler ultrasound and MRI are the imaging modalities of choice. Complete anticoagulation throughout pregnancy and the puerperium is required. Liver transplantation is often necessary in the acute phase.

Viral Hepatitis

Acute viral hepatitis (Table 1) is the most common cause of jaundice in pregnancy, with an incidence of approximately 1 to 2 per 1000. The outcome is usually benign, except in viral hepatitis E and herpes simplex virus (HSV) hepatitis.

Table 1 Viral Hepatitis in Pregnancy
Virus Risk of Transmission to Fetus Signs and Symptoms Treatment Outcome
HEV In utero, 50% Jaundice, viral syndrome, liver failure Prevention Mortality up to 40%
HSV In utero and during delivery, up to 50% Increases in bilirubin, transaminase levels, prothrombin time Acyclovir (often) Liver failure; mortality up to 40%
HAV Rare Viral syndrome or asymptomatic Supportive Benign
HBV High if mother is HBeAg+ and during third trimester Viral syndrome or asymptomatic Supportive Benign
HCV 3.8% Often asymptomatic Supportive Benign
CMV Up to 30%-40% Mononucleosis-like Supportive High morbidity to child

CMV, cytomegalovirus; HAV, hepatitis A virus; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HSV, herpes simplex virus.

Viral Hepatitis E

Hepatitis E virus (HEV) is rare in the United States but endemic in Asia and Africa. Acute viral hepatitis E is transmitted via the fecal-oral route and is associated with high morbidity and a maternal mortality rate of 30%. Vertical transmission of HEV to the newborn occurs in 50% of cases if the mother is viremic at the time of delivery. Treatment is supportive, and judicious hand washing prevents contamination. Pregnant women should avoid travelling to high-risk endemic areas, especially during the late stages of pregnancy.

Herpes Simplex Hepatitis

Approximately 2% of women acquire HSV during pregnancy. HSV hepatitis is a rare condition but may be devastating when primary infection occurs in pregnancy because it is associated with a 40% risk for fulminant liver failure and death. Treatment of choice for severe primary HSV infection is intravenous acyclovir (FDA category B).

Recurrent HSV infections usually manifest as genital mucocutaneous lesions. Transmission to the fetus is high (≤50%) when maternal acquisition occurs near the time of delivery. Oral acyclovir 400 mg three times daily for 7 to 10 days should be given. Cesarean section is strongly advisable if lesions are present at delivery.

Acute Viral Hepatitis A

Acute hepatitis A virus (HAV) infection is usually self-limited during pregnancy. Transmission to the newborn can occur when delivery takes place during the incubation period because of viral shedding and contamination during vaginal delivery. Treatment of the mother is supportive. Passive immunoprophylaxis should be given to the newborn.

Viral Hepatitis B

Acute and chronic HBV infections during pregnancy do not seem to affect the course of pregnancy but are associated with an increased risk of transmission to the newborn. The risk of vertical transmission of HBV is minimal if the infection is acquired and resolves in the first trimester. The risk is high, ranging from 60% to 90% if the infection is acquired during the third trimester or if the infected mother is positive for the envelope antigen (eAg) and the viral DNA count is elevated. Therefore, active and passive immunoprophylaxis should be administered to newborns of HBV-infected mothers as recommended by the CDC (Box 4). However, despite these prophylactic measures, failure rates are reported and nucleoside and nucleotide analogues have been used to prevent transmission to newborns of mothers with high HBV viral count. Although this practice appears safe (www.apregistry.com) the use of these agents remains controversial.

Box 4 Centers for Disease Control and Prevention (CDC) Recommendations for Hepatitis B Virus (HBV) Testing and Vaccination During Pregnancy
  All pregnant women should be tested routinely for hepatitis B surface antigen (HBsAg) during the first trimester in each pregnancy, even if they have been previously vaccinated or tested.
  Newborns of pregnant women who test positive for HBsAg should receive HBV vaccine and hepatitis B immunoglobulin during the first 12 hours of life and complete the three-dose HBV vaccine series by 9 to 18 months of age.
  For newborns of mothers not infected with HBV, the first vaccine should start at 1 month of age and the series should be completed by 18 months of age.
  Hepatitis B vaccination is not contraindicated in pregnancy. Limited data indicate no apparent risk for adverse events to developing fetuses when hepatitis B vaccine is administered to pregnant women. Current vaccines contain noninfectious HBsAg and should carry no risk for the fetus.
Viral Hepatitis C

The prevalence of hepatitis C virus (HCV) infection in women of childbearing age in the United States is approximately 1%. Treatment of HCV infection is contraindicated in pregnancy because of the teratogenicity of the drugs used. There is a 3.8% rate of vertical transmission to infants born to mothers who are viremic at the time of delivery. This rate increases to 25% in mothers coinfected with the human immunodeficiency virus (HIV). Breast-feeding should not be discouraged and the indication for cesarean section should be based on obstetrical reasons. The PCR assay is not sensitive for infants younger than 1 month, and the treatment of HCV is contraindicated in children younger than 3 years because of the potential for neurologic damage. Testing for HCV in children should be delayed until age 18 months.

Cytomegalovirus Hepatitis

Infection with cytomegalovirus (CMV) is common and usually inapparent. The overall prevalence in women of childbearing age is 50% to 80%. Acute CMV hepatitis in the pregnant woman can manifest as a mononucleosis-like illness. The risk of transmission to the fetus is high, occurring at a rate of 30% to 40% when the infection is acquired before 22 weeks of gestation. The infection can cause mental retardation and congenital malformations. There is no effective and safe therapy during pregnancy.

Alcohol and Pregnancy

More than 50% of all women of childbearing age have reported alcohol use, and one in eight has reported binge drinking. Many of these women are sexually active and do not take effective measures to prevent pregnancy. Women are more sensitive to the effects of alcohol than men, and ethanol consumption increases the frequency of alcoholic hepatitis, menstrual disturbances, infertility, abortions, and miscarriages. The U.S. Surgeon General and Secretary of Health and Human Services have recommended abstinence from alcohol for women planning pregnancy, at conception, and during pregnancy because a safe level of prenatal alcohol consumption has not been determined. Mothers who consume alcohol during pregnancy can have premature babies, stillbirths, babies with neonatal alcohol withdrawal (characterized by jitteriness, irritability, and poor feeding in the first 12 hours of life), and infants with fetal alcohol syndrome. Fetal alcohol syndrome is a serious congenital malformation diagnosed by the presence of dysmorphic facial features, prenatal and postnatal growth deficits, and central nervous system abnormalities. The prevalence of fetal alcohol syndrome among offspring of moderate to heavy drinkers (1-2 oz/day of absolute alcohol) and chronic alcoholics is 10% to 50%.

Gallstone Disease

Pregnancy and the hyperestrogenemic state promote biliary cholesterol saturation and inhibit the hepatic synthesis of chenodeoxycholic acid, thus favoring lithogenesis. In addition, prepregnancy obesity, low activity level, low serum leptin levels, and a history of gallbladder disease are reported to be strong risk factors for pregnancy-associated gallbladder disease. The risk increases as the pregnancy advances, and by the third trimester approximately 10% of pregnant women may have gallstones, compared with 5% at the beginning of the pregnancy. However, most gallstones regress in the postpartum period.

Symptoms of cholelithiasis are experienced by 8% to 25% of pregnant women and the symptoms recur in 38% during the same gestation, often requiring surgical management. Laparoscopic cholecystectomy for symptomatic cholelithiasis in pregnancy is particularly safe when performed during the second trimester because of the moderate size of the uterus, decreased number of days in the hospital, and reduced rate of labor induction and preterm deliveries.

Choledocholithiasis during pregnancy increases the risks of morbidity and mortality for both mother and fetus because of cholangitis and pancreatitis. Endoscopic retrograde cholangiopancreatography (ERCP) may be needed.

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Liver Diseases Unique to Pregnancy

AFLP, the HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count), eclampsia, and preeclampsia occur during the third trimester and are associated with increased morbidity and mortality to both the mother and fetus (Table 2). These disorders have been suggested to represent a spectrum of the same pathologic mechanisms, making the differentiation among them challenging. Of patients with AFLP, 50% have preeclampsia, and 20% of patients with severe eclampsia develop the HELLP syndrome. Delivery is the most important step in managing these disorders because it can be lifesaving to mother and child.

Table 2 Liver Diseases Unique to Pregnancy
Disorder Gestational Period at Presentation Prevalence Symptoms Specific Laboratory Tests Outcome Treatment
HG First trimester; resolves after 20 wk <2% primiparous Nausea and vomiting AST, ALT <1000 IU/L; ALT >AST; low TSH Benign for mother and child IV fluids; thiamine pyridoxine; promethazine; FDA category C
IHCP Second trimester <10% multifetal gestations Pruritus; resolves in postpartum period AST, ALT <1000 IU/L; GGT normal; bile acid levels high; PT normal; bilirubin <6 mg/dL Increased gallstones; recurs; risk for fetal distress increases Ursodiol; delivery when fetal distress is imminent
AFLP Third trimester; 50% have eclampsia 1/13,000; primiparous, multifetal gestations Progress quickly to FHF, diabetes insipidus, hypoglycemia Platelets <100,000/mm3; AST, ALT >300 IU/L; PT elevated; fibrinogen level low; bilirubin level increased; DIC Maternal mortality <20%; fetal mortality up to 45%; test for LCHAD Prompt delivery; liver transplantation
Eclampsia, preeclampsia Beyond 20 wk; recurs 5% multiparous, multifetal gestations High blood pressure, proteinuria, edema, seizures, renal failure, pulmonary edema Uric acid level elevated Maternal mortality, 1%; prematurity and fetal death, 5%-30% Beta blocker, methyldopa, magnesium sulfate; early delivery
HELLP syndrome Beyond 22 wk and after delivery; 20% progress from severe eclampsia 0.5% Abdominal pain, seizures, renal failure, pulmonary edema, liver hematoma and rupture Platelets <100,000/mm3; hemolysis; high LDH level; AST, ALT 70-6000 IU/L; DIC Hepatic rupture, with 60% maternal mortality; fetal death, 1%-30% Prompt delivery

AFLP, acute fatty liver of pregnancy; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DIC, disseminated intravascular coagulation; FHF, fulminant hepatic failure; GGT, γ-glutamyl transferase; HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count).

HG, hyperemesis gravidarum; IHCP, intrahepatic cholestasis of pregnancy; LCHAD, long-chain 3-hydroxylacyl-CoA dehydrogenase; LDH, lactate dehydrogenase; PT, prothrombin time; TSH, thyroid-stimulating hormone.

Acute Fatty Liver of Pregnancy

AFLP is a rare disorder of the third trimester, affecting less than 0.01% of pregnant women. It is most common in primiparous women older than 30 years and in women with multiple gestations carrying a male fetus. Initial symptoms are nonspecific and include nausea, vomiting, and abdominal pain. These manifestations should prompt vigilant monitoring because progression to jaundice, hypoglycemia, disseminated intravascular coagulation with marked decrease of antithrombin III activity, encephalopathy, and frank liver failure can rapidly ensue.

During pregnancy, levels of free fatty acids (FFAs) increase in maternal blood because of the effects of hormone-sensitive lipase and gestational insulin. Transport of fatty acids into the cell and oxidation of fatty acids by the mitochondrion provide the energy necessary for the growth of the fetus. Defects in the genes encoding for the transport and oxidation pathways of fatty acids are inherited as autosomal recessive traits and are known as fatty acid oxidation disorders. These have been shown to be associated with maternal, placental, and fetal complications. During the last trimester, the metabolic demands of the fetus increase, and mothers heterozygous for a fatty acid oxidation disorder and pregnant with an affected fetus can develop AFLP because of their inability to metabolize fatty acids for energy production and fetal growth. Fatty acids then deposit in the liver.

Liver biopsy may be necessary for diagnosis. AFLP is characterized by microvesicular fat deposition in centrilobular hepatocytes. Delivery of the fetus unloads the excess of fatty acid delivery to the liver and leads to rapid recovery without sequelae of chronic liver disease.

The most common disorder of fatty acid oxidation disorder in AFLP is a deficiency of long-chain 3-hydroxylacyl-CoA dehydrogenase (LCHAD). Infants homozygous for LCHAD born to heterozygous mothers suffer from failure to thrive, hepatic failure, cardiomyopathy, microvesicular steatosis, hypoglycemia, and death. Thus, mothers and children born to mothers with AFLP should be screened for the LCHAD gene defect and other disorders of fatty acid oxidation. Treatment of the infant consists of administering formula rich in medium-chain triglycerides. AFLP can recur in subsequent pregnancies, especially in women carrying the LCHAD mutations. However, the overall recurrence rate of AFLP is unclear.

Preeclampsia and Eclampsia

Preeclampsia and eclampsia affect 5% of pregnancies beyond the 22nd week of gestation and are more common in primiparous women with multifetal gestations. Other risk factors include preeclampsia in a previous pregnancy, chronic hypertension, pregestational diabetes, nephropathy, obesity, and antiphospholipid syndrome. Symptoms include hypertension of 140/90 mm Hg or higher and proteinuria higher than 0.3 g in 24 hours. Eclampsia is defined by the additional occurrence of new-onset seizures. Liver test abnormalities are present in 25% of cases. Overlap with the HELLP syndrome occurs in 20% of cases. The underlying mechanism is partly due to abnormal implantation of the placenta, with decreased perfusion, resulting in vasospasm and endothelial injury to various organs, notably the brain, liver, and kidneys. Genetic mechanisms have also been implicated. In a woman with a prior history of eclampsia, the recurrence rate is 20% to 30% for preeclampsia and 2% to 6% for eclampsia.

Liver histology is distinct from that of AFLP. It indicates fibrin deposition in sinusoids, periportal hemorrhage, and liver cell necrosis. Hypertensive crisis, abruptio placentae, and liver failure can occur. Maternal mortality is noted in 1% but can reach 15% of cases in developing countries. Fetal mortality rates range from 5% to 30%. Labetolol (FDA category C) and methyldopa (FDA category B) are the drugs of choice for managing hypertension. Magnesium sulfate (FDA category B) is the drug of choice for preventing and treating seizures in preeclamptic and eclamptic women. Early delivery is often required.

HELLP Syndrome

The HELLP syndrome complicates 0.5% of pregnancies and the recurrence rate is high, approaching 20% in severe cases. It is characterized by microangiopathic hemolysis with burr cells and schistocytes on peripheral smear; elevated liver enzyme levels, with aspartate transaminase (AST) exceeding alanine aminotransferase (ALT) levels; and a platelet count lower than 100,000/mm.

The HELLP syndrome is more common in multiparous women and can manifest in 30% after delivery. Abdominal pain is the usual symptom, and rapid progression to disseminated intravascular coagulation, renal failure, subcapsular liver hematoma, and hepatic rupture are described. Maternal mortality is about 1% but reaches 60% in cases of hepatic rupture. Perinatal death is variable and can reach 37% when the syndrome occurs at an earlier stage of pregnancy. Immediate delivery is the definitive treatment for HELLP syndrome.

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) occurs in the second half of pregnancy and affects less than 1% of all pregnancies. It is more common in multiparous women with twin gestations. It promptly resolves after delivery and usually recurs in subsequent pregnancies. Generalized pruritus is the main complaint, and jaundice occurs in up to 50% of cases. Bilirubin level remains lower than 6 mg/dL, AST level is increased, and total bile acid levels rise markedly, reaching 20 times normal. The etiology of ICP is unclear but might be due to a genetic mutation in the canalicular transporters of phospholipids.

Pruritus may be intense and distressing to the mother, thus requiring therapy. Ursodeoxycholic acid (FDA category B) is the treatment of choice for reducing pruritus. It also improves biochemical markers without adversely affecting the mother or the baby.

The main risk of ICP is to the fetus. High levels of bile acids have been implicated in premature labor, meconium staining and sudden death. These complications may be prevented with immediate delivery.

Recent data suggest long-term effects of ICP on the mother. Nonalcoholic cirrhosis and gallstone-related complications have been reported.

Hyperemesis Gravidarum

Hyperemesis gravidarum (HG) occurs in less than 2% of pregnancies, starting in the first trimester and resolving by week 20 of gestation. It is characterized by severe nausea and vomiting, with electrolyte disturbances that can require hospitalization. Weight loss exceeds 5% of prepregnancy body weight. HG is more common in primiparous women and may be associated with mild elevation of transaminase levels. The cause of HG is unclear, but predisposing factors might include female gender of the fetus. Rehydration and antiemetics are useful. The outcome for the mother is benign except when severe vomiting causes esophageal rupture, vascular depletion, and renal damage. Adverse infant outcomes such as prematurity and low birth weight are rare and seem to occur because of poor maternal weight gain later in the pregnancy.

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Conclusions

Liver disease in pregnancy can manifest as a benign disease with abnormal elevation of liver enzyme levels and a good outcome, or it can manifest as a serious entity affecting hepatobiliary function and resulting in liver failure and death to the mother and her fetus. There are no clinical markers that predict the course of a pregnancy and the pathophysiologic mechanisms are not always understood, but knowledge and management of the preconception liver disease and efficacious pre-pregnancy and prenatal care are essential. The overall mortality attributed to liver disorders in pregnancy has dramatically decreased in the past few years because of clinicians’ understanding of the physiologic changes that occur during pregnancy, their ability to identify and treat preconception liver disorders, and their vigilance in recognizing clinical and laboratory abnormalities in a timely manner. A coordinated team approach that involves the primary care physician, obstetrician, hepatologist, and transplant surgeon is often required to promote good maternal and fetal outcomes.

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Summary

  • Signs and symptoms of liver disease in pregnancy are not specific, but the underlying disorder can have significant morbidity and mortality effects on the mother and fetus. Early recognition can be lifesaving.
  • Acute viral hepatitis is the most common cause of jaundice in pregnancy. The outcome is usually benign. Intervention might not be required except in cases of viral hepatitis E and herpes simplex hepatitis.
  • Women with well-compensated cirrhosis and noncirrhotic portal hypertension may become pregnant. Preconception care and management of pregnant women with portal hypertension should be similar to that for nonpregnant women.
  • Fertility may be restored after liver transplantation and pregnancy might have a good outcome.
  • Vigilance in recognizing liver disorders in pregnancy and early coordinated management among the primary care physician, obstetrician, liver specialist, and transplant surgeon are essential for promoting good maternal and fetal outcomes.

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Suggested Readings

  • ACOG Committee on Practice Bulletins—Obstetrics: ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002;99:159-167.
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  • Chotiyaputta W, Lok AS: Role of antiviral therapy in the prevention of hepatitis B virus infection. J Viral Hepat. 2009 Feb;16(2):91-93. Czaja AJ, Freese DK: Diagnosis and treatment of autoimmune hepatitis. Hepatology 2002;36:479-497.
  • Ghany MG, Strader DB, Thomas DL, Seeff LB: Diagnosis, management and treatment of hepatitis C: an update. Hepatology 2009 April;49(4):1335-1374.
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  • Mast EE, Hwang LY, Seto DS, et al: Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880-1889.
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  • Wasley A, Grytdal S, Gallagher K; Centers for Disease Control and Prevention (CDC): Surveillance for acute viral hepatitis—United States 2006. MMWR Surveill Summ 2008;57(2):1-24.
  • Zapata R, Sandoval L, Palma J, et al: Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience. Liver Int 2005;25:548-554.

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