The Liver in Pregnancy

Drug Metabolism

Medication use during pregnancy is common and includes prescription, over-the-counter, and herbal products. A study of U.S. and Canadian women found that, on average, 2.3 drugs were used during pregnancy; however, 28% of women reported using more than four medications. The liver plays a major role in drug metabolism and detoxification. Various hemodynamic changes during pregnancy, such as the increase in blood volume, cardiac output, and glomerular filtration rate, may contribute to altered drug metabolism, disposition, and clearance. Gastrointestinal absorption or bioavailability of drugs may vary because of changes in gastric secretion and motility. Drug properties such as lipid solubility, protein-binding characteristics, and ionization constant influence the placental passage of drugs. Moreover, changes in the activity of maternal and fetal drug-metabolizing enzymes may affect maternal drug distribution and clearance.

Pregnancy alters the ability of a drug to be distributed within the body, in part by causing reduced concentrations of both albumin and α ₁ -acid glycoprotein. Moreover, the increase in body weight in late pregnancy results in a decrease in dose per kilogram. Caffeine metabolism is reduced during pregnancy because of decreased activity of cytochrome P-450 1A2. The activity of cytochrome P-450 2A6 is increased, and drugs such as nicotine exhibit substantially lower serum concentrations. Likewise, the activity of cytochrome P-450 3A4 is increased, and drugs such as nifedipine, carbamazepine, midazolam, indinavir, lopinavir, and ritonavir have an increased clearance. Drugs such as metoprolol, fluoxetine, citalopram, and nortriptyline may exhibit increased clearance. The dose of selective serotonin reuptake inhibitors must be increased to maintain efficacy in pregnancy. Furthermore, glomerular filtration rate is increased in pregnancy because of an increase in cardiac output; therefore drugs that are eliminated by renal mechanisms, such as ampicillin, cefuroxime, ceftazidime, cephradine, cefazolin, piperacillin, atenolol, sotalol, digoxin, and lithium, have increased clearance rates. Both estrogen intake and pregnancy impair hepatic activity of uridine 5'-diphospho-glucuronosyltransferase (UGT), and progestational agents induce hepatic mixed-function oxidase activity in animals. Acetaminophen (APAP) metabolism is unchanged in pregnancy. APAP crosses the placenta and is detected in the neonatal serum after birth. Glucuronidation, the main metabolic pathway that safely metabolizes APAP in adults, is markedly reduced in the neonate, leaving sulfation as the major pathway for APAP metabolism. APAP toxicity in pregnancy is not rare and can result in significant morbidity and mortality in both the mother and the fetus. N -Acetylcysteine can be safely administered during pregnancy and should be given early after APAP overdose. Clinicians must vigilantly monitor both the dose of drugs and the patient's response during pregnancy. Table 54-2 lists the categories by class of the Food and Drug Administration (FDA) during pregnancy for common drug therapy used in pregnant patients with liver disease.

Serum Proteins and Lipids

Normally, up to 10 g of albumin is produced and secreted by the liver daily. Serum albumin concentrations decrease during the second trimester and continue to decline throughout pregnancy, reaching concentrations approximately 70% to 80% of normal values at the time of delivery secondary to hemodilution. In pregnancy the intravascular mass of albumin does not change and the rates of albumin synthesis and catabolism are not affected. By contrast, there is an increase in serum concentration of some proteins, such as α ₂ -macroglobulin, α ₁ -antitrypsin, and ceruloplasmin.

The levels of fibrinogen and most coagulation factors (II [prothrombin], VIII, IX, and XII) increase, protein S levels decrease, and fibrinolysis is inhibited. These physiologic changes in hemostasis limit bleeding during delivery but are associated with an increased risk of thromboembolism during pregnancy and the postpartum period. Prothrombin time (PT) reflects the extrinsic clotting pathway involving prothrombin and factors V, VII, and X and is used to assess hepatic synthetic function. PT is considered a universal indicator of liver failure and is prolonged in acute liver failure. It is generally not affected by pregnancy, and any change in PT during pregnancy should be considered pathologic and warrants further investigation. Serum albumin has a long half-life of 20 days and is not a good indicator of hepatic synthetic function in acute liver disease. However, the half-lives of blood clotting factors are quite short (approximately 1 day) and are useful indicators of liver injury.

Serum cholesterol, triglyceride, and phospholipid concentrations increase in late pregnancy. The levels of total serum cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol increase by 25% to 50%, whereas the concentrations of serum triglycerides increase to twice to four times their nonpregnant levels. This hyperlipidemia is a result of the metabolic adaptation to the pregnancy state. Consequently, measurement of serum lipid concentrations is rarely useful during pregnancy, an exception being in the pregnant woman with from acute pancreatitis. Serum concentrations of α-globulins and β-globulins are increased whereas the levels of γ-globulins are decreased ( Table 54-3 ).

Bilirubin

Bilirubin is formed through the degradation of heme by heme oxygenase, which results in the formation of carbon monoxide, iron, and biliverdin as end products. Biliverdin is then converted to unconjugated bilirubin by biliverdin reductase. Normal serum bilirubin values represent a balance between the production of bilirubin as a result of heme degradation (unconjugated bilirubin) and the hepatic elimination of bilirubin (conjugated bilirubin). In the liver, UGTs conjugate the water-insoluble bilirubin to glucuronic acid, and conjugated bilirubin is then excreted into the bile. Defects in UGT activity result in indirect hyperbilirubinemia, and impaired biliary excretion results in direct hyperbilirubinemia. The normal value for serum total bilirubin level is 1 mg/dL, of which 70% is unconjugated bilirubin.

In pregnant women the total and free bilirubin concentrations are significantly lower during all three trimesters as are the concentrations of conjugated bilirubin during the second and third trimesters. Hemodilution could at least be partly responsible for the decrease in bilirubin concentration because albumin is the protein that transports bilirubin. Gilbert syndrome is characterized by mild unconjugated nonhemolytic hyperbilirubinemia and generally affects 7% to 10% of the average population. In 80% to 100% of patients with Gilbert syndrome, the TA insertion in the promoter region of the gene is present in the homozygous (TA) ₇ /(TA) ₇ form, and leads to a decrease in the amount of functionally active enzyme. This will result in mild indirect hyperbilirubinemia with serum total bilirubin levels of 5 mg/dL or less. The disease is not associated with cholestasis or pruritus, and serum bile acid level is normal. HELLP syndrome has been associated with postpartum indirect hyperbilirubinemia and should be differentiated from Gilbert syndrome. There is no association between HELLP syndrome and Gilbert syndrome. The treatment of patients with Gilbert syndrome is the same for both pregnant and nonpregnant patients. Conservative management and reassurance should be provided.

Patients with Crigler-Najjar syndrome type 1 have an unconjugated hyperbilirubinemia attributable to the complete absence of activity of UGT, a bilirubin-conjugating enzyme. In pregnant women with Crigler-Najjar syndrome type 1 the fetus is at high risk of being adversely affected by the bilirubin, because unconjugated bilirubin can cross the placenta and may cause kernicterus, a potentially neurotoxic condition. Successful pregnancy in patients with Crigler-Najjar syndrome has been reported with the use of phenobarbital and phototherapy.

Dubin-Johnson syndrome is a rare benign chronic disorder of bilirubin metabolism, characterized by conjugated hyperbilirubinemia, darkly pigmented liver, and the presence of abnormal pigment in hepatic parenchymal cells. Pregnancy and the use of oral contraceptives in women with Dubin-Johnson syndrome cause a reversible increase in serum conjugated bilirubin level. Placental concentrations of bile acids remain normal. Affected women may be deeply jaundiced during pregnancy but pruritus and signs of generalized cholestasis are absent.

Bile Acids

Increases in serum concentrations of certain bile acids have been reported during pregnancy, and it has been suggested that pregnancy could be associated with subclinical cholestasis. Organic anion transport, including transport of bilirubin and sulfobromophthalein, is impaired during pregnancy. These changes are likely caused primarily by estrogen- or pregnancy-induced decreases in the canalicular organic anion–transporting pump multidrug resistance–associated protein 2. The changes in concentrations of serum bile acids in pregnancy are minimal and are observed mainly in the postprandial state. The concentrations of bile salts in blood are within the normal range in most pregnant women but the levels of glycocholate, taurocholate, and chenodeoxycholate may rise progressively until term and exceed levels measured early in pregnancy by twofold to three-old. Pregnancy- or estrogen-induced decreases in bile salt transport are likely attributable to reductions in both sinusoidal (Na ⁺ -taurocholate cotransporting polypeptide) and canalicular (bile salt export pump) bile salt transporters. In clinical practice, when a woman experiences pruritus during pregnancy, the measurement of serum bile acid concentration may be useful for the diagnosis of cholestasis, especially when routine liver function test values are still within normal limits.

Changes in Liver Function Test Values

Close monitoring of serum liver function test values is essential in the management of liver diseases in both pregnant and nonpregnant patients. Routine liver function tests usually include measurement of the levels of total and conjugated bilirubin, aminotransferases, and alkaline phosphatase, as well as determination of PT. In addition, γ-glutamyltransferase or 5′-nucleotidase activity may be used to confirm the hepatobiliary origin of increased levels of alkaline phosphatase. Measurement of serum bile acid concentrations may be useful for the management of cholestasis, especially during pregnancy. Awareness of the physiologic changes in liver function tests is indispensable for the interpretation of these test values during pregnancy.

Measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity levels is the most useful test for the routine diagnosis of liver diseases. The effects of pregnancy on serum ALT and AST activity levels are somewhat controversial. In a few studies a slight increase in ALT and/or AST activity has been found during the third trimester. However, in most published studies, serum ALT and AST activity levels remain within the normal limits established in nonpregnant women. Thus it should be emphasized that serum AST or ALT activity values above the upper limit of normal values before labor should be considered pathologic and should lead to further investigations. Serum alkaline phosphatase activity levels increase in late pregnancy, mainly during the third trimester. By contrast, serum alkaline phosphatase levels have been found to be lower in oral contraceptive users. This increase during pregnancy is not due to an increase in the hepatic isoenzyme but rather is largely attributable to the production of the placental isoenzyme. During the third trimester there is also an increase in the production of the bone isoenzyme as documented by an increase in its serum level up to 6 weeks after delivery. These findings document that the measurement of serum alkaline phosphatase activity is not a suitable test for the diagnosis of cholestasis during late pregnancy and in the postpartum period.

Hepatitis A

HAV is a small (27-nm) RNA virus that causes either symptomatic or asymptomatic infection in humans. The average incubation period is 28 days (range 15 days to 50 days). HAV replicates within the liver and is excreted in bile, with the highest viral concentrations in the stool late in the incubation period. This represents the window of greatest infectivity. Person-to-person transmission is the primary means of HAV infection in the United States. Serious complications of HAV infection are uncommon; the overall case-to-fatality ratio among reported cases is less than 1%, and acute HAV does not lead to chronic infection, although 10% to 15% of symptomatic individuals can have a prolonged or relapsing disease lasting up to 6 months.

The rate of HAV infection in pregnant patients is very low and, therefore, predicting outcomes of HAV infection in pregnant patients is difficult. Traditionally it has been thought that if a pregnant woman becomes infected with HAV, generally the baby is not affected. However, two single-country studies found a high incidence of maternal and fetal complications in cases of HAV-infected pregnant patients. Intrauterine transmission of HAV is very rare; however, perinatal transmission could occur. The management of acute HAV infection in pregnancy does not differ from that used in nonpregnant patients and it consists of supportive therapy. Maternal immunization embraces the concepts that vaccines given to pregnant women enhance their resistance to vaccine-preventable diseases, and passive antibodies that cross the placenta protect the neonate for the first 3 months to 6 months of life.

The safety of hepatitis A vaccination during pregnancy has not been fully determined; however, because hepatitis A vaccine is produced from an inactivated HAV, the theoretical risk to the developing fetus is expected to be low. A review of a vaccine adverse event reporting system in the United States (under the auspices of the Centers for Disease Control and Prevention and the FDA) found no significant concerns for adverse events related to the hepatitis A vaccine. The risk associated with vaccination should be weighed against the risk of infection with HAV in women who may be at high risk of exposure to HAV. It was observed that passively acquired maternal anti-HAV resulted in a significantly lower antibody response in infants when hepatitis A vaccine was administered. This is possibly due to interference between maternal antibodies and hepatitis A vaccination in young infants. It is proposed that all pregnant women should be screened at delivery for anti-HAV antibodies and children born to anti-HAV–negative mothers should be vaccinated early during the first year of life, whereas vaccination may be postponed in children born to anti-HAV–positive mothers if necessary. Mothers infected with HAV are encouraged to breastfeed, and HAV infection is not a contraindication for breastfeeding.

Hepatitis B

HBV is a hepatotropic double-stranded DNA virus and a member of the family Hepadnaviridae . An estimated 350 million people worldwide are chronically infected with HBV, including approximately 1.25 million in the United States. Virtually 100% of hepatocytes are affected once infection is established. Carriers with chronic HBV infection are at risk of developing liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). HBV is generally noncytolytic but liver injury is attributed to host immune response. In rare cases, acute liver failure ensues. In contrast to HCV, which replicates in the cytoplasm of the hepatocyte, HBV (double-stranded DNA) enters the nucleus and its DNA is converted to a covalently closed circular form. This is a remarkably stable species from which all viral messenger RNAs are transcribed and is resistant to antiviral therapy. HBV is transmitted mainly by perinatal, sexual, and parenteral exposure. Perinatal transmission is the most common route in China and East Asia and sexual transmission is common in Europe and North America.

HBV has a high rate of vertical transmission, causing fetal and neonatal hepatitis. Because HBV is highly pathogenic and infectious, perinatal transmission of HBV infection is the single largest cause of chronic infection of individuals worldwide. Approximately 10% to 20% of women who are seropositive for hepatitis B surface antigen (HBsAg) alone transmit the virus to their neonates in the absence of neonatal immunoprophylaxis. However, if the mother is seropositive for both HBsAg and hepatitis B e antigen (HBeAg), the frequency of vertical transmission increases to approximately 90% without neonatal prophylaxis. Therefore the American Congress of Obstetricians and Gynecologists and the Centers for Disease Control and Prevention recommend universal screening for HBsAg in all pregnant women. If a neonate is given hepatitis B immunoglobulin (HBIG) and the hepatitis B vaccine, the rate of mother-to-child transmission is reduced to 5% to 10%. A review of the characteristics of mothers and children undergoing prenatal HBV screening and postnatal prophylaxis showed that pregnant patients with a negative HBeAg status and low viral load had an extremely low risk of mother-to-child HBV transmission.

The diagnosis of HBV infection is established by the detection of HBsAg in serum by enzyme immunoassays (EIAs). The presence of anti–hepatitis B surface antibody confers lifelong protective immunity. Testing for HBV is generally a standard test performed on all pregnant women at or before their first prenatal visit (usually before 12 weeks to 14 weeks of gestation). Pregnant women who are directly exposed to HBV should receive a HBIG injection ideally within 72 hours of exposure and then a hepatitis B vaccine within 7 days of exposure. Hepatitis B vaccine is then administered two more times—at 1 month and 6 months after the first vaccination. It is recommended that every infant receive three doses of hepatitis B vaccines. The current vaccines contain noninfectious HBsAg and should cause no potential risk to the fetus. Hepatitis B vaccine administration to pregnant women is relatively safe and its benefits outweigh its risks. Hepatitis B vaccination can be delayed more than 24 hours after the baby's birth but should be given within the first week of delivery. The combination of passive and active immunization is very effective in reducing the frequency of perinatal transmission of HBV (85% to 95% efficacy). Several antiviral therapies are currently available for HBV. The current (2015) FDA-approved therapy for HBV includes subcutaneous injection of interferon/pegylated interferon-alfa and orally administered nucleoside/nucleotide analogues such as lamivudine, adefovir, entecavir, telbivudine, and tenofovir. Telbivudine and tenofovir are classified as FDA category B drugs in terms of safety, whereas adefovir, entecavir, and lamivudine are classified as FDA category C drugs. An oral nucleoside/nucleotide analogue can be given to mothers with high HBV DNA levels during the second and third trimesters to reduce the risk of transmission at the time of delivery. Treatment is generally not recommended for use against HBV in the first trimester of pregnancy. However, potential benefits may justify the potential risk. In a study of 450 HBeAg-positive pregnant women, those who were given telbivudine between week 24 and week 32 of pregnancy had significantly lower rates of infant HBsAg positivity at 6 months (none tested positive in the telbivudine group) and higher rates of undetectable HBV DNA in the mother. Furthermore, there were no significant adverse events in the mothers or children. Other studies have shown telbivudine and lamivudine to be equally effective in reducing HBV transmission ,with no significant side effects, and a study has shown tenofovir to be effective in reducing mother-to-child HBV transmission.

European Association for the Study of the Liver guidelines recommend treatment in the last trimester with one of the class B agents for pregnant women with mild liver disease and high viremia. Other indications for HBV treatment during pregnancy to prevent mother-to-child transmission include treatment of mothers with HBsAg positivity who previously had a child in whom HBIG therapy and vaccination failed ( Fig. 54-1 ).

There is also concern for reactivation of HBV in the postpartum period. An analysis of the risk of HBV reactivation in HBeAg-negative pregnant patients showed that postpartum reactivation occurred in approximately 30% of HBeAg-negative patients, and a prepartum HBV DNA level greater than 10,000 IU/mL was predictive of reactivation. This should be considered when one is determining the need for treatment of HBV during pregnancy.

Hepatitis C

HCV is a hepatotropic positive single-stranded RNA virus of the genus Hepacivirus and a member of the family Flaviviridae . It replicates primarily in hepatocytes using both host and viral enzymes. HCV is the most common cause of chronic blood-borne infection in the United States. Chronic HCV infection is estimated to affect 170 million people worldwide, including 2 million to 3 million Americans (1.8% of the general population). There are six HCV genotypes (1, 2, 3, 4, 5, and 6), and a large number of subtypes (e.g., 1a, 1b, and 1c) have been identified. The major risk factor for HCV transmission is injection drug use. Other risk factors include exposure to clotting factor therapy before 1987, blood transfusion before 1992, contaminated therapeutic equipment, and occupational needlestick. Modes of HCV transmission also include sexual and perinatal transmission. The most remarkable feature of HCV is its ability to establish chronic infection in 55% to 85% of individuals with acute infection. Approximately 20% of chronically infected patients eventually develop cirrhosis, hepatic decompensation, and HCC after 20 years to 30 years of infection. The risk of HCC in HCV-infected patients with cirrhosis is 2% to 3.5% per year. The incidence of acute hepatitis C has declined markedly since 1990. Therefore data on vertical HCV transmission are based on chronic hepatitis C. Vertical HCV transmission rates range from 2% to 8%, with maternal viremia defined as detectable HCV RNA in blood, an almost uniform prerequisite for transmission. In pregnancies among HCV-infected mothers who were HCV RNA negative, vertical transmission was rare. Maternal coinfection with human immunodeficiency virus (HIV) significantly increases the risk of vertical HCV transmission to as much as 44%. A cohort study showed that risk factors associated with increased rate of vertical HCV transmission were higher maternal HCV viral titer, prolonged membrane rupture during labor (6 hours or longer), HIV coinfection, and use of internal fetal monitoring during labor. The risk of transmission through amniocentesis appears to be low for women who are chronically infected.

Serologic confirmation of exposure to HCV is performed by the detection of serum or plasma HCV antibodies by third-generation EIAs. Confirmation of viremia is established through testing for HCV RNA by a sensitive assay with a lower limit of detection of 50 U/mL or less. Unlike for HBV, there are no preventable measures available to lower the risk of vertical HCV transmission. Routine prenatal HCV screening is not recommended; however, women with significant risk factors for infection should be offered antibody screening. Both HCV antibodies and HCV RNA have been detected in colostrum; however, breastfeeding appears to be safe. In some studies HCV has been associated with an increased risk of cholestasis of pregnancy and preterm birth, although the increased association of HCV and preterm birth may be due to confounders, such as prior drug use, smoking, and alcohol use.

Before 2014 the treatment for chronic HCV infection in nonpregnant women was combination therapy of pegylated interferon-alfa and ribavirin. Ribavirin is an FDA pregnancy category X product (see Table 54-2 ), indicating that its use is contraindicated in women who are pregnant. However, new oral medications (including protease inhibitors and polymerase inhibitors) have been approved for treatment of HCV. These medications have not been studied extensively in pregnant women. Given the relatively short duration of treatment of the new HCV medication regimens, women are advised to, if possible, delay pregnancy until after treatment is completed.

Hepatitis E

The epidemiologic features of hepatitis E are similar to those of hepatitis A. The disease has been reported rarely in the United States, and the highest rates of infection occur in regions of the developing world or among immigrants or travelers from endemic countries. Hepatitis E is primarily a waterborne disease; epidemics have been reported in areas where fecal contamination of drinking water is common. In general, HEV produces a self-limited viral infection followed by recovery; the incubation period is 3 weeks to 8 weeks, with a mean of 40 days. One study from India showed an increased occurrence of HEV in pregnant women as compared with nonpregnant women, and also showed a higher mortality in the pregnant women. HEV infection is known to cause severe hepatitis, fulminant liver failure, preterm labor, and increased mortality in pregnant women, especially in their third trimester, with reported maternal death rates as high as 20% to 31.1%. The mechanism of fulminant hepatitis E in pregnancy is not clear but is thought to be attributable to induction of type 2 cytokines. Maternal-to-fetal transmission of HEV has been reported and may be as high as 79%. In two prospective studies conducted in India, mother-to-child transmission of HEV ranged between 33.3% and 50%. There is no current evidence regarding the transmissibility of HEV through breast milk. It appears that it would be especially important for mothers to continue breastfeeding during epidemics of HEV in underdeveloped and endemic areas to prevent a greater risk of infant mortality from other infectious diseases. Treatment of HEV during pregnancy is supportive.