Hepatitis

Epidemiology and Transmission

Hepatitis A virus infection is one of the most common causes of acute viral hepatitis in the general population; however, it has been infrequently reported among pregnant females. In a study from Ireland, in which 13,181 consecutive deliveries were retrospectively reviewed, only 2% developed HAV during pregnancy. Of 127 consecutive pregnant patients in an Indian series, no cases of acute or fulminant hepatitis from HAV were identified. No cases of HAV infection were identified among the 76-patient prospective 3-year study of pregnant women with acute hepatitis. In other retrospective patient series, the incidence of HAV infection during pregnancy was also extremely low. In a U.S. study of 313 patients affected by the urban HAV epidemic in Tennessee, 4 individuals were pregnant and 2 in their third trimester of pregnancy experienced premature delivery with subsequent full recovery of mothers and children.

In the United States, person-to-person transmission through the fecal-oral route is probably the primary mode of HAV transmission in all subjects, including pregnant women. Infections usually result from a contact from a family member or a sex partner. In most infected individuals, the stool contains a higher concentration of virus and is likely highly contagious during the 1 to 2 weeks before the illness compared with later in the course. The risk of transmission subsequently diminishes by 1 week after onset of jaundice. HAV can be detected in stool for longer periods, however, especially in neonates and young children. The majority of index cases, who are usually unaware of this risk, are international travelers to developing countries, regardless of travel budget, who account for 11% of documented cases of infection without a known source.

HAV is not commonly associated with a severe outcome or complications during pregnancy. Mother-to-child HAV transmission seems to be very rare. In four cases, infections occurred after maternal symptomatic hepatitis A in both second and third trimesters. Nosocomial transmission is unusual, but outbreaks caused by transmission from hospitalized patients to health care staff have been reported. In addition, outbreaks have occurred in neonatal intensive care units from neonates receiving infected transfused blood and subsequently transmitting HAV to other neonates and health care staff.

Microbiology and Pathogenesis

Hepatitis A virus is a single-stranded RNA virus classified as a member of the picornavirus group . Most human strains belong to genotype I or III. The three major proteins of viral capsid—VP1, VP2, and VP3 (structural proteins)—are encoded by P1 region on viral genome. The structural arrangement of capsid proteins VP1 and VP3 forms a single, dominant, serologic epitope on the virus capsid and accounts for a neutralizing antibody response. The virus can be stable in the environment for several months. HAV can live outside the body for months, which is likely explained by the slow translation rate, depending on the environmental conditions.

HAV crosses through the gastrointestinal tract by an uncharacterized mechanism to the liver, where it solely replicates in hepatocytes. The pathogenetic mechanism leading to liver tissue injury by HAV is not a viral cytopathogenic effect. Rather, it is suggested to be an immunopathologic reaction of sensitized cytotoxic T lymphocytes against infected hepatocytes, where these T lymphocytes are present as an antiviral reaction similar to that directed against HBV. A low translation rate and RNA replication rate may play a role in escaping host cell defenses. Almost all individuals infected with HAV develop immunoglobulin G (IgG) and IgM antibodies to VP1.

Pathology

After the availability of serology to confirm HAV, a liver histopathology study was performed in patients with acute viral hepatitis caused by HAV or HBV. The liver parenchymal changes in patients with HAV, including focal necrosis, hepatocellular ballooning, and acidophilic degeneration, were milder than changes seen in patients with HBV, but the degree of portal inflammation seemed similar in these two groups.

Clinical Manifestations

In pregnant women, HAV typically is an acute, self-limited illness associated with fever, malaise, jaundice, anorexia, nausea, and abdominal discomfort after an incubation period of approximately 28 days (range, 15-50 days). A significant number (69%) of pregnant women with acute HAV infection during the second and third trimesters of pregnancy have gestational complications leading to preterm labor, including premature contractions, placental separation, and premature rupture of membranes. Fulminant hepatitis from HAV was reported in one mother who received a liver transplant at the second trimester and lost her fetus after her transplant period.

Although uncommon, neonatal cholestasis resulting from maternal-to-fetal transmission has been reported. Four cases of intrauterine infection have been reported. Two mothers had symptomatic HAV at 20 and 13 weeks of gestation. The fetuses developed ascites, meconium peritonitis, and perforation of the distal ileum in utero, requiring surgery after birth. The newborn infants subsequently recovered. In two other mothers with HAV at 20 days before delivery, infants developed neonatal icteric hepatitis A on day 3 of life and had a full recovery. Mild acute hepatitis in newborn infants followed the onset of hepatitis in their mothers, developing in late third trimester (gestational week >33), probably resulting from a perinatal contact with infected blood or feces. Although typically self-limited, HAV can be potentially life threatening, with an estimated fatality rate of 0.3% to 0.6%, reaching 1.8% among adults older than 50 years. Fulminant hepatitis is rare, but is more common in people with underlying liver disease. Chronic infection does not occur with HAV. Rare extrahepatic manifestations include pancreatitis, renal failure, arthritis, vasculitis, thrombocytopenia, aplastic anemia, red blood cell aplasia, transverse myelitis, and toxic epidermal necrolysis. The appearance of jaundice usually leads to further investigation and the diagnosis of HAV; however, 70% of infected children younger than 6 years are anicteric or have a mild flulike illness. Jaundice is observed in only 7% of children younger than 4 years, including newborns. Symptoms usually last less than 2 months, although 10% to 15% of individuals with HAV have prolonged or relapsing hepatitis for up to 6 months.

Diagnosis

Serologic tests for HAV-specific total and IgM antibody are available commercially. Serum IgM is present at the onset of illness and usually disappears within 4 months but may persist for 6 months or longer. The presence of serum IgM may indicate current infection, recent infection, or HAV vaccination, although false-positive results can occur. Anti-HAV IgG is detectable shortly after the appearance of IgM. The presence of anti-HAV IgG alone indicates past infection and immunity.

Treatment

Treatment generally is supportive. In addition to standard precautions, contact precautions are recommended for diapered and incontinent patients for at least 1 week after the onset of symptoms. One of the most important aspects of management of infected individuals is active and passive immunization of close contacts (see “Prevention,” next). Some patients with cholestasis may not tolerate a fatty diet. In individuals with fulminant hepatitis or liver failure, specific management is determined by the complications, and evaluation for liver transplant may be required.

Prevention

Acute HAV infection during pregnancy and perinatal transmission seem to be rare, especially at the time of delivery. There have been no data to suggest cesarean section as a mode of delivery for HAV-infected pregnant women; infants born via vaginal delivery to mothers with acute HAV infection have a favorable outcome. No data exist about administration of the hepatitis A vaccine to pregnant women. Because the vaccine does not contain a live virus, the risk to mother and fetus should be extremely low to nonexistent. The prevalence of HAV infection in young children seems to be decreasing in countries that are moving from high-to-intermediate endemic areas. It is expected that an increased number of adolescents and adults susceptible to HAV may be associated with greater morbidity, mortality, and treatment costs. On the other hand, in areas of low endemicity for HAV, outbreaks of HAV infection could put individuals, including pregnant women who are not immune to HAV, at risk. Although rare, acute HAV infection during pregnancy is associated with a high risk of maternal complications and preterm labor; HAV serology and maternal immunization during prenatal or pre-pregnancy evaluation could be considered in areas in which adult populations are susceptible to HAV.

The infant usually has exposure to HAV before the diagnosis is made in the mother. HAV has been detected in breast milk, but only one newborn case of HAV transmission in breast milk has been reported. Although the efficacy has not yet been established, immunoglobulin (0.02 mL/kg) is advised to be administered to the infant if the mother’s symptoms of HAV began between 2 weeks before and 1 week after delivery. To prevent nosocomial transmission, particularly in the neonatal intensive care unit or newborn nursery, the infected mother and the neonate should be isolated, and careful hygiene practices should be emphasized.

The presence of passive maternal HAV antibody during the first 6 to 12 months of life would interfere with vaccine immunogenicity. HAV vaccination is recommended and licensed in the United States for all children 1 to 18 years of age; for adults who are at increased risk for infection; for adults who are at increased risk for complications from HAV, such as persons with underlying liver disease; and for any person wishing to obtain immunity to HAV. HAV vaccines are given intramuscularly in a two-dose schedule with a 6- to 12-month interval. Doses and schedules for HAV vaccines and formulations produced by different manufacturers are recommended by American Academy of Pediatrics (AAP). Current HAV vaccines have been shown to be safe, to be highly immunogenic, and to confer long-lasting protection. Vaccine-induced antibodies persist for longer than 12 years in vaccinated adults, and mathematical modeling predicts antibody persistence for longer than 25 years in greater than 95% of vaccine recipients. Intramuscular immunoglobulin is more than 85% effective in preventing symptomatic infection when given within 2 weeks after the most recent exposure to HAV in a household or sexual contact.

Epidemiology and Transmission

Acute HBV infection does not appear to increase mortality during pregnancy or to have teratogenic effects. However, a higher incidence of low birth weight and prematurity has been reported. In addition, acute HBV early in pregnancy is associated with a 10% perinatal transmission rate, and the rate increases substantially with HBV infection in the third trimester. The effects of chronic HBV infection on pregnancy outcomes have not been clearly defined. In a study of pregnancy outcome comparing hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative women, there were no differences in gestational age at delivery, birth weight, incidence of prematurity, neonatal jaundice, congenital anomalies, or perinatal mortality. In general, women with chronic hepatitis B do well during pregnancy. Although the infection is usually well tolerated, cases of exacerbation of hepatitis and even fulminant hepatic failure have been described in the peripartum period. The strategy to control HBV viremia during pregnancy is prudent.

Before the development of the combination vaccination strategy (hepatitis B immunoglobulin [HBIG] plus vaccine) for high-risk neonates, most neonates born to HBV-infected mothers were infected with HBV. Chen and colleagues reported that the presence of HBsAg in gastric aspirates of newborns was strongly associated with the acquisition of HBsAg by the infants; there was no correlation between the rate of infant antigenemia and the duration of the first stage of labor, and cesarean section did not decrease the rate of vertical HBV transmission.

The prevalence of chronic HBV infection in pregnant women in urban areas of the United States varies by race and ethnicity, the highest rate being in Asian women (6%); the rates in black, white, and Hispanic women are 1.0, 0.6, and 0.14%, respectively. European studies show similar data, with highest rates among immigrants and low immunization-induced protection rates. In areas of high endemicity, such as China, other Far East countries, and Africa, rates of chronic HBV infection are higher. According to recent data from the Centers for Disease Control and Prevention (CDC), prenatal screening for HBsAg in the United States showed that 97% of pregnant women undergo screening before delivery. Among infants at risk of acquiring HBV infection, 92% completed the three-dose vaccination by the time they are 3 years of age. Outside the United States, however, many high-prevalence countries lack immunization coverage, and perinatal transmission is common. In 87 countries with a prevalence of HBV infection that exceeds 8%, the infant immunization coverage was only 36%.

Perinatal transmission occurs at or near the time of birth because of exposure to cervical secretions and maternal blood. To a minor degree, transplacental transmission presumably is responsible for perinatal infections, depending on risk factors: maternal HBeAg positivity, HBsAg titer, and HBV DNA level. Despite the use of effective active and passive immunoprophylaxis, perinatal transmission might still occur. Mothers positive for HBeAg and mothers with very high serum DNA levels (e.g., 10 copies/mL) have the greatest risk of transmitting HBV to their offspring, despite adherence to the recommended combination of active and passive immunization of newborns within 24 hours of birth. In one Chinese study, 7.4% of infants born to HBV-infected mothers were infected with HBV during the first year of life, despite receiving passive and active immunoprophylaxis in the immediate newborn period. Mode of delivery does not influence the likelihood of HBV transmission. Wang and colleagues compared outcomes among three groups of 144 infants born by spontaneous vaginal delivery, 40 by forceps or vacuum extraction, and 117 by cesarean section. All infants received HBIG and HBV vaccine at the recommended schedule. Chronic HBV infection was detected at the rates of 7.3, 7.7, and 6.8%, respectively, and response rates to immunization were the same in all groups.

Sexual intercourse in the second trimester of pregnancy has also been implicated in HBV intrauterine transmission. Although the prevalence is low, another risk of HBV transmission is amniocentesis in HBsAg-positive mothers. In one series of 21 mothers with positive HBsAg who underwent amniocentesis for accepted indications at a mean of 19.5 weeks of gestation, none of the infants who received the HBIG and HBV vaccine as recommended was HBsAg positive at 1 or 12 months of age. In a study of 47 HBsAg positive women who presented for amniocentesis, 32% of the amniotic-fluid samples were HBsAg positive, but HBV DNA was undetectable in all. Although cord blood from 27% of the infants contained HBsAg, none contained HBV DNA. Although HBsAg can be detected in the breast milk of HBV-infected mothers, several studies have shown there is no additional risk of transmission of HBV to breastfed infants of infected mothers, provided that proper active and passive immunoprophylaxis is carried out.

Microbiology and Pathogenesis

Hepatitis B virus is a well-characterized, partially double-stranded DNA virus . HBsAg is the hallmark of chronic infection. This marker is the first to appear in acute infection. The presence of HBsAg for 6 months or more connotes chronic infection. HBeAg is associated with infectivity and indicates active replication of HBV. More recent reports have described “occult HBV,” as defined by the presence of HBV DNA in serum or tissue in the absence of other markers. Several HBV genotypes are now recognized, and knowledge is emerging regarding their clinical significance. It is recognized that HBV genotype C is associated with an increased risk of development of hepatocellular carcinoma, as are the basal core promoter mutant and the pre-S deletion mutant. Whether or not there is a role for quantification of HBV antigens or intrahepatic HBV covalently closed circular DNA, or both, is currently under investigation.

HBV is thought to cause liver injury in immunocompetent subjects via cytotoxic T cells directed to the infected hepatocyte. Functionally impaired dendritic cells may play a role in viral persistence, and B and T cells are involved in viral clearance. In immunocompromised subjects, such as individuals who have undergone liver transplantation, the virus itself may be hepatotoxic because HBV recurrence in the allograft is associated with poor patient and graft survival. The HB-X protein is a transcriptional activator of cellular genes and may play a role in the hepatocarcinogenesis of HBV via effects on apoptosis, DNA repair, mitogen-activated protein kinase, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways.