Hepatitis A virus (HAV) is a small, nonenveloped RNA virus that belongs to the picornavirus family. There are several genotypes of HAV, but only one known serotype. Its incubation period averages four weeks, with a range of 15 to 50 days. HAV replicates in the liver, and then is transported through the biliary tree and shed in the stool. Fecal excretion of the virus begins 1 to 2 weeks before the onset of the illness, and continues for at least 1 week after that. Infants and children can shed HAV in the stools for several months (741,742).

HAV infections are very common in early life in developing countries. In the United States, there were an estimated 90,000 persons with symptomatic hepatitis A and another 90,000 persons with subclinical infection in 1997. A third of reported cases are in children less than 15 years of age. There are geographic variations within the United States with regards to disease incidence, with higher rates in western states such as Arizona, Alaska, Oregon, and New Mexico. HAV infection rates are also highest for American Indians and Alaskan Natives, and lowest for Asian Americans (742).

Transmission of HAV is primarily by person-to-person contact through fecal contamination and oral ingestion of the virus during communitywide outbreaks (742). The virus is highly communicable. Approximately 16% to 30% of an inoculum of HAV can be recovered from infected hands after 4 hours (743). The most commonly reported source of HAV infection in the United States is household or sexual contact with a person with hepatitis A in 12% to 26% of instances. Other sources of exposure are day care attendance or employment, international travel, food or waterborne outbreaks, and injecting or noninjecting drug use (742). A study from Israel found that certain occupations such as yeshiva students, day care center and kindergarten staff, food industry workers, teachers, physicians, and dentists were at increased risk of hepatitis A infection (744).

Neonatal intensive care unit outbreaks of hepatitis A have been described (745,746,747,748). The initial infection in some outbreaks occurred through transfusion of neonates with blood or fresh frozen plasma from donors with hepatitis A viremia during the prodromal phase of their illness (746,747,748). In one nursery outbreak, 20% of infants, 24% of nurses, and several nonnursing staff and household contacts were affected. The study found that having long fingernails, not wearing gloves for certain procedures, smoking, and drinking beverages in the nursery facilitated direct hand-to-mouth contact (747). Other risk factors for spread of hepatitis A to new infants and nursery personnel includes asymptomatic infection, prolonged fecal virus shedding, frequent contact with soiled diapers, and breaks in infection control measures.

Most children younger than 6 years of age have asymptomatic or anicteric HAV infections, whereas most adults have symptomatic disease (742). The typical clinical illness seen
in over 80% of symptomatic individuals begins abruptly with fever, malaise, headache, anorexia, nausea, vomiting, and diarrhea; dark urine, clay-colored stool, and jaundice appear a week or two later (741,742). Other disease forms include relapsing hepatitis A, cholestatic hepatitis A, and fulminant hepatitis A. Extrahepatic manifestation such as vasculitis, arthritis, hemolytic anemia, or cryoglobulinemia are infrequent (741). In contrast to hepatitis A and hepatitis B, there is no chronic carrier state for HAV. About 100 persons in the United States die each year as a result of acute liver failure due to hepatitis A (742).

Approximately 33% to 38% of the US population are positive for HAV IgG (741,749). The incidence of acute hepatitis A in pregnancy is 1:1000 or less. Pregnant women are not more susceptible to HAV, nor do they have a worse clinical outcome, than nonpregnant women (749).

Serologic testing is needed to establish a diagnosis of acute hepatitis A. IgM antibodies to HAV are found 5 to 10 days before the onset of symptoms and for 3 to 6 months after that. HAV IgM is measurable for a longer time in patients with symptomatic hepatitis A than in those with asymptomatic infection (750). HAV RNA can be detected by PCR in serum, stool, or other body fluids during the acute phase of infection, but this test is rarely needed and is not readily available (741,742).

Treatment of hepatitis A is supportive. Management of infection usually includes bed rest, nutrition, avoidance of alcohol and hepatotoxic medications (741).

A number of published case reports suggest that intrauterine and perinatal transmission of HAV does occur, with resultant symptomatic disease in the neonate (751- 756). In some of these reports, the mothers developed hepatitis A shortly before or immediately after delivery (751,752,753). Other reports describe women with acute hepatitis A several weeks before parturition. One mother developed hepatitis A at 20 weeks of gestation; an abdominal ultrasound at 27 weeks of gestation showed polyhydramnios and fetal ascites. Cordocentesis allowed the detection of HAV IgM in fetal blood. Meconium peritonitis subsequently developed at 35 weeks of gestation, which required surgical intervention after delivery (754). In another report, a mother developed hepatitis A at week 13 of gestation and her fetus was noted to have ascites at 20 weeks; meconium peritonitis was found at 33 weeks of gestation. The infant was delivered at 35 weeks gestation and a perforated distal ileum was found (755). Another mother whose hepatitis A occurred during her fourth month of pregnancy had protracted jaundice until she delivered at 36 weeks of gestation. The neonate was small for age and subsequently developed acute hepatitis A infection at 4 weeks of age. HAV RNA was detected in the mother’s serum obtained at 4 months of pregnancy and the infant’s serum at the age of 4 weeks (756).

The prevention of hepatitis A can be accomplished by both passive and active immunization. Intramuscular immune globulin (IGIM) at a dose of 0.02 mL/kg given within 2 weeks of last exposure confers greater than 85% protection. Pregnancy is not a contraindication to IGIM administration, but only thimerosal-free preparations should be used. Two inactivated hepatitis A vaccines are available in the United States, and one combined inactivated hepatitis A and hepatitis B vaccine. Although the hepatitis A vaccines are not approved for use during pregnancy, the theoretical risk to the fetus should be weighed against the risk of hepatitis A to susceptible women at high risk of exposure to HAV (742). Hepatitis A vaccine is immunogenic in infants, but it is currently approved for use in persons 2 years of age or older. Placental transfer of HAV IgG occurs in both term and preterm newborns, and its presence has been shown to lower the antibody response to the vaccine in these infants (757,758).

HBV afflicts nearly 335,000 persons in the United States each year, about 5% of whom become chronic carriers of the virus (759,760). Estimates place the number of chronic, infectious HBV carriers in the United States at more than 1.25 million people (759). Globally, a third of the world population (about 2 billion) have been infected with HBV. The number of chronic HBV carriers worldwide is greater than 400 million, three-quarters of whom are Chinese, according to estimates by the World Health Organization (761). As many as 1 million people die each year from HBV-related acute and chronic hepatic disease (762). More than one-fourth of all carriers develop HBV-related chronic active hepatitis, liver cirrhosis, or hepatocellular carcinoma (759). Women who are chronic carriers of this virus can transmit HBV to their offspring during pregnancy; as many as 90% of perinatally infected infants become chronic carriers themselves (759).

The complete HBV is known as the Dane particle and consists of an outer lipid-containing envelope and an inner core or nucleocapsid. On the surface of the outer coat is the hepatitis B surface antigen (HBsAg), an antigenically complex glycoprotein. HBsAg has many antigenic epitopes that permit the identification of several HBV subtypes; the subtyping scheme is valuable as an epidemiologic tool, but it has no correlation with disease severity. The surface envelope contains three proteins (major, middle, and large S proteins) coded for by the HBV DNA genome. Variations in the major protein account for the subtype determinants, and the middle and large proteins are implicated in receptor-mediated virus uptake by hepatocytes (762).

The virus inner core consists of hepatitis B core antigen (HBcAg), hepatitis B e antigen (HBeAg), hepatitis B x antigen (HBxAg), a partially double-stranded DNA molecule, a DNA-dependent DNA polymerase enzyme with reverse transcription activity, and a protein kinase. HBcAg is found primarily in the nuclei of infected hepatocytes. In serum, HBcAg is found only as a component of circulating Dane particles, but it is never found in free form. HBeAg is a prematurely terminated polypeptide product of the same gene that codes for HBcAg; its presence in serum indicates infectivity. The function of HBeAg is not known. HBxAg directly and indirectly
affects host and viral gene expression, and the X protein is essential for in vivo replication and spread of HBV. HBV DNA is a partially double-stranded DNA, and HBV DNA polymerase repairs the single-stranded HBV DNA region to form a complete double-stranded molecule (762,763).

With very sensitive assays, HBsAg can be detected in the blood within 1 to 2 weeks of exposure to HBV. However, clinical disease usually occurs 1 to 3 months, and occasionally 6 months, after exposure. HBeAg can be detected late in the incubation period, usually coinciding with or within days of HBsAg appearance. HBV DNA polymerase and HBV DNA are measurable at this stage and generally peak by the latter part of the incubation period. Viral titers during the acute stage of the infection can reach 109 to 1010 virions/mL. In patients who recover, HBsAg usually can no longer be detected at about the time of clinical resolution (764).

The earliest antibodies to appear are those directed against HBcAg (anti-HBc), typically 2 to 4 weeks after HBsAg is first detected. Anti-HBc titers increase during the acute stage of infection and persist for many years. Antibodies to HBeAg (anti-HBe) appear immediately after or within several weeks of HBeAg clearance and usually while HBsAg is still present. A window period that occasionally can be as long as 20 weeks follows HBsAg clearance from the circulation, during which neither HBsAg nor anti-HBs are detectable. However, specific IgM and IgG anti-HBc antibodies usually are present. The patient is contagious during this period. After anti-HBs antibodies become measurable, their titers continue to increase for approximately 6 to 12 months (762,764). Low levels of HBV DNA may persist in the blood for years, despite the appearance of anti-HBs (763). HBV DNA can be found in liver biopsies of patients with self-limited hepatitis B, including those with negative serum HBV assays (765). Anti-HBs antibodies persist for life and protect against future HBV reinfections. Antibodies to HBxAg (anti-HBx) can be detected in only 17% of patients with acute HBV infection and usually appear 3 to 4 weeks after onset of clinical symptoms; their clinical significance is not yet defined (766).

Patients who continue to have detectable serum HBsAg for 20 weeks or longer, or HBeAg for 10 weeks or longer, are likely to become chronic HBsAg carriers. Their serum anti-HBc titers usually are high, and IgM anti-HBc tends to persist for a long time. Approximately 25% to 50% of chronic carriers are HBeAg positive, and the remainder have anti-HBe. Persons who are positive for HBeAg, HBV DNA polymerase, or HBV DNA are highly contagious. Chronically infected patients clear HBV particles from their plasma with a half-life of about 1 day, and about 10¹¹ virus particles are released daily into the periphery from HBV-infected cells (767). Among persistently infected patients, about 5% to 10% convert each year from being HBeAg-positive to having anti-HBe (763). Over a period of about 10 years, more than 70% will clear HBeAg from their serum (768). Most chronic carriers remain HBV infected for life, but 1.5% to 2% of carriers spontaneously lose their HBsAg each year.

Young age is an important risk factor for developing the chronic carrier state; 70% to 90% of infected newborns become carriers, compared with 25% to 50% of children infected before their fifth birthday and 5% (range of <1%-12%) of adults. Other risk factors include a positive HIV-1 antibody status, hemodialysis, other immunodeficiencies, Down syndrome, and male gender (769). Virus-specific T cell responses in chronic carriers are attenuated in comparison to individuals who clear HBV after their acute infection (763). Reactivation of chronic HBV infection can occur during pregnancy, but this is rare (770).

There are several HBV genotypes (A to H), each with a characteristic geographic distribution and some differences in disease profiles (761). Naturally occurring HBV variants that are unable to produce HBeAg are recognized; these patients have high HBV DNA but no detectable HBeAg during the acute infection, and often have fulminant disease (771).