Hepatitis viruses and the newborn: Clinical manifestations and treatment

INTRODUCTION — Neonatal infections with the hepatotropic viruses are usually the result of vertical transmission from infected mothers. The risk of perinatally or neonatal-acquired infection and its clinical manifestations and implications vary depending on the hepatotropic virus and are reviewed here.

Prevention, diagnosis, and management of hepatitis viruses in older infants, children, and adolescents are discussed separately:

●(See "Overview of hepatitis A virus infection in children".)

●(See "Hepatitis B virus immunization in infants, children, and adolescents".)

●(See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents".)

●(See "Management of hepatitis B virus infection in children and adolescents".)

●(See "Hepatitis C virus infection in children".)

HEPATITIS A — Hepatitis A virus (HAV) is a nonenveloped 27-nm RNA virus that is a member of the Picornaviridae family. The virus is transmitted by person-to-person contact through fecal-oral contamination. The infection is highly contagious, and epidemics frequently result from common exposure to contaminated food and water. (See "Overview of hepatitis A virus infection in children" and "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis".)

Transmission

●Maternal vertical transmission

•Intrauterine – Intrauterine transmission of HAV is rare, described in isolated case reports of intrauterine transmission of HAV in early pregnancy [1,2]. These cases presented with fetal ascites and meconium peritonitis. After birth, serologic testing confirmed HAV infection in both infants who required surgical intervention for meconium peritonitis. Their subsequent recovery was uneventful.

•Perinatal – The risk of perinatal transmission is low. Despite the widespread global distribution of HAV infection, only a few case reports describe vertical transmission of HAV during the weeks before or at birth [3-5]. For most of these infants, vertical transmission was identified when the infant presented with hepatitis during the newborn period.

There is no evidence that hepatitis A is transmitted through breast milk [6].

●Acquired neonatal disease – Neonatal-acquired HAV infection is rare. There are reported neonatal cases of HAV due to transfusion of contaminated blood or fresh frozen plasma [7-9] and horizontal transmission from healthcare personnel [3,8]. In an outbreak in a neonatal intensive care unit in Hawaii, 13 infants, 22 nurses, 8 other staff, and 4 household contacts were identified with HAV infection [8]. Two infants, who received blood transfusions from a donor with HAV infection, were identified as the primary cases and served as a common source of infection for the other infants and staff.

Clinical manifestations

●In utero – For the most part, HAV infection is self-limiting in pregnant women. Although maternal HAV infection does not appear to increase the risk of congenital malformations, intrauterine growth restriction, spontaneous abortion or stillbirth [10,11], there is an increased risk of preterm labor and premature rupture of membranes. (See "Overview of coincident acute hepatobiliary disease in pregnant women", section on 'Hepatitis A virus'.)

●In the newborn – Most newborn infants with HAV infection are asymptomatic, but symptomatic cases have been reported [4,12,13]. In one case series of six infants ranging from two weeks to eight months old, all of the patients presented with loss of appetite and jaundice and in four patients, elevated temperature and recurrent vomiting were also observed [12]. During the course of the disease, all six infants developed hepatomegaly and biochemical evidence of mild hepatitis. All infants had complete clinical and biochemical recovery three months after the acute disease with no long-term sequelae. Other reports have documented similar clinical findings in newborn infants infected with HAV [4,13].

Fulminant hepatitis resulting from infection with HAV is rare in children and, to our knowledge, has not been reported in the newborn infant. (See "Overview of hepatitis A virus infection in children".)

Prevention and treatment

●Infant of a mother with active HAV infection – For infants born to mothers with HAV symptoms in the perinatal period (two weeks before to one week after birth), some experts advise giving immune serum globulin (0.02 mL/kg intramuscularly) to the infant [14]. However, the efficacy of immune serum globulin in these circumstances has not been fully established, and immunoprophylaxis may be less effective in newborn infants than in older children.

●Management of an infected infant – The treatment for newborn infants with HAV infection is supportive. Strict attention to infection control is necessary because HAV-positive infants are infectious for many months [8]. Measures include strict handwashing by caregivers and ensuring that all caregivers and household contacts are fully immunized. HAV-infected mothers may continue to breastfeed.

●Universal immunization – In the United States, immunization with an inactivated hepatitis A vaccine is recommended for all children beginning at one year of age [14]. Vaccination of infants six months or older is recommended for those traveling to endemic areas. In endemic areas, newborn and premature infants born to seronegative mothers are potentially at risk and may benefit from early immunization with HAV vaccines [12,15]. However, vaccination trials in these patient populations are warranted before routine early immunization with HAV vaccines can be recommended. (See "Overview of hepatitis A virus infection in children" and "Hepatitis A virus infection: Treatment and prevention", section on 'Protection prior to exposure'.)

HEPATITIS B — Hepatitis B virus (HBV) is an enveloped DNA virus that is a member of the Hepadnaviridae family.

Transmission — Neonatal infection is a result of perinatal exposure from an HBV-infected mother. The infection rate among exposed infants with infected mothers who do not receive any form of prophylaxis is as high as 90 percent. Perinatal transmission, including risk factors and preventive measures, are discussed separately. (See "Hepatitis B and pregnancy", section on 'Effect of chronic HBV on pregnancy outcomes'.)

Breastfeeding by an HBV-infected mother is not contraindicated, as it does not increase the risk of transmission. Infants who received hepatitis B immune globulin (HBIG) and the first dose of vaccine at birth can be breastfed as long as they complete the course of vaccination. Mothers with HBV should not participate in donating breast milk. These issues are discussed separately. (See "Hepatitis B and pregnancy", section on 'Breastfeeding and transmission'.)

Clinical manifestations and course — Newborn infants with HBV infection rarely show clinical or biochemical signs of disease at birth. Most affected newborns remain asymptomatic and develop chronic antigenemia with mild and often persistent liver enzyme elevations beginning at two to six months of age. This is known as the immune-tolerant phase of HBV infection, which can persist for years or even decades or progress to the immune-active phase (figure 1) [10,16,17]. A small number of infants will develop acute hepatitis by two months of age and present with icteric and, occasionally, fulminant hepatitis [17-20]. Others may develop chronic liver disease later in life, with risks for cirrhosis and/or hepatocellular carcinoma. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Chronic hepatitis B virus infection'.)

Diagnosis — The diagnosis of HBV infection is based on serologic assays that identify the presence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and antibodies to these viral proteins (table 1 and figure 2). The presence of HBsAg in the infant after one to two months of age indicates vertically acquired HBV infection. HBsAg may be transiently positive in neonates up to 21 days following hepatitis B vaccination [21]. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Diagnostic algorithms'.)

Testing for HBV DNA is not recommended for screening, because this test may remain positive for months or years after clearance of HBV infection. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Serum HBV DNA assays' and "Hepatitis B and pregnancy", section on 'Mother-to-child transmission'.)

Prevention — Important strategies to prevent HBV infection in children are universal HBV immunization for all infants and the combination of immunoprophylaxis (HBIG) and HBV immunization for infants born to HBsAg-positive mothers.

●Universal immunization – Universal HBV immunization is recommended for all infants. The optimal intervals and need for HBIG are determined by the mother's HBsAg status and the infant's birth weight. (See "Hepatitis B virus immunization in infants, children, and adolescents", section on 'Routine infant immunization'.)

●Infant of an HBsAg-positive mother – Infants of HBsAg-positive mothers should receive monovalent hepatitis B vaccine and HBIG 0.5 mL as soon after birth as possible (preferably within 12 hours), regardless of birth weight. The schedule for subsequent doses of hepatitis B vaccine depends upon the infant's birth weight (algorithm 1). This combination of passive and active immunization dramatically reduces the rate of perinatally-acquired HBV from an infected mother. These and other recommendations for immunoprophylaxis and post-vaccination testing are discussed in a separate topic review. (See "Hepatitis B virus immunization in infants, children, and adolescents", section on 'HBsAg-positive mother or mother with other evidence of HBV infection'.)

Management — No specific therapy is generally warranted for infants and children with vertically transmitted HBV, as most patients are asymptomatic through infancy and childhood with consistently normal alanine aminotransferase (ALT) values (immune-tolerant). Management for most patients usually involves monitoring for disease progression by laboratory evaluation that includes liver enzyme testing and HBV serology (figure 1). Although several treatment options are available for children two years or older, these are typically ineffective in children in the immune-tolerant phase. As a result, the decision to treat is based on individual patient factors, which are discussed separately. (See "Management of hepatitis B virus infection in children and adolescents", section on 'Selection of patients for antiviral treatment'.)

For the very rare case of an infant with acute and fulminant HBV infection, off-label use of nucleos(t)ide analogs may be warranted. (See "Management of hepatitis B virus infection in children and adolescents", section on 'Nucleos(t)ide analogs'.)

HEPATITIS C — Hepatitis C virus (HCV) is a small, single-stranded, enveloped RNA virus that is a member of the Flaviviridae family.

●Transmission – Vertical transmission is the primary source of pediatric infection. The risk of transmitting the virus from an HCV-infected woman to her infant is approximately 5 percent but is higher if the mother is coinfected with human immunodeficiency virus (HIV). Horizontal transmission (child-to-child or adult-to-child) transmission of HCV in the neonatal period is rare. Breastfeeding is not contraindicated. (See "Vertical transmission of hepatitis C virus".)

●Clinical manifestations – Newborn infants with HCV infection usually are asymptomatic, and most have normal or only mildly elevated serum alanine aminotransferase (ALT) concentrations. Although a majority of infants with vertically acquired HCV develop chronic infection, liver disease usually is mild throughout childhood. (See "Vertical transmission of hepatitis C virus", section on 'Clinical manifestations'.)

●Diagnosis – The diagnosis of HCV is made by detecting antibodies to HCV. However, antibody testing of infants of women known to be infected with HCV should be delayed until the maternal antibodies transferred through the placenta are cleared and will no longer confound the results of serologic testing [22]. This typically takes at least 12 to 18 months. (See "Vertical transmission of hepatitis C virus", section on 'Diagnosis'.)

●Prevention – The best strategy for reducing the risk of vertical HCV transmission is to identify and treat HCV-infected women prior to conception, using direct-acting antiviral agents. These drugs should not be given during pregnancy, because their safety and efficacy for preventing perinatal transmission have not been evaluated. (See "Vertical transmission of hepatitis C virus", section on 'Screening and prevention'.)

●Management – Treatment of children with perinatally acquired HCV is generally recommended after three years of age, using a direct-acting antiviral agent. The decision to treat and options are discussed separately. (See "Hepatitis C virus infection in children", section on 'Management of chronic hepatitis C virus'.)

OTHER HEPATOTROPIC VIRUSES

Hepatitis D — Hepatitis D virus (HDV) is an RNA virus, the replication of which requires hepatitis B virus (HBV) as a helper virus. Infection occurs only in persons who are hepatitis B surface antigen (HBsAg)-positive, either as a coinfection (simultaneous infection with HBV and HDV) or as a superinfection (infection of a chronic HBV carrier with HDV).

Vertical transmission of HDV has been documented but is uncommon. Therapeutic strategies designed to prevent perinatal acquisition of HBV in infants born to HBsAg-positive mothers are also effective in preventing the transmission of HDV [23]. Because HDV cannot be transmitted in the absence of HBV, routine immunization of all newborn infants with the hepatitis B vaccine protects against HDV. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection" and "Treatment and prevention of hepatitis D virus infection".)

Hepatitis E — Hepatitis E virus (HEV) is a single-stranded RNA virus that is structurally similar to a calicivirus [24]. Infection with HEV usually causes a self-limiting acute hepatitis similar to hepatitis A virus (HAV), although fulminant hepatitis can occur. The virus is transmitted by the fecal-oral route. HEV infection is rare in the United States but endemic in many resource-limited countries. (See "Hepatitis E virus infection".)

●Vertical transmission and clinical manifestations – Although information regarding perinatal transmission is limited, several case series describe vertical transmission of HEV. Infants presented with signs of hepatitis, including jaundice, hyperbilirubinemia, elevated serum alanine aminotransferase (ALT) levels; hypothermia, and hypoglycemia [25-28]. HEV infection in survivors was usually self-limited with short-lasting viremia, but cases of severe illness, including massive hepatic necrosis and death, have been reported [25-27].

●Diagnosis – The diagnosis of HEV infection is based upon the detection of HEV in serum or stool by polymerase chain reaction (PCR) or by the detection of IgM antibodies to HEV. (See "Hepatitis E virus infection", section on 'Diagnosis'.)

●Treatment – Supportive care is the only available treatment as specific treatments for infected infants do not exist.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric liver disease".)

SUMMARY AND RECOMMENDATIONS

●Hepatitis A (see 'Hepatitis A' above):

•Transmission – The risk of vertical transmission of hepatitis A virus (HAV) from an infected mother is small. Neonatal-acquired HAV infection is also uncommon and is primarily due to transfusion of contaminated blood products and horizontal transmission from infected health care workers. (See 'Transmission' above.)

•Clinical manifestations – Most newborn infants with HAV infection are asymptomatic, and those who are symptomatic generally have mild hepatitis manifested by poor feeding and jaundice. (See 'Clinical manifestations' above.)

•Prevention and treatment – For infants born to mothers with HAV symptoms in the perinatal period (two weeks before to one week after birth), some experts advise giving immune serum globulin (0.02 mL/kg intramuscularly) to the infant. Treatment of neonatal HAV infection is supportive, and the infection self-resolves. (See 'Prevention and treatment' above.)

●Hepatitis B (see 'Hepatitis B' above):

•Transmission – The risk of vertical transmission of hepatitis B virus (HBV) is as high as 90 percent for infants born to mothers with HBV infection unless the infant is given immunoprophylaxis at birth. (See 'Transmission' above.)

•Clinical manifestations and diagnosis – Newborn infants with HBV infection are usually asymptomatic and rarely show clinical or biochemical signs of disease at birth. However, neonates with HBV infection are at risk to develop chronic infection, which may progress to cirrhosis and/or hepatocellular carcinoma. In infants, the diagnosis of HBV infection is most commonly made by the presence of hepatitis B surface antigen (HBsAg) after one or two months of age (table 1). (See 'Clinical manifestations and course' above and 'Diagnosis' above.)

•Prevention – Infants of HBsAg-positive mothers should receive monovalent hepatitis B vaccine and HBIG 0.5 mL as soon after birth as possible (preferably within 12 hours), regardless of birth weight. The schedule for subsequent doses of hepatitis B vaccine depends upon the infant's birth weight (algorithm 1). All infants should receive the hepatitis B vaccine as part of the routine childhood immunization program. (See 'Prevention' above and "Hepatitis B virus immunization in infants, children, and adolescents".)

•Treatment – No specific therapy is generally warranted for the majority of patients with vertically transmitted HBV, as they remain asymptomatic through childhood with normal alanine aminotransferase (ALT) values (immune-tolerant). Management for most patients usually only involves monitoring for disease progression by laboratory evaluation that includes liver enzyme testing and HBV serology (figure 1). (See 'Management' above.)

●Hepatitis C (see 'Hepatitis C' above):

•Transmission, prevention, clinical manifestations and diagnosis – The risk of vertical transmission of hepatitis C virus (HCV) from an infected woman to her infant is approximately 5 percent, which increases if the mother is coinfected with HIV. The best strategy for reducing the risk of vertical HCV transmission is to identify and treat HCV-infected women prior to conception. Newborn infants with HCV infection usually are asymptomatic, and a majority will develop chronic infection. (See "Vertical transmission of hepatitis C virus".)

•Management – Treatment of children with perinatally acquired HCV is generally recommended after three years of age, using a direct-acting antiviral agent. The decision to treat and options are discussed separately. (See "Hepatitis C virus infection in children", section on 'Management of chronic hepatitis C virus'.)

●Other hepatitis viruses – Vertical transmission of hepatitis D virus (HDV) and hepatitis E virus (HEV) appears to be uncommon. Because HDV cannot be transmitted in the absence of HBV, routine immunization of all newborn infants with the hepatitis B vaccine protects against HDV. (See 'Other hepatotropic viruses' above.)