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Viral hepatitis A, B, and C in the newborn infant
Viral Hepatitis A, B, and C in the Newborn Infant Eric E. Mast, MD, MPH, and MiriamJ. Alter, PhD Viral hepatitis in newborn infants rarely is recognized because most infected infants are asymptomatic. However, the consequences of viral hepatitis in newborns can be severe. In particular, infants infected with hepatitis B virus or hepatitis C virus usually develop chronic infection, which can lead to chronic liver disease, including cirrhosis and liver cancer. In addition, transmission of hepatitis A virus from infected infants has resulted in outbreaks among hospital staff and other persons providing care for these infants. This review focuses on the epidemiology, clinical features, diagnosis, treatment, and prevention of hepatitis A, B, and C virus infections in newborn infants. Copyright 9 1999 by W.B. Saunders Company
ive human hepatitis viruses have been identified to date: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D (delta) virus (HDV), and hepatitis E virus (HEV). Two of these (HAV and HEV) generally are transmitted enterically, whereas HBV, HCV, and HDV are primarily blood-borne. Two additional agents have been isolated from patients with posttransfusion hepatitis: hepatitis G virus (also called GB virus C) and TI" virus (the initials of the patient from whom it was isolated); however, neither of these agents has been shown to cause acute or chronic hepatitis. Each of the hepatitis viruses has potential consequences for the newborn infant, but limited data are available regarding HDV infection in neonates, and no neonatal HEV infections have been reported in the United States.
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Hepatitis A Virus Infection Epidemiology Hepatitis A virus is transmitted primarily by the fecal-oral route because it is present in highest concentrations in the feces of infected persons, with peak levels noted during the 2-week period before onset of clinical illness. Saliva, urine, and nasopharyngeal washings have been sho~a to transmit HAV in human volunteer and animal transmission studies/-4 However, exposure to these body fluids is not likely to result in transmission in most circumstances because the concentration of HAV is low.
From the Division of Viral and Ric~ettdal DiseaseJ; National Centerfor I@ctious Diseasea; Centersfor Disease Controland Prevention,Atlanta, GA. Use of trade names and commercialsourcesisfor identification only and does not imply endorsement by the Public Health Service or the US Department of Health and Human Services. This is a U.S. government work. Thereare no restrictionson its use. Address correspondence to Eric E. Mast, MD, MPH,, Hepatitis Branch, Mailstop G37, Centersfor Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333. Copyright 9 1,999by Wag. Saunders Company 1045-1870/99/1003-000850.00/0
Several hepatitis A outbreaks in neonatal intensive care units in which the index patient was infected by a blood transfusion have been reported. 5-8 However, this mode of transmission rarely occurs because of the short period of viremia and the low probability of blood donation during this period. No data are available regarding the detection of HAV in breast milk, but transmission via breast milk has not been reported. Intrauterine transmission of HAV appears to be rare. 9 The risk of transmission from pregnant women who have hepatitis A in the third trimester of pregnancy also appears to be low, even when infection occurs near the time of delivery. I~ However, transmission to her newborn infant occurring either before or during delivery was reported from a woman who had onset of jaundice 9 days after the birth of a child with an estimated gestational age of 25 weeks) 2 HAV then spread within the neonatal intensive care unit to 10 staff members and 4 other infants. Transmission to staff members was associated with failure to wash hands after contact with the infected infant.
Clinical Features As noted, maternal HAV infection during pregnancy usually has no effect on the fetus or newborn, l~ However, in a case report of intrauterine HAV transmission at 20 weeks' gestation that was verified by detection of IgM antibody to HAV in fetal blood, ultrasound examination at 27 weeks' gestation revealed polyhydramnios and fetal ascites. These findings persisted until 35 weeks gestation, when signs of meconium peritonitis were noted on fetal ultrasound; it was treated surgically after delivery. 9 Infants infected with HAV typically are asymptomatic and rarely have biochemical evidence of hepatitis. Infections in neonates usually are detected because of transmission to and subsequent occurrence of clinical hepatitis A in hospital staff or other persons providing care for the infant. 5,~2 HAV RNA has been detected in stools of infected neonates for up to 5 months; however, the infection is always self-limiting, and no chronic infection or chronic liver disease has been observed. 5
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Diagnosis Sensitive and specific serologic assays are available commercially to detect either total (IgM and IgG) antibody to the capsid proteins of HAV (anti-HAV) using a competitive inhibition (blocking) format or IgM anti-HAV using an IgM capture format. Serologic testing for IgM anti-HAV is required to confirm the diagnosis of recent HAV infection. In most persons, IgM anti-HAV becomes detectable 5 to 10 days after exposure and can persist for up to 6 months after infection. A small percentage of patients may not have detectable IgM anti-HAV when tested within several days after illness onset but will test positive for IgM anti-HAV within the first 2 weeks of illness. 16 The detection of total anti-HAV is not useful as a diagnostic marker of HAV infection in infants because maternal IgG anti-HAV is transferred passively across the placenta.~7 HAV infection also can be diagnosed by detecting fecal HAV antigen by enzyme immunoassay (EIA) or fecal HAV RNA by polymerase chain reaction (PCR). However, these assays cannot be used to determine whether an individual is infectious because they may detect evidence of both defective and infectious viral particles.
Treatment No specific therapy is available for HAV-infected patients. HAV infection is self-limited, and treatment generally is supportive. Hospitalization may be required for patients who are dehydrated from nausea or vomiting. Patients with evidence of fulminant hepatic failure (eg, elevated prothrombin time, encephalopathy) require supportive treatment in intensive care settings.
Prevention HAV infection can be prevented by general measures of good personal hygiene, particularly hand washing; preexposure or postexposure immunization with immune globulin (IG); and preexposure immunization with hepatitis A vaccine. In one study, hepatitis A vaccine has also been found to be effective for post exposure prophylaxis. 17~ Two hepatitis A vaccines currently are licensed in the United States: HAVRIX (SmithKline Beecham Biologicals, Rixensart, Belgium) and VAQTA (Merck & Co., Inc., West Point, PA). Few data are available regarding the use of hepatitis A vaccine in infants, and the vaccine is not approved by the Food and Drug Administration (FDA) for use in children younger than 2 years of age. Ultimately, hepatitis A vaccination is expected to be included in the childhood vaccination schedule. 18 However, results from one study indicated lower immunogenicity of hepatitis A vaccine when administered at 2, 4, and 6 months of age to infants who had passively transferred maternal anti-HAV compared with infants without detectable anti-HAV. 18 Thus, data are needed regarding the appropriate dose and timing of vaccination in the first or second year of life. Newborn infants may be at risk of infection if the mother is infected less than 2 weeks betbre or after delivery. In this circumstance, administration of IG to the infant may be considered to prevent infection. Because severe disease in infants is rare, the primary reason to administer prophylaxis to the infant is to prevent transmission to others who may have contact with
the infant. The dose of IG for administration to newborn infants exposed to HAV is 0.02 mL/kg. Pregnancy or lactation is not a contraindication to administration of IG, and IG prophylaxis should be administered to pregnant or lactating women who are exposed to HAV. 18 Although hepatitis A outbreaks have occurred in neonatal intensive care units, the frequency of such outbreaks is not sufficiently high to warrant routine vaccination of staff in these settings. Appropriate use of standard precautions, especially strict adherence to hand washing, is indicated when infected infants or newborn infants at risk of infection are recognized in these settings. 19 In addition, if transmission is recognized in a neonatal intensive care unit, postexposure administration of IG with the possible addition of hepatitis A vaccine may be considered for staff members who provide care for HAVinfected infants.
Hepatitis B Virus Infection Epidemiology Neonates are at risk of HBV infection primarily as a result of transmission from their infected mothers. Each year in the United States, approximately 20,000 infants are born to HBVinfected pregnant women, and without immunoprophylaxis approximately 5,500 of these infants would become chronically infected. Most neonatal HBV infections occur among infants of pregnant women with chronic HBV infection. Pregnant women with acute HBV infection in the first and second trimester rarely transmit HBV to the fetus or neonate. 11,2~However, the risk of transmission fiom pregnant women who acquire infection during the third trimester is approximately 60 percent. 2~ The risk of HBV infection among infants born to hepatitis B surface antigen (HBsAg)-positive mothers ranges from less than 10 to 85 percent, with higher rates among infants of hepatitis B e antigen (HBeAg)-positive mothers and lower rates among HBeAg-negative mothers. Higher rates of transmission also are associated with higher maternal serum HBV DNA titers. One study found maternal HBV DNA titers to be a stronger independent predictor of persistent infection in infants than was maternal HBeAg status. 21 HBV transmission fiom mother to infant may occur in utero, perinatally, or postnatally. Evidence of in utero transmission includes the detection of HBsAg in infants soon after delive~T and the detection of HBV DNA in liver tissue of aborted fetuses. 22 However, at least 90 percent of neonatal infections result from perinatal exposures to maternal blood, amniotic fluid, or vaginal fluid. The role of mode of delivery in the transmission of HBV from mother to infant has not been fully determined. In one study, no difference in transmission rates was found among infants delivered vaginally compared with infants delivered by cesarian section23; however, in another study, higher rates of infection were found in infants delivered vaginally.24 Although HBsAg has been detected in breast milk, an increased risk of transmission associated with breast-feeding has not been documented. 25 Infants of HBsAg-positive mothers who are not infected during the perinatal period have a high risk of becoming infected postnatally during the first 5 years of life26 Other
Viral Hepatitis in the Newborn Infant chronically infected children in the household are the primary source of infection in this setting. 27,28
Clinical Features The course of pregnancy generally is not affected by either acute or chronic HBV infection, and maternal HBV infection usually has no clinically apparent effect on the fetus or neonate. However, in two reported cases of transplacental infection of the fetus after acute maternal infection, infants were small for gestational age and had cholestatic hepatitis. 29 In addition, premature labor has been observed in mothers with acute HBV infection during pregnancy.2~ Most HBV-infected infants are as}q~nptomatic; however, these infants occasionally have clinical signs of hepatitis with jaundice. In addition, fulminant hepatitis has been reported among infants infected perinatally, including reports of fulminant hepatitis occurring among two infants born successively to the same mother~~ fulminant hepatitis with a galactosemia-like presentational; and fulminant hepatitis in an infant who received appropriate postexposure immunoprophylaxis.32 Some investigators have postulated that mutations in the precore region of the HBV DNA may contribute to the pathogenesis of fulminant hepatitis B in neonates. 33 However, the precore mutation does not appear to be either necessary or sufficient to cause fulminant hepatitis B. 3a Infants who are infected with HBV have an 85 to 90 percent risk of developing chronic infection,35 and they may have evidence of chronic liver disease with persistently elevated alanine aminotransferase (ALT) levels. Other clinical sequelae associated with chronic HBV infection are unusual in childhood; however, HBV-associated hepatocellular carcinoma has been reported. 36 Most sequelae associated with perinatally acquired infection occur during adulthood; up to 25 percent of chronically infected infants will eventually die of HBV-related chronic liver disease, including cirrhosis and hepatocell~lar carcinoma. 37 In one study, middle-aged men with chronic HBV infection were greater than 200 times more likely to develop primary hepatocellular carcinoma than were those without chronic infection.~8
Diagnosis Serologic tests (EIAs and radioimmunoassays [RIAs]) are available commercially for a variety of antigens and antibodies associated with HBV infection, including HBsAg, antibody to HBsAg (anti-HBs), total (lgG and IgM) antibody to hepatitis B core antigen (anti-HBc), IgM anti-HBc, HBeAg, and antibody to HBeAg (anti-HBe). In addition, hybridization assays and gene amplification techniques (eg, PCR) are available to detect HBV DNA. The diagnosis of HBV infection in infants usually is made by detecting HBsAg, which can be detected in the serum of infected persons as early as 1 to 2 months after exposure to HBV. This antigen is synthesized during viral replication and also may be produced from HBV DNA integrated into the chromosomes ofhepatocytes in the absence of replication. Thus, detection of HBsAg in serum indicates active HBV infection, but it does not distinguish new infection from chronic infection or determine whether viral replication is occurring. The presence of anti-HBs in serum generally indicates either recovery and
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immunity after past infection with HBV or an immune response to hepatitis B vaccine. Total anti-HBc can be detected in infected persons as early as 4 weeks after exposure to HBV, and this antibody persists both in persons who have self-limited infection and in persons who develop chronic infection. The detection of total anti-HBc is not useful as a diagnostic marker of HBV infection in infants because maternal IgG anti-HBc is transferred passively across the placenta. IgM anti-HBc is a very reliable test for diagnosis of recent HBV infection in older children and adults. However, this test is less sensitive for diagnosis of recent infections in young children who may not have an IgM anti-HBc response. 39 The presence of HBeAg and/or HBV DNA in serum correlates with higher titers of HBV and greater infectivity. Among patients with acute, self-limited infection, the appearance and disappearance of HBeAg and HBV DNA generally parallels that of HBsAg. Among patients with chronic HBV infection, HBeAg and HBV DNA titers generally decline over time. In one studyof perinatally infected children with chronic infection, 33 percent lost HBeAg during a follow-up period of 8 to 10 years, g~ Anti-HBe becomes detectable in most patients at the time HBeAg becomes undetectable.
Treatment As for hepatitis A, no specific treatment is available for HBVinfected infants, and treatment of acute disease is supportive. For adults with chronic hepatitis B, interferon alfa treatment for 4 to 6 months induces a long-term remission, with disappearance of HBeAg and HBV DNA fi-om serum in 25 to 40 percent of patients and consequent improvement in the biochemical and histological features of the disease. 41 Similar response rates have been found among children42,43; however, interferon alfa is approved by the FDA only for treatment of adults. Nucleoside analogues (eg, lamivudine, famciclovir) also have been evaluated extensively in clinical trials, and lamivudine recently has been approved by the FDA for treatment of adults with chronic hepatitis B. Short-term courses of these drugs result in rapid declines in serum HBV DNA levels; however, pretreatment levels of HBV DNA rapidly return after discontinuation of treatment, with no sustained improvement in clinical features of liver disease. Preliminary findings of clinical trials of long-term treatment with nucleoside analogues have shown sustained clearance ofHBV DNA from serum, lower aminotransferase levels, and histological improvement.41No published data are available regarding the use of combined therapy with nucleoside analogues and interferon or the use of nucleoside analogues for treatment of chronic HBV infection in children.
Prevention Postexposure immunoprophylaxis beginning at birth is highly effective in preventing infections in infants of HBV-infected mothers. More than 90 percent of infections transmitted from HBsAg-positive mothers can be prevented if the infected mother is identified and her infant receives immunoprophylaxis soon after birth. 44 The efficacies of active immunization with recombinant hepatitis B vaccine alone and of passive-active immunization with hepatitis B immune globulin (HBIG) and hepatitis B vaccine combined have been found to be essentially equivalent
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with higher vaccine doses.45The major factor that influences the efficacy of postexposure prophylaxis is the timing of the first dose of vaccine in relation to birth; optimum efficacy is achieved when the vaccine is administered within 24 hours after birth. To identify infants who require early immunoprophylaxis, all pregnant women should be routinely tested for HBsAg during an early prenatal visit in each pregnancy.46 HBsAg testing should be repeated in late pregnancy for HBsAg-negative women who have risk factors for HBV infection (ie, [injecting] drug use, intercurrent sexually transmitted diseases, multiple sex partners) or who have had clinical hepatitis. Infants born to HBsAg-positive mothers (including premature infants) should receive the appropriate dose of hepatitis B vaccine (5/xg ofRecombivax HB [Merck and Co, Inc] or 10/xgof EngerLx B [SmithKline Beecham Biologicals]) and HBIG (0.5 mL) within 12 hours of birth, administered concurrently but at separate sites by intramuscular injection.46 Infants who have begun immunoprophylaxisshould not be prevented from breastfeeding. Women admitted for delivery who have not been tested for HBsAg prenatally should have blood drawn for testing as soon as possible after admission. While test results are pending, the infant should receive hepatitis B vaccine (without HBIG) within 12 hours of birth. If the mother is later found to be HBsAg-positive, her infant should receive HBIG as soon as possible, but no later than 7 days after birth. All infants of HBsAg-positive mothers also should receive medical follow-up to ensure timely completion of subsequent doses of hepatitis B vaccine at 1 to 2 months and 6 months of age. After completion of the vaccine series, postvaccination testing for anti-HBs and HBsAg should be performed to determine the success of immunoprophylaxis and to identify infants who require further medical management. Postvaccination testing at 9 to 15 months of age minimizes the likelihood of detecting passively transferred anti-HBs from HBIG and maximizes the likelihood of detecting late HBsAg-positive infections. Infants who are anti-HBs-positive and HBsAg-negative are protected and do not need further medical management. Infants found to be anti-HBs-negative and HBsAg-negative should be revaccinated. Infants born to HBsAg-negative mothers also should receive active immunization against HBV, beginning within the first 2 months of life; such universal immunizationis recommended to ultimately eliminate transmission of HBV associated with highrisk behaviors later in life.46
Hepatitis C Virus Iniection Epidemiology Hepatitis C virus is transmitted most efficiently by direct percutaneous exposures to blood. Blood transfusion was a major route of transmission before donor screening practices were implemented in the 1980s and early 1990s; however, HCV currently is rarely transmitted by blood transfusion. The Centers for Disease Control and Prevention (CDC) recommends that persons be tested for evidence of HCV infection if they received a blood transfusion before July 1992, when multiantigen screening tests for antibody to HCV (anti-HCV) were widely implemented in blood collection facilities.47
Neonates are at risk of HCV infection primarily as a result of transmission from their infected mothers. Approximately 1 percent of pregnant women in the United States have serologic evidence of HCV infection, and most of these women are chronically infected. Thus, approximately 40,000 infants born to HCV-infected pregnant women each year are at risk of infection. The average rate of HCV infection among infants born to HCV-positive, human immunodeficiencyvirus (HIV)-negative women is 5 to 6 percent (range 0% to 25%), based on detection of serum anti-HCV and HCV RNA.48 Among infants born to women coinfected with HCV and HIV, the transmission rate is higher: 14 percent (range 5% to 36%) and 17 percent based on detection of anti-HCV and HCV RNA, respectively.4s The only factor consistently found to be associated with transmission has been the presence of serum HCV RNA in the mother at the time of birth. Although two studies of infants born to HCV-positive, HIV-negative women reported an association with maternal titer of HCV RNA, these studies reported different levels of HCV RNA to be related to transmission.49,5~ Studies of HCV- and HIV-coinfected women more consistently have indicated an association between virus titer and transmission of HCV. 51Data regarding the relationship between delivery mode and HCV transmission are limited and presently indicate no difference in infection rates between infants delivered vaginally or those delivered by cesarean section.52 Although HCV RNA has been detected in breast milk, transmission of HCV infection via breast milk has not been documented. In studies that have evaluated the risk of transmission from breast-feeding among infants born to HCV-infected women, the average rate of infection was 4 percent in both breast-fed and bottle-fed infants.48
Clinical Features Maternal HCV infection generally has no effect on the course of pregnancy, and no clinically apparent effects of maternal infection on the fetus or neonate have been reported. HCV-infected infants typically have no clinical signs or symptoms of liver disease, and no cases of fulminant hepatitis have been reported among infected infants. However, the majority become chronically infected, and most of these infants have elevated ALT levels.52Limited data suggest that infants infected with HCV at the time of birth do very well in the first years of life, with few clinical signs or symptoms of disease. However, no follow-up data are available to assess the long-term consequences of hepatitis C in these infants. Among infected adults, the course of chronic liver disease usually is insidious, progressing at a slow rate without symptoms or physical signs in the majority of patients for the first two or more decades after infection. In most long-term follow-up studies of persons with chronic hepatitis C, cirrhosis developed in 10 to 20 percent and hepatocellular carcinoma in 1 to 5 percent during a period of 20 to 30 years. 5~,54 In contrast, among 376 women who were infected after they received HCV-contaminated Rh factor immune globulin, only 2 percent had cirrhosis and none died after 17 years of follow-up.55
Diagnosis Diagnosis of HCV infection in infants can be made using either serologic assays that detect anti-HCV or gene amplification
Viral Hepatitis in the Newborn Infant techniques that qualitatively detect HCV RNA (eg, reverse transcriptase [RT]-PCR). 47 Serologic assays that detect antiH C V are the only tests currently approved by the FDA for diagnosing HCV infection. These tests detect anti-HCV in 97 percent or more of infected persons but do not distinguish among acute, chronic, or resolved infection. Testing for antiHCV should include use of both an EIA and supplemental or confirmatory testing with an additional, more specific assay (eg, RIBA [Chiron Corporation, Emeryville, CA]). Although not FDA approved, RT-PCR assays for H C V RNA are used commonly in clinical practice. H C V RNA can be detected in serum or plasma within 1 to 2 weeks after exposure to the virus. Because of assay variability, rigorous quality assurance and control should be in place in clinical laboratories performing this assay, and proficiency testing is recommended. Specific diagnostic criteria for perinatal HCV infection have not been established. Various patterns of anti-HCV detection have been observed in both infected and uninfected infants of anti-HCV-positive mothers. 56 In uninfected infants, passively acquired maternal antibody can persist for months, but probably not for more than 18 months. In most infected infants, endogenous production of antibody occurs before maternal anti-HCV declines below detectable levels. However, some studies have shown periods when HCV RNA is detected but antibody is not detectable. The period of antibody seronegativity in these infants was highly variable, ranging from 6 to 21 months of age. Based on these findings, testing of infants for anti-HCV should be performed no sooner than 2 years of age, when maternal anti-HCV will have decreased below detectable levels and endogenous anti-HCV is detectable in infected infants. If HCV infection is suspected in an anti-HCV-negative infant (eg, elevated ALT levels), anti-HCV testing may be repeated later or RT-PCR for H C V RNA may be performed. If earlier diagnosis of HCV infection is desired, RT-PCR for HCV RNA may be performed at or after the infant's first well-child visit at 1 to 2 months of age. Umbilical cord blood should not be used for RT-PCR testing because cord blood can be contaminated by maternal blood.
Treatment Interferon alfa and combination therapy with interferon and ribavirin have been approved by the FDA for treatment of adults with chronic hepatitis C. In adults, sustained response rates of 40 to 50 percent have been achieved with a combination of interferon and ribavirin compared with response rates of l0 to 20 percent with interferon alone. 57-59 However, combination therapy in patients with H C V genotype 1, the most common genotype in the United States, is not as successful, with sustained response rates of less than 30 percent. Experience is limited in treating children with chronic hepatitis C, and no treatments are approved for persons younger than 18 years. Data from preliminary interferon trials among children with chronic hepatitis C are promising, with sustained responses in 45 to 55 percent of treated children. 6~ No data are available regarding use of combination therapy in children.
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Prevention Measures to prevent hepatitis C are limited. The development of a vaccine is not likely in the foreseeable future, and immune globulin does not appear to be effective for postexposure prophylaxis. 63 No information is available regarding the use of antiviral agents (eg, interferon) for postexposure prophylaxis of HCV infection. The mechanism of the effect of interferon in treating patients with hepatitis C is poorly understood, and interferon may be effective only in established infection. 64 Routine serologic testing of pregnant women for HCV infection is not recommended because no measures are available to prevent perinatal transmission, no licensed therapy or guidelines for treatment of HCV-infected infants or children exist, and severe disease rarely occurs. However, health care professionals in settings where pregnant women are evaluated or receive routine care should obtain histories regarding risk factors from their patients to determine the need for testing. 47 Potential, expectant, and new parents should be advised that breast-feeding is not contraindicated by maternal HCV infection, although they should consider abstaining from breastfeeding if the nipples are cracked or bleeding. In addition, no evidence exists that mode of delivery is related to transmission; therefore, determining the need for cesarean versus vaginal delivery should not be made on the basis of HCV infection status.
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15. Ye JY: Outcome of pregnancy complicated by hepatitis A in the urban districts of Shanghai. Chung Hua Fu Chan Ko Tsa Chih [ChinJ Obstet Gynecol] 25:219-221, 1990 16. Liaw YF, Yang CY, Chu CM, et ah Appearance and persistence of hepatitis A IgM antibody in acute clinical hepatitis A observed in an outbreak. Infection 14:156-158, 1986 17. Franzen C, Frosner G: Placental transfer of hepatitis A antibody. N EnglJ Med 304:427, 1981 17a.Sagliocca L, Amoroso P, Stroffolini T, et ah Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection. Lancet 353:1136-1139, 1999 18. Centers for Disease Control and Prevention: Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 45(RR-15):1-30, 1996 19. Bolyard EA, Tablan OC, Williams WW, et ah Guidelines for infection control in health care personnel. Am J Infect Control 26:289-354, 1998 20. Schweitzer IL, Dunn AEG, Peters RL, et ah Viral hepatitis type B in neonates and infants. AmJ Med 55:762-763, 1973 21. Burk RD, Hwang LY, Ho GY, et ah Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load. J Infect Dis 170:1418-1423, 1994 22. Li L, Sheng M-H, Tong S-P, et al: Transplacental transmission of hepatitis B virus. Lancet 2:872, 1986 23. Beasley RP, Stevens CE: Vertical transmission of HBV and interruption with globulin, in Vyas GN, Cohen SN, Schmid R (eds): Viral Hepatitis. Philadelphia, PA, Franklin Institute Press, 1978, pp 333-345 24. Lee SD, Lo KJ, Tsai YT, et al: Role of cesarean section in prevention of mother-infant transmission of hepatitis B virus. Lancet 2:833-834, 1988 25. BeasleyRP, Stevens CE, Shiao I-S, et ah Evidence against breastfeeding as a mechanism for vertical transmission of hepatitis B. Lancet 2:740-741, 1975 26. Beasley RP, Hwang LY: Postnatal infectivity of hepatitis B surface antigen-carrier mothers.J Infect Dis 147:185-190, 1983 27. Hurie MB, Mast EE, Davis JP: Horizontal transmission of hepatitis B virus infection to United States-born children of Hmong refugees. Pediatrics 89:269-273, 1992 28. Mahoney FJ, Lawrence M, Scott C, et al: Continuing risk for hepatitis B virus transmission among Southeast Asian infants in Louisiana. Pediatrics 96:1113-1116, 1995 29. Lachaux A, Lapillonne A, Bouvier R, et ah Transplacental transmission of hepatitis B virus: A familial case. Pediatr Infect Dis J 14:60-63, 1995 30. Fawaz KA, Grady GF, Kaplan MM, et al: Repetitive maternal-fetal transmission of fatal hepatitis B. N EnglJ Med 293:1357-1359, 1975 31. Vajro P, Fontanella A, Tedesco M, et ah Fulminant hepatitis B and neonatal hepatitis with galactosemia-like presentation. Clin Pediatr 30:191-193, 1991 32. Rosh JR, Schwersenz AH, Groisman G, et ah Fatal fuhninant hepatitis B in an infant despite appropriate prophylaxis. Arch Pediatr Adolesc Med 148:1349-1351, 1994 33. Omata M, Ehata T, Kokosuka O, et ah Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N EnglJ Med 324:1699-1704, 1991 34. Hsu HY, Chang MH, Lee CY, et al: Precore mutant of hepatitis B virus in childhood fulminant hepatitis B: An infrequent association. J Infect Dis 171:776-781, 1995 35. McMahon BJ, Alward WL, Hall DB, et al: Acute hepatitis B virus infection: Relation of age to the clinical expression of disease and subsequent development of the carrier state.J Infect Dis 151:599603, 1985 36. Chang M-H, Chen C-J, Lai M-S, et al: Universal hepatitis B
vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N EnglJ Med 336:1855-1859, 1997 37. Beasley RP: Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61:1942-1956, 1988 38. Beasley RP, Hwang L-Y, Lin C, et al: Hepatocellular carcinoma and HBV: A prospective study of 22,707 men in Taiwan. Lancet 2:1129-1133, 1981 39. Margolis HS, Xu ZY, Nainan OV, et al: Poor IgM antibody response to hepatitis B core antigen in infants with hepatitis B virus infection. J Pediatr 115:609-611, 1989 40. Chan C-Y, Lee SD, Yu M-Y, et al: Long-term follow-up of hepatitis B virus carrier infants.J Med Viro144:336-339, 1994 41. Hoofnagle JH, di Bisceglie AM: The treatment of chronic viral hepatitis. N EnglJ Med 336:347-356, 1997 42. Sokal EM, Conjeevaram HS, Roberts EA, et al: Interferon alfa therapy for chronic hepatitis B in children: A muhinational randomized controlled trial. Gastroenterology 114:988,995, 1998 43. Torre D, Tambini R: Interferon-e~ therapy for chronic hepatitis B in children: A meta-analysis. Clin Infect Dis 23:131-137, 1996 44. Hadler SC, Margolis HS: Hepatitis B immunization: Vaccine types, efficacy, and indications for immunization, in RemingtonJS, Swartz MN (eds): Current Clinical Topics in Infectious Diseases. Boston, MA, Blackwell Scientific, 1992, pp 283-308 45. Andre FE, Zuckerman AJ: Review: Protective efficacy of hepatitis B vaccines in neonates.J Med Viro144:144-151, 1994 46. Centers for Disease Control: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the hnmunization Practices Advisory Committee (ACIP). MMWR 40 (RR- 13): 125, 1991 47. Centers for Disease Control and Prevention: Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic liver disease. MMWR 47 (RR- 19): 1-38, 1998 48. Mast EE, Alter MJ: Hepatitis C. Semin Pediatr Infect Dis 8:1-7, 1997 49. Ohto H, Terazawa S, Sasaki N, et ah Transmission of hepatitis C virus from mothers to infants. N EnglJ Med 330:744-750, 1994 50. Lin HH, KaoJH, Hsu HY, et al: Possible role of high-titer maternal viremia in perinatal transmission of hepatitis C virus. J Infect Dis 169:638-641, 1994 51. Thomas DL, Villano SA, Riester KA, et al: Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1-infected mothers. Women and Infants Transmission Study. J Infect Dis 177:1480-1488, 1998 52. Resti M, Azzari C, Mannelli F, et ah Mother to child transmission of hepatitis C virus: Prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. Tuscany Study Group on Hepatitis C Virus Infection. BMJ 17:437441, 1998 53. Di Bisceglie AM, Goodman ZD, Ishak KG, et al: Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis. Hepatology 14:969-974, 1991 54. Seeff LB, Buskell-Bales Z, Wright EC, et ah Long-term mortality after transfusion-associated non-A, non-B hepatitis. N EnglJ Med 327:1906-1911, 1992 55. Kenny-Walsh E, for the Irish Hepatology Research Group: Clinical outcomes after hepatitis C infection from contanfinated anti-D immune globulin. N EnglJ Med 340:1228-1233, 1999 56. Thomas SL, Newell ML, Peckham CS, et ah Use of polymerase chain reaction and antibody tests in the diagnosis of mother-to-child transmission of hepatitis C virus. EurJ Clin Microbiol 16:711-719, 1997 57. McHutchison JG, Gordon SC, Schiff ER, et ah Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N EnglJ Med 339:1485-1492, 1998
Viral Hepatitis in the Newborn Infant 58. Poynard T, Marcellin P, Lee SS, et ah Randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon oL2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 352:1426-1432, 1998 59. Davis GL, Esteban-Mur R, Rustgi V, et ah Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N EnglJ Med 339:1493-1499, 1998 60. Bortolotti F, Giacchino R, Vajro P, et ah Recombinant interferonalfa therapy in children with chronic hepatitis C. Hepatology 22:1623-1627, 1995
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61. Fujisawa T, Inui A, Ohkawa T, et ah Response to interferon therapy in children with chronic hepatitis C.J Pediatr 127:660-662, 1995 62. Ruiz-Moreno M, Rua MJ, Castillo I, et ah Treatment of children with chronic hepatitis C with recombinant interferon-o~. A pilot study. Hepatology 16:882-885, 1992 63. Krawczynski K, Alter MJ, Tankersly DL, et ah Effect of immune globulin on the prevention of experimental hepatitis C virus infection.J Infect Dis 173:822-828, 1996 64. Peters M, Davis GL, DoolyJS, et ah The interferon system in acute and chronic viral hepatitis. Prog Liver Dis 8:453-467, 1986
ive human hepatitis viruses have been identified to date: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D (delta) virus (HDV), and hepatitis E virus (HEV). Two of these (HAV and HEV) generally are transmitted enterically, whereas HBV, HCV, and HDV are primarily blood-borne. Two additional agents have been isolated from patients with posttransfusion hepatitis: hepatitis G virus (also called GB virus C) and TI" virus (the initials of the patient from whom it was isolated); however, neither of these agents has been shown to cause acute or chronic hepatitis. Each of the hepatitis viruses has potential consequences for the newborn infant, but limited data are available regarding HDV infection in neonates, and no neonatal HEV infections have been reported in the United States.
F
Hepatitis A Virus Infection Epidemiology Hepatitis A virus is transmitted primarily by the fecal-oral route because it is present in highest concentrations in the feces of infected persons, with peak levels noted during the 2-week period before onset of clinical illness. Saliva, urine, and nasopharyngeal washings have been sho~a to transmit HAV in human volunteer and animal transmission studies/-4 However, exposure to these body fluids is not likely to result in transmission in most circumstances because the concentration of HAV is low.
From the Division of Viral and Ric~ettdal DiseaseJ; National Centerfor I@ctious Diseasea; Centersfor Disease Controland Prevention,Atlanta, GA. Use of trade names and commercialsourcesisfor identification only and does not imply endorsement by the Public Health Service or the US Department of Health and Human Services. This is a U.S. government work. Thereare no restrictionson its use. Address correspondence to Eric E. Mast, MD, MPH,, Hepatitis Branch, Mailstop G37, Centersfor Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333. Copyright 9 1,999by Wag. Saunders Company 1045-1870/99/1003-000850.00/0
Several hepatitis A outbreaks in neonatal intensive care units in which the index patient was infected by a blood transfusion have been reported. 5-8 However, this mode of transmission rarely occurs because of the short period of viremia and the low probability of blood donation during this period. No data are available regarding the detection of HAV in breast milk, but transmission via breast milk has not been reported. Intrauterine transmission of HAV appears to be rare. 9 The risk of transmission from pregnant women who have hepatitis A in the third trimester of pregnancy also appears to be low, even when infection occurs near the time of delivery. I~ However, transmission to her newborn infant occurring either before or during delivery was reported from a woman who had onset of jaundice 9 days after the birth of a child with an estimated gestational age of 25 weeks) 2 HAV then spread within the neonatal intensive care unit to 10 staff members and 4 other infants. Transmission to staff members was associated with failure to wash hands after contact with the infected infant.
Clinical Features As noted, maternal HAV infection during pregnancy usually has no effect on the fetus or newborn, l~ However, in a case report of intrauterine HAV transmission at 20 weeks' gestation that was verified by detection of IgM antibody to HAV in fetal blood, ultrasound examination at 27 weeks' gestation revealed polyhydramnios and fetal ascites. These findings persisted until 35 weeks gestation, when signs of meconium peritonitis were noted on fetal ultrasound; it was treated surgically after delivery. 9 Infants infected with HAV typically are asymptomatic and rarely have biochemical evidence of hepatitis. Infections in neonates usually are detected because of transmission to and subsequent occurrence of clinical hepatitis A in hospital staff or other persons providing care for the infant. 5,~2 HAV RNA has been detected in stools of infected neonates for up to 5 months; however, the infection is always self-limiting, and no chronic infection or chronic liver disease has been observed. 5
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Diagnosis Sensitive and specific serologic assays are available commercially to detect either total (IgM and IgG) antibody to the capsid proteins of HAV (anti-HAV) using a competitive inhibition (blocking) format or IgM anti-HAV using an IgM capture format. Serologic testing for IgM anti-HAV is required to confirm the diagnosis of recent HAV infection. In most persons, IgM anti-HAV becomes detectable 5 to 10 days after exposure and can persist for up to 6 months after infection. A small percentage of patients may not have detectable IgM anti-HAV when tested within several days after illness onset but will test positive for IgM anti-HAV within the first 2 weeks of illness. 16 The detection of total anti-HAV is not useful as a diagnostic marker of HAV infection in infants because maternal IgG anti-HAV is transferred passively across the placenta.~7 HAV infection also can be diagnosed by detecting fecal HAV antigen by enzyme immunoassay (EIA) or fecal HAV RNA by polymerase chain reaction (PCR). However, these assays cannot be used to determine whether an individual is infectious because they may detect evidence of both defective and infectious viral particles.
Treatment No specific therapy is available for HAV-infected patients. HAV infection is self-limited, and treatment generally is supportive. Hospitalization may be required for patients who are dehydrated from nausea or vomiting. Patients with evidence of fulminant hepatic failure (eg, elevated prothrombin time, encephalopathy) require supportive treatment in intensive care settings.
Prevention HAV infection can be prevented by general measures of good personal hygiene, particularly hand washing; preexposure or postexposure immunization with immune globulin (IG); and preexposure immunization with hepatitis A vaccine. In one study, hepatitis A vaccine has also been found to be effective for post exposure prophylaxis. 17~ Two hepatitis A vaccines currently are licensed in the United States: HAVRIX (SmithKline Beecham Biologicals, Rixensart, Belgium) and VAQTA (Merck & Co., Inc., West Point, PA). Few data are available regarding the use of hepatitis A vaccine in infants, and the vaccine is not approved by the Food and Drug Administration (FDA) for use in children younger than 2 years of age. Ultimately, hepatitis A vaccination is expected to be included in the childhood vaccination schedule. 18 However, results from one study indicated lower immunogenicity of hepatitis A vaccine when administered at 2, 4, and 6 months of age to infants who had passively transferred maternal anti-HAV compared with infants without detectable anti-HAV. 18 Thus, data are needed regarding the appropriate dose and timing of vaccination in the first or second year of life. Newborn infants may be at risk of infection if the mother is infected less than 2 weeks betbre or after delivery. In this circumstance, administration of IG to the infant may be considered to prevent infection. Because severe disease in infants is rare, the primary reason to administer prophylaxis to the infant is to prevent transmission to others who may have contact with
the infant. The dose of IG for administration to newborn infants exposed to HAV is 0.02 mL/kg. Pregnancy or lactation is not a contraindication to administration of IG, and IG prophylaxis should be administered to pregnant or lactating women who are exposed to HAV. 18 Although hepatitis A outbreaks have occurred in neonatal intensive care units, the frequency of such outbreaks is not sufficiently high to warrant routine vaccination of staff in these settings. Appropriate use of standard precautions, especially strict adherence to hand washing, is indicated when infected infants or newborn infants at risk of infection are recognized in these settings. 19 In addition, if transmission is recognized in a neonatal intensive care unit, postexposure administration of IG with the possible addition of hepatitis A vaccine may be considered for staff members who provide care for HAVinfected infants.
Hepatitis B Virus Infection Epidemiology Neonates are at risk of HBV infection primarily as a result of transmission from their infected mothers. Each year in the United States, approximately 20,000 infants are born to HBVinfected pregnant women, and without immunoprophylaxis approximately 5,500 of these infants would become chronically infected. Most neonatal HBV infections occur among infants of pregnant women with chronic HBV infection. Pregnant women with acute HBV infection in the first and second trimester rarely transmit HBV to the fetus or neonate. 11,2~However, the risk of transmission fiom pregnant women who acquire infection during the third trimester is approximately 60 percent. 2~ The risk of HBV infection among infants born to hepatitis B surface antigen (HBsAg)-positive mothers ranges from less than 10 to 85 percent, with higher rates among infants of hepatitis B e antigen (HBeAg)-positive mothers and lower rates among HBeAg-negative mothers. Higher rates of transmission also are associated with higher maternal serum HBV DNA titers. One study found maternal HBV DNA titers to be a stronger independent predictor of persistent infection in infants than was maternal HBeAg status. 21 HBV transmission fiom mother to infant may occur in utero, perinatally, or postnatally. Evidence of in utero transmission includes the detection of HBsAg in infants soon after delive~T and the detection of HBV DNA in liver tissue of aborted fetuses. 22 However, at least 90 percent of neonatal infections result from perinatal exposures to maternal blood, amniotic fluid, or vaginal fluid. The role of mode of delivery in the transmission of HBV from mother to infant has not been fully determined. In one study, no difference in transmission rates was found among infants delivered vaginally compared with infants delivered by cesarian section23; however, in another study, higher rates of infection were found in infants delivered vaginally.24 Although HBsAg has been detected in breast milk, an increased risk of transmission associated with breast-feeding has not been documented. 25 Infants of HBsAg-positive mothers who are not infected during the perinatal period have a high risk of becoming infected postnatally during the first 5 years of life26 Other
Viral Hepatitis in the Newborn Infant chronically infected children in the household are the primary source of infection in this setting. 27,28
Clinical Features The course of pregnancy generally is not affected by either acute or chronic HBV infection, and maternal HBV infection usually has no clinically apparent effect on the fetus or neonate. However, in two reported cases of transplacental infection of the fetus after acute maternal infection, infants were small for gestational age and had cholestatic hepatitis. 29 In addition, premature labor has been observed in mothers with acute HBV infection during pregnancy.2~ Most HBV-infected infants are as}q~nptomatic; however, these infants occasionally have clinical signs of hepatitis with jaundice. In addition, fulminant hepatitis has been reported among infants infected perinatally, including reports of fulminant hepatitis occurring among two infants born successively to the same mother~~ fulminant hepatitis with a galactosemia-like presentational; and fulminant hepatitis in an infant who received appropriate postexposure immunoprophylaxis.32 Some investigators have postulated that mutations in the precore region of the HBV DNA may contribute to the pathogenesis of fulminant hepatitis B in neonates. 33 However, the precore mutation does not appear to be either necessary or sufficient to cause fulminant hepatitis B. 3a Infants who are infected with HBV have an 85 to 90 percent risk of developing chronic infection,35 and they may have evidence of chronic liver disease with persistently elevated alanine aminotransferase (ALT) levels. Other clinical sequelae associated with chronic HBV infection are unusual in childhood; however, HBV-associated hepatocellular carcinoma has been reported. 36 Most sequelae associated with perinatally acquired infection occur during adulthood; up to 25 percent of chronically infected infants will eventually die of HBV-related chronic liver disease, including cirrhosis and hepatocell~lar carcinoma. 37 In one study, middle-aged men with chronic HBV infection were greater than 200 times more likely to develop primary hepatocellular carcinoma than were those without chronic infection.~8
Diagnosis Serologic tests (EIAs and radioimmunoassays [RIAs]) are available commercially for a variety of antigens and antibodies associated with HBV infection, including HBsAg, antibody to HBsAg (anti-HBs), total (lgG and IgM) antibody to hepatitis B core antigen (anti-HBc), IgM anti-HBc, HBeAg, and antibody to HBeAg (anti-HBe). In addition, hybridization assays and gene amplification techniques (eg, PCR) are available to detect HBV DNA. The diagnosis of HBV infection in infants usually is made by detecting HBsAg, which can be detected in the serum of infected persons as early as 1 to 2 months after exposure to HBV. This antigen is synthesized during viral replication and also may be produced from HBV DNA integrated into the chromosomes ofhepatocytes in the absence of replication. Thus, detection of HBsAg in serum indicates active HBV infection, but it does not distinguish new infection from chronic infection or determine whether viral replication is occurring. The presence of anti-HBs in serum generally indicates either recovery and
903
immunity after past infection with HBV or an immune response to hepatitis B vaccine. Total anti-HBc can be detected in infected persons as early as 4 weeks after exposure to HBV, and this antibody persists both in persons who have self-limited infection and in persons who develop chronic infection. The detection of total anti-HBc is not useful as a diagnostic marker of HBV infection in infants because maternal IgG anti-HBc is transferred passively across the placenta. IgM anti-HBc is a very reliable test for diagnosis of recent HBV infection in older children and adults. However, this test is less sensitive for diagnosis of recent infections in young children who may not have an IgM anti-HBc response. 39 The presence of HBeAg and/or HBV DNA in serum correlates with higher titers of HBV and greater infectivity. Among patients with acute, self-limited infection, the appearance and disappearance of HBeAg and HBV DNA generally parallels that of HBsAg. Among patients with chronic HBV infection, HBeAg and HBV DNA titers generally decline over time. In one studyof perinatally infected children with chronic infection, 33 percent lost HBeAg during a follow-up period of 8 to 10 years, g~ Anti-HBe becomes detectable in most patients at the time HBeAg becomes undetectable.
Treatment As for hepatitis A, no specific treatment is available for HBVinfected infants, and treatment of acute disease is supportive. For adults with chronic hepatitis B, interferon alfa treatment for 4 to 6 months induces a long-term remission, with disappearance of HBeAg and HBV DNA fi-om serum in 25 to 40 percent of patients and consequent improvement in the biochemical and histological features of the disease. 41 Similar response rates have been found among children42,43; however, interferon alfa is approved by the FDA only for treatment of adults. Nucleoside analogues (eg, lamivudine, famciclovir) also have been evaluated extensively in clinical trials, and lamivudine recently has been approved by the FDA for treatment of adults with chronic hepatitis B. Short-term courses of these drugs result in rapid declines in serum HBV DNA levels; however, pretreatment levels of HBV DNA rapidly return after discontinuation of treatment, with no sustained improvement in clinical features of liver disease. Preliminary findings of clinical trials of long-term treatment with nucleoside analogues have shown sustained clearance ofHBV DNA from serum, lower aminotransferase levels, and histological improvement.41No published data are available regarding the use of combined therapy with nucleoside analogues and interferon or the use of nucleoside analogues for treatment of chronic HBV infection in children.
Prevention Postexposure immunoprophylaxis beginning at birth is highly effective in preventing infections in infants of HBV-infected mothers. More than 90 percent of infections transmitted from HBsAg-positive mothers can be prevented if the infected mother is identified and her infant receives immunoprophylaxis soon after birth. 44 The efficacies of active immunization with recombinant hepatitis B vaccine alone and of passive-active immunization with hepatitis B immune globulin (HBIG) and hepatitis B vaccine combined have been found to be essentially equivalent
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with higher vaccine doses.45The major factor that influences the efficacy of postexposure prophylaxis is the timing of the first dose of vaccine in relation to birth; optimum efficacy is achieved when the vaccine is administered within 24 hours after birth. To identify infants who require early immunoprophylaxis, all pregnant women should be routinely tested for HBsAg during an early prenatal visit in each pregnancy.46 HBsAg testing should be repeated in late pregnancy for HBsAg-negative women who have risk factors for HBV infection (ie, [injecting] drug use, intercurrent sexually transmitted diseases, multiple sex partners) or who have had clinical hepatitis. Infants born to HBsAg-positive mothers (including premature infants) should receive the appropriate dose of hepatitis B vaccine (5/xg ofRecombivax HB [Merck and Co, Inc] or 10/xgof EngerLx B [SmithKline Beecham Biologicals]) and HBIG (0.5 mL) within 12 hours of birth, administered concurrently but at separate sites by intramuscular injection.46 Infants who have begun immunoprophylaxisshould not be prevented from breastfeeding. Women admitted for delivery who have not been tested for HBsAg prenatally should have blood drawn for testing as soon as possible after admission. While test results are pending, the infant should receive hepatitis B vaccine (without HBIG) within 12 hours of birth. If the mother is later found to be HBsAg-positive, her infant should receive HBIG as soon as possible, but no later than 7 days after birth. All infants of HBsAg-positive mothers also should receive medical follow-up to ensure timely completion of subsequent doses of hepatitis B vaccine at 1 to 2 months and 6 months of age. After completion of the vaccine series, postvaccination testing for anti-HBs and HBsAg should be performed to determine the success of immunoprophylaxis and to identify infants who require further medical management. Postvaccination testing at 9 to 15 months of age minimizes the likelihood of detecting passively transferred anti-HBs from HBIG and maximizes the likelihood of detecting late HBsAg-positive infections. Infants who are anti-HBs-positive and HBsAg-negative are protected and do not need further medical management. Infants found to be anti-HBs-negative and HBsAg-negative should be revaccinated. Infants born to HBsAg-negative mothers also should receive active immunization against HBV, beginning within the first 2 months of life; such universal immunizationis recommended to ultimately eliminate transmission of HBV associated with highrisk behaviors later in life.46
Hepatitis C Virus Iniection Epidemiology Hepatitis C virus is transmitted most efficiently by direct percutaneous exposures to blood. Blood transfusion was a major route of transmission before donor screening practices were implemented in the 1980s and early 1990s; however, HCV currently is rarely transmitted by blood transfusion. The Centers for Disease Control and Prevention (CDC) recommends that persons be tested for evidence of HCV infection if they received a blood transfusion before July 1992, when multiantigen screening tests for antibody to HCV (anti-HCV) were widely implemented in blood collection facilities.47
Neonates are at risk of HCV infection primarily as a result of transmission from their infected mothers. Approximately 1 percent of pregnant women in the United States have serologic evidence of HCV infection, and most of these women are chronically infected. Thus, approximately 40,000 infants born to HCV-infected pregnant women each year are at risk of infection. The average rate of HCV infection among infants born to HCV-positive, human immunodeficiencyvirus (HIV)-negative women is 5 to 6 percent (range 0% to 25%), based on detection of serum anti-HCV and HCV RNA.48 Among infants born to women coinfected with HCV and HIV, the transmission rate is higher: 14 percent (range 5% to 36%) and 17 percent based on detection of anti-HCV and HCV RNA, respectively.4s The only factor consistently found to be associated with transmission has been the presence of serum HCV RNA in the mother at the time of birth. Although two studies of infants born to HCV-positive, HIV-negative women reported an association with maternal titer of HCV RNA, these studies reported different levels of HCV RNA to be related to transmission.49,5~ Studies of HCV- and HIV-coinfected women more consistently have indicated an association between virus titer and transmission of HCV. 51Data regarding the relationship between delivery mode and HCV transmission are limited and presently indicate no difference in infection rates between infants delivered vaginally or those delivered by cesarean section.52 Although HCV RNA has been detected in breast milk, transmission of HCV infection via breast milk has not been documented. In studies that have evaluated the risk of transmission from breast-feeding among infants born to HCV-infected women, the average rate of infection was 4 percent in both breast-fed and bottle-fed infants.48
Clinical Features Maternal HCV infection generally has no effect on the course of pregnancy, and no clinically apparent effects of maternal infection on the fetus or neonate have been reported. HCV-infected infants typically have no clinical signs or symptoms of liver disease, and no cases of fulminant hepatitis have been reported among infected infants. However, the majority become chronically infected, and most of these infants have elevated ALT levels.52Limited data suggest that infants infected with HCV at the time of birth do very well in the first years of life, with few clinical signs or symptoms of disease. However, no follow-up data are available to assess the long-term consequences of hepatitis C in these infants. Among infected adults, the course of chronic liver disease usually is insidious, progressing at a slow rate without symptoms or physical signs in the majority of patients for the first two or more decades after infection. In most long-term follow-up studies of persons with chronic hepatitis C, cirrhosis developed in 10 to 20 percent and hepatocellular carcinoma in 1 to 5 percent during a period of 20 to 30 years. 5~,54 In contrast, among 376 women who were infected after they received HCV-contaminated Rh factor immune globulin, only 2 percent had cirrhosis and none died after 17 years of follow-up.55
Diagnosis Diagnosis of HCV infection in infants can be made using either serologic assays that detect anti-HCV or gene amplification
Viral Hepatitis in the Newborn Infant techniques that qualitatively detect HCV RNA (eg, reverse transcriptase [RT]-PCR). 47 Serologic assays that detect antiH C V are the only tests currently approved by the FDA for diagnosing HCV infection. These tests detect anti-HCV in 97 percent or more of infected persons but do not distinguish among acute, chronic, or resolved infection. Testing for antiHCV should include use of both an EIA and supplemental or confirmatory testing with an additional, more specific assay (eg, RIBA [Chiron Corporation, Emeryville, CA]). Although not FDA approved, RT-PCR assays for H C V RNA are used commonly in clinical practice. H C V RNA can be detected in serum or plasma within 1 to 2 weeks after exposure to the virus. Because of assay variability, rigorous quality assurance and control should be in place in clinical laboratories performing this assay, and proficiency testing is recommended. Specific diagnostic criteria for perinatal HCV infection have not been established. Various patterns of anti-HCV detection have been observed in both infected and uninfected infants of anti-HCV-positive mothers. 56 In uninfected infants, passively acquired maternal antibody can persist for months, but probably not for more than 18 months. In most infected infants, endogenous production of antibody occurs before maternal anti-HCV declines below detectable levels. However, some studies have shown periods when HCV RNA is detected but antibody is not detectable. The period of antibody seronegativity in these infants was highly variable, ranging from 6 to 21 months of age. Based on these findings, testing of infants for anti-HCV should be performed no sooner than 2 years of age, when maternal anti-HCV will have decreased below detectable levels and endogenous anti-HCV is detectable in infected infants. If HCV infection is suspected in an anti-HCV-negative infant (eg, elevated ALT levels), anti-HCV testing may be repeated later or RT-PCR for H C V RNA may be performed. If earlier diagnosis of HCV infection is desired, RT-PCR for HCV RNA may be performed at or after the infant's first well-child visit at 1 to 2 months of age. Umbilical cord blood should not be used for RT-PCR testing because cord blood can be contaminated by maternal blood.
Treatment Interferon alfa and combination therapy with interferon and ribavirin have been approved by the FDA for treatment of adults with chronic hepatitis C. In adults, sustained response rates of 40 to 50 percent have been achieved with a combination of interferon and ribavirin compared with response rates of l0 to 20 percent with interferon alone. 57-59 However, combination therapy in patients with H C V genotype 1, the most common genotype in the United States, is not as successful, with sustained response rates of less than 30 percent. Experience is limited in treating children with chronic hepatitis C, and no treatments are approved for persons younger than 18 years. Data from preliminary interferon trials among children with chronic hepatitis C are promising, with sustained responses in 45 to 55 percent of treated children. 6~ No data are available regarding use of combination therapy in children.
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Prevention Measures to prevent hepatitis C are limited. The development of a vaccine is not likely in the foreseeable future, and immune globulin does not appear to be effective for postexposure prophylaxis. 63 No information is available regarding the use of antiviral agents (eg, interferon) for postexposure prophylaxis of HCV infection. The mechanism of the effect of interferon in treating patients with hepatitis C is poorly understood, and interferon may be effective only in established infection. 64 Routine serologic testing of pregnant women for HCV infection is not recommended because no measures are available to prevent perinatal transmission, no licensed therapy or guidelines for treatment of HCV-infected infants or children exist, and severe disease rarely occurs. However, health care professionals in settings where pregnant women are evaluated or receive routine care should obtain histories regarding risk factors from their patients to determine the need for testing. 47 Potential, expectant, and new parents should be advised that breast-feeding is not contraindicated by maternal HCV infection, although they should consider abstaining from breastfeeding if the nipples are cracked or bleeding. In addition, no evidence exists that mode of delivery is related to transmission; therefore, determining the need for cesarean versus vaginal delivery should not be made on the basis of HCV infection status.
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