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VIRAL HEPATITIS IN PREGNANCY
PREGNANCY AND LIVER DISEASE
1089-3261/99 $8.00
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VIRAL HEPATITIS IN PREGNANCY John F. Reinus, MD, and Enid L. Leikin, MD
Acute and chronic necro-inflammatory liver disease caused by hepatotropic virus infection continues to be a major worldwide health problem. Approximately 5% of the world’s population has chronic hepatitis B virus (HBV)82as many as 100% of the residents of nonindustrial nations and 70% of the residents of industrial nations have serologic evidence of prior exposure to hepatitis A virus (HAV)154,70 and in the United States, end-stage liver disease caused by chronic hepatitis C virus (HCV) is the most common indication for orthotopic liver transplantaAcute and chronic viral hepatitis often affects women of tion (OLT).23,54 child-bearing age and their infants. In regions of the world where chronic HBV is prevalent, most new cases are the result of perinatal or neonatal infection. HAV infection usually occurs during childhood or in young adults, including those in their early reproductive years.25,70 HCV infection often is acquired by teenagers and young adults as a result of drug use and also is common in persons with a history of sexual l9 promiscuity.lO, Thus, individuals providing health care to young women are likely to encounter patients with viral hepatitis and must be prepared to deal with issues related to acute and chronic infection, sexual and vertical transmission, and screening and treatment.
From the Division of Gastroenterology, Montefiore Medical Center, The Albert Einstein College of Medicine (JFR), Bronx; and the Division of Maternal-Fetal Medicine, WestChester County Medical Center, The New York Medical College (ELL), Valhalla, New York
CLINICS IN LIVER DISEASE
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VOLUME 3 NUMBER 1 FEBRUARY 1999
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CLINICAL FEATURES OF VIRAL HEPATITIS
The clinical features of each type of viral hepatitis are similar and almost exclusively the consequences of liver cell injury; on rare occasions, individuals with viral hepatitis will have extrahepatic (immunologic) manifestations of their The presentation of hepatitis in pregnant women, as a rule, is no different from that in nonpregnant individuals and is determined by the severity of the liver damage and whether or not it is acute or chronic. Acute Liver Disease
Acute viral hepatitis is the result of parenteral or enteral exposure to a hepatotropic virus (Table 1). The time interval from exposure to development of clinical liver disease (incubation period) is highly variable, ranging from 15 to 150 days, depending on the cause. During the incubation period, the virus spreads from the point of entry through the blood to hepatocytes and excites a host immune response, which, in almost every type of acute hepatitis, is the cause of liver cell injury and death. Damaged hepatocytes release aminotransferases into the blood. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations increase to levels of from 500 to 5,000 mU/mL, becoming abnormal approximately 1 week before and usually peaking approximately 1 week after symptoms develop.28Even asymptomatic persons with viral hepatitis, however, may have serum aminotransferase levels in the thousand^.^^ Most individuals who are exposed to.a hepatitis virus do not develop clinically apparent disease; those who do may have very mild, nonspecific symptoms, typical acute viral hepatitis or fulminant liver failure in rapidly decreasing order of frequency.54For this reason, many people are unaware that they have been infected with a hepatitis virus and are surprised if serologic testing demonstrates hepatitis virus antigens or antibodies.22 Persons with clinical viral hepatitis initially have nonspecific complaints, including fatigue, malaise, anorexia, nausea, headache, and myalgias, possibly associated with low-grade fever (Table 2).31If the illness resolves before there is sufficient liver-cell injury and secondary dysfunction to cause jaundice, it may be mistaken for a flu-like viral syndrome or even for the normal physiologic effects of pregnancy itself; otherwise, jaundice develops within 2 to 10 days of the onset of symptoms. Jaundice becomes apparent when the serum bilirubin concentration reaches 2 to 4 mg/dL, depending on the rate at which the bilirubin level increases. If the serum level rises slowly, there is ample time for bilirubin to diffuse into total body water, and jaundice is noticeable at lower serum concentrations. Conversely, if the serum level rises rapidly, there is little time for bilirubin to diffuse into total body water, and jaundice
Ib
5 1 Parenteral/sexual Yes 40-150 d 30% 5% <1% Serum
7 1 Fecal-oral No 15-50 d Pediatric, 5%/adult, 80% No
Serum Yes Yes
Serum
Hepadnaviridae
Orthohepadnavirus
Hepatovirus
Family Genus Genotypes Serotypes Main transmission Vertical transmission Incubation period Clinical illness Chronicity Fulminant course Antigen test Antibody test Nucleic acid test Vaccine
HBV
Picomaviridae
HAV
Species
Table 1. CLASSIFICATION AND BIOLOGIC PROPERTIES OF THE HEPATOTROPIC VIRUSES
>6 ? Parenteral Rare 14-140 d 5% 85% Rare or no None Serum Serum No No
Hepacivirus
Flaviviridae
HCV
Parenteral Rare 20-45 d 10% Yes <5% Serum Serum Serum Yes (HBV) No
?
Deltavirus 3
Deltaviridae
HDV
Feces No No
Serum
No Pregnancy Fecal
80%
Uncertain Unnamed 3 1 Fecal-oral Yes 15-65 d
HEV
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ultimately, death. Disappearance or persistence of symptoms are seen in the minority of individuals with clinical hepatitis who go on to have chronic viral liver disease. Chronic Liver Disease
In most affected individuals, chronic viral hepatitis is asymptomatic either indefinitely or until there is sufficient liver damage for the patient to develop manifestations of end-stage liver disease. Some persons experience periodic clinical exacerbations that resemble mild, moderate, or even severe acute hepatitis. Less frequently, patients have persistent symptomatic hepatitis that begins as an acute infection, progresses to chronic infection and finally causes liver failure. Many cases of chronic viral hepatitis, therefore, are diagnosed after serum aminotransferase levels incidentally are noted to be abnormal. This commonly occurs when an apparently healthy young woman becomes pregnant and consults an obstetrician. Serum aminotransferase levels in asymptomatic patients of this type usually are one and a half to five times the upper limit of normal depending on the cause. Results of other laboratory tests often are normal, but may be abnormal if the patient has asymptomatic cirrhosis and mildly abnormal liver function. Physical examination also may be normal or the patient may have subtle physical findings consistent with early cirrhosis, including palmar erythema, splenomegaly, and a small liver, possibly with enlargement of the left lobe. Examination of the abdomen is difficult and may be ambiguous in the later stages of pregnancy when the liver and spleen are not palpable and patients often have physiologic palmar erythema. In the minority of patients with chronic hepatitis who develop end-stage liver disease, clinical features of liver failure gradually become apparent and potentially may be mistaken for a hepatic complication of pregnancy. It is uncommon for women with significant pre-existing liver disease to become pregnant. Ultimately, the natural history of viral hepatitis in a given patient is determined by the particular agent causing the infection and the host response to it. HEPATITIS A VIRUS
HAV is a RNA virus (family, Picornaviridae; genus, Hepatovirus) with seven genotypes but only one serotype (see Table 1). Thus, anti-HAV IgG antibody confers immunity to infection with any genotype of HAV. Acute infection is diagnosed by a positive serum test for anti-HAV IgM antibody. Transmission of HAV is horizontal through fecal-oral exposure. Virus is shed in the stool in high titer beginning approximately 1 week after infection and ending just after the serum ALT level peaks.76HAV
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is resistant to environmental degradation and has a high attack rate; 70% to 90% of exposed individuals develop antibody. Prevalence of antibody indicating previous HAV infection depends on the quality of the local water supply, the level of sanitation, and the average age of the population tested. HAV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response; the virus is not cytopathic. The incubation period of HAV infection is 15 to 50 days (average, 25). Clinical illness frequently is mild and often unrecognized. Symptoms develop in 5% of infected children30,84 and 80% of infected severity is age related so that, as a rule, the older an individual with HAV infection, the severer the clinical liver disease. HAV infection is fulminant in less than 1% of patients and is never chronic.18 In areas of the world where HAV is prevalent, most persons are exposed during the first few years of life and have asymptomatic hepatitis.@In areas of low endemicity, HAV infection commonly develops in teenagers and in young adults; infections often occur in clusters and are symptomatic." In the United States, the prevalence of serologic markers of previous HAV infection increases from 11%in children under age 5 to 74% in adults over age 50.70 Risk factors for HAV infection include personal contact with infected individuals (26%), employment in a day care facility (14%), intravenous drug use (IVDU) (ll?'~),travel to an area where HAV infection is prevalent (4%), and ingestion of food or water contaminated with feces Symptoms and signs of liver disease in a pregnant woman with one of these risk factors in an area of low HAV endemicity are more likely than those in young people elsewhere to indicate acute HAV infection. HAV infection is no severer in pregnant women than in non-pregnant individual^.^^ I n t r a ~ t e r i n eand ~ ~ perinatal maternal-fetal transmis~ i o of n ~HAV ~ have been reported, however, maternal HAV infection during pregnancy is not associated with fetal loss or developmental abnormalities. Passive immunization with pooled human serum immunoglobulin (IG) containing anti-HAV IgG 3 to 6 months before, or within 2 weeks of exposure to HAV prevents or attenuates hepatitis in 85% to 95% of treated individual^.^^, 45 Passive immunization has been recommended for travelers to endemic areas and household contacts of infected pers o n ~An . ~ HAV ~ vaccine made from formalin-inactivated virus was approved for use in the United States in 1995. A single dose of this vaccine causes serum anti-HAV antibody production within 2 weeks of inoculation in 90% to 98% of patients.38,56 Vaccination has been recommended for individuals working in day care centers and for persons living in communities where there are case-clusters of HAV infection. Other candidates for HAV vaccination are
Recommended Travelers to endemic areas
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Military personnel Special populations (Native Americans, Native Alaskans) Potential Day care center children and employees Food handlers Homosexuals Drug addicts Residents and staff of institutions Health care workers Persons with chronic liver disease Sewage workers Residents of communities where there is an outbreak of HAV The IG and HAV vaccine both are safe for use in pregnant women. HEPATITIS B VIRUS
HBV is a DNA virus (family, Hepadnaviridae; genus, Orthohepudnavirus) with five genotypes but only one serotype (see Table 1). Thus, antibody to the HBV surface antigen (anti-HBs) confers immunity to infection with any genotype of HBV. Acute and chronic HBV infection are diagnosed by a positive serum HBV surface antigen (HBsAg) test. Recent infection is indicated by the presence in serum of IgM antibody to HBV core antigen (anti-HBc), whereas predominant serum IgG antiHBc is found in persons with chronic infection. Active viral replication in acute or chronic HBV infection is seen in patients with serum HBV e antigen (HBeAg). In contrast, serum antibody to HBeAg (anti-HBe) is found in individuals recovering from acute HBV infection and also in persons with chronic HBV infection without active viral replication. Transmission of HBV is both horizontal through parenteral (nonsexual and sexual) exposure to blood, blood products, semen, vaginal secretions and saliva, and vertical (from mother to infant). HBV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response; the virus is not cytopathic. The incubation period of HBV infection is 40 to 150 days (average, 75). Illness may be acute and subclinical (approximately 70% of adult infections), acute and symptomatic (approximately 30% of adult infections), chronic (less than 5% of acute adult infe~tions),3~ or fulminant (less than 1%of acute infections). Chronic HBV infection predisposes affected individuals to develop cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). In areas of the world where hepatitis B is prevalent, as many as 15% of the inhabitants have chronic HBV infection.5l Most of these individuals become infected at birth as a consequence of vertical transmission. Neonatal HBV infection is almost always asymptomatic and results in chronic infection in approximately 90% of cases.52Chronic HBV infection is moderately prevalent among indigenous Alaskan peoples (6.4Y0)~~; HBV infection in native Alaskans occurs at all ages, and the
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rate of chronic disease is maintained by vertical spread and acquisition during early childhood. In the rest of the United States, where the prevalence of HBV infection is low,54the majority of infections occur in young adults and may be symptomatic. Symptoms and signs of liver disease in a pregnant woman in the contiguous United States and other areas of low endemicity, therefore, are more likely than those in young people elsewhere to indicate acute HBV infection. In areas of high endemicity, symptoms and signs of liver disease in a pregnant woman are more likely than those in young people elsewhere to indicate chronic HBV infection. HBV infection is no severer in pregnant women than in nonpregnant individ~als,3~ although the disease may rarely be fatal in any affected person. Chronic HBV carriers usually have normal pregnancies, unless there is also severe chronic hepatitis or secondary cirrhosis and associated complications.69The significance of HBV infection during pregnancy derives, in major part, from its potential to be transmitted vertically.62Ten percent of infants born to women with acute HBV infection during the first trimester of pregnancy are HBsAg positive at and 80% to 90% of neonates become HBsAg-positive without prophylactic therapy if acute maternal infection develops during the third trimester of pregnancy.'2 This variable rate of vertical transmission from mothers with acute disease is explained by the fact that the placenta is a reasonably effective barrier to the spread of HBV infection; 85% of neonatal HBV infections are caused by intrapartum exposure to infectious blood and vaginal secretions, and the remaining 15% to hematogenous transplacental viral spread.61In the absence of appropriate prophylaxis, 40% of the neonates of mothers with HBeAg-negative chronic HBV infection and 90% of the neonates of mothers with HBeAg-positive chronic HBV themselves will develop chronic HBV As noted earlier, HBeAg is a marker for active viral replication and viremia similar to that seen in persons with acute disease. The possibility of vertical transmission lends added importance to diagnosis of acute or chronic HBV infection in pregnant women and justifies mandatory antepartum serum HBsAg testing.' Diagnosis of previously unsuspected chronic HBV infection in young, otherwise healthy individuals has the added benefit of making it possible to refer them for appropriate antiviral therapy before development of significant liver damage, associated functional insufficiency, and, possibly, hepatocellular carcinoma (HCC). The infants of potentially infectious mothers are treated with HBV human hyperimmune globulin (HBIG) at delivery and simultaneously inoculated with the first of three injections of HBV vaccine (Table 3).l This regimen is approximately 85% effective in preventing development of chronic HBV in neonates73;it is ineffective in cases of hematogenous transplacental infection (15%).Universal vaccination of children before age 2 months was recommended by the US Public Health Service in 199237and elicits an antibody response in 95% of individuals. Pregnant women suspected of having been exposed to HBV should be treated with HBIG and innoculated with HBV vaccine; this
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Table 3. RECOMMENDED HEPATITIS B VIRUS IMMUNOPROPHYLAXIS OF NEONATES HBsAg Status of Mother
HBsAg-positive mothers
HBsAg-unknown mothers
HBsAg-negative mothers
Vaccine (HBVV) and Immunoglobulin (HBIG)
HBIG, 0.5 mL IM HBW (first dose) HBW (second dose) HBW (third dose) HBIG, 0.5 mL IM HBW (first dose) HBW (second dose) HBW (third dose) HBW (first dose) HBW (second dose) HBW (third dose)
Age
Birth-age 12 h Birth-age 12 h 1 mo 6 mo Birth-age 12 h Birth-age 12 h 1 mo 6 mo Before discharge 1 mo 6 mo
therapy is safe and effective during pregnancy.13,48 Women with chronic HBV infection should be referred for appropriate evaluation and care after pregnancy. HEPATITIS C VIRUS
HCV is a RNA virus (family, Flaviviridae; genus, Hepacivirus) with six (and possibly more) major genotypes (designated with Arabic numerals), more than 50 subtypes (designated with lowercase letters) and an unknown number of serotypes (see Table l).57 Within a single infected individual, HCV is present in the form of multiple quasispecies: viral particles with very similar but heterogeneous RNA sequences that develop as a result of mutation during viral replication.80Antibodies to different isolates are specific, do not cross-react, and, therefore, do not provide protective immunity.80For this reason, a positive test for serum anti-HCV antibody indicates active infection in most instances. Transmission of HCV is horizontal through parenteral exposure to blood and blood products and, rarely, vertical. HCV replicates in hepatocyte cytoplasm; liver-cell injury most likely is caused by the host immune response to infection. The incubation period of hepatitis C is 14 to 140 days (average, 50). Acute infection almost always is subclinical and becomes chronic in over 85% of cases15, HCV rarely, if ever, is fulminant. Chronic HCV infection predisposes affected individuals to develop cirrhosis, end-stage liver disease and HCC. In addition, chronic HCV infection is associated with a number of extra-hepatic manifestations including arthritis, keratoconjunctivitis ~icca,2~ lichen planus,66porphyria cutanea tarda,2I and essential mixed cryoglobulinemia,3 with or without glomer~lonephritis~~; these disorders, presumably, may be diagnosed in pregnant women. Specific risk factors for HCV infection include receipt of a blood
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transfusion before 1992,19,68 IVDU,19, nasal cocaine use,I9 sexual promiscuity,19hemodialysis,5. and receipt of a transplanted organ.2, The world.~ wide prevalence of chronic HCV infection is approximately l y ~There are, however, significant demographic and socioeconomic variations in infection rates. In the United States, the highest prevalence of HCV infection is in persons ages 30 to 49 years (3% to 4%). This disease, therefore, is not uncommon in women of child-bearing age. Of 1700 pregnant women in our cohort receiving care at a suburban county 75 (4.5%) had a positive anti-HCV antibody test; none medical of these individuals was aware before evaluation that she had chronic HCV infection. There is no evidence that pregnancy alters the natural history of HCV or that HCV interferes with normal pregnancy, unless the patient has cirrhosis with associated complications. HCV, however, may be transmitted vertically when maternal viral titers are unusually high, for example, in persons with HCV and HIV coinfection (Table 4).27,77 HIV infection exacerbates HCV ~ i r e m i aCoinfection .~~ with HIV and HCV is not uncommon, inasmuch as the risk factors for acquiring each of these diseases are similar; most individuals with a history of IVDU also have hepatitis C. Maternal serum HCV RNA levels of greater than or equal to 1019copies per mL have been reported to be associated with vertical
Table 4. VERTICAL TRANSMISSION OF HEPATITIS C DIVIDED BY MATERNAL HUMAN IMMUNODEFICIENCY VIRUS STATUS Reference
Mothers with HIV Infection Manzini et alM Lam et a144 Novati et aP9 Reinus et alM Zanetti et alas Thaler et a1"
Total Mothers without HIV Infection Ni et a P Roudot-Thorval et a P Manzini et alM Lam et a144 Lin et a149 Aizaki et a14 Wejstdl et alE1 Reinus et alM Ohto et aPO Zanetti et alas Thaler et aln
Total
No. of Infants with HIV/No. Tested 1/18 3/48 4/8 0/4 8/22 3/5 19/l05 (18%) 2/11
0/18 0/27 1/17
1/15 1/35 1/14 0/20 3/54 0/94 5/5 14/310 (4.5%)
From The National Institutes of Health Consensus Development Conference: Management of Hepatitis C. Hepatology 26:S1, 1997; with permission.
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transmission in as many as 36% of cases.6oVertical transmission of HCV in other circumstances has been found to be exceedingly uncommon.64 Diagnosis of previously unsuspected chronic HCV infection in young, otherwise healthy individuals has the added benefit of making it possible to refer them for appropriate antiviral therapy before development of significant liver damage; associated functional insufficiency; and, possibly, HCC. We were able to identify a group of pregnant women that included most individuals in our cohort with HCV by using epidemiologic predictors in advance of antibody testing, potentially reducing the cost of screening by 55Y0.~~ HEPATITIS D VIRUS
Hepatitis D (delta) virus (HDV) is a RNA viroid (family, Delfaviridae; genus, Deltavirus), with three genotypes and an unknown number of serotypes (see Table 1). HDV infection may be acute or chronic, and does not occur in the absence of acute or chronic HBV infection because HDV requires HBV for coating and cell-to-cell spread. Thus, HDV is the result of either acute HDV and HBV coinfection or HDV infection in a chronic HBV carrier. Acute HDV is diagnosed by detection of serum anti-HDV IgM antibody in a patient who also has a positive serum HBsAg test,” whereas persons with chronic HDV and HBV infections have serum anti-HDV IgG antibody titers of greater than 1 to 1000 and positive serum HBsAg tests.71 Like HBV, HDV is transmitted through parenteral exposure to blood and blood products. HDV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response, and possibly a direct cytopathic effect. Most patients with acute HDV and HBV coinfection recover completely and develop immunity to reinfection, however, HDV superinfection in a person with chronic HBV results in chronic HDV in 90% of cases.16Most individuals with chronic HDV have hemophilia or a history of IVDU. Perinatal transmission of HDV is rare, and there are no documented cases of vertical transmission of HDV in the United States.85 HEPATITIS E VIRUS
Hepatitis E virus (HEV) is a RNA virus (family, uncertain; genus, unnamed) with three genotypes and one serotype (see Table 1). Thus, anti-HEV IgG antibody confers immunity to infection with any genotype of HEV. Acute infection may be diagnosed by a positive serum test for anti-HEV IgM antibody, but serologic tests for HEV infection are not available in most clinical laboratories. Transmission of HEV is primarily horizontal through fecal-oral exposure. In utero transmission with acute hepatitis in the newborn has been documented.4*”HEV is a disease of Third World peoples and
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usually occurs in large epidemics caused by fecal contamination of drinking water.17 Sporadic cases also are seen in areas where the virus is endemic.42,78 Secondary spread of HEV is uncommon55;secondary attack rates in households of infected individuals range from 0.7% to 2.270, in contrast to secondary attack rates of HAV of 50% to 75% in homes of HAV-infected persons. In Western, industrial nations, HEV infection is rare and has been diagnosed in only travelers returning from 2o Third World co~ntries.'~, HEV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response and, possibly, a direct cytopathic effect. The incubation period of HEV is 15 to 65 days (average, 40). HEV infection is most common in persons of child-bearing age (ages 15 to 40)55;clinical illness develops in 70% to 80% of infected individuals and may be mild to severe. In nonpregnant patients, HEV infection is fulminant in less than 1% of patients, whereas in pregnant women, it is fulminant in as many as 20% of patient^.^^,^^ Similarly, the overall fatality rate of HEV is 0.5% to 47'0, but the fatality rate is 1.5% during the first trimester, 8.5% during the second trimester, and 21% during the third trimester of pregnancy. The reasons why this virus causes especially severe disease in pregnant women are unknown. HEV infection during the third trimester of pregnancy is associated with an increased number of fetal complications,78and death of neonates caused by HEV infection is much more common than it is from other types of viral hepatitis. HEV infection is never chronic. Prevention of HEV epidemics depends on improvements in sanitation and protection of the purity of water supplies. In areas where the virus is endemic, boiling of drinking water, avoidance of locally produced bottled beverages, ice and unpeeled, uncooked fruits and vegetables seem to be effective in preventing HEV infection. Pregnant women should not travel to areas where there are known cases of HEV. Immunoprophylaxis against HEV infection is not available; administration of HEV-immune serum globulin to persons at risk of infection during an epidemic of HEV in India did not affect disease rates.40,41 An HEV vaccine currently is being tested. HEPATITIS F, G, AND X VIRUSES
Clinical and epidemiologic data support the conclusion that there is at least one, and possibly more than one, additional hepatitis virus remaining to be characterized (hepatitis X).ll, 33, 83 Between 5% and 20% of cases of acute and chronic hepatitis do not appear to be caused by known hepatitis viruses, or toxic, metabolic or immune-mediated mechanisms. Untyped hepatitis viruses may infect women during pregnancy and be a source of diagnostic confusion, particularly during the third trimester, when jaundice may be a complication of pregnancyinduced hypertension or a sign of acute fatty liver of pregtancy. A candidate hepatitis F virus (HFV) has been reported, but its
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existence has not been confirmed. Hepatitis G virus (HGV), also known as GB virus, type C (GBV-C), is a parenterally transmitted hepatotropic virus (family, FIuviviridue; genus, unnamed) that does not seem to be pathogenic and, therefore, may not be a true hepatitis virus.7* The majority of persons with chronic HGV infection have no evidence of associated liver disease unless they also are infected with HCV. Persistence of HGV viremia after recovery in cases of supposed acute HGV suggests that affected patients may be chronic HGV carriers who develop hepatitis X. Only a minority of hepatitis X patients have a positive serum test for HGV. There are no clinical data pertaining to HGV infection during pregnancy or in neonates, and no studies of vertical transmission of this agent. Clearly, there is more work to be done in this interesting field of investigation. References 1. ACOG Technical Bulletin. Hepatitis in pregnancy. 174 November 1992. 2. Aeder M, Shield C, Tegtmeier G, et al: Incidence and clinical impact of hepatitis C virus-positive donors in cadaveric transplantation. Transplant Proc 25:1469, 1993 3. Agnello V, Chung RT, Kaplan LM: A role of hepatitis C virus infection in type I1 cryoglobulinemia. N Engl J Med 3271490, 1992 4. Aizaki H, Saito A, Kusakawa I, et al: Mother-to-child transmission of a hepatitis C virus variant with an insertional mutation in its hypervariable region. J Hepatol 25:608, 1996 5. Alfurayh 0, Sobh M, Buali A, et al: Hepatitis C virus infection in chronic hemodialysis patients: A clinicopathologic study. Nephrol Dial Transplant 7327, 1992 6. Alivanis P, Derveniotis V, Dioudis C, et al: Hepatitis C virus antibodies in hemodialysed and in renal transplant patients: Correlation with chronic liver disease. Transplant Proc 23:2662, 1991 . 7. Alter HJ, Nakatsuji Y, Melpolder J, et al: The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease. N Engl J Med 336:747,1997 8. Alter MJ: Epidemiology of hepatitis C. Hepatology 26:62S, 1997 9. Alter MJ, Gallagher M, Morris TT, et al: Acute non-A-E hepatitis in the United States and the role of hepatitis G virus infection. N Engl J Med 336:741, 1997 10. Alter MJ, Hadler S, Judson F, et al: Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA 264:2231, 1990 11. Alter MJ, Margolis HS, Krawczynski K, et al: The natural history of communityacquired hepatitis C in the United States. N Engl J Med 327:1899, 1992 12. Arevalo ]A: Hepatitis B in pregnancy. West J Med 150:668, 1989 13. Ayoola EA, Johnson A 0 Hepatitis B vaccine in pregnancy: Immunogenicity, safety and transfer of antibodies to infants. Int J Gynaecol Obstet 25:297, 1987 14. Bader TF, Krawczynski K, Polish LB, et al: Hepatitis E in a US traveler to Mexico. N Engl J Med 3253659, 1991 15. Barrera JM, Bruguera M, Guadalupe-Ercilla M, et al: Persistent hepatitis C viremia after acute self-limiting post-transfusion hepatitis C. Hepatology 21:639, 1995 16. Caredda F, Antinori S, Re T, et al: Course and prognosis of acute HDV hepatitis. Prog Clin Biol Res 364:267, 1987 17. Centers for Disease Control: Enterically transmitted non-A, non-B hepatitis-East Africa. MMWR 36:241, 1987 18. Centers for Disease Control: Hepatitis surveillance report. 53:23, 1990 19. Conry-Cantilena C, VanRaden M, Gibble J, et al: Routes of infection, viremia and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 334:1691, 1996
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20. De Cock KM, Bradley DM, Sandford NL, et al: Epidemic non-A, non-B hepatitis in patients from Pakistan. Ann Intern Med 106:227, 1987 21. DeCastro M, Sanchez J, Herrera JF, et a1 Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology 17551, 1993 22. Denes AE, Smith JL, Maynard JE, et al: Hepatitis B infection in physicians: Results of a nationwide socioepidemiologic survey. JAMA 239210, 1978 23. Detre KM, Belle SH, Lombardero M Liver transplantation for chronic viral hepatitis. Viral Hepatitis Rev 2219, 1996 24. Eyster ME, Alter HJ, Aledort LM, et al: Heterosexual cotratransmission of hepatitis C virus (HCV) and human immunodeficiency virus. Ann Intern Med 115:764, 1991 25. Francis DP, Hadler SC, Prendergast TJ, et al: Occurrence of hepatitis A, B, and nonA, non-B in the United States: CDC sentinel county hepatitis study I. Am J Med 76:69, 1984 26. Garfein RS, Vlahov D, Galai N, et al: Viral infections in short-term injection drug users: The prevalence of the hepatitis C, hepatitis B, human immunodeficiency and human T-lymphotropic viruses. Am J Pub1 Health 86:655, 1996 27. Giovannini M, Tagger A, Ribero ML, et al: Maternal-infant transmission of hepatitis C virus and HIV infections: A possible interaction. Lancet 335:1166, 1990 28. Goldberg DM, Campbell DR Biochemical investigation of an outbreak of infectious hepatitis in a closed community. Br Med J 21435,1962 29. Haddad J, Deny P, Munz-Gotheil, et al: Lymphocytic sialadenitis of Sjogren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet 339:321, 1992 30. Hadler SC, Webster HM, Erben JJ, et a1 Hepatitis A in day-care centers: A communitywide assessment. N Engl J Med 302:1222, 1980 31. Havens WP, Jr: Viral hepatitis: Clinical patterns and diagnosis. Am J Med 32665,1962 32. Havens WP, Paul JR Prevention of infectious hepatitis with gamma globulin. JAMA 129:270, 1945 33. Hibbs JR, Frickhofen N, Rosenfeld SJ, et al: Aplastic anemia and viral hepatitis. NonA, non-B, non-C? JAMA 2672051,1992 34. Hieber JP: Hepatitis and pregnancy. J Pediatr 91:545, 1977 35. Hyams DC:Risks of chronicity following acute hepatitis B virus infection: A review. Clin Infect Dis 20:992, 1995 36. Immunization Practices Advisory Committee: Protection against viral hepatitis. MMWR 39(RR-2):1, 1990 37. Immunization Practices Advisory Committee: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. MMWR 40:1, 1991 38. Innis BL, Snitbhan R, Kunasol, et al: Protection against hepatitis A by an inactivated vaccine. JAMA 271:1328, 1994 39. Johnson RJ, Gretch DR, Yamabe H, et al: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328465,1993 40. Joshi Y, Babu S, Sarin S, et a1 Immunoprophylaxis of epidemic non-A, non-B hepatitis. Indian J Med Res 81:18, 1985 41. Khuroo M, Dar M Hepaitis E: Evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol 11:113, 1992 42. Khuroo M, Duermayer W, Zargar SA, et al: Acute sporadic non-A, non-B hepatitis in India. Am J Epidemiol 118360, 1983 4%. Khuroo MS, Kamili S, Jameel S Vertical transmission of Hepatitis E virus. Lancet 345:1035-1036, 1995 43. Khuroo MS, Teli MR, Skidmore S, et al: Incidence and severity of viral hepatitis in pregnancy. Am J Med 70252, 1981 44. Lam JPH, McOmish F, Bums SM, et al: Infrequent vertical transmission of hepatitis C virus. J Infect Dis 167572, 1993 45. Lednar W, Lemon S, Kirkpatrick J, et al: Frequency of illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol 122:226, 1985 46. Leikin EL, Lysikiewixz A, Garry D, et al: Intrauterine transmission of hepatitis A virus. Obstet Gynecol 88:690, 1996
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47. Leikin EL, Reinus JF, Schmell E, et al: Epidemiologic predictors of hepatitis C virus infection in pregnant women. Obstet Gynecol 84:529, 1994 48. Levy M, Koren G: Hepatitis B vaccine in pregnancy: Maternal and fetal safety. Am J Perinatol8227, 1991 49. Lin H-H, Kao J-H, Hsu H-Y, et al: Possible role of high-titer maternal viremia in perinatal transmission of hepatitis C virus. J Infect Dis 169:638, 1994 50. Manzini P, Saracco G, Cerchier A, et al: Human immunodeficiency virus infection as a risk factor for mother-to-child hepatitis C virus transmission: Persistence of antihepatitis C virus in children is associated with the mother’s anti-hepatitis C virus immunoblotting pattern. Hepatology 21:328, 1995 51. Margolis H, Alter M, Hadler S Hepatitis 8: Evolving epidemiology and implications for control. Semin Liver Dis 11234, 1991 52. McMahon BJ, Alward WLM, 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 151:599, 1985 53. McMahon B, Rhoades E, Heyward W, et a 1 A comprehensive program to reduce the incidence of hepatitis B virus infection and its sequelae in Aiascan natives. Lancet 2:1134, 1987 54. McQuillan GM, Alter MJ, Everhart J E Viral hepatitis. In Everhart JE (ed): Digestive Diseases in the United States: Epidemiology and Impact. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office, 1994; NIH Publication No. 94-1447 55. Myint H, Soe MM, Khin T, et al: A clinical and epidemiological study of an epidemic of non-A, non-B hepatitis in Rangoon. Am J Trop Med Hyg 341183,1985 56. Nalin D, Kuter B, Brown L, et al: Worldwide experience with CR326F-derived inactivated hepatitis A virus vaccine in pediatric and adult populations: An overview. J Hepatol 18:S51, 1993 57. The National Institutes of Health Consensus Development Conference: Management of Hepatitis C. Hepatology 26:S1,1997 58. Ni Y-H, Lin H-H, Chen P-J, et al: Temporal profile of hepatitis C virus antibody and genome in infants born to mothers infected with hepatitis C virus but without human immunodeficiency virus coinfection. J Hepatol 20:641, 1994 59. Novati R, Thiers V, Monforte A, et al: Mother-to-child transmission of hepatitis C virus detected by nested polymerase chain reaction. J Infect Dis 165:720, 1992 60. Ohto H, Terazawa S, Sasaki N, et al: Transmission of hepatitis C virus from mothers to infants. N Engl J Med 330:744, 1994 61. Okada K, Kamiyama I, Inomata M, et al: E antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to infants. N Engl J Med 294:746, 1976 62. Okada K, Yamada T, Miyakawa Y, et al: Hepatitis B surface antigen in the serum of infants after delivery from asymptomatic carrier mothers. J Pediatr 87360, 1975 63. Puoti M, Zonaro A, Ravaggi A, et al: Hepatitis C virus RNA and antibody response in the clinical course of acute hepatitis C virus infection. Hepatology 16:877, 1992 64. Reinus JF, Leikin EL, Alter HJ, et al: Failure to detect vertical transmission of hepatitis C virus. Ann Intern Med 117881, 1992 65. Roudot-Thorval F, Pawlotsky J-M, Thiers V, et a1 Lack of mother-to-infant transmission of hepatitis C virus in human immunodeficiency virus-seronegative women: A prospective study with hepatitis C virus RNA testing. Hepatology 17772, 1993 66. Sanchez-Perez J, DeCastro M, Buezo GF, et al: Lichen planus and hepatitis C virus: Prevalence and clinical presentation of patients with lichen planus and hepatitis C virus infection. Br J Dermatol 134715, 1996 67. Schneider AJ, Mosley J W Studies of variations of glutamic-oxalacetic transaminase in serum in infectious hepatitis. Pediatrics 24:367, 1959 68. Schreiber GB, Busch MP, Keinman SH, et al: The risk of transfusion-transmitted viral infections. N Engl J Med 334:1685, 1996 69. Schweitzer IL, Peters RL: Pregnancy in hepatitis B antigen positive cirrhosis. Obstet Gynecol48535, 1976
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70. Shapiro CN, Coleman PJ, McQuillan GM, et a1 Epidemiology of hepatitis A. Seroepidemiology and risk groups in the USA Vaccine 10:59,1992 71. Smedile A, Dentico P, Zanetti A, et al: Infection with HBV associated delta agent in HBsAg carriers. Gastroenterology 81:992, 1981 72. Smedile A, Lavarini C, Crivelli 0:Radioimmunoassay detection of IgM antibodies to the HBV-associated delta antigen: Clinical significance in delta infection. J Med Virol 9:131, 1982 73. Stevens CE, Taylor PE, Tong MJ, et al: Yeast-recombinant hepatitis B vaccine: Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission. JAMA 2572612, 1987 74. Sweet RL: Hepatitis B infection in pregnancy. Obstet Gynecol Report 2128, 1990 75. Swift WE, Jr, Gardner HT, Moore DJ, et al: Clinical course of viral hepatitis and the effect of exercise during convalescence. Am J Med 8614, 1950 76. Tassopoulos NC, Papaevangelou GJ, Ticehurst JR, et al: Fecal excretion of Greek strains of hepatitis A virus in patients with hepatitis A and in experimentally infected chimpanzees. J Infect Dis 154231, 1986 77. Thaler MM, Park C-K, Lander DV, et al: Vertical transmission of hepatitis C. Lancet 33817, 1991 78. Tsega E, Hansson BG, Krawczynski D, et al: Acute sporadic viral hepatitis in Ethiopia: Causes, risk factors and effects on pregnancy. Clin Infect Dis 14961, 1992 79. Watson JC, Flemin DW, Borella AJ, et al: Vertical transmission of hepatitis A resulting in an outbreak in a neonatal intensive care unit. J Infect Dis 167567, 1993 80. Weiner AJ, Geysen HM, Christopherson C, et al: Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: Potential role in chronic HCV infections. Proc Natl Acad Sci USA 89:3468, 1992 81. Wejstal R, Widell A, Mansson A-S, et al: Mother-to-infant transmission of hepatitis C virus. Ann Intern Med 117887, 1992 82. World Health Organization: Technical report series: Viral hepatitis. Geneva, World Health Organization, 1975 83. Wright TL, Hsu H, Donegan E, et al: Hepatitis C virus not found in fulminant nonA, non-B hepatitis. Ann Intern Med 115111, 1991 84. Yang NY, Yu PH, Mao ZY, et a1 Inapparent infection of hepatitis A virus. Am J Epidemiol 127599, 1988 85. Zanetti AR, Ferroni P, Magliano EM, et al: Perinatal transmission of the hepatitis B virus associated delta a g e s from mothers to offspring in northern Italy. J Mid Virol 9:139. 1982 86. Zanetti AR, Tanzi E, Paccagnini S, et al: Mother-to-infant transmission of hepatitis C virus. Lancet 345:289, 1995 87. Zhang RL, Zeng ZS, Zhang H Z Survey of 34 pregnant women with hepatitis A and their neonates. Chin Med J 103522, 1990 88. Zuckerman AJ: Viral hepatitis. Br Med Bull 46,1990
Address reprint requests to John F. Reinus, MD Division of Gastroenterology Montefiore Medical Center 111 East 210th Street Bronx, NY 10467
1089-3261/99 $8.00
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.OO
VIRAL HEPATITIS IN PREGNANCY John F. Reinus, MD, and Enid L. Leikin, MD
Acute and chronic necro-inflammatory liver disease caused by hepatotropic virus infection continues to be a major worldwide health problem. Approximately 5% of the world’s population has chronic hepatitis B virus (HBV)82as many as 100% of the residents of nonindustrial nations and 70% of the residents of industrial nations have serologic evidence of prior exposure to hepatitis A virus (HAV)154,70 and in the United States, end-stage liver disease caused by chronic hepatitis C virus (HCV) is the most common indication for orthotopic liver transplantaAcute and chronic viral hepatitis often affects women of tion (OLT).23,54 child-bearing age and their infants. In regions of the world where chronic HBV is prevalent, most new cases are the result of perinatal or neonatal infection. HAV infection usually occurs during childhood or in young adults, including those in their early reproductive years.25,70 HCV infection often is acquired by teenagers and young adults as a result of drug use and also is common in persons with a history of sexual l9 promiscuity.lO, Thus, individuals providing health care to young women are likely to encounter patients with viral hepatitis and must be prepared to deal with issues related to acute and chronic infection, sexual and vertical transmission, and screening and treatment.
From the Division of Gastroenterology, Montefiore Medical Center, The Albert Einstein College of Medicine (JFR), Bronx; and the Division of Maternal-Fetal Medicine, WestChester County Medical Center, The New York Medical College (ELL), Valhalla, New York
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CLINICAL FEATURES OF VIRAL HEPATITIS
The clinical features of each type of viral hepatitis are similar and almost exclusively the consequences of liver cell injury; on rare occasions, individuals with viral hepatitis will have extrahepatic (immunologic) manifestations of their The presentation of hepatitis in pregnant women, as a rule, is no different from that in nonpregnant individuals and is determined by the severity of the liver damage and whether or not it is acute or chronic. Acute Liver Disease
Acute viral hepatitis is the result of parenteral or enteral exposure to a hepatotropic virus (Table 1). The time interval from exposure to development of clinical liver disease (incubation period) is highly variable, ranging from 15 to 150 days, depending on the cause. During the incubation period, the virus spreads from the point of entry through the blood to hepatocytes and excites a host immune response, which, in almost every type of acute hepatitis, is the cause of liver cell injury and death. Damaged hepatocytes release aminotransferases into the blood. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations increase to levels of from 500 to 5,000 mU/mL, becoming abnormal approximately 1 week before and usually peaking approximately 1 week after symptoms develop.28Even asymptomatic persons with viral hepatitis, however, may have serum aminotransferase levels in the thousand^.^^ Most individuals who are exposed to.a hepatitis virus do not develop clinically apparent disease; those who do may have very mild, nonspecific symptoms, typical acute viral hepatitis or fulminant liver failure in rapidly decreasing order of frequency.54For this reason, many people are unaware that they have been infected with a hepatitis virus and are surprised if serologic testing demonstrates hepatitis virus antigens or antibodies.22 Persons with clinical viral hepatitis initially have nonspecific complaints, including fatigue, malaise, anorexia, nausea, headache, and myalgias, possibly associated with low-grade fever (Table 2).31If the illness resolves before there is sufficient liver-cell injury and secondary dysfunction to cause jaundice, it may be mistaken for a flu-like viral syndrome or even for the normal physiologic effects of pregnancy itself; otherwise, jaundice develops within 2 to 10 days of the onset of symptoms. Jaundice becomes apparent when the serum bilirubin concentration reaches 2 to 4 mg/dL, depending on the rate at which the bilirubin level increases. If the serum level rises slowly, there is ample time for bilirubin to diffuse into total body water, and jaundice is noticeable at lower serum concentrations. Conversely, if the serum level rises rapidly, there is little time for bilirubin to diffuse into total body water, and jaundice
Ib
5 1 Parenteral/sexual Yes 40-150 d 30% 5% <1% Serum
7 1 Fecal-oral No 15-50 d Pediatric, 5%/adult, 80% No
Serum Yes Yes
Serum
Hepadnaviridae
Orthohepadnavirus
Hepatovirus
Family Genus Genotypes Serotypes Main transmission Vertical transmission Incubation period Clinical illness Chronicity Fulminant course Antigen test Antibody test Nucleic acid test Vaccine
HBV
Picomaviridae
HAV
Species
Table 1. CLASSIFICATION AND BIOLOGIC PROPERTIES OF THE HEPATOTROPIC VIRUSES
>6 ? Parenteral Rare 14-140 d 5% 85% Rare or no None Serum Serum No No
Hepacivirus
Flaviviridae
HCV
Parenteral Rare 20-45 d 10% Yes <5% Serum Serum Serum Yes (HBV) No
?
Deltavirus 3
Deltaviridae
HDV
Feces No No
Serum
No Pregnancy Fecal
80%
Uncertain Unnamed 3 1 Fecal-oral Yes 15-65 d
HEV
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ultimately, death. Disappearance or persistence of symptoms are seen in the minority of individuals with clinical hepatitis who go on to have chronic viral liver disease. Chronic Liver Disease
In most affected individuals, chronic viral hepatitis is asymptomatic either indefinitely or until there is sufficient liver damage for the patient to develop manifestations of end-stage liver disease. Some persons experience periodic clinical exacerbations that resemble mild, moderate, or even severe acute hepatitis. Less frequently, patients have persistent symptomatic hepatitis that begins as an acute infection, progresses to chronic infection and finally causes liver failure. Many cases of chronic viral hepatitis, therefore, are diagnosed after serum aminotransferase levels incidentally are noted to be abnormal. This commonly occurs when an apparently healthy young woman becomes pregnant and consults an obstetrician. Serum aminotransferase levels in asymptomatic patients of this type usually are one and a half to five times the upper limit of normal depending on the cause. Results of other laboratory tests often are normal, but may be abnormal if the patient has asymptomatic cirrhosis and mildly abnormal liver function. Physical examination also may be normal or the patient may have subtle physical findings consistent with early cirrhosis, including palmar erythema, splenomegaly, and a small liver, possibly with enlargement of the left lobe. Examination of the abdomen is difficult and may be ambiguous in the later stages of pregnancy when the liver and spleen are not palpable and patients often have physiologic palmar erythema. In the minority of patients with chronic hepatitis who develop end-stage liver disease, clinical features of liver failure gradually become apparent and potentially may be mistaken for a hepatic complication of pregnancy. It is uncommon for women with significant pre-existing liver disease to become pregnant. Ultimately, the natural history of viral hepatitis in a given patient is determined by the particular agent causing the infection and the host response to it. HEPATITIS A VIRUS
HAV is a RNA virus (family, Picornaviridae; genus, Hepatovirus) with seven genotypes but only one serotype (see Table 1). Thus, anti-HAV IgG antibody confers immunity to infection with any genotype of HAV. Acute infection is diagnosed by a positive serum test for anti-HAV IgM antibody. Transmission of HAV is horizontal through fecal-oral exposure. Virus is shed in the stool in high titer beginning approximately 1 week after infection and ending just after the serum ALT level peaks.76HAV
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is resistant to environmental degradation and has a high attack rate; 70% to 90% of exposed individuals develop antibody. Prevalence of antibody indicating previous HAV infection depends on the quality of the local water supply, the level of sanitation, and the average age of the population tested. HAV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response; the virus is not cytopathic. The incubation period of HAV infection is 15 to 50 days (average, 25). Clinical illness frequently is mild and often unrecognized. Symptoms develop in 5% of infected children30,84 and 80% of infected severity is age related so that, as a rule, the older an individual with HAV infection, the severer the clinical liver disease. HAV infection is fulminant in less than 1% of patients and is never chronic.18 In areas of the world where HAV is prevalent, most persons are exposed during the first few years of life and have asymptomatic hepatitis.@In areas of low endemicity, HAV infection commonly develops in teenagers and in young adults; infections often occur in clusters and are symptomatic." In the United States, the prevalence of serologic markers of previous HAV infection increases from 11%in children under age 5 to 74% in adults over age 50.70 Risk factors for HAV infection include personal contact with infected individuals (26%), employment in a day care facility (14%), intravenous drug use (IVDU) (ll?'~),travel to an area where HAV infection is prevalent (4%), and ingestion of food or water contaminated with feces Symptoms and signs of liver disease in a pregnant woman with one of these risk factors in an area of low HAV endemicity are more likely than those in young people elsewhere to indicate acute HAV infection. HAV infection is no severer in pregnant women than in non-pregnant individual^.^^ I n t r a ~ t e r i n eand ~ ~ perinatal maternal-fetal transmis~ i o of n ~HAV ~ have been reported, however, maternal HAV infection during pregnancy is not associated with fetal loss or developmental abnormalities. Passive immunization with pooled human serum immunoglobulin (IG) containing anti-HAV IgG 3 to 6 months before, or within 2 weeks of exposure to HAV prevents or attenuates hepatitis in 85% to 95% of treated individual^.^^, 45 Passive immunization has been recommended for travelers to endemic areas and household contacts of infected pers o n ~An . ~ HAV ~ vaccine made from formalin-inactivated virus was approved for use in the United States in 1995. A single dose of this vaccine causes serum anti-HAV antibody production within 2 weeks of inoculation in 90% to 98% of patients.38,56 Vaccination has been recommended for individuals working in day care centers and for persons living in communities where there are case-clusters of HAV infection. Other candidates for HAV vaccination are
Recommended Travelers to endemic areas
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Military personnel Special populations (Native Americans, Native Alaskans) Potential Day care center children and employees Food handlers Homosexuals Drug addicts Residents and staff of institutions Health care workers Persons with chronic liver disease Sewage workers Residents of communities where there is an outbreak of HAV The IG and HAV vaccine both are safe for use in pregnant women. HEPATITIS B VIRUS
HBV is a DNA virus (family, Hepadnaviridae; genus, Orthohepudnavirus) with five genotypes but only one serotype (see Table 1). Thus, antibody to the HBV surface antigen (anti-HBs) confers immunity to infection with any genotype of HBV. Acute and chronic HBV infection are diagnosed by a positive serum HBV surface antigen (HBsAg) test. Recent infection is indicated by the presence in serum of IgM antibody to HBV core antigen (anti-HBc), whereas predominant serum IgG antiHBc is found in persons with chronic infection. Active viral replication in acute or chronic HBV infection is seen in patients with serum HBV e antigen (HBeAg). In contrast, serum antibody to HBeAg (anti-HBe) is found in individuals recovering from acute HBV infection and also in persons with chronic HBV infection without active viral replication. Transmission of HBV is both horizontal through parenteral (nonsexual and sexual) exposure to blood, blood products, semen, vaginal secretions and saliva, and vertical (from mother to infant). HBV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response; the virus is not cytopathic. The incubation period of HBV infection is 40 to 150 days (average, 75). Illness may be acute and subclinical (approximately 70% of adult infections), acute and symptomatic (approximately 30% of adult infections), chronic (less than 5% of acute adult infe~tions),3~ or fulminant (less than 1%of acute infections). Chronic HBV infection predisposes affected individuals to develop cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). In areas of the world where hepatitis B is prevalent, as many as 15% of the inhabitants have chronic HBV infection.5l Most of these individuals become infected at birth as a consequence of vertical transmission. Neonatal HBV infection is almost always asymptomatic and results in chronic infection in approximately 90% of cases.52Chronic HBV infection is moderately prevalent among indigenous Alaskan peoples (6.4Y0)~~; HBV infection in native Alaskans occurs at all ages, and the
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rate of chronic disease is maintained by vertical spread and acquisition during early childhood. In the rest of the United States, where the prevalence of HBV infection is low,54the majority of infections occur in young adults and may be symptomatic. Symptoms and signs of liver disease in a pregnant woman in the contiguous United States and other areas of low endemicity, therefore, are more likely than those in young people elsewhere to indicate acute HBV infection. In areas of high endemicity, symptoms and signs of liver disease in a pregnant woman are more likely than those in young people elsewhere to indicate chronic HBV infection. HBV infection is no severer in pregnant women than in nonpregnant individ~als,3~ although the disease may rarely be fatal in any affected person. Chronic HBV carriers usually have normal pregnancies, unless there is also severe chronic hepatitis or secondary cirrhosis and associated complications.69The significance of HBV infection during pregnancy derives, in major part, from its potential to be transmitted vertically.62Ten percent of infants born to women with acute HBV infection during the first trimester of pregnancy are HBsAg positive at and 80% to 90% of neonates become HBsAg-positive without prophylactic therapy if acute maternal infection develops during the third trimester of pregnancy.'2 This variable rate of vertical transmission from mothers with acute disease is explained by the fact that the placenta is a reasonably effective barrier to the spread of HBV infection; 85% of neonatal HBV infections are caused by intrapartum exposure to infectious blood and vaginal secretions, and the remaining 15% to hematogenous transplacental viral spread.61In the absence of appropriate prophylaxis, 40% of the neonates of mothers with HBeAg-negative chronic HBV infection and 90% of the neonates of mothers with HBeAg-positive chronic HBV themselves will develop chronic HBV As noted earlier, HBeAg is a marker for active viral replication and viremia similar to that seen in persons with acute disease. The possibility of vertical transmission lends added importance to diagnosis of acute or chronic HBV infection in pregnant women and justifies mandatory antepartum serum HBsAg testing.' Diagnosis of previously unsuspected chronic HBV infection in young, otherwise healthy individuals has the added benefit of making it possible to refer them for appropriate antiviral therapy before development of significant liver damage, associated functional insufficiency, and, possibly, hepatocellular carcinoma (HCC). The infants of potentially infectious mothers are treated with HBV human hyperimmune globulin (HBIG) at delivery and simultaneously inoculated with the first of three injections of HBV vaccine (Table 3).l This regimen is approximately 85% effective in preventing development of chronic HBV in neonates73;it is ineffective in cases of hematogenous transplacental infection (15%).Universal vaccination of children before age 2 months was recommended by the US Public Health Service in 199237and elicits an antibody response in 95% of individuals. Pregnant women suspected of having been exposed to HBV should be treated with HBIG and innoculated with HBV vaccine; this
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Table 3. RECOMMENDED HEPATITIS B VIRUS IMMUNOPROPHYLAXIS OF NEONATES HBsAg Status of Mother
HBsAg-positive mothers
HBsAg-unknown mothers
HBsAg-negative mothers
Vaccine (HBVV) and Immunoglobulin (HBIG)
HBIG, 0.5 mL IM HBW (first dose) HBW (second dose) HBW (third dose) HBIG, 0.5 mL IM HBW (first dose) HBW (second dose) HBW (third dose) HBW (first dose) HBW (second dose) HBW (third dose)
Age
Birth-age 12 h Birth-age 12 h 1 mo 6 mo Birth-age 12 h Birth-age 12 h 1 mo 6 mo Before discharge 1 mo 6 mo
therapy is safe and effective during pregnancy.13,48 Women with chronic HBV infection should be referred for appropriate evaluation and care after pregnancy. HEPATITIS C VIRUS
HCV is a RNA virus (family, Flaviviridae; genus, Hepacivirus) with six (and possibly more) major genotypes (designated with Arabic numerals), more than 50 subtypes (designated with lowercase letters) and an unknown number of serotypes (see Table l).57 Within a single infected individual, HCV is present in the form of multiple quasispecies: viral particles with very similar but heterogeneous RNA sequences that develop as a result of mutation during viral replication.80Antibodies to different isolates are specific, do not cross-react, and, therefore, do not provide protective immunity.80For this reason, a positive test for serum anti-HCV antibody indicates active infection in most instances. Transmission of HCV is horizontal through parenteral exposure to blood and blood products and, rarely, vertical. HCV replicates in hepatocyte cytoplasm; liver-cell injury most likely is caused by the host immune response to infection. The incubation period of hepatitis C is 14 to 140 days (average, 50). Acute infection almost always is subclinical and becomes chronic in over 85% of cases15, HCV rarely, if ever, is fulminant. Chronic HCV infection predisposes affected individuals to develop cirrhosis, end-stage liver disease and HCC. In addition, chronic HCV infection is associated with a number of extra-hepatic manifestations including arthritis, keratoconjunctivitis ~icca,2~ lichen planus,66porphyria cutanea tarda,2I and essential mixed cryoglobulinemia,3 with or without glomer~lonephritis~~; these disorders, presumably, may be diagnosed in pregnant women. Specific risk factors for HCV infection include receipt of a blood
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transfusion before 1992,19,68 IVDU,19, nasal cocaine use,I9 sexual promiscuity,19hemodialysis,5. and receipt of a transplanted organ.2, The world.~ wide prevalence of chronic HCV infection is approximately l y ~There are, however, significant demographic and socioeconomic variations in infection rates. In the United States, the highest prevalence of HCV infection is in persons ages 30 to 49 years (3% to 4%). This disease, therefore, is not uncommon in women of child-bearing age. Of 1700 pregnant women in our cohort receiving care at a suburban county 75 (4.5%) had a positive anti-HCV antibody test; none medical of these individuals was aware before evaluation that she had chronic HCV infection. There is no evidence that pregnancy alters the natural history of HCV or that HCV interferes with normal pregnancy, unless the patient has cirrhosis with associated complications. HCV, however, may be transmitted vertically when maternal viral titers are unusually high, for example, in persons with HCV and HIV coinfection (Table 4).27,77 HIV infection exacerbates HCV ~ i r e m i aCoinfection .~~ with HIV and HCV is not uncommon, inasmuch as the risk factors for acquiring each of these diseases are similar; most individuals with a history of IVDU also have hepatitis C. Maternal serum HCV RNA levels of greater than or equal to 1019copies per mL have been reported to be associated with vertical
Table 4. VERTICAL TRANSMISSION OF HEPATITIS C DIVIDED BY MATERNAL HUMAN IMMUNODEFICIENCY VIRUS STATUS Reference
Mothers with HIV Infection Manzini et alM Lam et a144 Novati et aP9 Reinus et alM Zanetti et alas Thaler et a1"
Total Mothers without HIV Infection Ni et a P Roudot-Thorval et a P Manzini et alM Lam et a144 Lin et a149 Aizaki et a14 Wejstdl et alE1 Reinus et alM Ohto et aPO Zanetti et alas Thaler et aln
Total
No. of Infants with HIV/No. Tested 1/18 3/48 4/8 0/4 8/22 3/5 19/l05 (18%) 2/11
0/18 0/27 1/17
1/15 1/35 1/14 0/20 3/54 0/94 5/5 14/310 (4.5%)
From The National Institutes of Health Consensus Development Conference: Management of Hepatitis C. Hepatology 26:S1, 1997; with permission.
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transmission in as many as 36% of cases.6oVertical transmission of HCV in other circumstances has been found to be exceedingly uncommon.64 Diagnosis of previously unsuspected chronic HCV infection in young, otherwise healthy individuals has the added benefit of making it possible to refer them for appropriate antiviral therapy before development of significant liver damage; associated functional insufficiency; and, possibly, HCC. We were able to identify a group of pregnant women that included most individuals in our cohort with HCV by using epidemiologic predictors in advance of antibody testing, potentially reducing the cost of screening by 55Y0.~~ HEPATITIS D VIRUS
Hepatitis D (delta) virus (HDV) is a RNA viroid (family, Delfaviridae; genus, Deltavirus), with three genotypes and an unknown number of serotypes (see Table 1). HDV infection may be acute or chronic, and does not occur in the absence of acute or chronic HBV infection because HDV requires HBV for coating and cell-to-cell spread. Thus, HDV is the result of either acute HDV and HBV coinfection or HDV infection in a chronic HBV carrier. Acute HDV is diagnosed by detection of serum anti-HDV IgM antibody in a patient who also has a positive serum HBsAg test,” whereas persons with chronic HDV and HBV infections have serum anti-HDV IgG antibody titers of greater than 1 to 1000 and positive serum HBsAg tests.71 Like HBV, HDV is transmitted through parenteral exposure to blood and blood products. HDV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response, and possibly a direct cytopathic effect. Most patients with acute HDV and HBV coinfection recover completely and develop immunity to reinfection, however, HDV superinfection in a person with chronic HBV results in chronic HDV in 90% of cases.16Most individuals with chronic HDV have hemophilia or a history of IVDU. Perinatal transmission of HDV is rare, and there are no documented cases of vertical transmission of HDV in the United States.85 HEPATITIS E VIRUS
Hepatitis E virus (HEV) is a RNA virus (family, uncertain; genus, unnamed) with three genotypes and one serotype (see Table 1). Thus, anti-HEV IgG antibody confers immunity to infection with any genotype of HEV. Acute infection may be diagnosed by a positive serum test for anti-HEV IgM antibody, but serologic tests for HEV infection are not available in most clinical laboratories. Transmission of HEV is primarily horizontal through fecal-oral exposure. In utero transmission with acute hepatitis in the newborn has been documented.4*”HEV is a disease of Third World peoples and
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usually occurs in large epidemics caused by fecal contamination of drinking water.17 Sporadic cases also are seen in areas where the virus is endemic.42,78 Secondary spread of HEV is uncommon55;secondary attack rates in households of infected individuals range from 0.7% to 2.270, in contrast to secondary attack rates of HAV of 50% to 75% in homes of HAV-infected persons. In Western, industrial nations, HEV infection is rare and has been diagnosed in only travelers returning from 2o Third World co~ntries.'~, HEV replicates in hepatocyte cytoplasm. Liver-cell injury is caused by the host immune response and, possibly, a direct cytopathic effect. The incubation period of HEV is 15 to 65 days (average, 40). HEV infection is most common in persons of child-bearing age (ages 15 to 40)55;clinical illness develops in 70% to 80% of infected individuals and may be mild to severe. In nonpregnant patients, HEV infection is fulminant in less than 1% of patients, whereas in pregnant women, it is fulminant in as many as 20% of patient^.^^,^^ Similarly, the overall fatality rate of HEV is 0.5% to 47'0, but the fatality rate is 1.5% during the first trimester, 8.5% during the second trimester, and 21% during the third trimester of pregnancy. The reasons why this virus causes especially severe disease in pregnant women are unknown. HEV infection during the third trimester of pregnancy is associated with an increased number of fetal complications,78and death of neonates caused by HEV infection is much more common than it is from other types of viral hepatitis. HEV infection is never chronic. Prevention of HEV epidemics depends on improvements in sanitation and protection of the purity of water supplies. In areas where the virus is endemic, boiling of drinking water, avoidance of locally produced bottled beverages, ice and unpeeled, uncooked fruits and vegetables seem to be effective in preventing HEV infection. Pregnant women should not travel to areas where there are known cases of HEV. Immunoprophylaxis against HEV infection is not available; administration of HEV-immune serum globulin to persons at risk of infection during an epidemic of HEV in India did not affect disease rates.40,41 An HEV vaccine currently is being tested. HEPATITIS F, G, AND X VIRUSES
Clinical and epidemiologic data support the conclusion that there is at least one, and possibly more than one, additional hepatitis virus remaining to be characterized (hepatitis X).ll, 33, 83 Between 5% and 20% of cases of acute and chronic hepatitis do not appear to be caused by known hepatitis viruses, or toxic, metabolic or immune-mediated mechanisms. Untyped hepatitis viruses may infect women during pregnancy and be a source of diagnostic confusion, particularly during the third trimester, when jaundice may be a complication of pregnancyinduced hypertension or a sign of acute fatty liver of pregtancy. A candidate hepatitis F virus (HFV) has been reported, but its
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existence has not been confirmed. Hepatitis G virus (HGV), also known as GB virus, type C (GBV-C), is a parenterally transmitted hepatotropic virus (family, FIuviviridue; genus, unnamed) that does not seem to be pathogenic and, therefore, may not be a true hepatitis virus.7* The majority of persons with chronic HGV infection have no evidence of associated liver disease unless they also are infected with HCV. Persistence of HGV viremia after recovery in cases of supposed acute HGV suggests that affected patients may be chronic HGV carriers who develop hepatitis X. Only a minority of hepatitis X patients have a positive serum test for HGV. There are no clinical data pertaining to HGV infection during pregnancy or in neonates, and no studies of vertical transmission of this agent. Clearly, there is more work to be done in this interesting field of investigation. References 1. ACOG Technical Bulletin. Hepatitis in pregnancy. 174 November 1992. 2. Aeder M, Shield C, Tegtmeier G, et al: Incidence and clinical impact of hepatitis C virus-positive donors in cadaveric transplantation. Transplant Proc 25:1469, 1993 3. Agnello V, Chung RT, Kaplan LM: A role of hepatitis C virus infection in type I1 cryoglobulinemia. N Engl J Med 3271490, 1992 4. Aizaki H, Saito A, Kusakawa I, et al: Mother-to-child transmission of a hepatitis C virus variant with an insertional mutation in its hypervariable region. J Hepatol 25:608, 1996 5. Alfurayh 0, Sobh M, Buali A, et al: Hepatitis C virus infection in chronic hemodialysis patients: A clinicopathologic study. Nephrol Dial Transplant 7327, 1992 6. Alivanis P, Derveniotis V, Dioudis C, et al: Hepatitis C virus antibodies in hemodialysed and in renal transplant patients: Correlation with chronic liver disease. Transplant Proc 23:2662, 1991 . 7. Alter HJ, Nakatsuji Y, Melpolder J, et al: The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease. N Engl J Med 336:747,1997 8. Alter MJ: Epidemiology of hepatitis C. Hepatology 26:62S, 1997 9. Alter MJ, Gallagher M, Morris TT, et al: Acute non-A-E hepatitis in the United States and the role of hepatitis G virus infection. N Engl J Med 336:741, 1997 10. Alter MJ, Hadler S, Judson F, et al: Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA 264:2231, 1990 11. Alter MJ, Margolis HS, Krawczynski K, et al: The natural history of communityacquired hepatitis C in the United States. N Engl J Med 327:1899, 1992 12. Arevalo ]A: Hepatitis B in pregnancy. West J Med 150:668, 1989 13. Ayoola EA, Johnson A 0 Hepatitis B vaccine in pregnancy: Immunogenicity, safety and transfer of antibodies to infants. Int J Gynaecol Obstet 25:297, 1987 14. Bader TF, Krawczynski K, Polish LB, et al: Hepatitis E in a US traveler to Mexico. N Engl J Med 3253659, 1991 15. Barrera JM, Bruguera M, Guadalupe-Ercilla M, et al: Persistent hepatitis C viremia after acute self-limiting post-transfusion hepatitis C. Hepatology 21:639, 1995 16. Caredda F, Antinori S, Re T, et al: Course and prognosis of acute HDV hepatitis. Prog Clin Biol Res 364:267, 1987 17. Centers for Disease Control: Enterically transmitted non-A, non-B hepatitis-East Africa. MMWR 36:241, 1987 18. Centers for Disease Control: Hepatitis surveillance report. 53:23, 1990 19. Conry-Cantilena C, VanRaden M, Gibble J, et al: Routes of infection, viremia and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 334:1691, 1996
128
REINUS & LEIKIN
20. De Cock KM, Bradley DM, Sandford NL, et al: Epidemic non-A, non-B hepatitis in patients from Pakistan. Ann Intern Med 106:227, 1987 21. DeCastro M, Sanchez J, Herrera JF, et a1 Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology 17551, 1993 22. Denes AE, Smith JL, Maynard JE, et al: Hepatitis B infection in physicians: Results of a nationwide socioepidemiologic survey. JAMA 239210, 1978 23. Detre KM, Belle SH, Lombardero M Liver transplantation for chronic viral hepatitis. Viral Hepatitis Rev 2219, 1996 24. Eyster ME, Alter HJ, Aledort LM, et al: Heterosexual cotratransmission of hepatitis C virus (HCV) and human immunodeficiency virus. Ann Intern Med 115:764, 1991 25. Francis DP, Hadler SC, Prendergast TJ, et al: Occurrence of hepatitis A, B, and nonA, non-B in the United States: CDC sentinel county hepatitis study I. Am J Med 76:69, 1984 26. Garfein RS, Vlahov D, Galai N, et al: Viral infections in short-term injection drug users: The prevalence of the hepatitis C, hepatitis B, human immunodeficiency and human T-lymphotropic viruses. Am J Pub1 Health 86:655, 1996 27. Giovannini M, Tagger A, Ribero ML, et al: Maternal-infant transmission of hepatitis C virus and HIV infections: A possible interaction. Lancet 335:1166, 1990 28. Goldberg DM, Campbell DR Biochemical investigation of an outbreak of infectious hepatitis in a closed community. Br Med J 21435,1962 29. Haddad J, Deny P, Munz-Gotheil, et al: Lymphocytic sialadenitis of Sjogren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet 339:321, 1992 30. Hadler SC, Webster HM, Erben JJ, et a1 Hepatitis A in day-care centers: A communitywide assessment. N Engl J Med 302:1222, 1980 31. Havens WP, Jr: Viral hepatitis: Clinical patterns and diagnosis. Am J Med 32665,1962 32. Havens WP, Paul JR Prevention of infectious hepatitis with gamma globulin. JAMA 129:270, 1945 33. Hibbs JR, Frickhofen N, Rosenfeld SJ, et al: Aplastic anemia and viral hepatitis. NonA, non-B, non-C? JAMA 2672051,1992 34. Hieber JP: Hepatitis and pregnancy. J Pediatr 91:545, 1977 35. Hyams DC:Risks of chronicity following acute hepatitis B virus infection: A review. Clin Infect Dis 20:992, 1995 36. Immunization Practices Advisory Committee: Protection against viral hepatitis. MMWR 39(RR-2):1, 1990 37. Immunization Practices Advisory Committee: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. MMWR 40:1, 1991 38. Innis BL, Snitbhan R, Kunasol, et al: Protection against hepatitis A by an inactivated vaccine. JAMA 271:1328, 1994 39. Johnson RJ, Gretch DR, Yamabe H, et al: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328465,1993 40. Joshi Y, Babu S, Sarin S, et a1 Immunoprophylaxis of epidemic non-A, non-B hepatitis. Indian J Med Res 81:18, 1985 41. Khuroo M, Dar M Hepaitis E: Evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol 11:113, 1992 42. Khuroo M, Duermayer W, Zargar SA, et al: Acute sporadic non-A, non-B hepatitis in India. Am J Epidemiol 118360, 1983 4%. Khuroo MS, Kamili S, Jameel S Vertical transmission of Hepatitis E virus. Lancet 345:1035-1036, 1995 43. Khuroo MS, Teli MR, Skidmore S, et al: Incidence and severity of viral hepatitis in pregnancy. Am J Med 70252, 1981 44. Lam JPH, McOmish F, Bums SM, et al: Infrequent vertical transmission of hepatitis C virus. J Infect Dis 167572, 1993 45. Lednar W, Lemon S, Kirkpatrick J, et al: Frequency of illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol 122:226, 1985 46. Leikin EL, Lysikiewixz A, Garry D, et al: Intrauterine transmission of hepatitis A virus. Obstet Gynecol 88:690, 1996
VIRAL HEPATITIS IN PREGNANCY
129
47. Leikin EL, Reinus JF, Schmell E, et al: Epidemiologic predictors of hepatitis C virus infection in pregnant women. Obstet Gynecol 84:529, 1994 48. Levy M, Koren G: Hepatitis B vaccine in pregnancy: Maternal and fetal safety. Am J Perinatol8227, 1991 49. Lin H-H, Kao J-H, Hsu H-Y, et al: Possible role of high-titer maternal viremia in perinatal transmission of hepatitis C virus. J Infect Dis 169:638, 1994 50. Manzini P, Saracco G, Cerchier A, et al: Human immunodeficiency virus infection as a risk factor for mother-to-child hepatitis C virus transmission: Persistence of antihepatitis C virus in children is associated with the mother’s anti-hepatitis C virus immunoblotting pattern. Hepatology 21:328, 1995 51. Margolis H, Alter M, Hadler S Hepatitis 8: Evolving epidemiology and implications for control. Semin Liver Dis 11234, 1991 52. McMahon BJ, Alward WLM, 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 151:599, 1985 53. McMahon B, Rhoades E, Heyward W, et a 1 A comprehensive program to reduce the incidence of hepatitis B virus infection and its sequelae in Aiascan natives. Lancet 2:1134, 1987 54. McQuillan GM, Alter MJ, Everhart J E Viral hepatitis. In Everhart JE (ed): Digestive Diseases in the United States: Epidemiology and Impact. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office, 1994; NIH Publication No. 94-1447 55. Myint H, Soe MM, Khin T, et al: A clinical and epidemiological study of an epidemic of non-A, non-B hepatitis in Rangoon. Am J Trop Med Hyg 341183,1985 56. Nalin D, Kuter B, Brown L, et al: Worldwide experience with CR326F-derived inactivated hepatitis A virus vaccine in pediatric and adult populations: An overview. J Hepatol 18:S51, 1993 57. The National Institutes of Health Consensus Development Conference: Management of Hepatitis C. Hepatology 26:S1,1997 58. Ni Y-H, Lin H-H, Chen P-J, et al: Temporal profile of hepatitis C virus antibody and genome in infants born to mothers infected with hepatitis C virus but without human immunodeficiency virus coinfection. J Hepatol 20:641, 1994 59. Novati R, Thiers V, Monforte A, et al: Mother-to-child transmission of hepatitis C virus detected by nested polymerase chain reaction. J Infect Dis 165:720, 1992 60. Ohto H, Terazawa S, Sasaki N, et al: Transmission of hepatitis C virus from mothers to infants. N Engl J Med 330:744, 1994 61. Okada K, Kamiyama I, Inomata M, et al: E antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to infants. N Engl J Med 294:746, 1976 62. Okada K, Yamada T, Miyakawa Y, et al: Hepatitis B surface antigen in the serum of infants after delivery from asymptomatic carrier mothers. J Pediatr 87360, 1975 63. Puoti M, Zonaro A, Ravaggi A, et al: Hepatitis C virus RNA and antibody response in the clinical course of acute hepatitis C virus infection. Hepatology 16:877, 1992 64. Reinus JF, Leikin EL, Alter HJ, et al: Failure to detect vertical transmission of hepatitis C virus. Ann Intern Med 117881, 1992 65. Roudot-Thorval F, Pawlotsky J-M, Thiers V, et a1 Lack of mother-to-infant transmission of hepatitis C virus in human immunodeficiency virus-seronegative women: A prospective study with hepatitis C virus RNA testing. Hepatology 17772, 1993 66. Sanchez-Perez J, DeCastro M, Buezo GF, et al: Lichen planus and hepatitis C virus: Prevalence and clinical presentation of patients with lichen planus and hepatitis C virus infection. Br J Dermatol 134715, 1996 67. Schneider AJ, Mosley J W Studies of variations of glutamic-oxalacetic transaminase in serum in infectious hepatitis. Pediatrics 24:367, 1959 68. Schreiber GB, Busch MP, Keinman SH, et al: The risk of transfusion-transmitted viral infections. N Engl J Med 334:1685, 1996 69. Schweitzer IL, Peters RL: Pregnancy in hepatitis B antigen positive cirrhosis. Obstet Gynecol48535, 1976
130
REINUS & LEIKIN
70. Shapiro CN, Coleman PJ, McQuillan GM, et a1 Epidemiology of hepatitis A. Seroepidemiology and risk groups in the USA Vaccine 10:59,1992 71. Smedile A, Dentico P, Zanetti A, et al: Infection with HBV associated delta agent in HBsAg carriers. Gastroenterology 81:992, 1981 72. Smedile A, Lavarini C, Crivelli 0:Radioimmunoassay detection of IgM antibodies to the HBV-associated delta antigen: Clinical significance in delta infection. J Med Virol 9:131, 1982 73. Stevens CE, Taylor PE, Tong MJ, et al: Yeast-recombinant hepatitis B vaccine: Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission. JAMA 2572612, 1987 74. Sweet RL: Hepatitis B infection in pregnancy. Obstet Gynecol Report 2128, 1990 75. Swift WE, Jr, Gardner HT, Moore DJ, et al: Clinical course of viral hepatitis and the effect of exercise during convalescence. Am J Med 8614, 1950 76. Tassopoulos NC, Papaevangelou GJ, Ticehurst JR, et al: Fecal excretion of Greek strains of hepatitis A virus in patients with hepatitis A and in experimentally infected chimpanzees. J Infect Dis 154231, 1986 77. Thaler MM, Park C-K, Lander DV, et al: Vertical transmission of hepatitis C. Lancet 33817, 1991 78. Tsega E, Hansson BG, Krawczynski D, et al: Acute sporadic viral hepatitis in Ethiopia: Causes, risk factors and effects on pregnancy. Clin Infect Dis 14961, 1992 79. Watson JC, Flemin DW, Borella AJ, et al: Vertical transmission of hepatitis A resulting in an outbreak in a neonatal intensive care unit. J Infect Dis 167567, 1993 80. Weiner AJ, Geysen HM, Christopherson C, et al: Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: Potential role in chronic HCV infections. Proc Natl Acad Sci USA 89:3468, 1992 81. Wejstal R, Widell A, Mansson A-S, et al: Mother-to-infant transmission of hepatitis C virus. Ann Intern Med 117887, 1992 82. World Health Organization: Technical report series: Viral hepatitis. Geneva, World Health Organization, 1975 83. Wright TL, Hsu H, Donegan E, et al: Hepatitis C virus not found in fulminant nonA, non-B hepatitis. Ann Intern Med 115111, 1991 84. Yang NY, Yu PH, Mao ZY, et a1 Inapparent infection of hepatitis A virus. Am J Epidemiol 127599, 1988 85. Zanetti AR, Ferroni P, Magliano EM, et al: Perinatal transmission of the hepatitis B virus associated delta a g e s from mothers to offspring in northern Italy. J Mid Virol 9:139. 1982 86. Zanetti AR, Tanzi E, Paccagnini S, et al: Mother-to-infant transmission of hepatitis C virus. Lancet 345:289, 1995 87. Zhang RL, Zeng ZS, Zhang H Z Survey of 34 pregnant women with hepatitis A and their neonates. Chin Med J 103522, 1990 88. Zuckerman AJ: Viral hepatitis. Br Med Bull 46,1990
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