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Hepatitis in pregnancy
Hepatitis in Pregnancy Patrick Duff
Currently, six distinct types o f hepatitis virus have been identified: A, B, C, D, E, and G. Hepatitis A virus infection does not cause a chronic carrier state, and perinatal transmission is extremely uncommon. Hepatitis B can be transmitted perinatally, but immunization of the newborn with hepatitis B immune globulin and hepatitis B vaccine markedly reduces the risk o f neonatal infection. Hepatitis D virus is dependent on coinfection with the hepatitis B virus for replication, lmmunoprophylaxis against hepatitis B also is effective against hepatitis D. Hepatitis C virus is primarily transmitted by the parenteral route and is particularly likely to cause chronic liver disease. Perinatal t r a ~ m i ~ sion o f hepatitis C principally occurs in women who have high titers o f HCV-RNA or who are coinfected with human immunodeficiency virus. At this time, no immunoprophylaxis for hepatitis C is available. Hepatitis G, a recently described organism, is related to hepatitis C. Its clinical significance remains undetermined. Hepatitis E is transmitted in a manner similar tO hepatitis A. Perinatal transmission is unusual, but maternal disease is often severe. Copyright 9 1998 by W.B. Saunders Company
epatitis is one of the most c o m m o n and most highly contagious viral infections. Currently, six distinct types of hepatitis virus have been identified: A, B, C, D, E, and G. Each type of hepatitis has a slightly different clinical implication for the pregnant woman and her fetus.
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Hepatitis A Hepatitis A is responsible for approximately 45% of cases of acute hepatitis in the United States.1 It is caused by a n o n e n v e l o p e d 27-nm RNA virus that is a m e m b e r o f the picornavirus family. The virus is transmitted by person to person contact through fecal-oral contamination. Poor hygiene, p o o r sanitation, and intimate personal or sexual contact facilitate transmission. Epidemics frequently result from c o m m o n exposure to contaminated food and water. In the United States, individuals at particular risk for hepatitis A are those who have recently immigrated from, or traveled to, developing nations of the world where the disease is endemic. Drug abusers, homosexual men, patients receiving factor VIII concentrates, children and supervisors in day care centers, and patients with chronic liver disease also are at increased risk of acquiring hepatitis A. TM T h e incubation period of hepatitis A ranges from 15 to 50 days, with a mean of 28 to 30 days. The highest concentration of viral particles is in fecal material. The virus is not normally excreted in urine or other body fluids.
Some patients with hepatitis A are asymptomatic. When symptoms do occur, they typically include malaise, fatigue, anorexia, nausea and vomiting, and right u p p e r quadrant pain, T h e characteristic physical findings o f acute hepatitis A are jaundice, hepatic tenderness, darkened urine, and acholic stools. T h e most useful diagnostic test for hepatitis A is identification of IgM-specific antibody, which is detectable 25 to 30 days after the initial exposure and persists in the serum for up to 6 months. IgG antibody is detectable within 35 to 40 days of exposure, persists indefinitely, and confers lifelong immunity. In addition, the serum concentrations o f alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin are usually moderately to markedly elevated. Liver biopsy is rarely indicated today to confirm the diagnosis of viral hepatitis in pregnancy. 5 Fortunately, acute hepatitis A is usually a selflimited illness, and only supportive care is required for the majority of patients. Recovery is typically complete within 4 to 6 weeks. Fulminant From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, GainesviUe, FL. Address rep+int requests to Patrick Duff, MD, University of Florida College of Medicine, Department of Obstetrics and Gynecology,Division of Maternal-Fetal Medicine, PO Box 100294, Gainesville, FL 32610-0294. Cop)~ght 9 1998 by W.B. Saunders Company 0146-0005/98/2204-0006508. 00/0
Seminars in Perinatology, Vol 22, No 4 (August), 1998: pp 277-283
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hepatitis, coagulopathy, or encephalopathy develop in fewer than 0.5% of affected patients. Infected patients should be advised of the n e e d for good nutrition. Physical activity should be limited to prevent u p p e r abdominal trauma. Drugs with potential hepatotoxicity such as isoniazid, ketoconazole, or alpha-methyldopa should be avoided until the patient recovers. Sexual and household contacts should receive i m m u n o p r o phylaxis with a single intramuscular dose of immunoglobulin, 0.02 m L / k g , within 2 weeks of exposure. 6 In addition, they also should receive the formalin-inactivated hepatitis A vaccine. Two hepatitis A vaccines have been licensed in the United States: Havrix (SmithKline Beecham Pharmaceuticals, Philadelphia, PA) and Vaqta (Merck & Co, West Point, PA). Both preparations contain formalin-inactivated viral particles p r o d u c e d in h u m a n fibroblasts. The intramuscular dose of Havrix is 1 mL; the corresponding dose of Vaqta is 0.5 mL. The approximate cost of a single dose of vaccine is $50-$60.1 Both vaccine preparations are highly immunogenic and are safe for use in pregnancy. Protective levels o f antibody after vaccination develop in over 95% o f healthy adults. Duration o f immunity appears to persist for at least 10 years. In addition to contacts o f acutely infected patients, o t h e r candidates for vaccination include individuals who anticipate travel to areas of the world where hepatitis is endemic, children living in high-prevalence areas or attending daycare, intravenous drug abusers, daycare workers, residents and staff m e m b e r s of institutions for developmentally disabled persons, and patients over the age of 30 with chronic liver disease. 1 A booster dose of the vaccine is indicated 6 to 12 m o n t h s after the first dose if the patient has c o n t i n u i n g risk of exposure to hepatitis A infection. 1'7 Both hepatitis A vaccine preparations are very safe. Mild reactions at the site of injection occur in 20% to 50% of recipients, and fever occurs in approximately 5%. Life-threatening reactions such as anaphylaxis and Guillain-Barre synd r o m e are distinctly u n c o m m o n . The vaccine should not be administered to anyone with an allergy to one of its c o m p o n e n t s or to children u n d e r 2 years of a g e ) As a general rule, unless the pregnant m o t h e r becomes severely ill, hepatitis A does not pose a serious risk to the fetus. A chronic carrier state
does not exist, and only isolated cases of perinatal transmission have been reported. In one recent case, Leikin, et al, 8 described a fetus with polyhydramnios and ascites in whom hepatitis A infection was confirmed by cordocentesis. T h e fetus was delivered because of m e c o n i u m peritonitis and required corrective surgery. Subseq u e n t recovery was uneventful. An infant delivered to an acutely infected m o t h e r should receive immunoglobulin to reduce the risk of horizontal transmission of infection after delivery. Unfortunately, such immunoprophylaxis is not perfectly protective. Hepatitis B Approximately 35% of all cases of hepatitis in the United States are caused by hepatitis B virus. 1 Over 300,000 new cases of hepatitis B occur annually, and about one million Americans are chronic viral carriers. The frequencies of acute and chronic hepatitis B in pregnancy are 1 to 2 per 1,000 and 5 to 15 per 1,000, respectively. 5'9 Hepatitis B is caused by a highly infectious, enveloped DNA virus. The intact virus is t e r m e d the Dane particle, and its three major structural antigens are surface antigen (HbsAg), core antigen (HbcAg), and e antigen (HbeAg). Transmission of hepatitis B occurs primarily as a result of parenteral injection, sexual contact, and perinatal exposure. Certain population groups have an increased prevalence of hepatitis B: Asians, Eskimos, drug addicts, transfusion recipients, dialysis patients, residents and employees of chronic care residencies, prisoners, and recipients of tatoos. 5 After an acute infection caused by hepatitis B virus, less than 1% of patients get fulminant hepatitis and die. Eighty-five percent to 90% experience complete resolution of their physical findings, acquire protective levels of antibody, and gain lifeqong immunity. T e n percent to 15% of patients b e c o m e chronically infected. O f these, chronic active or persistent hepatitis or cirrhosis develops in 15% to 30%, and hepatocellular carcinoma develops in a small percentage. Chronic liver disease is particularly likely to occur in patients who remain seropositive for HbeAg and who b e c o m e superinfected with the hepatitis D virus. 5 T h e diagnosis of " a c u t e " hepatitis B is confirmed by detection of the surface antigen and
Hepatitis
Table 1. Serological Diagnosis of Hepatitis B Infection
Serological Test Condition Susceptible Immune Acute infection Chronic infection
HBsAg HB, Ag anti-HBc anti-HBs . -+ +
. -+
.
. +IgG +IgM
+IgG --
+
+IgG
--
Abbreviations: anti-HBc,antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen.
IgM antibody to the core antigen. Identification of HbeAg is indicative of an exceptionally high viral inoculum and active viral replication. Patients who have chronic hepatitis B infection have persistence of the surface antigen in the serum and liver tissue. Some individuals, particularly Asians, also remain seropositive for HbeAg (Table 1). 5'6'1~ Patients with acute and chronic hepatitis B infection pose a major threat of transmission to o t h e r household members, especially their sexual partner. In addition, infected w o m e n may transmit infection to their fetus. Perinatal transmission occurs primarily as a result of the infant's exposure to infected blood and genital secretions during delivery. In the absence of imm u n o p r o p h y l a x i s for the neonate, perinatal transmission occurs in 10% to 20% o f w o m e n who are seropositive for HbsAg. T h e frequency of perinatal transmission increases to almost 90% in w o m e n who are seropositive for b o t h HbsAg and HbeAg. 5'6'1~ Fortunately, a combination o f passive and active immunization is highly effective in preventing both horizontal a n d vertical transmission of hepatitis B infection. All individuals who have had household or sexual exposure to ano t h e r person with hepatitis B infection should be tested to d e t e r m i n e if they have antibody to the virus. If they are seronegative, they should immediately receive i m m u n o p r o p h y l a x i s with hepatitis B i m m u n o g l o b u l i n (HBIG), 0.06 m L / kg intramuscularly. They then should receive the hepatitis B vaccination series. Similarly, infants who are delivered to seropositive mothers should receive HBIG, 0.5 m L intramuscularly, immediately after birth. They then should begin the hep-
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atitis B vaccination series within 12 hours of birth.5,6,1~ Two r e c o m b i n a n t hepatitis B vaccines now are available, Recombivax-HB (Merck & Co) and Engerix-B (SmithKline Beecham Pharmaceuticals). Both products are c o m p o s e d o f inactivated portions of the surface antigen and are p r e p a r e d by r e c o m b i n a n t DNA technology f r o m Saccharomyces cerevisiae. Neither poses a risk of transmission of a blood-borne pathogen, and both are safe for administration during pregnancy to patients at risk. T h e routine vaccination series for hepatitis B consists of three intramuscular injections. T h e second and third injections should be administered 1 and 6 months, respectively, after the initial dose. Injections should be administered into the deltoid rather than gluteal muscle. Gluteal injections and intradermal injections result in significantly lower rates o f seroconversion. Table 2 summarizes the dosage schedules for the two vaccine preparations. 1'5'6 T h e two vaccine preparations are essentially equivalent in efficacy and can be used interc h a n g e a b l y ) Protective antibody titers (->10 m I U / m L ) develop in approximately 95% to 99% of healthy vaccine recipients, but the frequency of seroconversion is reduced in i m m u n o c o m p r o m i s e d patients and in individuals over the age of 40. I m m u n o g e n e c i t y is not affected when the vaccine is injected simultaneously, at different sites, with H B I G or when hepatitis B vaccine is administered with o t h e r vaccines. T h e duration of immunity after vaccination appears to be longlasting, and routine monitorTable 2. Recommended Doses of Hepatitis B Vaccine
Vaccine Recipient
Recombivax HB
Children and adolescents 5/lg 11-19 yr old (0.5 mL) Adults -->20yr old 10 #g (1 mE) Immunocompromised 40/zg patients (1 mL)*
Engerix-B 20 #g (1 mL) 20/zg (1 mE) 40/zg (2 mL)t
NOTE. The approximate cost of the vaccine preparations are $25-30 for the pediatric doses, $50-60 for the conventional adult doses, and $110-170 for the special high-dose formulations.l * Special formulation. t Two 1.0-mL doses administered at one site in a four-dose schedule at 0, 1, 2, and 6 months. Data from references 5 and 11.
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ing of antibody titers or administration of booster doses is not r e c o m m e n d e d . However, if a previously vaccinated person experiences a definite exposure, an antibody titer should be checked. If it is less than 10 m I U / m L , a booster dose of vaccine, along with HBIG, should be administered. 1'6 Mild reactions at the site o f injection o c c u r in a p p r o x i m a t e l y 20% o f vaccine recipients. Severe adverse reactions such as anaphylaxis are rare. T h e only c o n t r a i n d i c a t i o n to the vaccine is hypersensitivity to yeast or a c o m p o n e n t of the vaccine. 1 I m m u n o p r o p h y l a x i s is approximately 85% to 95% effective in preventing neonatal hepatitis B infection. In view of the extremely favorable results of immunoprophylaxis, the Centers for Disease Control and Prevention (CDC) recently r e c o m m e n d e d universal hepatitis B vaccination for all infants, n Infants b o r n to seronegative m o t h e r s require only the vaccine. Infants b o r n to seropositive m o t h e r s should receive b o t h the vaccine and HBIG. Therefore, obstetricians must continue to screen all of their patients for hepatitis B at some point during pregnancy. Selective screening on the basis of acknowledged risk factors will fail to identify 30% to 50% of seroposifive women. 5 Patients infected with hepatitis B virus also may transmit infection to medical and nursing p e r s o n n e l who care for them. Each year approximately 12,000 American health care workers contract hepatitis B as a result of an occupational injury such as a needle stick or splash to a mucous m e m b r a n e . O f these, approximately 200 acquire fulminant hepatitis and subsequently die. 12 Health care workers can protect themselves f r o m hepatitis in three principal ways. First, they should be vaccinated for hepatitis B. Second, they should encourage all y o u n g adults and other individuals who have a specific risk factor to receive the hepatitis B vaccine. Third, they should consistently follow universal precautions to prevent sharp injuries and splashes to exposed mucous m e m b r a n e or skin surfaces. Conversely, health care workers who are infected with hepatitis B also pose a risk to others. 6 They, too, must observe safeguards to prevent horizontal transmission of infection to their patients. Infection is most likely to occur as a consequence of direct blood-to-blood exposure during invasive surgical procedures. Unless the
patient has d o c u m e n t e d immunity to hepatitis B, the infected health care worker has an ethical obligation to inform the patient that some risk of transmission exists during invasive procedures. During the actual procedure, the o p e r a t o r must take every precaution to ensure that a sharp injury does not occur.
Hepatitis D Hepatitis D, or delta hepatitis, is caused by an RNA virus that is d e p e n d e n t on coinfection with the hepatitis B virus for replication. H e p a titis D has an external coat o f hepatitis B surface antigen a n d an internal delta antigen that is e n c o d e d by its own g e n o m e . T h e e p i d e m i o l o g y o f hepatitis D is essentially identical to that o f hepatitis B. 13 Acute hepatitis D occurs in two forms: coinfection and superinfection. Coinfection represents the simultaneous occurrence of acute hepatitis B and D. It is usually a self-limited disorder and rarely leads to chronic liver disease. Superinfection occurs when acute hepatitis D develops in a patient who is a chronic hepatitis B carrier. Approximately 20% to 25% o f patients with chronic hepatitis B b e c o m e superinfected with the delta virus, and chronic hepatitis subsequently develops in a b o u t 80% of these individuals. O f those who have chronic hepatitis, cirrhosis and portal hypertension develop in 70% to 80%, and almost 25% ultimately die of hepatic failure) 3-15 T h e diagnosis of acute coinfection can be confirmed by detection of delta antigen in hepatic tissue or serum a n d IgM-specific antibody in serum. In addition, the tests for HbsAg and antiHBc-IgM are positive. In patients with acute superinfection, serological tests reflect acute hepatitis D (positive antigen, positive IgM antibody) and chronic hepatitis B infection (positive surface antigen, anti-HBc IgG). Patients with chronic hepatitis D usually have detectable ser u m levels of IgG-specific antibody for the delta virus and are seropositive for HbsAg. Unfortunately, IgG antibody does n o t eradicate the delta viremia, and the antigen still can be identified in serum and hepatic t i s s u e . 14A5 Patients with acute hepatitis D should receive the general supportive care outlined for hepatitis A. Patients with chronic infection should be m o n i t o r e d periodically for worsening hepatic
Hepatitis
function and coagulopathy. At present, there is no specific antiviral agent or i m m u n o t h e r a p y that is curative for either acute or chronic delta infection. Perinatal transmission of hepatitis D virus has been reported. Fortunately, transmission is u n c o m m o n because the neonatal immunoprophylaxis for hepatitis B is almost uniformly effective against hepatitis D. 1'~
Non-A, Non-B Hepatitis Non-A, non-B hepatitis accounts for 10% to 20% of cases o f hepatitis in the United States. 1'5 NonA, non-B hepatitis occurs in three forms: hepatitis C, G, and E. Hepatitis C Hepatitis C is a 30- to 38-nm, single-stranded enveloped RNA virus, that is similar in structure to flaviviruses and pestiviruses. Its incubation period is 5 to 10 weeks. The principal risk factors for hepatitis C are intravenous drug abuse, transfusion, and sexual intercourse.~6 In a recent survey by O s m o n d et al, 17 two thirds of a selected population of drug abusers were seropositive for hepatitis C. In a similar survey of patients attending a sexually transmitted disease (STD) clinic in San Francisco, Weinstock et al, TM found the prevalence of hepatitis C to be 7.7%. Approximately 90% o f all cases o f posttransfusion hepatitis are caused by hepatitis C, and 2.5% to 15% of patients who receive multiple transfusions become infected with this virus. Hepatitis C infection is particularly likely to result in chronic liver disease. Biochemical evidence of hepatic dysfunction develops in approximately 50% o f infected patients, and of these, chronic active hepatitis or cirrhosis subsequently develops in about
20%. Approximately 75% of patients with hepatitis C are asymptomatic. The diagnosis of hepatitis C infection is confirmed by identification of antiC antibody. Initial screening for this antibody should be p e r f o r m e d with an enzyme immunoassay (EIA). A positive EIA should be followed with a recombinant i m m u n o b l o t assay (RIBA). The present RIBA is able to detect four specific viral antigens. If at least two antigens are identified, the test result is considered positive. If only one antigen is identified, the test result is considered indeterminant. T h e present generation of labo-
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ratory assays does not precisely discriminate between IgM and IgG antibody. Moreover, antibody may not be detectable until 6 to 16 weeks after the onset of clinical illness. Direct detection of hepatitis C-RNA also is possible with polymerase chain reaction methodology, and identification of C-RNA denotes a high level of infectivity. 19 In a general obstetric population, the prevalence of hepatitis C is 1% to 3%. The principal risk factors that identify an obstetric patient at high risk for hepatitis C include c o n c u r r e n t STDs, such as hepatitis B and h u m a n immunodeficiency virus (HIV) infection; multiple sexual partners; history of recent multiple transfusions; and history o f intravenous drug abuse. 16"2~ T h e frequency o f perinatal transmission of hepatitis C is highly variable, ranging from less than 10% to as high as 44%. Higher rates of transmission are most likely to occur when the m o t h e r is coinfected with HIV or when she has high serum titers of C - R N A . 21-24 For example, Weintraub e t a122 studied 43 mothers who were intravenous drug users. Seventeen infants had passively transmitted anti-HCV, indicating that approximately 40% of the mothers were seropositive for hepatitis C virus. Four infants (24%) delivered to seropositive mothers were persistently seropositive. All of these infants were coinfected with HIV. Similarly, Ohto e t al, 24 recently surveyed 53 mothers who were seropositive for HCV antibody. Twenty-two women were antibody positive but HCV RNA negative, and n o n e of their infants became infected. Thirty-one women had positive findings for both antibody and RNA, and three (10%) o f their babies became infected. Currently, a vaccine for hepatitis C is not available. Passive immunization with immunoglobulin (0.06 m L / k g intramuscularly) should be administered after percutaneous exposure to a person with hepatitis C. The benefit of immunoprophylaxis for the neonate has not been proven in controlled clinical trials. Although a-interferon has shown some activity against the virus, relapses occur in 44% to 80% of patients within 6 to 12 months o f discontinuation o f therapy, and the drug has not been tested in a controlled m a n n e r in pregnant women. 5 Hepatitis G Identification of the hepatitis G virus (HGV or GBV-C) is a relatively recent discovery. The or-
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ganism is a single-stranded, RNA flavivirus that is related to hepatitis C. T h e organism is m o r e prevalent, but less virulent, than hepatitis C. It causes acute and persistent infection in humans, but the clinical significance of infection remains unsettled. Nucleic acid f r o m hepatitis G virus can be identified in serum by polymerase chain reaction ( P C R ) . 25'26 Hepatitis G c o m m o n l y occurs in association with hepatitis B, hepatitis C, and HIV infection. A chronic carrier state exists, a n d perinatal transmission can occur. In a recent report, Feucht et al, 27 studied nine w o m e n who had hepatitis G viremia by PCR. Vertical transmission occurred in three cases. Two of the m o t h e r s were coinfected with H I V a n d one with hepatitis C virus. T h e prognosis for neonates infected in this manner remains to be determined.
Hepatitis E Hepatitis E virus is a n o n e n v e l o p e d RNA virus that i s closely related to the calicivirus family. It may present in b o t h an icteric and anicteric form. T h e virus is transmitted by the fecal-oral route, and, therefore, the epidemiology of hepatitis E is similar to that of hepatitis A. T h e incubation period ranges f r o m 2 to 9 weeks, with a m e a n of 45 days. 28'29 Hepatitis E is rare in the United States but is endemic in developing countries. In these countries, the m a t e r n a l mortality rate has been alarmingly high, ranging f r o m 10% to 20%. 3~ Extreme poverty, coexisting medical illnesses, malnutrition, and p o o r prenatal care are at least partially responsible for the p o o r maternal prognosis. T h e only cases of hepatitis E in the United States have occurred in patients who traveled to countries in which the disease was endemic, zz T h r e e diagnostic tests are available for confirmation of hepatitis E infection. Viral-like particles can be identified in the stool of infected patients by electron microscopy. These particles will agglutinate when c o m b i n e d with serum f r o m the patient. In addition, a fluorescent antibody blocking assay and Western blot assay are now available for use. TM Patients with acute hepatitis E should be treated as described previously for patients with hepatitis A. A chronic carrier state does not develop, and perinatal transmission usually does not occur. Recently, however, Khuroo et a135 de-
scribed eight m o t h e r s who contracted hepatitis E in the third trimester. Six of their infants had clinical or serological evidence of hepatitis E. Two infants had h y p o t h e r m i a and hypoglycemia a n d died within 24 hours of birth. In view o f these observations, infants delivered to acutely infected m o t h e r s should receive i m m e d i a t e supp o r t a n d close monitoring.
References 1. Lemon SM, Thomas DL: Vaccines to prevent viral hepatitis. N Engl J Med 336:196-204, 1997 2. Shapiro CN, Coleman PJ, McQuillan GM et al: Epidemiology of hepatitis A: Seroepidemiology and risk groups in the USA. Vaccine 10:$59-$62, 1992 (suppl) 3. Centers for Disease Control: Hepatitis A among drug abusers. MMWR 37:297-305, 1988 4. Hepatitis A among homosexual m e n - - U n i t e d States, Canada, and Australia. MMWR 41:155-164, 1992 5. American College of Obstetricians and Gynecologists: Hepatitis in pregnancy. ACOG Tech Bull 174:1-9, 1992 6. Centers for Disease Control: Protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee. MMWR 39:1-26, 1990 7. Werzberger A, Mensch B, Kuter B, et al: A controlled trial of a formalin-inactivated hepatitis: A vaccine in healthy children. N EnglJ Med 327:453-457, 1992 8. Leikin E, Lysikiewicz A, Garry D, et al: Intrauterine transmission of hepatitis A virus. Obstet Gynecol 88:690-691, 1996 9. Syndman DR: Hepatitis in pregnancy. N Engl J Med 313:1398-1401, 1985 10. Hoofnagle JH: Chronic hepatitis B. N Engl J Med 323:337-339, 1990 11. Centers for Disease Control: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 40:1-25, 1991 12. Jagger J, Hunt EH, Brand-Elnaggar J, et al: Rates of needle-stick injury caused by various devices in a university hospital. N EnglJ Med 319:284-288, 1988 13. Rizzetto M: The delta agent. Hepatology 3:729-737, 1983 14. HoofnagleJH: Type D (delta) hepatitis.JAMA 261:13211325, 1989 15. Jacobson IM, DienstagJL, Werner BG, et al: Epidemiolo g y and clinical impact of hepatitis D virus (delta) infection. Hepatology 5:188-191, 1985 16. Lynch-Salamon DI, Combs CA: Hepatitis C in obstetrics and gynecology. Obstet Gynecol 79:621-629, 1992 17. Osmond DH, Padian NS, Sheppard HW, et al: Risk factors for hepatitis C virus positivity in heterosexual couples. JAMA 269:361-365, 1993 18. Weinstock HS, Bolan G, Reingold AL, et al: Hepatitis C virus infection among patients attending a clinic for sexually transmitted diseases. JAMA 269:392-394, 1993 19. Lau JY, Davis GL, Kniffen J, et al: Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet 341:1501-1504, 1993
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20. Bohman VR, Stetder RW, Little BB, et al: Seroprevalence and risk factors for hepatitis C virus antibody in pregnant women. Obstet Gynecol 80:609-613, 1992 21. Giovannini M, Tagger A, Ribero ML, et al: Maternalinfant transmission of hepatitis C virus and HIV infections: A possible interaction. Lancet 335:1166, 1990 22. Weintraub PS, Veereman-Wauters G, Cowan MJ, et al: Hepatitis C virus infection in infants whose mothers took street drugs intravenously. J Pediatr 119:869-874, 1991 23. 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 165:720-723, 1992 24. Ohto H, Terazawa S, Sasaki N, et al: Transmission of hepatitis C virus from mothers to infants. N EnglJ Med 330:744-750, 1994 25. Kew MC, Kassianides C: HGV: Hepatitis G virus or harmless G virus? Lancet 348:10, 1996 (suppl II) 26. Jarvis LM, Davidson F, Hanley JP, et al: Infection with hepatitis G virus among recipients of plasma products. Lancet 348:1352-1355, 1996 27. Feucht HH, Zollner B, Polywka S, et al: Vertical transmission of hepatitis G. Lancet 347:615-616, 1996
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28. Chauhan A, Jameel S, Chawla YK, et al: Common aetiological agent for epidemic and sporadic non-A, non-B hepatitis. Lancet 339:1509-1510, 1992 29. Bradley DW, Maynard JE: Etiology and natural history of post-transfusion and enterically transmitted non-A, non-B hepatitis. Semin Liver Dis 6:56-66, 1986 30. Velazquez O, Stetler HC, Avila C, et al: Epidemic transmission of enterically transmitted non-A, non-B hepatitis in Mexico, 1986-1987. JAMA 263:3281-3285, 1990 31. Wong DC, Purcell RH, Sreenivasan MA, et al: Epidemic and endemic hepatitis in India: Evidence for a non-A, non-B hepatitis virus aetiology. Lancet 2:876-878, 1980 32. Thomas DL, Mahley RW, Badur S, et al: Epidemiology of hepatitis E virus infection in Turkey. Lancet 341:15611562, 1993 33. Centers for Disease Control: Hepatitis E among U.S. travelers, 1989-1992. MM~,]~. 42:1-4, 1993 34. Favorov MO, Fields HA, Purdy MA, et al: Serologic identification of hepatitis E virus infections in epidemic and endemic settings. J Med Virol 36:246-250, 1992 35. Khuroo M, Kamili S, Jameel s: Vertical transmission of hepatitis E virus. Lancet 345:1025-1026, 1995
Currently, six distinct types o f hepatitis virus have been identified: A, B, C, D, E, and G. Hepatitis A virus infection does not cause a chronic carrier state, and perinatal transmission is extremely uncommon. Hepatitis B can be transmitted perinatally, but immunization of the newborn with hepatitis B immune globulin and hepatitis B vaccine markedly reduces the risk o f neonatal infection. Hepatitis D virus is dependent on coinfection with the hepatitis B virus for replication, lmmunoprophylaxis against hepatitis B also is effective against hepatitis D. Hepatitis C virus is primarily transmitted by the parenteral route and is particularly likely to cause chronic liver disease. Perinatal t r a ~ m i ~ sion o f hepatitis C principally occurs in women who have high titers o f HCV-RNA or who are coinfected with human immunodeficiency virus. At this time, no immunoprophylaxis for hepatitis C is available. Hepatitis G, a recently described organism, is related to hepatitis C. Its clinical significance remains undetermined. Hepatitis E is transmitted in a manner similar tO hepatitis A. Perinatal transmission is unusual, but maternal disease is often severe. Copyright 9 1998 by W.B. Saunders Company
epatitis is one of the most c o m m o n and most highly contagious viral infections. Currently, six distinct types of hepatitis virus have been identified: A, B, C, D, E, and G. Each type of hepatitis has a slightly different clinical implication for the pregnant woman and her fetus.
H
Hepatitis A Hepatitis A is responsible for approximately 45% of cases of acute hepatitis in the United States.1 It is caused by a n o n e n v e l o p e d 27-nm RNA virus that is a m e m b e r o f the picornavirus family. The virus is transmitted by person to person contact through fecal-oral contamination. Poor hygiene, p o o r sanitation, and intimate personal or sexual contact facilitate transmission. Epidemics frequently result from c o m m o n exposure to contaminated food and water. In the United States, individuals at particular risk for hepatitis A are those who have recently immigrated from, or traveled to, developing nations of the world where the disease is endemic. Drug abusers, homosexual men, patients receiving factor VIII concentrates, children and supervisors in day care centers, and patients with chronic liver disease also are at increased risk of acquiring hepatitis A. TM T h e incubation period of hepatitis A ranges from 15 to 50 days, with a mean of 28 to 30 days. The highest concentration of viral particles is in fecal material. The virus is not normally excreted in urine or other body fluids.
Some patients with hepatitis A are asymptomatic. When symptoms do occur, they typically include malaise, fatigue, anorexia, nausea and vomiting, and right u p p e r quadrant pain, T h e characteristic physical findings o f acute hepatitis A are jaundice, hepatic tenderness, darkened urine, and acholic stools. T h e most useful diagnostic test for hepatitis A is identification of IgM-specific antibody, which is detectable 25 to 30 days after the initial exposure and persists in the serum for up to 6 months. IgG antibody is detectable within 35 to 40 days of exposure, persists indefinitely, and confers lifelong immunity. In addition, the serum concentrations o f alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin are usually moderately to markedly elevated. Liver biopsy is rarely indicated today to confirm the diagnosis of viral hepatitis in pregnancy. 5 Fortunately, acute hepatitis A is usually a selflimited illness, and only supportive care is required for the majority of patients. Recovery is typically complete within 4 to 6 weeks. Fulminant From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, GainesviUe, FL. Address rep+int requests to Patrick Duff, MD, University of Florida College of Medicine, Department of Obstetrics and Gynecology,Division of Maternal-Fetal Medicine, PO Box 100294, Gainesville, FL 32610-0294. Cop)~ght 9 1998 by W.B. Saunders Company 0146-0005/98/2204-0006508. 00/0
Seminars in Perinatology, Vol 22, No 4 (August), 1998: pp 277-283
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hepatitis, coagulopathy, or encephalopathy develop in fewer than 0.5% of affected patients. Infected patients should be advised of the n e e d for good nutrition. Physical activity should be limited to prevent u p p e r abdominal trauma. Drugs with potential hepatotoxicity such as isoniazid, ketoconazole, or alpha-methyldopa should be avoided until the patient recovers. Sexual and household contacts should receive i m m u n o p r o phylaxis with a single intramuscular dose of immunoglobulin, 0.02 m L / k g , within 2 weeks of exposure. 6 In addition, they also should receive the formalin-inactivated hepatitis A vaccine. Two hepatitis A vaccines have been licensed in the United States: Havrix (SmithKline Beecham Pharmaceuticals, Philadelphia, PA) and Vaqta (Merck & Co, West Point, PA). Both preparations contain formalin-inactivated viral particles p r o d u c e d in h u m a n fibroblasts. The intramuscular dose of Havrix is 1 mL; the corresponding dose of Vaqta is 0.5 mL. The approximate cost of a single dose of vaccine is $50-$60.1 Both vaccine preparations are highly immunogenic and are safe for use in pregnancy. Protective levels o f antibody after vaccination develop in over 95% o f healthy adults. Duration o f immunity appears to persist for at least 10 years. In addition to contacts o f acutely infected patients, o t h e r candidates for vaccination include individuals who anticipate travel to areas of the world where hepatitis is endemic, children living in high-prevalence areas or attending daycare, intravenous drug abusers, daycare workers, residents and staff m e m b e r s of institutions for developmentally disabled persons, and patients over the age of 30 with chronic liver disease. 1 A booster dose of the vaccine is indicated 6 to 12 m o n t h s after the first dose if the patient has c o n t i n u i n g risk of exposure to hepatitis A infection. 1'7 Both hepatitis A vaccine preparations are very safe. Mild reactions at the site of injection occur in 20% to 50% of recipients, and fever occurs in approximately 5%. Life-threatening reactions such as anaphylaxis and Guillain-Barre synd r o m e are distinctly u n c o m m o n . The vaccine should not be administered to anyone with an allergy to one of its c o m p o n e n t s or to children u n d e r 2 years of a g e ) As a general rule, unless the pregnant m o t h e r becomes severely ill, hepatitis A does not pose a serious risk to the fetus. A chronic carrier state
does not exist, and only isolated cases of perinatal transmission have been reported. In one recent case, Leikin, et al, 8 described a fetus with polyhydramnios and ascites in whom hepatitis A infection was confirmed by cordocentesis. T h e fetus was delivered because of m e c o n i u m peritonitis and required corrective surgery. Subseq u e n t recovery was uneventful. An infant delivered to an acutely infected m o t h e r should receive immunoglobulin to reduce the risk of horizontal transmission of infection after delivery. Unfortunately, such immunoprophylaxis is not perfectly protective. Hepatitis B Approximately 35% of all cases of hepatitis in the United States are caused by hepatitis B virus. 1 Over 300,000 new cases of hepatitis B occur annually, and about one million Americans are chronic viral carriers. The frequencies of acute and chronic hepatitis B in pregnancy are 1 to 2 per 1,000 and 5 to 15 per 1,000, respectively. 5'9 Hepatitis B is caused by a highly infectious, enveloped DNA virus. The intact virus is t e r m e d the Dane particle, and its three major structural antigens are surface antigen (HbsAg), core antigen (HbcAg), and e antigen (HbeAg). Transmission of hepatitis B occurs primarily as a result of parenteral injection, sexual contact, and perinatal exposure. Certain population groups have an increased prevalence of hepatitis B: Asians, Eskimos, drug addicts, transfusion recipients, dialysis patients, residents and employees of chronic care residencies, prisoners, and recipients of tatoos. 5 After an acute infection caused by hepatitis B virus, less than 1% of patients get fulminant hepatitis and die. Eighty-five percent to 90% experience complete resolution of their physical findings, acquire protective levels of antibody, and gain lifeqong immunity. T e n percent to 15% of patients b e c o m e chronically infected. O f these, chronic active or persistent hepatitis or cirrhosis develops in 15% to 30%, and hepatocellular carcinoma develops in a small percentage. Chronic liver disease is particularly likely to occur in patients who remain seropositive for HbeAg and who b e c o m e superinfected with the hepatitis D virus. 5 T h e diagnosis of " a c u t e " hepatitis B is confirmed by detection of the surface antigen and
Hepatitis
Table 1. Serological Diagnosis of Hepatitis B Infection
Serological Test Condition Susceptible Immune Acute infection Chronic infection
HBsAg HB, Ag anti-HBc anti-HBs . -+ +
. -+
.
. +IgG +IgM
+IgG --
+
+IgG
--
Abbreviations: anti-HBc,antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen.
IgM antibody to the core antigen. Identification of HbeAg is indicative of an exceptionally high viral inoculum and active viral replication. Patients who have chronic hepatitis B infection have persistence of the surface antigen in the serum and liver tissue. Some individuals, particularly Asians, also remain seropositive for HbeAg (Table 1). 5'6'1~ Patients with acute and chronic hepatitis B infection pose a major threat of transmission to o t h e r household members, especially their sexual partner. In addition, infected w o m e n may transmit infection to their fetus. Perinatal transmission occurs primarily as a result of the infant's exposure to infected blood and genital secretions during delivery. In the absence of imm u n o p r o p h y l a x i s for the neonate, perinatal transmission occurs in 10% to 20% o f w o m e n who are seropositive for HbsAg. T h e frequency of perinatal transmission increases to almost 90% in w o m e n who are seropositive for b o t h HbsAg and HbeAg. 5'6'1~ Fortunately, a combination o f passive and active immunization is highly effective in preventing both horizontal a n d vertical transmission of hepatitis B infection. All individuals who have had household or sexual exposure to ano t h e r person with hepatitis B infection should be tested to d e t e r m i n e if they have antibody to the virus. If they are seronegative, they should immediately receive i m m u n o p r o p h y l a x i s with hepatitis B i m m u n o g l o b u l i n (HBIG), 0.06 m L / kg intramuscularly. They then should receive the hepatitis B vaccination series. Similarly, infants who are delivered to seropositive mothers should receive HBIG, 0.5 m L intramuscularly, immediately after birth. They then should begin the hep-
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atitis B vaccination series within 12 hours of birth.5,6,1~ Two r e c o m b i n a n t hepatitis B vaccines now are available, Recombivax-HB (Merck & Co) and Engerix-B (SmithKline Beecham Pharmaceuticals). Both products are c o m p o s e d o f inactivated portions of the surface antigen and are p r e p a r e d by r e c o m b i n a n t DNA technology f r o m Saccharomyces cerevisiae. Neither poses a risk of transmission of a blood-borne pathogen, and both are safe for administration during pregnancy to patients at risk. T h e routine vaccination series for hepatitis B consists of three intramuscular injections. T h e second and third injections should be administered 1 and 6 months, respectively, after the initial dose. Injections should be administered into the deltoid rather than gluteal muscle. Gluteal injections and intradermal injections result in significantly lower rates o f seroconversion. Table 2 summarizes the dosage schedules for the two vaccine preparations. 1'5'6 T h e two vaccine preparations are essentially equivalent in efficacy and can be used interc h a n g e a b l y ) Protective antibody titers (->10 m I U / m L ) develop in approximately 95% to 99% of healthy vaccine recipients, but the frequency of seroconversion is reduced in i m m u n o c o m p r o m i s e d patients and in individuals over the age of 40. I m m u n o g e n e c i t y is not affected when the vaccine is injected simultaneously, at different sites, with H B I G or when hepatitis B vaccine is administered with o t h e r vaccines. T h e duration of immunity after vaccination appears to be longlasting, and routine monitorTable 2. Recommended Doses of Hepatitis B Vaccine
Vaccine Recipient
Recombivax HB
Children and adolescents 5/lg 11-19 yr old (0.5 mL) Adults -->20yr old 10 #g (1 mE) Immunocompromised 40/zg patients (1 mL)*
Engerix-B 20 #g (1 mL) 20/zg (1 mE) 40/zg (2 mL)t
NOTE. The approximate cost of the vaccine preparations are $25-30 for the pediatric doses, $50-60 for the conventional adult doses, and $110-170 for the special high-dose formulations.l * Special formulation. t Two 1.0-mL doses administered at one site in a four-dose schedule at 0, 1, 2, and 6 months. Data from references 5 and 11.
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ing of antibody titers or administration of booster doses is not r e c o m m e n d e d . However, if a previously vaccinated person experiences a definite exposure, an antibody titer should be checked. If it is less than 10 m I U / m L , a booster dose of vaccine, along with HBIG, should be administered. 1'6 Mild reactions at the site o f injection o c c u r in a p p r o x i m a t e l y 20% o f vaccine recipients. Severe adverse reactions such as anaphylaxis are rare. T h e only c o n t r a i n d i c a t i o n to the vaccine is hypersensitivity to yeast or a c o m p o n e n t of the vaccine. 1 I m m u n o p r o p h y l a x i s is approximately 85% to 95% effective in preventing neonatal hepatitis B infection. In view of the extremely favorable results of immunoprophylaxis, the Centers for Disease Control and Prevention (CDC) recently r e c o m m e n d e d universal hepatitis B vaccination for all infants, n Infants b o r n to seronegative m o t h e r s require only the vaccine. Infants b o r n to seropositive m o t h e r s should receive b o t h the vaccine and HBIG. Therefore, obstetricians must continue to screen all of their patients for hepatitis B at some point during pregnancy. Selective screening on the basis of acknowledged risk factors will fail to identify 30% to 50% of seroposifive women. 5 Patients infected with hepatitis B virus also may transmit infection to medical and nursing p e r s o n n e l who care for them. Each year approximately 12,000 American health care workers contract hepatitis B as a result of an occupational injury such as a needle stick or splash to a mucous m e m b r a n e . O f these, approximately 200 acquire fulminant hepatitis and subsequently die. 12 Health care workers can protect themselves f r o m hepatitis in three principal ways. First, they should be vaccinated for hepatitis B. Second, they should encourage all y o u n g adults and other individuals who have a specific risk factor to receive the hepatitis B vaccine. Third, they should consistently follow universal precautions to prevent sharp injuries and splashes to exposed mucous m e m b r a n e or skin surfaces. Conversely, health care workers who are infected with hepatitis B also pose a risk to others. 6 They, too, must observe safeguards to prevent horizontal transmission of infection to their patients. Infection is most likely to occur as a consequence of direct blood-to-blood exposure during invasive surgical procedures. Unless the
patient has d o c u m e n t e d immunity to hepatitis B, the infected health care worker has an ethical obligation to inform the patient that some risk of transmission exists during invasive procedures. During the actual procedure, the o p e r a t o r must take every precaution to ensure that a sharp injury does not occur.
Hepatitis D Hepatitis D, or delta hepatitis, is caused by an RNA virus that is d e p e n d e n t on coinfection with the hepatitis B virus for replication. H e p a titis D has an external coat o f hepatitis B surface antigen a n d an internal delta antigen that is e n c o d e d by its own g e n o m e . T h e e p i d e m i o l o g y o f hepatitis D is essentially identical to that o f hepatitis B. 13 Acute hepatitis D occurs in two forms: coinfection and superinfection. Coinfection represents the simultaneous occurrence of acute hepatitis B and D. It is usually a self-limited disorder and rarely leads to chronic liver disease. Superinfection occurs when acute hepatitis D develops in a patient who is a chronic hepatitis B carrier. Approximately 20% to 25% o f patients with chronic hepatitis B b e c o m e superinfected with the delta virus, and chronic hepatitis subsequently develops in a b o u t 80% of these individuals. O f those who have chronic hepatitis, cirrhosis and portal hypertension develop in 70% to 80%, and almost 25% ultimately die of hepatic failure) 3-15 T h e diagnosis of acute coinfection can be confirmed by detection of delta antigen in hepatic tissue or serum a n d IgM-specific antibody in serum. In addition, the tests for HbsAg and antiHBc-IgM are positive. In patients with acute superinfection, serological tests reflect acute hepatitis D (positive antigen, positive IgM antibody) and chronic hepatitis B infection (positive surface antigen, anti-HBc IgG). Patients with chronic hepatitis D usually have detectable ser u m levels of IgG-specific antibody for the delta virus and are seropositive for HbsAg. Unfortunately, IgG antibody does n o t eradicate the delta viremia, and the antigen still can be identified in serum and hepatic t i s s u e . 14A5 Patients with acute hepatitis D should receive the general supportive care outlined for hepatitis A. Patients with chronic infection should be m o n i t o r e d periodically for worsening hepatic
Hepatitis
function and coagulopathy. At present, there is no specific antiviral agent or i m m u n o t h e r a p y that is curative for either acute or chronic delta infection. Perinatal transmission of hepatitis D virus has been reported. Fortunately, transmission is u n c o m m o n because the neonatal immunoprophylaxis for hepatitis B is almost uniformly effective against hepatitis D. 1'~
Non-A, Non-B Hepatitis Non-A, non-B hepatitis accounts for 10% to 20% of cases o f hepatitis in the United States. 1'5 NonA, non-B hepatitis occurs in three forms: hepatitis C, G, and E. Hepatitis C Hepatitis C is a 30- to 38-nm, single-stranded enveloped RNA virus, that is similar in structure to flaviviruses and pestiviruses. Its incubation period is 5 to 10 weeks. The principal risk factors for hepatitis C are intravenous drug abuse, transfusion, and sexual intercourse.~6 In a recent survey by O s m o n d et al, 17 two thirds of a selected population of drug abusers were seropositive for hepatitis C. In a similar survey of patients attending a sexually transmitted disease (STD) clinic in San Francisco, Weinstock et al, TM found the prevalence of hepatitis C to be 7.7%. Approximately 90% o f all cases o f posttransfusion hepatitis are caused by hepatitis C, and 2.5% to 15% of patients who receive multiple transfusions become infected with this virus. Hepatitis C infection is particularly likely to result in chronic liver disease. Biochemical evidence of hepatic dysfunction develops in approximately 50% o f infected patients, and of these, chronic active hepatitis or cirrhosis subsequently develops in about
20%. Approximately 75% of patients with hepatitis C are asymptomatic. The diagnosis of hepatitis C infection is confirmed by identification of antiC antibody. Initial screening for this antibody should be p e r f o r m e d with an enzyme immunoassay (EIA). A positive EIA should be followed with a recombinant i m m u n o b l o t assay (RIBA). The present RIBA is able to detect four specific viral antigens. If at least two antigens are identified, the test result is considered positive. If only one antigen is identified, the test result is considered indeterminant. T h e present generation of labo-
281
ratory assays does not precisely discriminate between IgM and IgG antibody. Moreover, antibody may not be detectable until 6 to 16 weeks after the onset of clinical illness. Direct detection of hepatitis C-RNA also is possible with polymerase chain reaction methodology, and identification of C-RNA denotes a high level of infectivity. 19 In a general obstetric population, the prevalence of hepatitis C is 1% to 3%. The principal risk factors that identify an obstetric patient at high risk for hepatitis C include c o n c u r r e n t STDs, such as hepatitis B and h u m a n immunodeficiency virus (HIV) infection; multiple sexual partners; history of recent multiple transfusions; and history o f intravenous drug abuse. 16"2~ T h e frequency o f perinatal transmission of hepatitis C is highly variable, ranging from less than 10% to as high as 44%. Higher rates of transmission are most likely to occur when the m o t h e r is coinfected with HIV or when she has high serum titers of C - R N A . 21-24 For example, Weintraub e t a122 studied 43 mothers who were intravenous drug users. Seventeen infants had passively transmitted anti-HCV, indicating that approximately 40% of the mothers were seropositive for hepatitis C virus. Four infants (24%) delivered to seropositive mothers were persistently seropositive. All of these infants were coinfected with HIV. Similarly, Ohto e t al, 24 recently surveyed 53 mothers who were seropositive for HCV antibody. Twenty-two women were antibody positive but HCV RNA negative, and n o n e of their infants became infected. Thirty-one women had positive findings for both antibody and RNA, and three (10%) o f their babies became infected. Currently, a vaccine for hepatitis C is not available. Passive immunization with immunoglobulin (0.06 m L / k g intramuscularly) should be administered after percutaneous exposure to a person with hepatitis C. The benefit of immunoprophylaxis for the neonate has not been proven in controlled clinical trials. Although a-interferon has shown some activity against the virus, relapses occur in 44% to 80% of patients within 6 to 12 months o f discontinuation o f therapy, and the drug has not been tested in a controlled m a n n e r in pregnant women. 5 Hepatitis G Identification of the hepatitis G virus (HGV or GBV-C) is a relatively recent discovery. The or-
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Patrick Duff
ganism is a single-stranded, RNA flavivirus that is related to hepatitis C. T h e organism is m o r e prevalent, but less virulent, than hepatitis C. It causes acute and persistent infection in humans, but the clinical significance of infection remains unsettled. Nucleic acid f r o m hepatitis G virus can be identified in serum by polymerase chain reaction ( P C R ) . 25'26 Hepatitis G c o m m o n l y occurs in association with hepatitis B, hepatitis C, and HIV infection. A chronic carrier state exists, a n d perinatal transmission can occur. In a recent report, Feucht et al, 27 studied nine w o m e n who had hepatitis G viremia by PCR. Vertical transmission occurred in three cases. Two of the m o t h e r s were coinfected with H I V a n d one with hepatitis C virus. T h e prognosis for neonates infected in this manner remains to be determined.
Hepatitis E Hepatitis E virus is a n o n e n v e l o p e d RNA virus that i s closely related to the calicivirus family. It may present in b o t h an icteric and anicteric form. T h e virus is transmitted by the fecal-oral route, and, therefore, the epidemiology of hepatitis E is similar to that of hepatitis A. T h e incubation period ranges f r o m 2 to 9 weeks, with a m e a n of 45 days. 28'29 Hepatitis E is rare in the United States but is endemic in developing countries. In these countries, the m a t e r n a l mortality rate has been alarmingly high, ranging f r o m 10% to 20%. 3~ Extreme poverty, coexisting medical illnesses, malnutrition, and p o o r prenatal care are at least partially responsible for the p o o r maternal prognosis. T h e only cases of hepatitis E in the United States have occurred in patients who traveled to countries in which the disease was endemic, zz T h r e e diagnostic tests are available for confirmation of hepatitis E infection. Viral-like particles can be identified in the stool of infected patients by electron microscopy. These particles will agglutinate when c o m b i n e d with serum f r o m the patient. In addition, a fluorescent antibody blocking assay and Western blot assay are now available for use. TM Patients with acute hepatitis E should be treated as described previously for patients with hepatitis A. A chronic carrier state does not develop, and perinatal transmission usually does not occur. Recently, however, Khuroo et a135 de-
scribed eight m o t h e r s who contracted hepatitis E in the third trimester. Six of their infants had clinical or serological evidence of hepatitis E. Two infants had h y p o t h e r m i a and hypoglycemia a n d died within 24 hours of birth. In view o f these observations, infants delivered to acutely infected m o t h e r s should receive i m m e d i a t e supp o r t a n d close monitoring.
References 1. Lemon SM, Thomas DL: Vaccines to prevent viral hepatitis. N Engl J Med 336:196-204, 1997 2. Shapiro CN, Coleman PJ, McQuillan GM et al: Epidemiology of hepatitis A: Seroepidemiology and risk groups in the USA. Vaccine 10:$59-$62, 1992 (suppl) 3. Centers for Disease Control: Hepatitis A among drug abusers. MMWR 37:297-305, 1988 4. Hepatitis A among homosexual m e n - - U n i t e d States, Canada, and Australia. MMWR 41:155-164, 1992 5. American College of Obstetricians and Gynecologists: Hepatitis in pregnancy. ACOG Tech Bull 174:1-9, 1992 6. Centers for Disease Control: Protection against viral hepatitis. Recommendations of the Immunization Practices Advisory Committee. MMWR 39:1-26, 1990 7. Werzberger A, Mensch B, Kuter B, et al: A controlled trial of a formalin-inactivated hepatitis: A vaccine in healthy children. N EnglJ Med 327:453-457, 1992 8. Leikin E, Lysikiewicz A, Garry D, et al: Intrauterine transmission of hepatitis A virus. Obstet Gynecol 88:690-691, 1996 9. Syndman DR: Hepatitis in pregnancy. N Engl J Med 313:1398-1401, 1985 10. Hoofnagle JH: Chronic hepatitis B. N Engl J Med 323:337-339, 1990 11. Centers for Disease Control: Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 40:1-25, 1991 12. Jagger J, Hunt EH, Brand-Elnaggar J, et al: Rates of needle-stick injury caused by various devices in a university hospital. N EnglJ Med 319:284-288, 1988 13. Rizzetto M: The delta agent. Hepatology 3:729-737, 1983 14. HoofnagleJH: Type D (delta) hepatitis.JAMA 261:13211325, 1989 15. Jacobson IM, DienstagJL, Werner BG, et al: Epidemiolo g y and clinical impact of hepatitis D virus (delta) infection. Hepatology 5:188-191, 1985 16. Lynch-Salamon DI, Combs CA: Hepatitis C in obstetrics and gynecology. Obstet Gynecol 79:621-629, 1992 17. Osmond DH, Padian NS, Sheppard HW, et al: Risk factors for hepatitis C virus positivity in heterosexual couples. JAMA 269:361-365, 1993 18. Weinstock HS, Bolan G, Reingold AL, et al: Hepatitis C virus infection among patients attending a clinic for sexually transmitted diseases. JAMA 269:392-394, 1993 19. Lau JY, Davis GL, Kniffen J, et al: Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet 341:1501-1504, 1993
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20. Bohman VR, Stetder RW, Little BB, et al: Seroprevalence and risk factors for hepatitis C virus antibody in pregnant women. Obstet Gynecol 80:609-613, 1992 21. Giovannini M, Tagger A, Ribero ML, et al: Maternalinfant transmission of hepatitis C virus and HIV infections: A possible interaction. Lancet 335:1166, 1990 22. Weintraub PS, Veereman-Wauters G, Cowan MJ, et al: Hepatitis C virus infection in infants whose mothers took street drugs intravenously. J Pediatr 119:869-874, 1991 23. 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 165:720-723, 1992 24. Ohto H, Terazawa S, Sasaki N, et al: Transmission of hepatitis C virus from mothers to infants. N EnglJ Med 330:744-750, 1994 25. Kew MC, Kassianides C: HGV: Hepatitis G virus or harmless G virus? Lancet 348:10, 1996 (suppl II) 26. Jarvis LM, Davidson F, Hanley JP, et al: Infection with hepatitis G virus among recipients of plasma products. Lancet 348:1352-1355, 1996 27. Feucht HH, Zollner B, Polywka S, et al: Vertical transmission of hepatitis G. Lancet 347:615-616, 1996
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28. Chauhan A, Jameel S, Chawla YK, et al: Common aetiological agent for epidemic and sporadic non-A, non-B hepatitis. Lancet 339:1509-1510, 1992 29. Bradley DW, Maynard JE: Etiology and natural history of post-transfusion and enterically transmitted non-A, non-B hepatitis. Semin Liver Dis 6:56-66, 1986 30. Velazquez O, Stetler HC, Avila C, et al: Epidemic transmission of enterically transmitted non-A, non-B hepatitis in Mexico, 1986-1987. JAMA 263:3281-3285, 1990 31. Wong DC, Purcell RH, Sreenivasan MA, et al: Epidemic and endemic hepatitis in India: Evidence for a non-A, non-B hepatitis virus aetiology. Lancet 2:876-878, 1980 32. Thomas DL, Mahley RW, Badur S, et al: Epidemiology of hepatitis E virus infection in Turkey. Lancet 341:15611562, 1993 33. Centers for Disease Control: Hepatitis E among U.S. travelers, 1989-1992. MM~,]~. 42:1-4, 1993 34. Favorov MO, Fields HA, Purdy MA, et al: Serologic identification of hepatitis E virus infections in epidemic and endemic settings. J Med Virol 36:246-250, 1992 35. Khuroo M, Kamili S, Jameel s: Vertical transmission of hepatitis E virus. Lancet 345:1025-1026, 1995