This chapter should be cited as follows:
Silverman, N, Glob. libr. women's med.,
(ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10181
Last reviewed: October 2008

Hepatitis Virus Infections During Pregnancy

Neil S. Silverman, MD
Director, Inpatient Obstetric Services, Division of Maternal–Fetal Medicine, Cedars-Sinai Medical Center; Associate Professor, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California, USA

INTRODUCTION

Our evolving understanding of the immunology of the hepatitis B virus (HBV) has led to the development of safe and effective therapies for preexposure and postexposure virus-specific prophylaxis. Perinatal transmission of HBV from mothers with chronic infection to their at-risk neonates remains a significant route for the perpetuation of the HBV carrier state, with its concomitant health risks, worldwide. This section outlines the evidence supporting antenatal identification of HBV-carrier mothers and targeted HBV immunoprophylaxis in their newborn children. Widespread adoption of such approaches, combined with ongoing HBV vaccination protocols in high-risk populations, including medical personnel, will make significant inroads against the overall prevalence of HBV-related disease.

Biology and Serology

Although an exhaustive discussion of HBV biology is beyond the scope of this chapter, an understanding of the basic structures and serologic tests associated with the virus is essential to understanding the logistics of perinatal transmission and prevention.

HBV is a small (42-nm) DNA virus that contains partially double-stranded DNA within its core.1 Using its own DNA polymerase for replication, the virus is able to reproduce within a host's infected hepatocytes, drawing from the cell's pool of nucleotide precursors.

Much attention has been paid to the use of HBV-specific markers in serum to distinguish active from previous infection and to determine the relative infectiousness of a particular individual. Not surprisingly, these concerns are directly applicable to determining relative risks for vertical (maternal–fetal) transmission of the virus.

Hepatitis B surface antigen (HBsAg) is the HBV serum marker that has come to be used most commonly in clinical situations and screening protocols. Discovered by Blumberg and co-workers in 1965,2 it initially was not known to be a virus-associated marker. The antigen, first isolated in the serum of an Australian aborigine during a study of serum protein polymorphisms (hence its being labeled the “Australia antigen”),3 was found incidentally to cross-react with the serum of multiply transfused patients. Later found to be present in the serum of institutionalized patients, it was even believed to be possibly associated with Down syndrome.4 Subsequent work by Blumberg's group and others established a link between the newly identified antigen and acute hepatitis B, an association confirmed by electron microscopy identification of particles dense with the antigen in the serum of patients who were acutely ill with hepatitis.5 Those particles now are known to represent incomplete portions of the viral envelope, synthesized in great excess during the process of virus replication. In addition, intact viral particles bear the surface antigen on their outer envelope. The presence of HBsAg in serum indicates infectivity, although such presence alone cannot distinguish acute from chronic infection, an often confusing exercise that requires a more complete elaboration of HBV-related serologies.

Although HBsAg is the first antigen detectable in the course of HBV infections, predating even the appearance of symptoms in those patients who become clinically ill, it is the predictable appearance and disappearance of other HBV-associated antigens and antibodies over time that allows patterns compatible with either acute or chronic infection to be described. Currently, six distinct antigens and antibodies are assayable in clinical specimens through the use of commercially available test kits and machinery. The agar gel precipitation techniques first used by Blumberg's group to demonstrate HBsAg antigen–antibody complex formation has given way to fully automated, multisample readers that capitalize on advances in molecular biology to detect the presence or absence of the specific immunogens in question.

The complete hepatitis B viral particle, also known as the Dane particle, after Dane and co-workers who described it in 1970,6 consists of the viral core surrounded by its HBsAg-rich envelope (Fig. 1). If the envelope is removed by the use of detergents in vitro, a viral core antigen (HBcAg) can be identified. Unlike HBsAg, HBcAg does not circulate free in serum and is found in blood only as an integral component of the internal viral nucleocapsid. A third antigen, the e antigen (HBeAg), is serologically distinct from both HBsAg and HBcAg. HBeAg is associated primarily with the core antigen in the virus's internal structure, but unlike HBcAg, it can be found circulating in serum, frequently in complexes with immunoglobulin.7 All three serologically unique antigens stimulate the production of equally distinct antibodies (HBsAb, HBcAb, and HBeAb) in the course of nonchronic host infection.

Fig. 1. Diagrammatic structure of the hepatitis B virus. (Cooper BW, Klimek JJ: The pathogenesis and prevention of hepatitis B infection, p 640. In: Infections in Surgery. New York, SCP Communications, 1987)

Also located within the viral core are the viral DNA and DNA polymerase. The presence of HBeAg has been closely correlated with both the infectivity of a particular patient's serum and the microscopic detection in serum of the HBV virus itself8, 9 and an increased risk for chronic liver disease.10, 11 Seropositivity for HBeAg should be taken as a marker of active viral replication, the most infectious phase of the disease, either in acute or in chronic illness. Practically, however, HBsAg is used in screening protocols because of the high concentrations of this antigen produced in response to viral presence and replication. More vigorous HBV serologic testing is performed, along with liver function evaluation, in HBsAg-positive individuals, both symptomatic and symptom-free, to characterize the nature and extent of their disease. The appearance of HBsAb in the serum of patients occurs in the setting of resolution of acute infection; it is this antibody that appears to confer protective immunity. However, both HBcAb and HBeAb have been shown experimentally to be protective against reinfection.12, 13, 14, 15 Still, the currently available HBV vaccine's efficacy is conferred by stimulating production of HBsAb by exposure to HBsAg; vaccine-related immunity can be distinguished from natural immunity in most cases by the absence of HBcAb in the serum of successfully vaccinated patients.16

 

Epidemiology, Transmission, and Prevention

Infection with HBV has been accepted as a health concern of worldwide importance, because 5% to 10% of those infected become chronic HBV carriers,17 and 25% to 30% of those carriers die as a result of long-term sequelae of HBV-related disease.18 Workers in an endemic area in Asia (Taiwan) found more than 15% of subjects screened in a general program to be HBsAg-positive; deaths in 54% of the carriers were attributable to primary hepatocellular carcinoma (PHC) and cirrhosis compared with 1.5% of deaths among noncarriers.19 Since that initial linkage, the virus has been shown to be the cause of approximately 80% of all cases of PHC globally.20

In areas endemic for HBV, up to 20% of the general population is chronically infected, with perinatal/neonatal and childhood infections existing as a primary route for expanding the reservoir of carriers (Table 1). This is especially significant because the risk of chronic HBV infection for a child infected in the newborn period in the absence of prophylactic therapy is 70% to 90%.21, 22

 

Table 1. Global Distribution of Hepatitis B Virus (HBV) Infection


  Low Prevalence Intermediate Prevalence High Prevalence
HBsAb-positive rate 0.2%–0.5% 2%–7% 8%–20%
HBsAb-positive rate 4%–6% 20%–55% 70–90%
Childhood infection Uncommon Common Very common
Locations North American, Western Europe, Australia Eastern Europe, Middle East, Soviet Union, South America China, southeast Asia, sub Saharan Africa, Pacific Islands

HBsAg, hepatitis B surface antigen; HBsAb, hepatitis B antibody
(Adapted from Maynard JE, Kane MA, Hadler SC: Global control of hepatitis B through vaccination: Role of hepatitis B vaccine in the expanded programme on immunization. Rev Infect Dis [suppl 3] 11:574, 1989)

 

In areas of low endemicity for HBV carriage, however, such as the United States, screening programs for the general population have been targeted to decrease household, transfusion, sexual, and perinatal transmission risks among contacts of HBsAg-positive individuals. Population subsets have been identified that are at increased risk for HBV acquisition, and HBV vaccination is recommended for individuals within those groups who are serologically negative for HBsAg and HBsAb. The efficacy of a serum-derived HBV vaccine was demonstrated initially on a large scale in a cohort of more than 1000 homosexual men in the United States; this trial showed an antibody (HBsAb) response in 96% of those vaccinated, with an overall protective efficacy of 88% against all HBsAg-positive events for vaccine compared with placebo.23 More recently, a recombinant vaccine consisting of purified HBsAg particles derived from yeast cells was licensed in the United States,24eliminating even the theoretical (but never proven) risk of transmitting other viral agents with a serum-based vaccine.25 Controlled trials in homosexual men showed an equivalent prevalence of acquired immune deficiency syndrome (AIDS) in groups receiving either the placebo or the serum-derived HBV vaccine.26

Estimates in the United States tabulate approximately 200,000 new primary cases of HBV infection per year, only 25% of which are associated with acute symptomatic infection.27 The dose of initial viral infection appears to correlate negatively with the risk of development of persistent disease. Survivors of fulminant hepatitis rarely have chronic infection, whereas experimental infections with low doses of virions result in longer incubation periods, milder clinical disease, and persistent antigenemia.28

Blood and blood products are the most thoroughly established sources of hepatitis B infection, although HBsAg has been demonstrated in a variety of body fluids. Of those, however, only serum, saliva, and semen have been associated consistently with transmission in experimental models.29, 30, 31 Despite the presence of HBsAg in feces, past attempts to produce infection using feces of experimentally infected subjects were unsuccessful, suggesting blood from the gastrointestinal tract to be the uncommon infectious vector present in feces of carrier individuals.32

Percutaneous transfer of the virus is the most obvious route of transmission in the medical setting, either through blood products or through needle-stick accidents. Contact of infectious material with broken skin or mucous membranes also can result in effective transmission. Recent surveys, however, show that approximately 50% of health care workers at risk for contracting HBV have not been vaccinated against the virus.33

Compared with other transmissible viruses, such as the human immunodeficiency virus (HIV), HBV is a fairly stable virus and remains infectious on household surfaces that may then contact mucous membranes, such as toothbrushes, baby bottles, razors, and eating utensils.34, 35 Although transmission in households is more common through sexual contact than through fomite contact,36, 37 nonsexual household transmission has been established as a route for HBV infection.38, 39, 40 In areas of the world with higher HBV carrier rates than the United States, nonparenteral transmission would be expected to constitute the major route of person-to-person HBV infection. Vertical transmission is a major source; investigators in Taiwan estimated that 40% to 50% of HBsAg carriers became infected in the perinatal period.21, 41

Children born to carrier mothers who escape the neonatal period without evidence of infection are still at risk for childhood acquisition of HBV. One of the early vaccine trials conducted in Senegal showed that among children seronegative at the beginning of a randomized HBV vaccination trial, almost 10% acquired HBV infection in the absence of vaccination by the end of a 12-month follow-up period.42

Immunoprophylaxis regimens to prevent HBV transmission in the perinatal period, to be discussed later in the chapter, were a direct extension of the success of these therapies in high-risk adult populations. Postexposure immunization was first demonstrated through the use of immunoglobulin preparations with high titers of HBsAb, when administered within 4 hours of experimental infection with HBV.43 Before the development of an effective HBV-specific vaccine, transient preexposure prophylaxis was demonstrated using hyperimmune globulin (HBIG),44, 45 although such use of HBIG is now of purely historical interest in terms of understanding the evolution of therapeutic standards. Currently, postexposure treatment consists of a single dose of HBIG administered as temporally as possible to the exposure. Immediate therapy is, of course, optimal for maximal protection, although 75% efficacy has been shown when HBIG is administered within 7 days of exposure.46 Although it does not increase the efficacy of HBIG therapy, a series of HBV vaccination also should be initiated if the exposure was within a setting of ongoing risk, such as a health care or institutional setting. This regimen consists of injections at 0, 1, and 6 months and results in high antibody titers in more than 90% of those younger than age 60 years.47, 48, 49 Administration of HBV vaccine simultaneously with HBIG does not diminish the immunologic response to the vaccine.50, 51

 

Clinical Disease and Pregnancy

Hepatitis B is distinguished from the other viral hepatitides by its long incubation period (1–6 months), by the presence of extrahepatic symptoms in up to 20% of patients (arthralgia, rash, and myalgia thought to be a result of antigen–antibody complex deposition),52, 53 and, eventually, by the detection of HBV-specific serum markers (Fig. 2). The appearance of HBsAg usually predates any clinical symptoms by 4 weeks, on average, and remains detectable for 1 to 6 weeks in most patients.54 In the 90% to 95% of patients in whom chronic infection does not develop, HBsAg titers decrease as symptoms diminish. The appearance of HBsAb defines the absence of the carrier state; titers increase slowly during the clinical recovery period and may continue to increase up to 10 to 12 months after HBsAg is no longer detectable. In most patients with self-limited, acute hepatitis B, HBsAb is detectable only after HBsAg titers in serum disappear.55, 56 A “window” of time has been described in which a patient still with clinical hepatitis is negative for both HBsAg and HBsAb. During this time, HBV infection still can be diagnosed by the detection of HBcAb, which begins to appear 3 to 5 weeks after HBsAg does. HBcAb titers may decrease in the first 1 to 2 years after infection, although the antibody is still detectable years after acute disease in most patients.55 The appearance of HBeAg parallels that of HBsAg; in self-limited infections, HBeAb is detectable soon after the time that HBeAg disappears.

Fig. 2. Serologic changes in self-limited hepatitis B infection. (Fallon HJ: Liver diseases, p 331. In: Burrow GN, Ferris TF [eds]: Medical Complications During Pregnancy. Philadelphia, WB Saunders, 1988)

The chronic HBV carrier state usually can be predicted by HBsAg seropositivity for 20 weeks or more (Fig. 3). A test for HBV–DNA polymerase activity is positive in 50% of persistently HBsAg-positive patients, indicating ongoing viral replication57; Dane particles also can be identified in serum from these patients through electron microscopy.58 HBcAb is detectable in the serum of carriers at levels higher than those seen in either acute or recovering self-limited infections, and e-antigen markers are variable. HBeAb develops, with the disappearance of HBeAg, in one half to three quarters of carriers,59, 60 and its presence is inversely related to the relative infectivity index of a patient's serum.61

Fig. 3. Serologic changes in chronic hepatitis B infection. (Hollinger FB: Immunodiagnosis, p 156. In: Hollinger FB, Melnick JL, Robinson WS [eds]: Viral Hepatitis, New York, Raven Press, 1985)

Acute HBV infection during pregnancy is treated mainly by supportive measures, as in the nonpregnant state. An increase in fulminance and mortality rates with acute HBV infection during pregnancy has been demonstrated in some HBV-endemic areas,62, 63 although other investigators in Western countries have suggested that these adverse outcomes were related more to health care conditions and maternal malnutrition.64, 65 No teratogenic association has been established for maternal HBV infections,64, 66 even though evidence of HBV infection at birth in children of HBV-carrier women have suggested the possibility of transplacental leakage of HBV-infected blood from mother to fetus in utero.67, 68, 69 Encouragement is necessary to maintain adequate nutrition during the early symptomatic phase, and liver-metabolized drugs, if not avoidable, need to be monitored carefully through blood levels. Phenothiazine may be used, if needed, to control nausea and vomiting. In addition, household and sexual contacts of patients should be offered passive immunization with HBIG after their HBsAg seronegativity is established.

Universal screening protocols for prenatal patients have been advocated by a number of groups and are discussed more fully in the next section. Routine screening with HBsAg testing detects both chronic carriers and asymptomatic, acutely infected patients. A positive HBsAg result in early pregnancy should be followed-up by tests for liver function, as well as HBeAg and HBeAb; HBcAb is not helpful in distinguishing acute from chronic disease, and HBsAb rarely is present if HBsAg is still circulating. Repeating the tests for HBsAg and liver function later in pregnancy, however, does help to make the diagnosis and guide the need for perinatal prophylaxis of the neonate. Although a recent multicenter study indicated that treatment of chronic HBV carriers with alfa-interferon was effective in achieving remission, both biochemically and histologically, in one third of patients,70 such therapy cannot be recommended in pregnant HBV carriers. No information currently exists to guide the use of genetic prenatal diagnostic procedures in HBsAg-positive women and the potential risk of producing in utero infection, although studies have demonstrated that such infection is possible in the face of preterm labor or placental abruption.67, 68, 69 HBIG, administered periprocedurally to HBsAg-positive women, may protect the fetus from infection in a manner comparable with the use of Rh-immune globulin in Rh-negative women, but again, such statements are purely speculative and await further investigation before they take the shape of recommendations.

 

Perinatal Hepatitis B Virus Transmission

Discussion of perinatal HBV infection focuses on the following three major areas: (1) the transmissibility of the virus from mother to fetus; (2) the sequelae of neonatal infection; and (3) the effectiveness of currently available modalities for prophylaxis.

Finally, the extensive variance in prevalence rates worldwide requires that the feasibility of prenatal screening programs to identify carrier mothers be addressed.

The potential for vertical transmission of HBV at birth is significant. Most infants born to carrier mothers are HBsAg-negative at birth experience seroconversion in the first 3 months after delivery, suggesting acquisition of the virus at birth.71, 72, 73, 74 Mothers positive for both HBsAg and HBeAg are at highest risk for transmitting the virus; 85% to 100% of their offspring become infected, with 70% to 90% becoming chronic carriers. Mothers who are HBsAg-positive but HBeAg-negative, presumably indicating lower levels of replicating virus, do have a lower risk of transmitting the virus, but up to 35% of their children still will become carriers in the absence of neonatal therapy.75, 76, 77, 78 In addition to the long-term risks of HBV-related sequelae in chronic carriers, such as cirrhosis and hepatocellular carcinoma, both fulminant fetal neonatal hepatitis79, 80, 81 and childhood-onset hepatic carcinoma,82 have been described in children born to HBsAg-positive mothers.

Early attempts at interrupting the perinatal transmission cycle used HBIG alone, administered in the neonatal period. Globulin alone had a protective efficacy against the carrier state of 70% to 75%, although the protection was not permanent, and many children eventually became infected after the passively acquired antibody was cleared, undoubtedly through household contact.83, 84, 85 With the advent of the hepatitis B vaccine, trials were established to test its efficacy when administered in the newborn period, both alone and in conjunction with HBIG. A combination of HBIG and vaccine in the newborn period conferred significantly greater protection against perinatally transmitted HBV than even the vaccine alone, increasing efficacy from a range of 75% to 85% up to 90% to 95%.42, 77, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92 The small but identifiable percentage of babies who become infected, despite even combined HBV therapy at birth, is believed to represent in utero infection.93, 94 HBV DNA has been identified in abortus tissue extracted from an HBsAg-positive mother,95 and other reports show evidence of intrauterine infection in clinical situations, increasing risks for transplacental leakage, such as preterm labor associated with placental abruption.68, 69 Still, combination HBV-specific immunotherapy provides the best opportunity to prevent the chronic carrier state in the offspring of HBsAg-positive mothers. In the United States alone, approximately 16,500 births occur in HBsAg-positive women each year, approximately 4300 of whom are also HBeAg-positive.96 Infants born to these women should receive HBIG (0.5 mL) intramuscularly (IM), ideally within 12 hours of birth. HBV vaccine should be administered concurrently at a different site (0.5 mL IM) or can be administered up to 7 days after birth if it is not immediately available.96 The timing of HBIG appears to be more critical than that of vaccine in achieving maximal effectiveness of passive–active therapy. Subsequent vaccination is performed, also 0.5 mL IM, at ages 1 month and 6 months. Follow-up for these infants is crucial, because one recent study confirms the concern that in the United States, groups at highest risk for HBV infection are also least likely to be compliant with follow-up care.97

 

Hepatitis B Screening in Pregnancy

The unique opportunity to provide almost complete protection against perinatally acquired HBV infection makes antenatal identification of HBV carriers critical so that combined neonatal prophylaxis can be administered in a timely fashion. In nonendemic areas such as the United States, screening protocols were organized initially to test pregnant women who are in the HBV risk groups, as defined by the United States Public Health Service (Table 2).98 Such recommendations, however, were not without problems. Reports from a number of groups working in geographically diverse areas around the country found that using risk groups alone for prenatal HBV screening would miss 40% to 60% of all HBsAg-positive parturients.99, 100, 101, 102, 103, 104, 105 Overall, in these studies, the HBsAg-positive rate ranged from 0.3% to 1.5% (Table 3). Even if risk factors were to be used to identify these women, however, evidence from one survey shows that only 60% of obstetricians could name more than two HBV risk groups, and less than 30% knew the recommended treatment for infants born to carrier mothers.106

 

Table 2. Public Health Service Risk Groups for Prenatal Hepatitis B Virus (HBV) Screening Protocols (1984)


Asian, Pacific-Island, or Alaskan Eskimo descent, whether immigrant or born in the United States
Born in Haiti or sub-Saharan Africa
History of acute or chronic liver disease
Rejection as a blood donor
Staff or patient in a hemodialysis unit
Staff or patient in an institution for the mentally retarded
Occupational exposure to blood in medical/dental settings
Repeated blood transfusions
Household contact with HBV carrier or hemodialysis patient
Multiple episodes of veneral disease
Percutaneous use of illicit drugs

(Immunization Practices Advisory Committee: Postexposure prophylaxis of hepatitis B. MMWR Morb Mortal Wkly Rep 33:285, 1984)

 

 

Table 3. Hepatitis B Surface Antigen (HBsAg) Positivity in Different U.S. Populations and Relation to Centers for Disease Control Risk Criteria


  HBsAg-Positive (%) Detected by Risk Group (%)
Palm Beach (FL), 198699 1.1 38
Miami, 1987100 1.2 53
Cleveland, 1987101 0.5 45
New Orleans, 1987102 0.9 50
Chicago, 1987103 1.4 38
El Paso, 1990104 0.8 50
San Antonio, 1990105 0.3 42

 

Such findings have led to recommendations by the Public Health Service96 and, most recently, by the American College of Obstetricians and Gynecologists107 that HBsAg screening be performed as part of routine prenatal testing in all pregnant women. An elegant cost-analysis study by Arevalo and Washington108 shows that such a program, taking into account both acute and long-term costs of neonatally acquired HBV disease, is cost-effective at a prenatal population prevalence for HBsAg of only 0.06%. In countries where HBsAg carriage is endemic, funding for medical screening programs tends to be limited. In these settings, especially as the cost for HBV vaccine begins to decrease, workers have advocated consideration of empiric vaccination for all newborns.109, 110 Such a policy also has been recommended for children of Southeast Asian immigrants to the United States to prevent both perinatal and household acquisition of HBV.111

However, protocols establishing prenatal HBsAg screening policies do not address the problematic issue of deliveries in inner-city populations among women with minimal to no prenatal care. Maternal HBsAg status, in the absence of prenatal testing, then can only be known in the 1 to 2 days after delivery, and the newborn may miss out on maximally effective HBV prophylaxis. Investigators have recognized this problem because most hospital laboratories perform HBsAg testing at best on a daily basis.112 This fact is particularly important because evidence suggests that HBIG administered as perinatal prophylaxis may have limited efficacy if it is not administered as soon as possible after birth.113 A recent study has shown the rate of HBsAg carriage to be significantly higher among such unregistered women than in a comparison group enrolled in an inner-city clinic (7.8% vs 0.8%) and that the increase was specifically related to substance abuse. Among unregistered women with positive urine drug screens, moreover, the HBsAg-positive rate was 15%, and a maternal urine drug screen was suggested as a rapid screening test to target neonates at highest risk for HBV infection for prophylaxis, before the 24 to 48 hours required awaiting maternal HBsAg status.114

 

Impact of Perinatal Hepatitis B Virus Vaccination Programs

The efficacy of perinatal HBV vaccination programs in preventing infection in children born to carrier mothers has led to the inclusion of the HBV vaccine series in the American Academy of Pediatrics' current recommendations for childhood vaccines for the general population.115 Still, investigators have demonstrated that even in high-risk groups for perinatal HBV transmission, appropriate neonatal surveillance is critical. Among 426 children born to HBsAG-positive mothers in one longitudinal series, only 68% were completely vaccinated with the full three-dose sequence. Among the children followed-up, it was shown that the third vaccine dose was least likely to be received (64%). Serologic evaluation of the children in this well-conceived surveillance program showed 4% to have acquired chronic carrier status, with an additional 10% having evidence of resolved natural infection, as demonstrated by positive tests for antiHBc. Not surprisingly, incompletely vaccinated children were more likely to be HBsAg-positive than those completing the series (12% vs 1%; relative risk 7.9 [confidence interval = 1.5–41.2]).116 These findings underscore the need for reinforcement of complete vaccination for all children enrolled in the HBV vaccine series, particularly those born to carrier or other high-risk mothers.

The beneficial impact of adequate childhood vaccination for HBV recently has been demonstrated dramatically in reports from Taiwan, where large-scale mass vaccination programs were begun in 1984. Researchers there have conclusively proven a link between HBV and hepatocellular carcinoma (HCC) by showing a significant decrease in the average annual incidence of childhood HCC since the institution of the program.117, 118 The decrease in the rate of childhood HCC was also paralleled by a decrease in the rate of HBsAg carriage among children born before the vaccination program was started, suggesting a herd immunity effect from the mass inoculation of children in the much more infectious younger birth cohorts, and resulting in a lower rate of horizontal HBV infection among the older unvaccinated children.117 These researchers had demonstrated previously that 5 years into the institution of the vaccination program in Taipei, the HBsAg carrier rate in children younger than age 5 years had decreased from 9.3% in 1984 to 2% in 1989.119 These results even further bolster the need to identify HBsAg carrier mothers and provide timely and complete HBV vaccination to their children.

 

HEPATITIS C VIRUS

Description and Diagnosis of the Virus

The term “non-A non-B hepatitis” (NANBH) traditionally was used to describe the clinical picture of posttransfusion hepatitis in the absence of positive serologic markers for either hepatitis A or hepatitis B viral infections. Molecular investigation of the serum of such affected patients led to the reporting in 1989 of the identification of a novel viral agent, named hepatitis C (hepatitis C virus [HCV] ), with a uniquely sequenced viral genome.120 That pioneering work led to the development of HCV-specific antibody assays, from the initial first-generation enzyme-linked immunosorbent assay (ELISA), through recombinant immunosorbent assays (RIBA), to the currently available third-generation ELISA and chemiluminescent assays, with increased diagnostic sensitivity as a result of their detection of several, rather than a single, nonstructural viral protein antigens.121,122,123,124,125

While antiHCV testing includes initial screening with an immunoassay, the false-positive rate of approximately 1%, especially for a low-risk patient, raises the possibility of an improper diagnosis being given without appropriate confirmatory testing. In contrast to serologic diagnosis of HBV, in which certified laboratories are required to perform supplemental confirmatory testing before issuing a positive HbsAg test result, no such automatic “reflex” testing has been mandated for HCV antibody screening. In a patient at high risk for HCV infection with a positive antiHCV test result, the chance of a false-positive ELISA is exceedingly low. However, recognizing that most laboratories report positive antiHCV results using screening assays alone126 despite previous recommendations,127 the CDC expanded its HCV testing algorithm to include an option for supplemental testing based on “signal-to-cutoff” (s/co) ratios of positive assay results.126 Because pregnant women do not constitute a high-risk group requiring HCV screening by CDC guidelines unless other risk factors exist (Table 4), both the importance of understanding the limitations of even the most currently available screening assays and the ability to interpret test results for patients are critical for clinicians who might be ordering HCV screening tests.

 

Table 4. Risk Factors Warranting Hepatitis C Screening: CDC Guidelines127


Individuals Who Should Be Screened Routinely
 Persons who ever injected illegal drugs (even once)
 Persons notified that they received blood/blood products from a donor who later tested positive for hepatitis C virus
Recipients of transfusions or organ transplants, particularly if received before July 1992
 Persons ever on long-term hemodialysis
 Persons with persistently elevated alanine aminotransferase (ALT) levels or other evidence of liver disease
Individuals for Whom Routine Testing Is of Uncertain Need
 Recipients of tissue transplants (e.g., corneal, skin, sperm, ova)
 Users of intranasal cocaine or other illegal noninjected drugs
 Persons with a history of tattooing or body piercing
 Persons with a history of sexually transmitted diseases or multiple sexual partners
 Long-term steady sex partner of an HCV-infected individual

 

HCV itself has been characterized as an enveloped single-stranded RNA virus of the family Flaviviridae, with a genomic structure that includes core (nucleocapsid), and envelope proteins at the 5' end and five nonstructural proteins extending to the 3' end of the genome. The newer antibody tests combine detection of nonstructural proteins toward the 3' end of the genome with detection of c22–3, a viral core antigen located just distal to the 5' conserved end of the genome. The improved detection rates with the use of these newer antibody tests have led one authority to say that, as useful as the first-generation assay had been, it is now virtually obsolete for diagnostic purposes.128

Diagnosis of HCV infection also has been assisted by the use of the polymerase chain reaction (PCR) to amplify and detect extremely small amounts of HCV-RNA in serum, with both qualitative and quantitative tests currently available commercially.129 PCR is still a technically demanding procedure, however, with a need to maintain stringent testing conditions to assure both accuracy and precision. Heparinized samples interfere with the polymerase in the assay, and sample storage techniques can have great impact on detectable viral particles. Prolonged sample storage at room temperature, for example, reduces PCR signal detection, as do repeated freeze-thaw cycles, even when the sample is otherwise stored appropriately at −70°C.130

At least six distinct HCV genotypes have been identified with broad geographic variation,131,132 and this mutability may limit the reproducibility of results from laboratory to laboratory, and from study to study, if primer standardization is not verified. Genotype prevalence of HCV infection varies widely by geographic location; variants of genotype 1 are the most prevalent types seen among infected individuals in the United States and Japan, for example.133,134 This genotypic variability has been found to have a significant impact on disease progression and response to therapy for infected individuals, with genotype 1 associated with poorer outcomes and responses overall.135,136,137,138 Despite this fact, HCV genotype has not been determined to be an independent risk factor for perinatal HCV transmission.139 The 5' noncoding terminal region of the HCV genome appears to be strongly conserved, although viral isolates with nucleotide sequence variability have been identified within that region as well.140,141

Epidemiology

Soon after HCV was identified, a number of studies used screening with the first-generation assays for antiHCV to describe seroprevalence rates for groups perceived to be both at high and low risks for HCV infection. Among presumably low-risk volunteer blood donors in the general population, rates of 0.5% to 1.4% for antiHCV seropositivity were described.142,143 Higher risk groups, using HBV infection patterns as a model, were shown to have higher rates of HCV antibody positivity, also. These high-risk groups have included patients in sexually transmitted disease clinics (seroprevalence 1.5%–6.2%),144,145 commercial sex workers (2%–10%),146,147 people with hemophilia (64%–86%),142,148 and patients with drug abuse histories (56%–86%)145,149,150,151

Overall, the principal risk factors for HCV transmission are blood and blood products, transfusion, and use of intravenous drugs. At least 90% of reported cases of posttransfusion hepatitis can be traced to HCV, usually within 5 to 10 weeks of the transfusion.152,153,154 Although mass screening of banked blood products for HCV antibodies has reduced the risk of transfusion-associated HCV substantially, up to 10% of donors later implicated in transfusion-related HCV may be seronegative carriers at the time of blood donation.155,156,157,158 Current estimates place the risk of transfusion-associated HCV infection at approximately 1 in 100,000 per unit transfused (range 1 in 28,000 to 1 in 288,000).156 This rate is significantly lower than was reported from the period before the use of HCV-specific assays for screening donated blood, when only surrogate markers of NANBH, such as elevated liver-function tests, were used. Still, it is higher than current estimates of transmission risks by transfusion for other viral vectors, specifically HIV (1 in 500,000 per transfused unit) and HTLV-1 (1 in 641,000 per unit).156,159,160 In contrast, the risk of HBV transmission is approximately 1 in 63,000 per unit, so that HBV and HCV together account for 88% of the aggregate risk of transfusion-related infection of 1 in 34,000.156 As the risk of HCV infection resulting from blood transfusions has diminished, a direct result of mass screening of blood products, the proportion of HCV infections attributable to drug use has markedly increased, from 20% to 60%.127

Sexual transmission of HCV has been implicated variably. A report before the availability of specific HCV tests suggested that up to 11% of NANBH cases, in the absence of other identifiable risk factors, could be related to heterosexual activity, particularly multiple sexual partners.161 Subsequently, reports using antiHCV assays have shown lower rates of HCV transmission from seropositive partners, approximately 0% to 4%.144,162 Sexual promiscuity was identified as an independent risk factor for HCV seropositivity in one recent study,163 however, and an interaction increasing the risk of concomitant transmission of HCV and HIV has been described. In these reports, men with evidence of infection with both HCV and HIV were five-times more likely to transmit both viruses to a female partner than would have been expected by chance.164,165 This potential interaction of HIV and HCV to increase transmissibility of either or both agents also has become important in describing issues surrounding maternal–fetal HCV transmission.

Pathogenesis and Clinical Issues

Acute HCV infection occurs after an incubation period of 30 to 60 days. Asymptomatic infection occurs in 75% of patients; the remaining 25% present with the typical manifestations of other viral hepatitides. Fulminant hepatitis and hepatic failure attributable to HCV, as compared with that from other viral hepatitis agents, are uncommon.

Chronic liver disease occurs frequently after acute HCV infection; at least 50% of disease progresses to chronicity, regardless of the mode of acquisition or severity of initial infection.166,167,168 Chronic hepatitis C infection has also been associated with an increased risk of developing a monoclonal gammopathy, particularly in conjunction with genotype 2a/2c infections,169 theorized to possibly be related to the impact of chronic antigenic stimulation over time by a long-standing latent viral infection such as HCV.170 Similarly, chronic HCV infection has also been associated with an increased risk of developing B-cell lymphomas and cryoglobulinemia.171,172,173 HCV antibody has been detected in serum from patients with both cryptogenic cirrhosis and HCC, although a linkage between the latter and HCV is controversial and geographically may be quite variable.174,175,176,177,178 Evidence also exists that coexisting HIV and HCV infections may accelerate progression of hepatic injury.179

Pregnancy and Effects on the Fetus and Neonate

Seroprevalence data describing HCV antibody status among pregnant women or women of reproductive age emerged quickly as HCV testing became more readily available. In Taiwan, for example, where HBV infection is endemic, the prevalence of antiHCV among a cohort of pregnant women was reported as 0.6%.162 An early general seroprevalence study in Spain used 241 “healthy” pregnant women as part of a control group and showed an antiHCV positive rate of 1.2%. However, additional information related to other risk factors among these women was not provided.142 Another group of Spanish investigators reported a 2.9% antiHCV-positive rate among pregnant women, 17% of whom had no identifiable risk factors.180

A number of studies to date have looked specifically at HCV antibody seroprevalence in prenatal populations in the United States. One, designed as a vertical transmission study, reported a 4.5% positive rate in a county hospital in New York; 74% reported a parenteral source of exposure, and 17% reported no risk factors. Of these, 17% (14 of 23) were also HIV-positive.181 Investigators in Dallas studied 1013 obstetric patients and found 2.3% to be positive for antiHCV. Risk factors for infection were specifically studied, with history of intravenous drug use, previous sexually transmitted disease, substance-abusing partner, and more than three lifetime sexual partners being significantly associated with HCV antibody positivity.182 A study from Philadelphia detected antiHCV antibodies in 4.3% of pregnant women screened, which was significantly higher than infection rates for HIV (0.5%), HTLV-1 (0.8%), and HBV (0.8% HBsAg). The relative risk of other coexisting viral infections was significantly higher among antiHCV positive women than for those who were antibody-negative. Risk factor-targeted screening would have failed to detect half the antiHCV-positive women in the study.183 A follow-up study from this group, using a larger cohort of more than 1400 women from a heterogenous socioeconomic sample, showed an HCV seropositive rate of 3.2%, with only 19% having HCV–RNA-positive test results in newborn cord blood samples. Women who were antibody-positive were also more likely to need to undergo cesarean section, suggesting an increased risk of other coexisting obstetric complications in that subpopulation.184

Information regarding the maternal–fetal transmission of HCV has continued to steadily accumulate. Although reported rates of transmission have been variable, overall it is encouraging that most series show the risk to be generally less than 5%. However, the definition of which mothers are most infectious dramatically alters the relative risks of vertical transmission. Before the identification of HCV, newborns of women with NANBH were followed-up serially with surveillance of transaminase levels. A study from Sweden showed no increased risk to the women followed-up during their pregnancies, although 16% (2 of 12) of their children had persistent unexplained transaminase elevations through infancy.185 This report was consistent with an earlier study demonstrating alanine aminotransferase (ALT) elevations in 6 of 12 infants born to women with NANBH, followed-up to 8 weeks after delivery.186

Surveillance of mothers and their newborns using HCV-specific antibodies in published reports has, on the whole, demonstrated low rates of transmission from antiHCV-positive mothers to their offspring.162 The designs of these earlier studies, however, were mostly retrospective, with limited neonatal follow-up. Subsequent work has used HCV–RNA as a marker of neonatal infection rather than antibody seropositivity only, with rates of newborn RNA retrieval averaging 5% to 10% when the mother is also HCV–RNA-positive.181,187,188

More recent studies from Asia and Europe have established what appears to be a correlation between maternal viral titer of HCV near delivery and the risk of neonatal infection. These studies have used newer technologies to determine quantitative, rather than qualitative, PCR results. One team in Japan showed significantly higher (2 logs) HCV–RNA titers in transmitting mothers than in those whose infants remained uninfected (106 vs 104 HCV-RNA copies/mL).189 Using similar techniques, another group in China drew similar conclusions, also demonstrating that perinatal transmission occurred only in those women whose serum was HCV–RNA positive.190 A group from the United States, however, failed to establish a similar viral burden correlation in their series, suggesting a possible role for geographic variability in genotype and virulence in explaining the variance in results.188 More recent reports have continued to confirm clearly that maternal viremia (usually defined as HCV–RNA detected in maternal blood) is a key determinant for vertical HCV transmission, regardless of maternal HIV status. Still, the independent impact of quantitative maternal viremia (“viral load”) on vertical transmission remains less uniformly established across the studies than the presence of viremia at all,191,192,193,194,195,196,197,198,199 in direct contrast to previous experience with vertical HIV transmission.

Recent investigators also have confirmed earlier reports that women coinfected with HCV and HIV had significantly higher rates of perinatal infection than women infected with HCV alone. Earlier, smaller series suggested rates ranging from 15% to 87% in the face of maternal coinfection.200,201,202 The more recent series have narrowed but have not lowered the risk range of 23% to 44%.188,191,202,203,204,205,206,207

The interaction between maternal and fetal humoral and immunologic is thought to be a critical contributor to both the occurrence and persistence of perinatally acquired neonatal HCV infection. The fact that maternal and/or neonatal coinfection with HIV increases the risk of vertical HCV infection suggests that HIV-infected infants, who are known to have early deficits in cell-mediated and humoral immunity, may be less able to clear small amounts of perinatally presented HCV than HIV-uninfected infants.206,207 Although no large-scale longitudinal follow-up studies exist into the natural history of perinatal HCV infection through childhood, at least one published case report has documented clearance of neonatally documented HCV–RNA by age 24 months in a child born to an HIV-negative, HCV–RNA-positive mother.208 Therefore, an intact neonatal immune system may allow for HCV clearance in early infancy as can occur in HIV-uninfected adults. More recently, Italian investigators have presented provocative data demonstrating that HCV infection of maternal peripheral blood mononuclear cells (PBMNC) was a stronger independent predictor of vertical HCV transmission than either quantitative HCV–RNA titer or viral genotype in a cohort of HIV-uninfected women.209 These researchers had previously shown the presence of an HCV–RNA strand in infected PBMNC to be a marker of active viral replication rather than one of uptake of cellular debris, as had been alternatively proposed,210 and its association with perinatal infection further emphasizes the complex interplay between maternal and fetal factors in determining the risk of neonatal HCV infection.

Although the impact of maternal HCV infection on perinatal HCV transmission has been extensively studied, the potential impact of pregnancy on maternal infection and HCV-related illness is less well-documented. One large study of more than 15,000 HCV-infected pregnant women in northern Italy, however, demonstrated a downward trend (almost 50% lower) in transaminase levels as pregnancy progressed, with no concomitant change in the proportion of women with documented viremia. The authors hypothesized that a favorable immuno-mediated positive effect of pregnancy on liver cell necrosis might be one explanation for these findings, although liver biopsy samples were not a routine prospective component of their study.199 A group in China similarly reported that HCV levels did not change significantly as pregnancy progressed but did show a significant decrease in those levels at 1 and 3 months postpartum.211

Optimal route of delivery, if one exists, remains an area of controversy in the context of maternal HCV infection. This debate, to some degree, parallels the one that evolved regarding maternal HIV infection. However, unlike with HCV infection, maternal HIV viral load was a clearly established independent predictor of vertical transmission212,213 and had a direct bearing on the current guidelines regarding route of delivery and maternal HIV infection, specifically when maternal HIV viral load is durably suppressed to less than 1000 RNA copies/mL.214,215 Route of delivery appears to be much less clearly associated with risk of HCV transmission, however.191,193,195,196,199,206 While the rate of cesarean section in HCV-infected mothers is higher than that for uninfected women, this is thought to be more related to the higher rates of obstetric complications and comorbidities in a subgroup of women whose primary risk factor for HCV infection is illicit drug use.173,193,199 Current consensus opinions, therefore, recommend cesarean delivery in HCV-infected women only for usual obstetric indications.216,217

The experience with antiretroviral treatment in decreasing both maternal viral load and the risk of neonatal HIV infections218,219,220,221 raises the question of potential comparable treatment options in the context of maternal HCV infection. Recent advances in combination therapy of HCV infection in nonpregnant adults have made sustained normalization of transaminase levels and clearance of HCV–RNA a reality, even in individuals with the less favorable HCV genotype 1.136,137,138,222 More recently, the modification of interferon alfa-2a via a branched-chain polyethylene glycol moiety has produced a compound, peginterferon alfa-2a, with prolonged absorption, slower clearance, and a longer half-life than standard interferon, with once-weekly dosing possible.223,224 Randomized trials have shown peginterferon to be superior to standard interferon, either alone or combined with ribavirin, for the treatment of chronic hepatitis C infection in adults.225,226,227 While the use of ribavirin is contraindicated during pregnancy,228 interferon has been used safely for the treatment of T-cell leukemias during pregnancy,229,230,231 and its potential role as an antiHCV therapy for both maternal and fetal/neonatal benefits warrants further exploration.

Finally, questions surrounding the safety of breastfeeding frequently arise from HCV-infected women. Many of these women have other risk factors, such as ongoing substance addiction or coexisting HIV infection, which preclude breastfeeding in general and override concerns about transmission of HCV through breast milk. For those women who have no other obstetric or medical issues that prevent nursing, limited data have failed to demonstrate breast milk as an effective route for HCV transmission. Although most of these studies were not designed to specifically address this topic, the authors' evaluation of mother–infant pairs enrolled in some of the published vertical HCV transmission studies failed to document any neonatal HCV infection in breast-fed infants, even when the mother was HCV–RNA-positive.203,204,232 One study from China that did look at breast milk specifically found a correlation between maternal HCV serum titer and detection of HCV by means of PCR in breast milk; however, no infants in this small series (n = 15) became infected with HCV.232 More recent studies from Australia,233 United Arab Emirates,234 and Switzerland235 have studied an additional 100 pregnancies in HCV-infected women who breast-fed (up to two-thirds of whom were HCV–RNA-positive in sera), with no detectable impact of breastfeeding on the risk of neonatal infection. As a result of the currently available supporting data, consensus opinions do not view maternal HCV infection as a contraindication to breastfeeding except, perhaps, in cases in which a mother experiences cracked or bleeding nipples.216,217

REFERENCES

1

Robinson WS, Clayton DA, Greenman RL: DNA of a human hepatitis B virus candidate. J Virol 14:384, 1975

 

2

Blumberg BS, Alter HJ, Visnich S: A “new” antigen in leukemia sera. JAMA 191:541, 1965

 

3

Alter HJ, Blumberg BS: Further studies on a new human isoprecipitin system (Australia antigen). Blood 27:297, 1966

 

4

Blumberg BS, Gerstley JS, Hungerford DA et al: A serum antigen (Australia antigen) in Down's syndrome, leukemia, and hepatitis. Ann Intern Med 66:924, 1967

 

5

Bayer ME, Blumberg BS, Werner B: Particles associated with Australia antigen in the sera of patients with leukemia, Down's syndrome, and hepatitis. Nature (Lond) 218:1057, 1968

 

6

Dane DS, Cameron CH, Briggs M: Virus-like particles in serum of patients with Australia antigen-associated hepatitis. Lancet 2:695, 1970

 

7

Magnius LO: Characterization of a new antigen-antibody system associated with hepatitis B. Clin Exp Immunol 20:209, 1975

 

8

Alter HJ, Seeff LB, Kaplan PM et al: Type B hepatitis: The infectivity of blood positive for e antigen and DNA polymerase after accidental needlestick exposure. N Engl J Med 296:909, 1976

 

9

Ohori H, Onodera S, Ishida N: Demonstration of hepatitis B e antigen (HBeAg) with intact Dane particles. J Genet Virol 43:423, 1979

 

10

Magnius LO, Lindholm A, Lundin P et al: A new antigen-antibody system. Clinical significance in long-term carriers of hepatitis B surface antigen JAMA 231:356, 1975

 

11

Trepo C, Mangius L, Schaefer RA et al: Detection and clinical significance of e antigen and anti-e antibody in hepatitis B surface antigen carriers. Gastroenterology 69:872, 1975

 

12

Hoofnagle JH, Seeff LB, Bales ZB et al: Serologic responses in hepatitis B. In Vyas GN, Cohen SN, Schmid T (eds): Viral Hepatitis: A Contemporary Assessment of Etiology, Epidemiology, Pathogenesis, and Prevention. pp 219–242. Philadelphia, Franklin Institute Press, 1978

 

13

Tabor E, Gerety RJ: Possible role of immune response to hepatitis B core antigen in protection against hepatitis B infection. Lancet 1:172, 1984

 

14

Murray K, Bruce SA, Hinnen A et al: Hepatitis B virus antigens made in microbial cells immunise against viral infection. EMBO J 3:645, 1984

 

15

Prince AM: Mechanism of protection against hepatitis B infection by immunization with hepatitis B virus cores. Lancet 1:512, 1984

 

16

Purcell RH, Gerin JL: Hepatitis B subunit vaccine: A preliminary report of safety and efficacy tests in chimpanzees. Am J Med Sci 270:395, 1975

 

17

Hoofnagle JH: Toward universal vaccination against hepatitis B virus. N Engl J Med 321:1333, 1989

 

18

Beasley RP, Hwang LY: Epidemiology of hepatocellular carcinoma. In: Vyas GN, Dienstag JL, Hoofnagle JH (eds): Viral Hepatitis and Liver Disease, pp 209–224. Proceedings of the 1984 International Symposium on Viral Hepatitis. Orlando, Grune & Stratton, 1984

 

19

Beasley RP, Hwang LY, Lin CC et al: Hepatocellular carcinoma and hepatitis B virus. Lancet 2:1129, 1981

 

20

World Health Organization: Prevention of liver cancer: Report of a WHO meeting. WHO Tech Rep Ser 691:8, 1988

 

21

Stevens CE, Beasley RP, Tsui J et al: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 292:771, 1975

 

22

Stevens CE, Toy PT, Tong MJ et al: Perinatal hepatitis B virus transmission in the United States: Prevention by passive-active immunization. JAMA 253:1740, 1985

 

23

Szmuness W, Stevens CE, Harley EJ et al: Hepatitis B vaccine: Demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med 303:833, 1980

 

24

Scolnick EM, McLean AA, West DJ et al: Clinical evaluation in healthy adults of a hepatitis B vaccine made by recombinant DNA. JAMA 251:2812, 1984

 

25

Gerety RJ, Tabor E: Newly licensed hepatitis B vaccine: Known safety and unknown risks. JAMA 249:745, 1983

 

26

Stevens CE: No increased incidence of AIDS in recipients of hepatitis B vaccine. N Engl J Med 308:1163, 1983

 

27

Centers for Disease Control: Inactivated hepatitis B virus vaccine. MMWR Morb Mortal Wkly Rep 31:318, 1982

 

28

Barker LF, Murray R: Relationship of virus dose to incubation time of clinical hepatitis and time of appearance of hepatitis-associated antigen. Am J Med Sci 263:27, 1972

 

29

Bancroft WH, Snitbhan R, Scott RM et al: Transmission of hepatitis B virus to gibbons by exposure to human saliva containing hepatitis B surface antigen. J Infect Dis 135:79, 1977

 

30

Alter JH, Purcell RH, Gerin JL et al: Transmission of hepatitis B to chimpanzees by hepatitis B surface antigen-positive saliva and semen. Infect Immun 16:928, 1977

 

31

Centers of Disease Control: Hepatitis transmitted by a human bite. MMWR Morb Mortal Wkly Rep 23:24, 1974

 

32

Neefe JR, Gellis SS, Stokes J: Homologous serum hepatitis and infectious (epidemic) hepatitis: Studies in volunteers bearing on immunological and other characteristics of the etiological agents. Am J Med 1:3, 1946

 

33

Centers for Disease Control: Update on hepatitis B prevention. MMWR Morb Mortal Wkly Rep 36:353, 1989

 

34

Gocke DJ: Type B hepatitis: Good news and bad news. N Engl J Med 291:1409, 1974

 

35

Pattison CP, Boyer KM, Maynard JE et al: Epidemic hepatitis in a clinical laboratory: Possible association with computer card handling. JAMA 230:854, 1974

 

36

Mirick GS, Shank RE: An epidemic of serum hepatitis studied under controlled conditions. Trans Am Climatol Assoc 71:176, 1959

 

37

Hersh T, Melnick JL, Goyal RK et al: Nonparenteral transmission of viral hepatitis type B (Australia antigen-associated serum hepatitis). N Engl J Med 285:1363, 1971

 

38

Szmuness W, Harley EJ, Prince AM: Intrafamilial spread of asymptomatic hepatitis B. Am J Med Sci 270:293, 1975

 

39

Vechon TM, Wright RA, Kohler PF et al: Hepatitis A and B in the family unit: Nonparenteral transmission by asymptomatic children. JAMA 235:2829, 1976

 

40

Bernier RH, Sampliner R, Gerety R et al: Hepatitis B infection in households of chronic carriers of hepatitis B surface antigen: Factors associated with prevalence of infection. Am J Epidemiol 116:199, 1982

 

41

Beasley RP, Hwang LY, Lin CC et al: Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis 146:198, 1982

 

42

Maupas P, Chiron JP, Barin F et al: Efficacy of hepatitis B vaccine in prevention of early HBsAg carrier state in children: Controlled trial in an endemic area (Senegal). Lancet 1:289, 1981

 

43

Krugman S, Giles JP: Viral hepatitis, type B (MS-2 strain): Further observations on natural history and prevention. N Engl J Med 288:755, 1973

 

44

Desmyter J, Bradbourne AF, Vermylen C et al: Hepatitis B immunoglobulin in prevention of HBsAg antigenaemia in haemodialysis patients. Lancet 2:377, 1975

 

45

Iwarson S, Ahlmen J, Erickson E et al: Hepatitis B immune serum globulin and standard gamma globulin in prevention of hepatitis B infection among hospital staff: A preliminary report. Am J Med Sci 270:385, 1975

 

46

Grady GF: Viral hepatitis passive prophylaxis with globulins: State of the art in 1978. In Vyas GN, Cohen SN, Schmidt R (eds): Viral Hepatitis: A Contemporary Assessment of Etiology, Epidemiology, Pathogenesis, and Prevention, pp 467–476. Philadelphia, Franklin Institute Press, 1978

 

47

Szmuness W, Stevens CE, Zange A et al: A controlled clinical trial on the efficacy of the hepatitis B vaccine (Heptavax B): A final report. Hepatology 1:377, 1981

 

48

Dienstag JL, Werner BG, Polk BF et al: Hepatitis B vaccine in health-care personnel: A randomized, double-blind, placebo-controlled trial. Hepatology 2:696, 1982

 

49

Francis DP, Hadler SC, Thompson SE et al: The prevention of hepatitis B with vaccine: Report of the Centers for Disease Control multi-center trial among homosexual men. Ann Intern Med 97:362, 1982

 

50

Deinhardt F: Aspects of vaccination against hepatitis B: Passive-active immunization schedules and immune responses in different age groups. Scand J Infect Dis 38:(suppl) 17, 1983

 

51

Szmuness W, Stevens CE, Oleszko WR et al: Passive-active immunization against hepatitis B: Immunogenicity studies in adult Americans. Lancet 1:575, 1981

 

52

Gocke JD: Immune complex phenomena associated with hepatitis. In: Vyas GN, Cohen SN, Schmidt R (eds): Viral Hepatitis: A Contemporary Assessment of Etiology, Epidemiology, Pathogenesis, and Prevention, p 277. Philadelphia, Franklin Institue Press, 1978

 

53

Wands JR, Mann EA, Alpert E et al: The pathogenesis of arthritis associated with acute hepatitis B surface antigen positive hepatitis: Complement activation and characterization of circulating immune complexes. J Clin Invest 55:930, 1975

 

54

Shulman RN: Hepatitis-associated antigen. Am J Med 49:669, 1971

 

55

Krugman S, Overby LR, Mushahwar IK et al: Viral hepatitis, type B: Studies on natural history and prevention reexamined. N Engl J Med 300:101, 1979

 

56

Lander JJ, Giles JP, Purcell RH: Frequency of antibody to hepatitis-associated antigen as measured by a new radioimmunoassay technique. J Immunol 106:1166, 1971

 

57

Robinson WS: DNA and DNA polymerase in the core of Dane particles. Am J Med Sci 270:151, 1975

 

58

Nielsen JO, Nielsen MH, Elling P: Differential distribution of Australia-antigen-associated particles in patients with liver disease and normal carriers. N Engl J Med 288:484, 1973

 

59

Takahashi K, Fukuda M, Baba K et al: Determination of e antigen and antibody to e by means of passive hemagglutination method. J Immunol 119:1556, 1977

 

60

Aldershvile J, Skinhoj P, Frosner GG et al: The expression pattern of hepatitis B e antigen and antibody in different ethnic and clinical groups of hepatitis B surface antigen carriers. J Infect Dis 142:18, 1980

 

61

Scullard G, Greenberg HB, Smith JL et al: Antiviral treatment of chronic hepatitis B virus infection: Infectious virus cannot be detected in patient serum after permanent responses to treatment. Hepatology 2:39, 1982

 

62

Christie AB, Allam AA, Aref MK et al: Pregnancy hepatitis in Libya. Lancet 2:827, 1976

 

63

Borhanmanesh F, Haghighi P, Hekmat K et al: Viral hepatitis during pregnancy: Severity and effect on gestation. Gastroenterology 64:304, 1973

 

64

Hieber JP, Dalton D, Shorey J et al: Hepatitis and pregnancy. J Pediatr 91:545, 1977

 

65

Shalev E, Bassan HM: Viral hepatitis during pregnancy in Israel. Int J Gynaecol Obstet 20:73, 1982

 

66

Towers CV, Keegan KA: The many forms of viral hepatitis. Contemp Obstet Gynecol 8:39, 1987

 

67

Arakawa K, Tsuda F, Takahashi K et al: Maternofetal transmission of IgG-bound hepatitis e antigen. Pediatr Res 16:247, 1982

 

68

Lin HH, Lee TY, Chen DS et al: Transplacental leakage of HBeAg-positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus. J Pediatr 111:877, 1987

 

69

Ohto H, Lin HH, Kawana T et al: Intrauterine transmission of hepatitis B virus is closely related to placental leakage. J Med Virol 21:1, 1987

 

70

Perrillo RP, Schiff ER, Davis GL et al: A randomized controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med 323:295, 1990

 

71

Schweitzer IL, Wing A, McPeak C et al: Hepatitis and hepatitis-associated antigen in 56 mother-infant pairs. JAMA 220:1092, 1972

 

72

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 87:360, 1975

 

73

Gerety RJ, Schweitzer IL: Viral hepatitis type B during pregnancy, the neonatal period, and infancy. J Pediatr 90:368, 1977

 

74

Lee AKY, Ip HMH, Wong VCW: Mechanisms of maternal-fetal transmission of hepatitis B virus. J Infect Dis 138:668, 1978

 

75

Okada K, Kamiyama I, Inomata M et al: The e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 294:746, 1976

 

76

Beasley RP, Trepo C, Stevens CE et al: The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 105:94, 1977

 

77

Stevens CE, Toy PT, Tong MJ et al: Perinatal hepatitis B virus transmission in the United States: Prevention by passive-active immunization. JAMA 253:1740, 1985

 

78

Biswas SC, Gupta I, Ganguly NK et al: Prevalence of hepatitis B surface antigen in pregnant mothers and its perinatal transmission. Trans R Soc Trop Med Hyg 83:698, 1989

 

79

Dupuy JM, Frommel D, Alagille D: Severe viral hepatitis B in infancy. Lancet 1:191, 1975

 

80

Fawaz KA, Grady GF, Kaplan MM et al: Repetitive maternal-fetal transmission of fetal hepatitis B. N Engl J Med 293:1357, 1975

 

81

Delaplane D, Yogev R, Crussi F et al: Fatal hepatitis B in early infancy: The importance of identifying HBsAg-positive pregnant women and providing immunoprophylaxis to their newborns. Pediatrics 72:176, 1983

 

82

Chang MH, Chen DS, Hsu HC et al: Maternal transmission of hepatitis B virus in childhood hepatocellular carcinoma. Cancer 64:2377, 1989

 

83

Reesink HW, Reesink-Brongers EE, Lafeber-Schut BJT et al: Prevention of chronic HBsAg carrier state in infants of HBsAg-positive mothers by hepatitis B immunoglobulin. Lancet 1:436, 1979

 

84

Beasley RP, Hwang LY, Lin CC et al: Hepatitis B immune globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state: Initial report of a randomized double-blind placebo-controlled trial. Lancet 2:388, 1981

 

85

Beasley RP, Hwang LY, Lee GC et al: Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2:1099, 1983

 

86

Tada H, Yanagida M, Mishina J et al: Combined passive and active immunization for preventing perinatal transmission of hepatitis B virus carrier state. Pediatrics 70:613, 1982

 

87

Wong VCW, Ip HMH, Reesink HW et al: Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitis-B immunoglobulin: Double-blind randomized placebo-controlled study. Lancet 2:921, 1984

 

88

Pongpipat D, Suvatte V, Assateerawatts A: Efficacy of hepatitis-B immunoglobulin and hepatitis-B vaccine in prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg. Asian Pac J Allergy Immunol 4:33, 1986

 

89

Xu ZY, Liu CB, Francis DP et al: Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: Preliminary report of a randomized, double-blind placebo-controlled and comparative trial. Pediatrics 76:713, 1985

 

90

Schaln SW, Mazel JA, deGast GC et al: Prevention of hepatitis B infection in newborns through mass screening and delayed vaccination of all infants of mothers with hepatitis B surface antigen. Pediatrics 83:1041, 1989

 

91

Poovorawan Y, Sanpavat S, Pongpunlert W et al: Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBe antigen-positive mothers. JAMA 269:3278, 1989

 

92

Chen DS, Hsu HM, Sung JL et al: Immunization of newborns of HBsAg-positive mothers: Ag-positive mothers: A successful first step in control of hepatitis B virus in Taiwan. Hepatology 9:900, 1989

 

93

London WT, O'Connell AP: Transplacental transmission of hepatitis B virus. Lancet 1:1037, 1986

 

94

Tang SX, Yu GL: Intrauterine infection with hepatitis B virus. Lancet 335:302, 1990

 

95

Li L, Shen MH, Li YQ et al: A study of mother-infant transmission of hepatitis B virus. Shanghai, International Symposium on Liver Cancer and Hepatitis, 1986

 

96

Centers for Disease Control: Recommendations of the Immunization Practices Advisory Committee. Prevention of perinatal transmission of hepatitis B virus: Prenatal screening of all pregnant women for hepatitis B surface antigen MMWR Morb Mortal Wkly Rep 37:341, 1988

 

97

Jonas MM, Reddy RK, DeMedina M et al: Hepatitis B infection in a large municipal obstetrical population: Characterization and prevention of perinatal transmission. Am J Gastroenterol 85:277, 1990

 

98

Immunization Practices Advisory Committee: Post-exposure prophylaxis of hepatitis B. MMWR Morb Mortal Wkly Rep 33:285, 1984

 

99

Malecki JM, Guarin O, Hulbert A et al: Prevalence of hepatitis B surface antigen among women receiving prenatal care at the Palm Beach County Health Department. Am J Obstet Gynecol 154:625, 1986

 

100

Kumar ML, Dawson NV, McCullough AJ et al: Should all pregnant women be screened for hepatitis B? Ann Intern Med 107:273, 1987

 

101

Jonas MM, Schiff ER, O'Sullivan MJ et al: Failure of Centers for Disease Control criteria to identify hepatitis B infection in a large municipal obstetrical population. Ann Intern Med 107:335, 1987

 

102

Summers PR, Biswas MK, Pastorek JG II et al: The pregnant hepatitis B carrier: Evidence favoring comprehensive antepartum screening. Obstet Gynecol 156:166, 1987

 

103

Wetzel AM, Kirz DS: Routine hepatitis screening in adolescent pregnancies: Is it cost effective. ? Ann J Obstet Gynecol 156:166, 1987

 

104

Butterfield CR, Shockley M, SanMiguel G et al: Routine screening for hepatitis B in an obstetric population. Obstet Gynecol 76:25, 1990

 

105

Dinsmoor MJ, Gibbs RS: Prevalence of asymptomatic hepatitis B infection in pregnant Mexican-American women. Obstet Gynecol 76:239, 1990

 

106

Kane MA, Hadler SC, Margolis HS et al: Routine prenatal screening for hepatitis B surface antigen. JAMA 259:408, 1988

 

107

ACOG Committee Opinion: Guidelines for hepatitis B virus screening and vaccination during pregnancy. Washington DC, American College of Obstetricians and Gynecologists, January 1990

 

108

Arevalo JA, Washington AE: Cost-effectiveness of prenatal screening and immunization for hepatitis B virus. JAMA 259:365, 1988

 

109

Maynard JE, Kane MA, Hadler SC: Global control of hepatitis B through vaccination: Role of hepatitis B vaccine in the expanded programme on immunization. Rev Infect Dis 11:(S3):S574, 1989

 

110

Toukan A: Strategy for the control of hepatitis B virus infection in the Middle East and North Africa: The Middle East Regional Study Group. Vaccine 8:S117, 1990

 

111

Franks AL, Berg CJ, Kane MA et al: Hepatitis B virus infection among children born in the United States to Southeast Asian refugees. N Engl J Med 321:1301, 1989

 

112

Kane MA, Hadler SC, Margolis HS: Prenatal screening for hepatitis B antigen: Reply. JAMA 261:1727, 1989

 

113

Beasley RP, Stevens CE: Vertical transmission of HBV and interruption with globulin. In: Vyas GM, Cohen SN, Schmid T (eds): Viral Hepatitis: A Contemporary Assessment of Etiology, Epidemiology, Pathogenesis and Prevention, pp 333–345. Philadelphia, Franklin Institute Press, 1978

 

114

Silverman NS, Darby MJ, Ronkin SL et al: Hepatitis B prevalence in an unregistered prenatal population–Implications for neonatal therapy. JAMA 266:2852, 1991

 

115

Advisory Committee on Immunization Practices, American Academy of Pediatrics, American Academy of Family Physicians. Recommended childhood vaccination schedule: United States, January–June 1996 Pediatrics 97:145, 1996

 

116

Kohn MA, Farley TA, Scott C: The need for more aggressive follow-up of children born to hepatitis B surface antigen-positive mothers: Lessons from the Louisiana Perinatal Hepatitis B Immunization Program. Pediatr Infect Dis J 15:535, 1996

 

117

Chang MH, Chen CJ, Lai MS et al: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 336:1855, 1997

 

118

Lee CL, Ko YC: Hepatitis B vaccination and hepatocellular carcinoma in Taiwan. Pediarics 99:351, 1997

 

119

Tsen YJ, Chang MH, Hsu HY et al: Seroprevalence of hepatitis B virus infection in children in Taipei, 1989: Five years after a mass hepatitis B vaccination program. J Med Virol 34:96, 1991

 

120

Choo QL, Kuo G, Weiner AJ et al: Isolation of a cDNA clone derived from a blood-born non-A, non-B hepatitis genome. Science 244:359, 1989

 

121

Kuo G, Choo QL, Alter HJ et al: An assay for circulating antibodies to a major etiologic virus of human non-A, non B hepatitis. Science 244:362, 1989

 

122

Chaudhary RK, MacLean C: Evaluation of first and second-generation RIBA kits for detection of antibody to hepatitis C virus. J Clin Microbiol 29:2329, 1991

 

123

McHutchinson JG, Person JL, Govindarajan S et al: Improved detection of hepatitis C virus antibodies in high-risk populations. Hepatology 5:19, 1992

 

124

Vallari DS, Jett BW, Alter HJ et al: Serological markers of posttransfusion hepatitis C viral infection. J Clin Microbiol 30:552, 1882

 

125

Wang JT, Wang TH, Lin JT et al: Improved serodiagnopsis of postransfusion hepatitis C virus infection by a second-generation immunoassay based on multiple recombinant antigens. Vox Sang 62:21, 1992

 

126

CDC. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus MMWR Morb Mortal Wkly Rep 52:(RR-3):1-13, 2003

 

127

CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease MMWR Morb Mortal Wkly Rep 47:(RR-19):1-33, 1998

 

128

Alter HJ: New kit on the block: Evaluation of second-generation assays for detection of antibody to the hepatitis C virus. Hepatology 15:350, 1992

 

129

Inchauspe G, Abe K, Zebedee S et al: Use of conserved sequences from hepatitis C virus for the detection of viral RNA in infected sera by polymerase chain reaction. Hepatology 14:595, 1991

 

130

Wang JT, Wang TH, Sheu JC et al: Effects of anticoagulants and storage of blood samples on efficacy of the polymerase chain reaction assay for hepatitis C virus. J Clin Microbiol 30:750, 1992

 

131

Cha TA, Beall E, Irvine B et al: At least five related but distinct, hepatitis C viral genotypes exist. Proc Natl Acad Sci USA 89:7144, 1992

 

132

vanderPoel CL, Cuypers HT, Reesink HW: Hepatitis C virus six years on. Lancet 344:1475-1479, 1994

 

133

McOmish F, Yap PL, Dow BC et al: Geographical distribution of hepatitis C virus genotypes in blood donors: An international collaborative survey. J Clin Microbiol 32:884-892, 1994

 

134

Gretch D: Mechanism of interferon resistance in hepatitis C. Lancet 358:1662-1663, 2001

 

135

Jessner W, Gschwantler M, Steindl-Munda P et al: Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study. Lancet 358:1241-1242, 2001

 

136

Booth JC, O'Grady J, Neuberger J: Clinical guidelines on the management of hepatitis C. Gut 49:(Suppl 1):I1-I21, 2001

 

137

Lai MY, Kao JH, Yang PM et al: Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenetrology 111:1307-1312, 1996

 

138

Poynard T, Marcellin P, Lee SS et al: Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 352:1426-1432, 1998

 

139

Resti M, Azzari C, Mannelli F et al: Mother to child transmission of hepatitis C virus: prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. Br Med J 317:437-441, 1998

 

140

Bukh J, Purcell RH, Miller RH: Sequence analysis of the 5' noncoding region of hepatitis C virus. Proc Natl Acad Sci USA 89:4942, 1992

 

141

Lee CH, Cheng C, Wang J et al: Identification of hepatitis C viruses with a nonconserved sequence of the 5' untranslated region. J Clin Microbiol 30:1602, 1992

 

142

Esteban JI, Esteban R, Viladomiu L et al: Hepatitis C virus antibodies among high risk groups in Spain. Lancet 2:294, 1989

 

143

Stevens CE, Taylor PE, Pindyck J et al: Epidemiology of hepatitis C virus; A preliminary study in volunteer blood donors. JAMA 263:49, 1990

 

144

Van Doornum GJJ, Hookas C, Cuypers MT et al: Prevalence of hepatitis C virus infections among heterosexuals with multiple partners. J Med Virol 35:22, 1991

 

145

Fairley CK, Leslie DE, Nicholson S et al: Epidemiology of hepatitis C virus in Victoria. Med J Aust 153:274, 1990

 

146

Sanchez-Quijano A, Rey C, Aguado I et al: Hepatitis C virus infection in sexually promiscuous groups. Eur J Clin Microbiol Infec Dis 9:610, 1990

 

147

Widell A, Hanson BG, Berntop E et al: Antibody to a hepatitis C virus related protein among patients at high risk for hepatitis. B Scand J Infect Dis 10:19, 1991

 

148

Brettler DB, Alter HJ, Dienstag JL et al: Prevalence of hepatitis C virus antibody in a cohort of hemophilia patients. Blood 76:254, 1990

 

149

Yenen OS, Badur S: Prevalence of antibodies to hepatitis C virus in blood donors and risk groups in Istanbul, Turkey. Eur J Clin Microbiol Infect Dis 23:19, 1991

 

150

Bell J, Batey RG, Farrell AC et al: Hepatitis C virus in intravenous drug users. Med J Aust 153:274, 1990

 

151

Van den Hoek JAR, van Haastrecht HJA, Goudsmit J et al: Prevalence, incidence, and risk factors of hepatitis C virus infection among drug users in Amsterdam. J Infect Dis 162:823, 1990

 

152

Alter MJ, Sampliner RE: Hepatitis C: And miles to go before we sleep. N Engl J Med 321:1538, 1989

 

153

Esteban JI, Gonzalez A, Hernandez JM et al: Evaluation of antibodies to hepatitis. N Engl J Med 323:1107, 1990

 

154

Japanese Red Cross Non-A, Non-B H hepatitis Research Group: Effect of screening for hepatitis C virus antibody and hepatitis B virus core antibody on incidence of post-transfusion hepatitis. Lancet 338:1040, 1991

 

155

Donahue JG, Munoz A, Ness PM et al: The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 327:369, 1992

 

156

Schreiber GB, Busch MP, Kleinman SH et al: The risk of transfusion transmitted viral infections. N Engl J Med 334:1685, 1996

 

157

Sugitani M, Inchauspe H, Shindo M et al: Sensitivity of serologic assays to identify blood donors with hepatitis C viremia. Lancet 339:1018, 1992

 

158

Alter MJ, Margolis HS, Krawcynski K et al: The natural history of community acquired hepatitis C in the United States. N Engl J Med 327:1899, 1992

 

159

Lackritz EM, Satten GA, Aberle-Grasse J et al: Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med 333:1721, 1995

 

160

Vyas GN, Rawal BD, Busch MP: The risk of HIV transmission by screened blood. N Engl J Med 334:992, 1996

 

161

Alter MJ, Coleman PJ, Alexander WJ et al: Importance of heterosexual activity in the transmission of hepatitis B and non-A, non-B hepatitis. JAMA 262:1201, 1989

 

162

Lin HH, Hsu HY, Chang MH et al: Low prevalence of hepatitis C virus and infrequent perinatal or spouse infections in pregnant women in Taiwan. J Med Virol 35:237, 1991

 

163

Cony-Cantilena C, Van Raden 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

 

164

Tor J, Libre JM, Carbonell M et al: Sexual transmission of hepatitis C virus and its relation with hepatitis B virus and HIV. BMJ 301:1130, 1990

 

165

Eyster ME, Alter HJ, Aledort LM et al: Heterosexual co-transmission of hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Ann Intern Med 115:764, 1991

 

166

Brown J, Dourakis S, Karayyiannis P et al: Seroprevalence of hepatitis C virus nucleocapsid antibodies in patients with cryptogenic chronic liver disease. Hepatology 15:175, 1992

 

167

Okamoto H, Tsuda F, Machida A et al: Antibodies against synthetic oligopeptided deduced from the putative core gene for the diagnosis of hepatitis C virus infection. Hepatology 15:180, 1992

 

168

Liddle C, Crew EB, Swanson NR et al: Does hepatitis C virus play a role in “nonviral” chronic liver disease. ? Med J Aust 153:265, 1990

 

169

Andreone P, Zigneno AL, Cursaro C et al: Prevalence of monoclonal gammopathies in patients with hepatitis C virus infection. Ann Intern Med 129:294-298, 1998

 

170

Gramenzi A, Buttino I, D'Avanzo B et al: Medical history and the risk of multiple myeloma. Br J Cancer 63:769-772, 1991

 

171

Zignego AL, Ferri C, Giannini C et al: Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia. Ann Intern Med 124:31-34, 1996

 

172

Pawlotsky JM, Roudot-Thoraval F, Simmonds P et al: Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes. Ann Intern Med 122:169-173, 1995

 

173

Ferri C, La Civita L, Monti M et al: Can type C hepatitis infection be complicated by malignant lymphoma. ? Lancet 346:1426-1427, 1995

 

174

Jeffers LJ, Hasan F, deMedina M et al: Prevalence of antibodies to hepatitis C virus among patients with cryptogenic chronic hepatitis and cirrhosis. Hepatology 15:187, 1992

 

175

Kiyosawa K, Sodeyama T, Tanaka et al Inter-relationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: Analysis by detection of antibody to hepatitis C virus. Hepatology 12:671, 1990

 

176

Sbolli G, Zanetti AR, Tanzi E et al: Serum antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma. J Med Virol 30:230, 1990

 

177

Kew MC, Houghton M, Choo QL et al: Hepatitis C virus in southern African blacks with hepatocellular carcinoma. Lancet 335:873, 1990

 

178

Bruix J, Barrera JM, Calvet X et al: Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 2:1004, 1989

 

179

Martin P: Hepatitis C: More than just a liver disease. Gastroenterology 104:320, 1993

 

180

Coll O, Torne A, Martinez JM et al: HCV vertical transmission: Preliminary data of a prospective study. Abstract No. 32, Infectious Disease Society for Obstetrics and Gynecology Annual Meeting, August 1991

 

181

Reinus JF, Leikin EL, Alter HJ et al: Failure to detect vertical transmission of hepatitis C virus. Ann Intrn Med 117:881, 1992

 

182

Bohman VR, Slettler W, Little BB et al: Seroprevalence and risk factors for hepatitis C virus antibody in pregnant women. Obstet Gynecol 80:609, 1992

 

183

Silverman NS, Jenkin BK, Wu C et al: Hepatitis C virus in pregnancy: Seroprevalence and risk factors for infection. Ann J Obstet Gynecol 169:583, 1993

 

184

Silverman NS, Snyder M, Hodinka RL et al: Detection of hepatitis C virus antibodies and specific hepatitis C virus ribonucleic acid sequences in cord bloods from a heterogeneous prenatal population. Am J Obstet Gynecol 173:1396, 1995

 

185

Wejstal R, Norkrans G: Chronic non-A, non-B hepatitis in pregnancy: Outcome and possible transmission to the offspring. Scand J Infect Dis 21:485, 1989

 

186

Wejstal R, Hermodsson S, Iwarson S et al: Mother to infant transmission of hepatitis C virus infection. J Med Virol 30:178, 1990

 

187

Wejstal R, Widell A, Mansson AS et al: Mother-to-infant transmission of hepatitis C virus. Ann Intern Med 117:887, 1992

 

188

Silverman NS, Jaffee FN, Hadinka RL: Hepatitis C virus infection in pregnancy: Is maternal viral burden related to vertical transmission. ? Infect Dis Obstet Gynecol 4:357, 1996

 

189

Ohto H, Terazawa S, Sasaki N et al: Transmission of hepatitis C virus from mothers to infants. N Engl J Med 330:744, 1994

 

190

Lin HH, Kao JH, Hsu HY et al: Possible role of high-titer maternal viremia in perinatal transmission of hepatitis C virus. J Infect Dis 169:638, 1994

 

191

Thomas DL, Villano SA, Riester KA et al: Perinatal transmission of hepatitis C virus from hunam innumodeficiency virus type 1-infected mothers. Women and Infants Transmission Study JID 177:1480-1488, 1998

 

192

Giacchino R, Tasso L, Timitilli A et al: Vertical transmission of hepatitis C virus infection: usefulness of viremia detection in HIV-seronegative hepatitis C virus-seropositive mothers. J Pediatr 132:167-169, 1998

 

193

Hillemanns P, Dannecker C, Kimmig R et al: Obstetric risks and vertical transmission of hepatitis C virus in pregnancy. Acta Obstet Gynecol Scand 79:543-547, 2000

 

194

Steininger C, Kundi M, Jatzko G et al: Increased risk of mother-to-infant transmission of hepatitis C virus by intrapartum infantile exposure to maternal blood. J Infect Dis 187:345-351, 2003

 

195

Paternoster DM, Santarossa C, Grella P et al: Viral load in HCV RNA-positive women. Am J Gastroenterol 96:2751-2754, 2001

 

196

Resti M, Bortolotti F, Giacchino R et al: Transmission of hepatitis C virus from infected mother to offspring during subsequent pregnancies. J Pediatr Gastroenterol Nutr 30:491-493, 2000

 

197

Gibb DM, Goodall RL, Dunn DT et al: Mother-to-child transmission of hepatitis C virus: Evidence for preventable peripartum transmission. Lancet 356:904-907, 2000

 

198

Dal Molin G, D'Aqgaro P, Ansaldi F et al: Mother-to-infant transmission of hepatitis C virus: rate of infection and assessment of viral load and IgM anti-HCV as risk factors. J Med Virol 67:137-142, 2002

 

199

Conte D, Fraquelli M, Prati D et al: Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology 31:751-755, 2000

 

200

Giovannini M, Tagger A, Ribero ML et al: Maternal-infant transmission of hepatitis C virus and HIV infections: A possible interaction. Lancet 335:1216, 1990

 

201

Thaler MM, Park CK, Landers DV et al: Vertical transmission of hepatitis C virus. Lancet 338:17, 1991

 

202

Novati R, Thiers V, Monforte AD et al: Mother-to-child transmission of hepatitis C virus detected by nested polymerase chain reaction. J Infect Dis 165:720, 1992

 

203

Zanetti AR, Tanzi E, Paccapini S et al: Mother-to-infant transmission of hepatitis virus. Lancet 345:289, 1995

 

204

Paccagnini S, Principi N, Massironi E et al: Perinatal transmission and manifestation of hepatitis C virus infection in a high-risk population. Pediatr Infect Dis J 14:195, 1995

 

205

Zuccotti GV, Ribero ML, Giovanini M et al: Effect of hepatitis C genotype on mother-to-infant transmission. J Pediatr 127:278, 1995

 

206

Papaevangelou V, Pollack H, Rochford G et al: Increased transmission of vertical hepatitis C virus (HCV) infection to human immunodeficiency virus (HIV)-infected infants of HIV- and HCV-coinfected women. JID 178:1047-1052, 1998

 

207

Borkowsky W, Rigaud M, Krasinski K et al: Cell-mediated and humoral responses in children infected with human immunodeficiency virus during the first four years of life. J Pediatr 120:371-375, 1992

 

208

Padula D, Rodella A, Spandrio M et al: Spontaneous recovery from perinatal infection due to hepatitis C virus. CID 28:141-142, 1999

 

209

Azzari C, Resti M, Moriondo M et al: Vertical transmission of HCV is related to maternal peripheral blood mononuclear infection. Blood 96:2045-2048, 2000

 

210

Lerat H, Rumin S, Habersetzer F et al: In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. Blood 91:3841-3849, 1998

 

211

Lin HH, Kao JH: Hepatitis C virus load during pregnancy and puerperium. Br J Obstet Gynecol 107:1503-1506, 2000

 

212

Mofenson LM, Lambert JS, Stiehm ER et al: Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 team N Engl J Med 341:394-402, 1999

 

213

Garcia PM, Kalish LA, Pitt J et al: Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group N Engl J Med 341:394-402, 1999

 

214

ACOG: Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection. Committee Opinion 234, May 2000

 

215

The International Perinatal HIV Group: The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1: A meta-analysis of 15 prospective cohort studies. N Engl J Med 340:977-987, 1999

 

216

Burns DN, Minkoff H: Hepatitis C: Screening in pregnancy. Obstet Gynecol 94:1044-1048, 1999

 

217

ACOG: Viral hepatitis in pregnancy. Educational Bulletin #248, July 1998

 

218

Connor EM, Sperling RS, Gelber R et al: Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group N Engl J Med 331:1173-1180, 1994

 

219

Watts DH: Management of human immunodeficiency virus infection in pregnancy. N Engl J Med 346:1879-1891, 2002

 

220

Cooper ER, Chaurat M, Mofenson L et al: Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and the prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 29:484-494, 2002

 

221

Minkoff H: Human Immunodeficiency virus infection in pregnancy. Obstet Gynecol 101:797-810, 2003

 

222

McHutchison JG, Gordon SC, Schiff ER et al: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 339:1485-1492, 1998

 

223

Heathcote EJ, Shiffman ML, Cooksley WG et al: Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl Med 343:1673-1680, 2000

 

224

Lindsay KL, Trepo C, Heintges T et al: A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 34:395-403, 2001

 

225

Fried MW, Shiffman ML, Reddy R et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975-982, 2002

 

226

Zeuzem S, Feinman SV, Rasenack J et al: Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 343:1666-1672, 2000

 

227

Manns MP, McHutchison JG, Gordon SC et al: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet 358:958-965, 2001

 

228

Briggs GG, Freeman RK, Yaffe SJ eds: Drugs in Pregnancy and Lactation. 5th edition. pp 942–943, Williams & Wilkins, Baltimore, MD, 1998

 

229

Hiratsuka M, Minakami H, Koshizuka S et al: Administration of interferon-alpha during pregnancy: Effects on fetus. J Perinat Med 28:372-376, 2000

 

230

Crump M, Wang XH, Sermer M et al: Successful pregnancy and delivery during alpha-interferon therapy for chronic myeloid leukemia. Am J Hematol 40:238-239, 1992

 

231

Baer MR, Ozer H, Foon KA: Interferon-alpha therapy during pregnancy in chronic myelogenous leukaemia and hairy cell leukaemia. Br J Haematol 81:167-169, 1992

 

232

Lin HH, Kao JH, Hsu HY et al: Absence of infection in breast-fed infants born to hepatitis C virus-infected mothers. J Pediatr 126:589, 1995

 

233

Garland SM, Tabrizi S, Robinson P et al: Hepatitis C–Role of perinatal transmission. Aus NZ J Obstet Gynecol 38:424-427, 1998

 

234

Kumar RM, Shahul S: Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers. J Hepatol 29:191-197, 1998

 

235

Zimmermann R, Perucchini D, Fauchere JC et al: Hepatitis C virus in breast milk. Lancet 345:928, 1995