hepatitis

668

Clinical .Rev. _ _ jiet_r
T~~~1
d

*I-ws

Hepatitis B in Pregnancy
JOSE ALBERTO AREVALO, MD, Sacramento, California

Chronic infection with the hepatitis B virus can result in the development of serious liver disease such as chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Vertical transmission from infected mothers to infants is thought to be partially responsible for the high prevalence of infection in certain high-risk groups. Immunoprophylaxis using hepatitis B vaccine and hepatitis immune globulin has been highly effective in decreasing the probability of chronic hepatitis B virus infection in infants with exposure. Previously, the Centers for Disease Control recommended screening pregnant women considered at high risk of hepatitis B infection to detect newborns who would benefit from postnatal immunizations directed at preventing the HBV carrier state. Because of the poor sensitivity of high-risk criteria in distinguishing pregnant women who harbor the hepatitis B virus, these recommendations have recently been revised to call for the routine screening of all pregnant women in the United States.
(Arevalo JA: Hepatitis B in pregnancy. West J Med 1989 Jun; 150:668-674)

Our understanding of the wide spectrum of hepatitis B viral infection has broadened dramatically since the discovery of the Australian antigen by Blumberg in 1965.1 Using modern serologic and immunohistochemical markers and sophisticated hybridization techniques, investigators have uncovered the role of the hepatitis B virus (HBV) in the development of acute and chronic hepatic infections. Convincing evidence has associated the hepatitis B virus with the development of serious long-term sequelae such as chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma.2 Epidemiologic research has also revealed a surpiisingly high prevalence in certain populations. Data suggest that unlike the hepatitis A virus, another common cause of viral hepatitis, the hepatitis B virus can persist in the host lifelong, predisposing the person to the development of significant and serious chronic sequelae. Perinatal transmission, the transmission of infection from a gravid woman to her newborn, has been documented to result in a high rate of transfer of the HBV and may be the primary mechanism responsible for the high prevalence of this infection in high-risk third world populations. Most of these infections take place during birth or in the first few months of life. Data from Asia and Africa disclose that infants born to carrier mothers have a probability as high as 90% of acquiring the HBV from their mothers during the first year of life.3 Once infected, these infants may continue to harbor the HBV for prolonged periods and, as a consequence, chronic active hepatitis, cirrhosis, or hepatocellular carcinoma may develop. The Centers for Disease Control (CDC) recently revised their recommendations regarding the routine screening of pregnant women for HBV to decrease the probability of neonatally acquired infection.4'5 Viral hepatitis was the third most common infectious disease (behind varicella and gonorrhea) reported to the CDC last year. The incidence of HBV infection in the United

States appears to be increasing, with more than 25,000 cases of hepatitis B reported in 1984, a 25% increase from the previous five years.6

Virology
The hepatitis B virus is classified in the Hepadna group and is the only virus from this group that is known to affect humans. It has a propensity to infect and replicate in hepatocytes but appears to have no intrinsic cytopathic activity. The exact mechanism of hepatocyte destruction is not known, although evidence suggests that this process is mediated by the host immune system.7 This explanation may partly account for the variation in the clinical presentation of HBV infection. The intact viral particle-referred to as the Dane particle (Figure 1)-has been identified in the serum of patients with acute and chronic hepatitis B viral infections. It consists of a 42-nm outer shell known as the hepatitis B surface antigen (HBsAg) and an inner shell known as the hepatitis B core antigen (HBcAg), which houses the DNA. The DNA is double stranded and contains 3,200 kilobases. A soluble extractable protein, the hepatitis B e antigen (HBeAg), is thought to be a subunit of the HBcAg and is used as a marker for a highly infective state. Chimpanzee data, although not directly applicable to humans, suggest that serum containing both the HBsAg and the HBeAg is 108 times more infective than serum that is positive for HBsAg and anti-HBe.8 Pure HBsAg, formerly known as the Australian antigen or hepatitis-associated antigen, is noninfectious. Inoculation of an immune-competent host with pure HBsAg can elicit a specific antibody response that is highly successful in protecting a person from a subsequent clinical infection.9'10

Epidemiology
Worldwide an estimated 200 million people make up the total pool of ongoing carriers of HBV. Considerable geo-

From the Department of Family Practice, University of California, Davis, School of Medicine, Sacramento. Reprint requests to Jose Alberto Arevalo, MD, Department of Family Practice, University of California, Davis, School of Medicine, 2221 Stockton Blvd, Sacramento, CA 95817.

THI

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ABBREVIATIONS USED IN TEXT
CDC = Centers for Disease Control HBcAg = hepatitis B core antigen HBeAg = hepatitis B e antigen HBIG = hepatitis B immune globulin HBsAg = hepatitis B surface antigen HBV = hepatitis B virus Ig = immunoglobulin

graphic variability in the prevalence of the HBV carrier state exists from a high of 5% to 15% in Alaskan Eskimo and Asian populations to less than 0.5 % in the general population of the United States. The hepatitis B virus has been documented to be transmitted through exposure to body fluids and through parenteral routes. Blood transfusions, needle-stick injuries, and the use of contaminated needles or syringes have resulted in its transmission. Besides perinatal transmission, other nonparenteral spread, usually through close, intimate, or sexual contact, has also been associated with the spread of this virus. I I Numerous factors have been shown to predict the outcome of transmission in adults and children, including the presence of HBeAg, the age of a newly infected host, the immune status of the newly infected host, and the site and route of inoculation. 12

three to four weeks, but symptoms may be present for as long as six months. If the clinical course is prolonged beyond six months, then the acute infection has progressed into a chronic state. TIypically this chronic state may persist for months to years and occasionally lasts for life. Fulminant hepatitis, the most dreaded form of clinical hepatitis, occurs in a small percentage of patients with acute hepatitis and is characterized by acute liver failure with hepatic encephalopathy and coma. About 70% to 80% of patients in whom fulminant hepatitis develops will die. The serologic markers in fulminant hepatitis are similar to those in typical acute hepatitis, although recent data suggest that viral replication and HBeAg production may actually be diminished in patients with fulminant HBV hepatitis.15 In addition, several reports have demonstrated coinfection of HBV with the delta hepatitis virus in some cases of fulminant hepatitis. 16

Serology of Infection
The first serologic marker to appear in acute HBV hepatitis is the HBsAg, which is present before the clinical onset of symptoms (Figure 1). Shortly thereafter, aminotransferase levels begin to rise and may reach peaks 20 to 100 times normal. At about the same time as the appearance of HBsAg, HBeAg may be detected in the serum. The HBeAg disappears before clinical symptoms resolve and is typically followed by the appearance of antibody to the HBeAg (anti-HBe). This seroconversion from HBeAg to anti-HBe suggests that the acute stage of the infection is resolving. Anti-HBs usually is detectable in the serum after the clinical symptoms have resolved and during the convalescent phase. Anti-HBs is usually not present until the HBsAg has disappeared such that in about 50% of symptomatic patients, a "window" period exists between the disappearance of HBsAg and the appearance of anti-HBs. High titers of anti-HBs can be construed as an indication of immunity. Antibody to the core antigen (anti-HBc) can usually be detected early in the incubation period of acute HBV infection. This antibody consists of a mixture of both immunoglobulin (Ig) G and IgM and can persist in the serum for long periods of time. In adults, the IgM component can be present 1 for as long as a year after acute infection. The IgG component usually persists for many years and may persist lifelong. The presence of anti-HBc IgM during the window period has been accepted as presumptive evidence of a recent HBV infection. The hepatitis B core antigen is currently not a useful clinical marker since even in cases of acute hepatitis, it is usually not present in the serum in sufficient quantities to justify routine assay. 18 Chronic infection with HBV can be characterized by two overlapping clinical scenarios, an asymptomatic carrier state and a chronic symptomatic hepatitis (Figure 2). 19 The "healthy" carrier state is characterized by a lack of symptoms and usually normal serum aminotransferase levels but with the serologic presence of the surface antigen (HBsAg). Persons with these signs usually have no detectable evidence of HBV replication or circulating virus particles, and liver biopsies in these patients are typically normal or show minimal changes.20'1 Essentially all of these patients will show serologic evidence of anti-HBc primarily of the IgG class. The symptomatic carrier state is similar to the healthy carrier state serologically but differs in that patients who are symptomatic have constant or intermittent elevation of

Clinical Course of Infection In a typical case scenario, acute hepatitis B infection in pregnancy does not appear to portend a more aggressive clinical course as was previously thought. Acute infection in the first or second trimester is rarely transmitted to the newborn if clinical resolution occurs before labor begins. 13 This infection, however, may pose a more substantial danger to the newborn if the acute stage occurs in the third trimester; 60 % of these women will transmit the infection to the at-risk infant. 14 The incubation period for acute HBV infection varies from 45 to 150 days. In healthy adults and children, only 50 % of infections with HBV are manifested by clinical signs and symptoms; thus, most infections go unrecognized. Infants infected during the first year of life are more likely to be asymptomatic. When the infection does result in symptoms, the course of acute hepatitis is characterized by anorexia, nausea, malaise, weakness, and abdominal pain. The usual clinical signs are jaundice, icterus, hepatic tenderness, and weight loss. This acute infection will usually run its course in
HBsA

.. :.

HB

A

HBeAg

.

.....DNA polymerase

Double-stranded DNA

Figure 1.-On the left is a representation of an intact hepatitis B viral particle. On the right, two polymeric forms of the hepatitis B surface antigen (HBsAg) are represented consisting of HBsAg only in 22-nm spherical and cylindrical forms. HBcAg hepatitis B core antigen, HBeAg hepatitis B extractable antigen, DNA polymerase, and viral
=
=

DNA

670

serum aminotransferase values and presumptive biochemical evidence of continued liver inflammation (Figure 3). Many of these patients have symptoms that wax and wane. A liver biopsy in patients with symptomatic chronic liver disease can reveal chronic persistent, chronic active, and chronic lobular hepatitis as well as cirrhosis or hepatocellular carcinoma. Evidence to date indicates that persons in the chronic carrier state will lose serum positivity to HBsAg at a rate of 1 % to 2 % per year.22

High-Risk Groups Table 1 shows the high-risk groups for HBV infection and the estimated size of each group in the US population.4'23 Evidence for Perinatal Transmission Stokes, Wolman, and co-workers in 1951 investigated several reports of newborn infants in whom signs of viral hepatitis developed within the first two months of life. They speculated that perinatal infection from an asymptomatic mother who harbored the "serum hepatitis" virus could be responsible for this perinatal transmission.24 Three years later, Stokes and associates confirmed the presence of the serum hepatitis virus in the asymptomatic mother of one infant infected during the perinatal period by injecting serum from the mother and the infant into healthy volunteers.25 In 1970, Schweitzer and Spears reported that out of four mothers manifesting acute HBV infection during delivery or immediately postpartum, hepatitis developed in three of the infants who had serologic evidence of HBsAg.26 Numerous
-Eievated ALT-]
l

0 0

c~~~
__

X.- -Bz z tanti-HBs -g anti-HBe I anti-HBc
-

.L

0

Figure 2.-The typical course of acute hepatitis B virus infection shows a characteristic elevation in serum alanine aminotransferase (ALT) levels preceded by the presence of hepatitis B surface and e antigens (HBsAg and HBeAg) in serum with clearing of both antigens before 6 months and the presence of antibody to hepatitis B core antigen (anti-HBc), anti-HBs, and anti-HBe in the convalescent phase (adapted with permission from Hoof nagle'9).
Elevated ALT

o

H}FBsAg=
l
x

C

X I

0 1
i

YearsFigure 3.-The typical course of chronic hepatitis B virus infection is shown, with greater than 6 months of elevated serum alanine aminotransferase (ALT) levels and a persistence of hepatitis B surface antigen (HBsAg) without detectable antibody (adapted with permission from Hoofnagle'9). anti-HBc = antibody to hepatitis B core antigen, HBeAg = hepatitis B e antigen, IgM = immunoglobulin M
Time

WA,o;~.
HBsAg

HEPATITIS

HEPATITIS B IN PREGNANCY
B IN

PREGNANCY

other studies followed, predominantly from Asia, that showed that the HBV could be transmitted from infected asymptomatic mothers to their infants.2729 In these studies, infants who contracted perinatal HBV infections were frequently asymptomatic. The highest risk infants, those born of mothers with HBeAg-positive serum, have an incidence of perinatal infection as high as 85 % to 95% .3,29 Although the exact mechanism of neonatal infection is not known, it is postulated that most perinatal infections occur at birth. Hepatitis B surface antigen tends to appear in an infant's blood at 3 to 4 months of age, consistent with infection occurring during the birthing process. The presence of HBsAg in the cord blood, however, originally thought to be associated with a high probability of infection, has been poorly correlated with the subsequent occurrence of the carrier state.29.30 The presence of maternal HBeAg has been shown to predict a high likelihood of perinatal transmission because it seems to correlate with the presence of high titers of viral DNA in the blood. If the mother is HBsAg-positive but HBeAg and antibody to HBe are absent in the maternal serum, the risk of infection to the neonate is approximately 31 %. If HBeAg is absent but anti-HBe is present, the risk falls to approximately 10% .29,31 Cases of fulminant hepatitis, however, have been reported to occur in infants born to women in the lower risk group, prompting the CDC and other experts to recommend that prophylaxis in these infants be instituted.3234 Studies in the United States suggest that

TABLE 1.-Estimated Prevalence of Heptitis B Carriers in Selected Populations
Population Prevalence, Percent Estimated Total Number of Carriers

|Jaundice

anti-HBc Total _

______

.-0
gM

HeAg

,

I

I

1

[

4 3 5 - Months t

2

6

1

2

3

4

5

6

Time

-e

Years-

Asian-Americans* ................. Alaskan Eskimos* . Subsaharan Africans* . Pacific Islanders* . Haitians* . United States population* . Intravenous drug addictstt . Institutionalized for mental retardationtt ...

Medical personneltt ............... Centers for Disease Control highest risk§ groupt ....... ....... 7 Centers for Disease Control
recommended screening groupt
....
..

8-15 14 6-14 5-10 7 0.2 7 7 1

480,000
6,720 4,400 20,800 6,510 1,000,000 52,500 9,800

23,000
604,000

4

755,000

T=
4

*Data adapted from US Census Bureau, 1980. tAdapted with permission from Krugman.23 tFrom the Centers for Disease Control.4 §These are the recommended screening groups with greater than 7% prevalence.

anti-tc Total
;;...........................................

TABLE 2.-Prevalence of Hepatitis B Surface Antigen and Hepatitis B e Antigen Positivity in Selected Prenatal Populations
Location

..

-anti-HBc 1gM
l
2 3 4 5 6 7 8

Screened,

Total Women No.

Positive for HBsAg, No. (9)

Percent Positive for Positive for HBeAG, HBeIHBs, No. (96) 96

2 3 4 5 6 7 8 9 10 11 Months |

I-

472 New York City* .. 18 ( 3.8) 6 ( 1.3) 484 49 (10.0) 18 (10.0) Oakland, Calift .. United Statest . 18,842 1,639 ( 8.7) 565 ( 3.0)
*From Friedman et al.35

33 37 34

tFrom Klontz.36 tFrom Stevens et al.37 This was a multicenter study: New York, San Francisco, and Los Angeles.

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approximately 30 % of HBsAg-positive pregnant women also possess the HBeAg (Table 2).3 Although about 5 % of cases of vertical transmission are thought to occur transplacentally, the exact mechanisms leading to fetal infection are unclear. Whether prepartum microabruptions or direct invasion of the virus through an intact placental barrier is responsible for the subsequent intrauterine infection is still open to debate. 38 The possibility that breast-feeding plays a role in perinatal transmission has been postulated after studies have shown breast milk of infected mothers to contain the antigen.39 Current evidence, however, does not support the hypothesis that the virus can be transmitted through breast milk.40

primary hepatocellular tumor cells has led to the speculation that viral DNA integration may be the initial event leading to the oncogenic transformation of infected hepatocytes. Hybridization techniques and Southern blot analysis have consistently shown the presence of hepatitis B viral genome sequences in some human hepatocellular carcinoma cells.5153

Prophylactic Immunization Recommendations High-titer anti-HBs was used in the mid- 1970s to treat four newborns of mothers with acute HBV infection and appeared to successfully prevent HBV transmission to these infants.54
In 1981 data from an investigation in Taiwan showed a

Consequences of Neonatal HBV Infection
The presence of nonfatal acute neonatal hepatitis in eight Greek infants born of mothers found to harbor the Australian antigen prompted the consideration that certain maternal factors could be used to predict acute neonatal hepatitis.41 Reports of acute fatal neonatal HBV hepatitis later helped to fuel the need to identify those factors that could successfully predict maternal transmission.42 Although the presence of anti-HBe in HBsAg-positive carrier mothers was found to predict a low likelihood of transmission to the neonate, when transmission did occur, acute hepatitis developed in some of these infants, occasionally leading to death.3234 The association of chronic HBV infection with the development of known sequelae-chronic active hepatitis, chronic persistent hepatitis, cirrhosis, and primary hepatocellular carcinoma-has been confirmed by a substantial body of evidence.43 Sherlock and colleagues first described the association between the presence of HBsAg and primary hepatocellular carcinoma in 1970.44 With the availability of a more sensitive radioimmunoassay for the detection of HBsAg, reports have surfaced that link higher rates of serologic evidence of HBV infection in patients with diagnosed hepatocellular carcinoma. Data from Africa and Asia have shown that 40 % to 80% of patients with this cancer are also positive for HBsAg.45 Epidemiologic and geographic data have shown that areas of high prevalence of HBsAg are also identified as concurrently manifesting a high prevalence of documented cases of hepatocellular carcinoma.46 Furthermore, a case-control study from Senegal has shown the increased presence of HBV markers in the serum of mothers of patients with hepatocellular carcinoma, leading to speculation that viral transmission may be responsible for the development of the liver cancer.47 Perhaps the strongest evidence as to the causal association between active HBV infection and the development of liver cancer stems from the work of Beasley and associates. More than 22,000 Taiwanese male government employees were observed for the development of hepatocellular carcinoma over 41/2 years in this study.45 More than 3,400 (15.2%) were found to be carriers of HBV, and these HBsAg-positive men had a higher rate of liver cancer than their HBsAg-negative cohorts (a relative risk of 94).4548 Using death registry data, this same group has estimated that the lifetime risk of death from hepatocellular carcinoma or cirrhosis or both is 40% to 50% for a male Chinese HBsAg carrier. Several reports have documented primary hepatocellular carcinoma occurring in HBsAg-positive children as young as 4 and 5 years old.49 50 The finding of HBV DNA integrated into the DNA of

75% efficacy in reducing the rate of HBV carriers in infants
born to HBsAg- and HBeAg-positive mothers in a controlled trial of multiple doses of hepatitis B immune globulin (HBIG).55 This was followed by a report from the same group of a randomized controlled trial using a revised schedule of HBIG and a plasma-derived hepatitis B vaccine that showed a 90 % efficacy rate.56 A similar trial in Hong Kong reported a 96 % efficacy rate.57 Stevens and coworkers, in a multicenter trial in the United States that observed 113 infants immunized using a similar protocol, found an 85% reduction in the expected carrier rate.37 These same investigators revised the immunization protocol in a similar study of 122 infants receiving the new recombinant HBV vaccine and found a greater than 90% level of protection.58 The Advisory Committee on Immunization Practices of the CDC has recently revised its previous recommendation and now urges that all pregnant women be screened during a prenatal visit for the presence of HBsAg, preferably early in pregnancy when blood specimens for routine laboratory tests are drawn.5 On the other hand, if the patient population contains a significant number of pregnant women at risk for contracting the HBV during pregnancy, the screening test may be delayed until the 32nd to the 36th week of gestation. In addition, as soon as an HBsAg-positive pregnant woman presents in labor, the obstetrical and neonatal staff should be advised of the HBV status of the patient so that appropriate precautions are observed. Newborn infants of these mothers should be immunized as soon as possible after birth once the TABLE 3.-Routine Pediatric Vaccination Schedule and Hepatitis B Virus (HBV) Prophylaxis for Infants of Mothers Positive for the Hepatitis B Surface Antigen (HBsAg)
Age, months

Hepatitis B Prevention Schedule

HBV Marker

Screening

Routine Pediatric Schedule
...

Birth HBIG* HB vaccinet 1 .. HB vaccine ... ... 2.. ...
HB vaccine HBsAg test§ ... HBsAG and anti-HBs testH ... ... 15..

DPTJ polio
DPT, polio
DPT
...

4 6. . 12-15

...

...

MMR,¶ DPT, polio

be given. IA test positive for HBsAg indicates therapeutic failure. A test positive for

*Hepatitis B immune globulin, 0.5 ml given intramuscularly within 12 hours of birth. tHepatitis B vaccine, 0.5 ml given intramuscularly within 12 hours of birth. tDiphtheria and tetanus toxoids and pertussis vaccine adsorbed. §Optional. If positive, indicates infection, and a third hepatitis B vaccine need not

antibodies to HBsAg (anti-HBs) indicates therapeutic success. ¶Measles, mumps, and rubella virus vaccine, live.

672

PREGNANCY~~~-

HEPATITIS B IN PREGNANCY

infant's condition is stable. Routine isolation of the infant is not necessary once the infanit's condition is stable and all maternal blood is washed off. The newborn need not be isolated from the mother, but caution regarding maternal lochia should be exercised. The accepted routine neonatal immunization schedule (Table 3) uses HBIG, 0.5 ml given intramliuscularly, and hepatitis B vaccine and either recombinant (5 grams per dose) or plasma-derived hepatitis B vaccine (10 grams per dose), both preferably within 12 hours of birth. Both the HBIG and the hepatitis B vaccine can be given at the same time at different sites with no documented decrease in efficacy. The HBIG should be administered within 48 hours because delay in administration has been shown to result in a decreased protection of the newborn.59 The vaccine nmay be given as long as seven days later if it is not immediately available. The hepatitis B vaccination is then repeated at 1 month and 6 months. No further HBIG is indicated. The vaccine can be given with the routine childhood disease immunizations with no decrease in their efficacy. A test of immunization success may be done at 12 to 15 months using HBsAg and anti-HBs, the absence of HBsAg and the presence of anti-HBs implying successful immunization. If HBsAg screening has not been carried out by the time the mother is in labor or if test results are not available, then HBsAg screening should be done at the time of hospital admission or as soon as possible to ensure that the at-risk infant receives the recommended immunizations in a timely manner. If the hospital facility does not have the availability of HBsAg test results within a 48-hour period, strong consideration should be given to routinely administering HBIG to infants born of very-high-risk mothers-Asians, Haitians, Subsaharan Africans born outside the US, Alaskan Eskimos, and intravenous drug abusers. Several factors are important in considering the empiric therapy under these circumstances. The HBV carrier rate in these very-high-risk women may be as high as 15 % and averages about 7 % (see Table 1). In addition, the administration of HBIG after 48 hours has been found to result in a greatly diminished protection.59 Both HBIG and hepatitis B vaccines have been found to be remarkably safe, with local mild reactions being the most commonly reported side effects. Finally, there is currently no proven antiviral therapy that has been shown to be efficacious in eradicating chronic HBV infection. Thus, routine administration while awaiting maternal HBsAg test results is justified in this setting to protect infants who would otherwise become HBV carriers. Once the HBsAg test results are available, then the decision for subsequent vaccine doses can be made. If the infant was not identified as high risk antenatally but is the product of a high-risk mother and is older than 1 month, then the infant should be screened for the presence of HBsAg at the initial visit. If the HBsAg is absent, then the infant should be treated with HBIG and hepatitis B vaccines as soon as possible with repeat doses of vaccine at one and six months following the original vaccination (Table 3). Most investigators think that breast-feeding does not play a major role in the establishment of chronic HBV infections, particularly once an infant has been adequately immunized. Thus, little justification exists to discourage breast-feeding. Although the CDC recommends that for screening purposes testing for HBsAg is sufficient, once the maternal serum is found positive for the HBsAg, then a thorough

history and physical examination with evaluation of the liver function of the mother should be carried out to assess the potential for transmission and to detect occult acute or chronic hepatitis. Other immediate family and sexual contacts of the identified carrier should be evaluated for the presence of past or current HBV infection and to evaluate their candidacy for the hepatitis B vaccine. The hepatitis B vaccine available in the United States is derived from pooled plasma of hepatitis B carriers and purified by a three-step process that appears to eliminate other serious potential infectious agents. This vaccine appears to elicit a protective antibody response in a high percentage of recipients. In July 1986, a new yeast-derived vaccine formulation produced by recombinant DNA technology (Recombivax HB) was licensed by the Food and Drug Administration. A large multicenter trial carried out in the United States has shown that the use of the yeast-recombinant vaccine is as effective as the plasma-derived vaccine in preventing the HBV carrier state in at-risk infants.58 Both vaccines have been proved to be safe and effective in adults, children, and newborns. The HBIG, which is pooled from serum containing high titers of anti-HBs, has also been shown to be safe and effective in adults and newborns.60 Who Should Be Screened? The previous recommendations from the CDC identified 11 categories of high-risk women for whom screening for HBV was originally recommended (Table 4). The experiences of several large metropolitan centers established that using these recommended criteria to select patients for HBsAg screening resulted in missing 33% to 67% of HBsAg-carrier pregnant women. Investigators from the University of Florida screened all pregnant women during the two-year period of 1983 to 1985 and found that the CDC's previous recommended screening criteria identified only 14 of 43 pregnant women with HBsAg in their serum.6" The sensitivity was 50 % to 60 %, specificity 71 % to 75 %, and a predictive value of 11 % to 19% of these same CDC-recommended screening criteria in identifying laboring women with evidence of HBV infection in a large Ohio hospital.62 A similar study from Dade County, Florida, of more than 5,300 pregnant women found the sensitivity of the screening criteria to be only 47% .63 A comparison ofthe cost-benefit of routine screening for HBsAg with routine screening for syphilis in a population of pregnant adolescents revealed
TABLE 4.-Women for Whom Prenatal Hepatitis B Surface Antigen Screening Was Previously Recommended*
Women of Asian, Pacific Island, or Alaskan Eskimo descent, whether immigrant or United States born Women born in Haiti or Subsaharan Africa Women with histories of Acute or chronic liver disease Work or treatment in a hemodialysis unit Work or residence in an institution for the mentally retarded Rejection as a blood donor Blood transfusion on repeated occasions Frequent occupational exposure to blood in medical or dental

settings

Household contact with a hepatitis B virus carrier or hemodialysis

patient Multiple episodes of venereal disease Percutaneous use of illicit drugs
*From Centers for Disease Control.4

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comparable costs in case identification." Finally, a decision analysis comparing the direct and indirect costs of a routine prenatal screening and newborn immunization program in the United States was shown to be cost-effective.65 After delivery, close follow-up of the mother is recommended, although specific guidelines for surveillance have not been agreed on. Because no proven therapy exists to resolve chronic HBV infection, efforts surrounding therapy for these persons are currently directed at the early detection of and early therapy for hepatocellular carcinoma. Preliminary results using a-fetoprotein screening in HBsAg-positive patients in China, South Africa, and Alaskan Eskimos have shown promise, particularly when used in combination
with ultrasound evaluation ofthe liver.48"66

Summary
Routine screening of all pregnant women during the prenatal period has been shown to result in more effective and efficient means of identifying infants at risk for becoming long-term HBV carriers. Long-term sequelae of chronic liver disease can be averted if those infants born to positive mothers are immunized using a schedule of hepatitis B vaccine and HBIG at birth with follow-up hepatitis B immunizations. Standard precautionary measures should be taken during labor for those women found to carry the HBV, but isolating the infant and segregating from the mother need not take place. Breast-feeding need not be discouraged. Routine testing of the infant to determine immunization success should be done at 12 to 18 months. Close surveillance of the mother with frequent follow-up visits to look for evidence of chronic sequelae should be instituted.
REFERENCES

19. Hoofnagle JH: Types A and B Viral Hepatitis. Perspectives on Viral Hepatitis Monograph. North Chicago, Ill, Hepatitis Information Center, Abbott Diagnostics Division, 1980 20. De Franchis R, D'Arminio A, Vecchi M, et al: Chronic asymptomatic HBsAg carriers: Histologic abnormalities and diagnostic and prognostic value of serologic markers of the HBV. Gastroenterology 1980; 79:521-527 21. Sakoma K, Takahara T, Okuda K, et al: Prognosis of hepatitis B virus surface antigen carriers in relation to routine liver function tests: A prospective study. Gastroenterology 1982; 83:114-117 22. Sampliner RE, Hamilton FA, Isseri OA, et al: The liver histology and frequency of clearance of the hepatitis B surface antigen (HBsAg) in chronic carriers. Am J Med Sci 1979; 277:17-22 23. Krugman S: Hepatitis B Immunoprophylaxis. Perspectives on Viral Hepatitis Monograph. North Chicago, III, Hepatitis Information Center, Abbott Diagnostics Division, 1983 24. Stokes J, Wolman IJ, Blanchard MC, et al: Viral hepatitis in the newborn: Clinical features, epidemiology and pathology. AmJ Dis Child 1951; 82:213-216 25. Stokes J, Berk JE, Malamut LL, et al: The carrier state in viral hepatitis. JAMA 1954; 154:1059-1065 26. Schweitzer IL, Spears RLP: Hepatitis-associated antigen (Australia antigen) in mother and infant. N Engl J Med 1970; 283:570-572 27. Schweitzer IL, Wing A, McPeak C, et al: Hepatitis and the hepatitis-associated antigen in 56 mother-infant pairs. JAMA 1972; 220:1092-1095 28. Okada K, Yamada T, Miyakowa Y, et al: Hepatitis B surface antigen in the serum of infants after delivery from asymptomatic carrier mothers. J Pediatr 1975; 87:360-363 29. Beasley RP, Trepo C, Stevens CE, et al: The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977; 105:94-98 30. Stevens CE, Beasley RP, Tsui J, et al: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 1975; 292:771-774 31. Beasley RP, Hwang LY: Postnatal infectivity of hepatitis B surface antigencarrier mother. J Infect Dis 1983; 147:185-190 32. Shiraki K, Yoshihara N, Sakurai M, et al: Acute hepatitis B in infants born to carrier mothers with the antibody to hepatitis B e antigen. J Pediatr 1980; 97:768-770 33. Sinatra FR, Shah P, Weissman JY, et al: Perinatal transmitted acute icteric

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