Prevention of Perinatal Transmission of the Hepatitis B Virus Outcome of Infants in Manette T.

Niu, MD; Paul

V.

Targonski, MPH;

a

Community Prevention Program

Barbara

Objective.\p=m-\To assess the outcome of infants born to hepatitis B surface antigen (HBSAg)-positive mothers who received prenatal and infant care in a large, public health

\s=b\

care

system.

Design. Follow-up of a cohort of infants born to HBSAg\x=req-\ positive mothers. \p=m-\

Setting. \p=m-\Large, urban hospital providing prenatal care and obstetric services to county health departments. Participants.\p=m-\Forty-two infants born to HBsAg-positive women.

Interventions.\p=m-\Prentaltesting of women and immunoprophylaxis of infants with hepatitis B immune globulin at birth and hepatitis B vaccine at birth and ages 1 and 6 months. Results.\p=m-\All 42 infants received hepatitis B immune globulin and the first dose of vaccine. Of forty-one infants

(98%) who received the second dose of vaccine, 37 received it by age 4 months. Thirty-two infants (76%) completed the three-dose vaccine series by age 12 months, and 34 infants (81%) completed the series by age 18 months. The rate of completion of the hepatitis B vaccine series was comparable to that of infants receiving the third dose of diphtheriapertussis-tetanus vaccine. Of 26 infants who completed the hepatitis B vaccine series and had follow-up serologic testing, 24 (92%) had adequate levels of antibody to HBsAg. Only one infant who did not complete the vaccine series had serologic evidence of hepatitis B virus infection. No infant was

HBsAg-positive.

serving urban populations can effectively deliver hepatitis B immunoprophylaxis to infants born to HBsAg-positive mothers. Conclusions. \p=m-\Public programs

(AJDC. 1992;146:793-796)

Accepted for publication January 17,

1992. From the Hepatitis Branch, World Health Organization Collaborating Center for Research and Reference in Viral Hepatitis, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control (Drs Niu and Margolis and Mr Targonski), and the Department of Pediatrics, Emory University School of Medicine (Drs Stoll and Albert), Atlanta Ga. Reprint requests to Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control, 1600 Clifton Rd, Mailstop A33, Bldg 6, Room 154, Atlanta, GA 30333 (Dr Margolis).

J.Stoll, MD; George

P.

Albert, MD; Harold S. Margolis,

hepatitis The Infants born

virus is

MD

efficiently transmitted perinatally

to women chronically infected with the born to women who test positive for both the

to Infants

virus.

hepatitis surface antigen (HBsAg) and the hepatitis e an¬ tigen (HBeAg) have a 70% to 90% risk of infection, whereas infants born to women who test positive for only HBsAg have as high as a 20% risk of infection.I_s Infections acquired soon after birth are almost always asymptomatic and are most likely to become persistent. However, some infants in¬ fected from HBsAg-positive, HBeAg-negative mothers ap¬ pear to be at high risk of developing fulminant hepatitis, probably because of a mutation in the precore region of the genome.6'7,910 Infants born to HBsAg-positive mothers who do not become infected at birth remain at high risk of infec¬ tion until age 5 to 6 years.811 As adults, a high proportion of hepatitis carriers die of cirrhosis or primary hepatocellular carcinoma.12

In the United States, it has been estimated that 22 000 in¬ fants are born to HBsAg-positive women each year.13 Uni¬ versal testing of pregnant women has identified a substantial number who were not considered to be at high risk of chronic infection with the hepatitis virus but who tested positive for HBsAg.14-16 By identifying HBsAg-positive women through prenatal testing, immunoprophylaxis can be deliv¬ ered to their infants soon after birth to prevent hepatitis infection. Administration of hepatitis immune globulin and hepatitis vaccine soon after birth, followed by hepatitis vaccination at ages 1 month and 6 months (thereby com¬ pleting the vaccine series), has been shown to prevent more than 90% of infections in infants born to HBeAg-positive women.21617 Universal screening of pregnant women to identify HBsAg and the development of programs to pre¬ vent perinatal hepatitis infection have raised a number of issues, including the need for follow-up serologie testing of infants receiving immunoprophylaxis. We report the out¬ come of infants born to HBsAg-positive mothers who re¬ ceived follow-up vaccination and serologie testing. Mothers were identified as HBsAg-positive with prenatal screening performed at a large, urban hospital that is the referral center for patients receiving public health care.

PATIENTS AND METHODS based at a large, 900-bed urban hospital that study provides prenatal and obstetric care for an estimated 8000 The

was

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Comparison of Administration of Three

Doses of

Hepatitis

Vaccine

by Targeted Delivery Time*

Vaccine Dose

Dose Administered Within 2 wk of Target Date

Dose Administered Within 4 mo of Target Date

1

41 (98)

2

32 (76) 22 (52)

42 (100) 37 (88)

Dose Administered by Age 18 mo

3 32 (76)t •Values are number (percentage) of infants. =42. tNumber (percentage) of children who received dose 2 within 6 months of the target date. women

annually. The hospital primarily serves two counties of

greater metropolitan Atlanta, Ga, and these

two

county health

departments provide ambulatory pediatric well-child care and immunization services for most infants born at the hospital. In¬ fants of women who tested positive for HBsAg during a prenatal visit between July 1, 1988, and June 30, 1989, who were born at the hospital, and who received pediatric care at either of the two county health department clinics were included in the study. Mother and infant hospital records and the infant's immuni¬

zation records were reviewed to determine demographic char¬ acteristics such as age, sex, and race; the infant's birth weight; and the type, dose, and dates of hepatitis immune globulin administration and hepatitis vaccination. When infants reached ages 12 to 26 months, their mothers were contacted by telephone and letter to request serologie testing to determine the outcome in their infants after hepatitis immunoprophylaxis. Testing was performed after informed consent was obtained. Serum specimens were tested by radioimmunoassay for anti¬ body to HBsAg (anti-HBs), HBsAg, and total antibody to hepa¬ core antigen (anti-HBc) using commercially available titis reagents (Abbott Laboratories, North Chicago, 111). If specimens were positive for anti-HBc, they were tested for IgM anti-HBc. The presence of anti-HBs was determined quantitatively, and values were expressed in milli-international units per milliliter. A protective antibody response was considered to be 3=10 mlU/mL of anti-HBs per liter of serum.

During

the

1-year

RESULTS period, 85 HBsAg-positive

women

through prenatal HBsAg testing by the hospital laboratory. Forty-two women and their infants fulfilled the criteria for inclusion in the study. Five (12%)

were

identified

were white, 30 (71%) were black, and seven (17%) were Asian. The mean age of the women was 27 years (range, 17 to 41 years). Forty-three mothers and their infants did not fulfill the in¬ clusion criteria. Eleven women were initially HBsAgpositive and became HBsAg-negative by the time of deliv¬ ery, one mother had a false-positive HBsAg test result, eight women had no record of a live birth at the hospital more than 5 months after their due dates, seven women had pregnan¬ cies that did not result in a live birth (four abortions, two mis¬ carriages, and one misdiagnosis of pregnancy), two women moved out of state shortly after their infants' births, two in¬ fants were followed up by private physicians, one mother went to another hospital for delivery, and 11 mothers who went to the study hospital for delivery did not seek health care for their infants at the two county health department clinics served by the hospital. The standard hospital protocol for infants of HBsAgpositive mothers is administration of hepatitis immune globulin and 0.5 mL (10 µg) of hepatitis vaccine (Heptavax, Merck Sharp & Dohme, West Point, Pa) as soon as possible after delivery. All of the 42 infants were given 0.5 mL of hepatitis immune globulin (Abbott Laboratories) within 12 hours of birth. However, one infant did not re¬ ceive the first dose of vaccine before discharge, but

(100) (98) 34 (81) 42 41

received vaccine at age 1 month (Table). At discharge from the hospital, 40 infants (95%) had been scheduled for hepatitis vaccination at their county clinics. Thirty-two infants (76% ) received theirsecond dose of vac¬ cine within 2 weeks of the recommended 1-month visit (Ta¬ ble). Five infants received the second dose by 4 months of age, and four infants received the second dose by age 18 months. One infant had not received a second dose of vac¬ cine by the time of the follow-up study. Fewer infants re¬ ceived the third dose of vaccine on schedule. Only 22 infants (52%) received the third dose within 2 weeks of the sched¬ uled 6-month visit, 32 infants (76%) completed the series by age 12 months, and 34 infants (81%) completed the series by age 18 months (Table). The proportion of infants who com¬ pleted the hepatitis vaccine series was slightly higher than that for infants who received the third dose of diphtheria-

pertussis-tetanus vaccine (81% vs 79%).

Thirty

infants (71%) underwent follow-up serologie between testing ages 12 and 27 months. The demographic makeup of these infants did not differ significantly from that of the total group: 18 (60%) were female, three (10%) were white, 22 (73%) were black, and five (17%) were Asian. Twenty-six infants (87%) had received hepatitis immune globulin and three doses of hepatitis vaccine. Of these, 24 (92%) had adequate levels of anti-HBs when tested at a mean of 12 months after their last dose of vac¬ cine. The two infants with anti-HBs levels of less than 10 mlU/mL (1.3 and 7 mlU/mL) were tested 12 and 13 months after receiving the third dose of vaccine, and neither in¬ fant had evidence of hepatitis infection. Of the remaining four infants who had not completed the hepatitis vaccine series at follow-up for serologie testing, three had anti-HBs levels of more than 10 mlU/ mL, and one tested positive for anti-HBc and anti-HBs (evidence of hepatitis B). This infant had received hepa¬ titis immune globulin and vaccine at birth and a second dose of vaccine at age 5 months, but did not receive the third dose of vaccine. No infant was HBsAg-positive. Anti-HBs levels were determined for 23 of the 24 infants who received three doses of vaccine, and the geometric mean titer was 104 mlU/mL. The remaining infant was anti-HBs-positive, at a level of more than 10 mlU/mL, but the titer was not determined. Among fully vaccinated in¬ fants, the geometric mean titer of anti-HBs was slightly higher for those tested 7 to 12 months after receiving the third dose of vaccine than for those tested 13 to 17 months after receiving the third dose of vaccine (112 mlU/mL vs 95 mlU/mL, respectively; P>.05). COMMENT The purpose of our study was to evaluate the outcome of infants born to women who tested positive for HBsAg

during prenatal care delivered at a large hospital as part a public health care program. Testing women for the

of

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presence of HBsAg during pregnancy identifies a large number of infants who will require hepatitis immuno¬ prophylaxis. Such immunoprophylaxis must begin soon after birth and be completed by age 6 months.16,17 Pro¬ grams to prevent perinatal hepatitis infection must deal with a number of operational issues to ensure that infants are completely vaccinated.1618 Results of this follow-up study show that public health care programs serving ur¬ ban populations can successfully provide hepatitis im¬ munoprophylaxis. However, infants who do not com¬ plete the vaccine series may be at increased risk of

contracting hepatitis B.

Several factors were identified that may have initially contributed to hepatitis vaccine not being delivered on schedule to these infants. In one county, hepatitis vac¬ cine was only available at a centrally located clinic and could not be delivered during other visits for routine in¬ fant vaccination.18 However, the proportion of infants who completed the hepatitis vaccine series was slightly higher than that of infants who received the third dose of diphtheria-pertussis-tetanus vaccine. This reinforces the need to improve general vaccination coverage through improved health education efforts and tracking systems. The prevention of perinatal hepatitis infections requires that each component of the health care system responsi¬ ble for prenatal, obstetric, and pediatric care communicate effectively. Results of this study emphasize the impor¬ tance of reviewing the health care system "downstream" that will continue the care of at-risk infants identified in maternal HBsAg testing programs. Although 85 women were identified as HBsAg-positive during prenatal testing, not all had infants who required hepatitis immunoprophylaxis. Eleven women (13%) were tested at least twice during pregnancy and were subsequently found to be HBsAg-negative and, in some cases, anti-HBs-positive at or near delivery. This suggests a high rate of resolving acute hepatitis infection in this population, an observation made by others serving highrisk urban populations.1819 Of the remaining 74 women, 15 had no record of live birth, and one had a documented false-positive HBsAg test result. Of the remaining 58 women who were considered HBsAg-positive at delivery, 42 (72%) were included in the study. The 16 infants not included in the study were not followed up in the health care systems of the two counties served by the hospital. The study hospital provides prenatal and obstetric care for an estimated 9000 women annually, but it is estimated that only 8000 infants receive pediatric care through the county health department clinics served by the hospital. Infants unavailable for follow-up create a significant problem in the prevention of perinatal hepatitis infec¬ tion. On the other hand, 15 infants initially identified but not included in the study received hepatitis immune globulin and hepatitis vaccine before discharge. It could be anticipated that most of these infants would be protected from chronic hepatitis infection. One dose of hepatitis immune globulin has been shown to prevent 40% of chronic infections.4 In addition, 20% to 40% of in¬ fants develop protective levels of anti-HBs after one dose vaccine (Centers for Disease Control, of hepatitis unpublished data, October 1991).220 Thus, most of the in¬ fants who were unavailable for follow-up probably did not become chronically infected with hepatitis B, al¬ though not all would be protected from infections that

occur

during early childhood unless they completed their

vaccine series. The efficacy of hepatitis

irnmunoprophylaxis in pre¬ is emphasized by the chronic infection venting hepatitis results of serologie testing during follow-up of these infants. More than 90% of the infants tested for anti-HBs had protective levels of vaccine-induced antibody at follow-up. The two infants who had suboptimal levels of anti-HBs despite completion of the vaccine series were tested 12 to 13 months after receiving the third dose. Their low titers may represent waning antibody levels in a vac¬ cine responder. Of the four infants who underwent sero¬ logie testing during follow-up but who did not complete the vaccine series, only one had evidence of hepatitis infection. This infant, who received only hepatitis im¬ mune globulin and one dose of vaccine, was anti-HBcpositive 12 months later. Anti-HBs levels determined an average of 6 months after the third dose of plasma-derived vaccine have ranged from 407 to 765 rnlU/mL.17,21 The lower anti-HBs levels in our infants may have been due to the longer time between administration of the last dose of vaccine and follow-up; however, it can be expected that these infants will continue to be protected from hepatitis infection.22-23 Of the 12 infants from the original study group who did not undergo follow-up serologie testing, three missed appointments, three moved out of state, and six could not be contacted. Of the nine infants presumed to still reside in the area, three (33%) had received only two doses of vaccine compared with four (30%) in the group that had undergone serologie testing. This selection bias appears to represent mothers who were more likely to not comply with health care requirements for their infants. It has recently been recommended that hepatitis vac¬ cine be routinely included in infant immunization sched¬ ules regardless of maternal HBsAg status.23 Unique to this immunization strategy is that the first dose of vaccine can be administered before discharge from the hospital.111315"20 Results of this study confirm that hepati¬ tis vaccine can be effectively delivered during the new¬ born period. However, delivery of subsequent doses of vaccine requires attention to follow-up, especially in hard-to-reach populations. Use of trade names or commercial sources is for identification only and does not imply endorsement by the Public Health Service or US Department of Health and Human Services. We thank Pauline Washington, Medical Records Department, Grady Memorial Hospital, Atlanta, Ga; Judy Sarver, RN, Bob Fenton, MSPh, and Winnie Miller, RN, Fulton County (Georgia) Health Department; Shelby Abernathy, RN, and Alan Sievert, MD, De Kalb County (Georgia) Health Department; Patrick Coleman, PhD, and Tracy Greene, Centers for Disease Control, Atlanta, Ga, for statisti¬ cal consultations and antibody testing, respectively; and Claudia Kiedl, University of Wisconsin School of Medicine, Milwaukee, for patient interviews. References 1. Stevens CE, Neurath RA, Beasley RP, Szmuness W. HBeAg and anti-HBe detection by radioimmunoassay: correlation with vertical transmission of hepatitis B virus in Taiwan. J Med Virol. 1979;3:237\x=req-\

241. 2. 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. 1985;76:713-718. 3. Lee SD, Lo KJ, Wu JC, et al. Prevention of maternal-infant hepatitis B transmission by immunization: the role of serum hepatitis B virus

DNA.

Hepatology. 1986;6:369-373.

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Beasley RP, Hwang LY, Stevens CE, et al. Efficacy of hepatitis B imglobulin (HBIG) for prevention of perinatal transmission of the HBV carrier state: final report of a randomized double-blind, placebocontrolled trial. Hepatology. 1983;3:135-141. 5. Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol.

1987;126:484-491. 15. Jonas MM, Schiff ER, O'Sullivan MJ,

4.

et al. Failure of Centers for Disease Control criteria to identify hepatitis B infection in a large municipal obstetric population. Ann Intern Med. 1987;107:335-337. 16. Centers for Disease Control. Prevention of perinatal transmission of hepatitis B virus: prenatal screening of all pregnant women for hepatitis B surface antigen. MMWR. 1988;37:341-346, 351. 17. Stevens CE, Taylor PE, Tong MJ, et al. Yeast-recombinant hepatitis B vaccine: efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission. JAMA. 1987;257:2612\x=req-\

mune

1977;105:94-98.

6. Shiraki K, Yoshihara N, Sakurai M, Eto T, Kawana T. Acute hepatitis B in infants born to carrier mothers with antibody to hepatitis B e antigen. J Pediatr. 1980;97:768-770. 7. Tong MJ, Sinatra FR, Thomas DW, Nair PV, Merritt RJ, Wang DW. Need for immunoprophylaxis in infants born to HBSAg-positive carrier mothers who are HBeAg negative. J Pediatr. 1984;105:945-947. 8. Beasley RP, Hwang LY. Postnatal infectivity of hepatitis B surface antigen-carrier mothers. J Infect Dis. 1983;147:185-190. 9. Sinatra FR, Shah P, Weissman JY, Thomas DW, Merritt RJ, Tong MJ. Perinatal transmitted acute icteric hepatitis B in infants born to hepatitis B surface antigen-positive and anti-hepatitis B e-positive carrier mothers. Pediatrics. 1982;70:557-559. 10. Terazawa S, Kojima M, Yamanaka T, et al. Hepatitis B virus mutants with precore-region defects in two babies with fulminant hepatitis and their mothers positive for antibody to hepatitis B e antigen. Pediatr Res. 1991;29:5-9. 11. 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. 1989;321:1301-1305. 12. Beasley RP. Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer. 1988;61:1942-1956. 13. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis. 191;11:84-92. 14. McQuillan GM, Townsend TR, Johannes CB, et al. Prevention of perinatal transmission of hepatitis B virus: the sensitivity, specificity, and predictive value of the recommended screening questions to detect high-risk women in an obstetric population. Am J Epidemiol.

2616. 18. Centers for Disease Control. Hepatitis B screening and follow-up vaccination of infants of carrier mothers\p=m-\Atlanta,1988 and 1989. MMWR.

1990;39:405-407.

19. Henning KJ, Pollack DM, Friedman SM. Neonatal hepatitis B surveillance and vaccination program: the New York City experience, 1987-1988. AM J Public Health. In press. 20. Greenberg DP, Vadheim CM, Marcy SM, Wong V, Margolis HS, Ward JI. Safety and immunogenicity of two recombinant hepatitis B vaccines given to 5000 infants as part of routine immunization of 2, 4, and 6 months of age. In: Program and Abstracts of the 31st I nterscience Conference on Antimicrobial Agents and Chemotherapy; September 29-October 2, 1991; Chicago, Ill. Abstract 1290. 21. Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med. 1986;315:209-214. 22. Wainwright RB, McMahon BJ, Bulkow LR, et al. Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo

population. JAMA. 1989;261:2362-2366.

23. Centers for Disease Control. Hepatitis B virus: a comprehensive transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR. 1991;40(suppl RR-

strategy for eliminating

13):11-13.

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