hepatitis b immunisation for

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EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL

Evid.-Based Child Health 2: 67155 (2007)

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.120

Hepatitis B immunisation for newborn infants of hepatitis B

surface antigen-positive mothers (Review)

Lee C, Gong Y, Brok J, Boxall EH, Gluud C

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration, first published in The Cochrane

Library 2007, Issue 1

http://www.thecochranelibrary.com

67Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)

Copyright 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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T A B L E O F C O N T E N T S

70ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .

72SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .

72METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

74METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

74RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .

77ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

110Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111Table 01. Search strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

113Table 02. Intervention by group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

115ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

115Comparison 01. Vaccine versus placebo or no intervention . . . . . . . . . . . . . . . . . . . .

116Comparison 02. RV versus PDV . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

116Comparison 03. High-dose versus low-dose vaccine . . . . . . . . . . . . . . . . . . . . . . .

116Comparison 04. Three-dose PDV plus HBIG versus two-dose PDV plus HBIG . . . . . . . . . . . . .

116Comparison 05. PDV at birth versus PDV at one month . . . . . . . . . . . . . . . . . . . . .

116Comparison 06. One type of PDV versus another type of PDV . . . . . . . . . . . . . . . . . . .117Comparison 07. Four RV vaccinations versus three RV vaccinations . . . . . . . . . . . . . . . . .

117Comparison 08. One type of RV versus another type of RV with the same vaccination schedule . . . . . . . .

117Comparison 09. HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . . . . . .

117Comparison 10. Multiple HBIG plus PDV versus single HBIG plus PDV . . . . . . . . . . . . . . .

117Comparison 11. PDV plus HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . .

118INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119Analysis 01.01. Comparison 01 Vaccine versus placebo or no intervention, Outcome 01 Hepatitis B events according

to type of vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


to methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

121Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events - Sensitivityanalyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


to the mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . .


to first time of vaccine administration . . . . . . . . . . . . . . . . . . . . . . . . .

125 Analysis 02.01. Comparison 02 RV versus PDV, Outcome 01 Hepatitis B events . . . . . . . . . . . . .

126Analysis 02.02. Comparison 02 RV versus PDV, Outcome 02 Hepatitis B events according to methodological quality

127Analysis 02.03. Comparison 02 RV versus PDV, Outcome 03 Hepatitis B events - sensitivity analyses . . . . . .




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129Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mothers HBeAg

status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

130 Analysis 02.05. Comparison 02 RV versus PDV, Outcome 05 Anti-HBs less than 10 IU/L . . . . . . . . .

130Analysis 03.01. Comparison 03 High-dose versus low-dose vaccine, Outcome 01 Hepatitis B events . . . . . .

131Analysis 03.02. Comparison 03 High-dose versus low-dose vaccine, Outcome 02 Hepatitis B events according to

methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events - sensitivity analyses

134Analysis 03.04. Comparison 03 High-dose versus low-dose vaccine, Outcome 04 Hepatitis B events according to the

mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

135Analysis 03.05. Comparison 03 High-dose versus low-dose vaccine, Outcome 05 Anti-HBs less than 10 IU/L . . .

135Analysis 04.01. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 01 Hepatitis

B events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

136Analysis 04.02. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 02 Anti-

HBs less than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

136Analysis 05.01. Comparison 05 PDV at birth versus PDV at one month, Outcome 01 Hepatitis B events . . . .

137Analysis 06.01. Comparison 06 One type of PDV versus another type of PDV, Outcome 01 Hepatitis B events . .

137Analysis 07.01. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 01 Hepatitis B events .

138Analysis 07.02. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 02 Anti-HBs level less

than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Analysis 08.01. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule,

Outcome 01 Hepatitis B events . . . . . . . . . . . . . . . . . . . . . . . . . . . .

139Analysis 08.02. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule,

Outcome 02 Anti-HBs less than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . .

139Analysis 09.01. Comparison 09 HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events . . . .

141Analysis 09.02. Comparison 09 HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events according to

methodological quality of the trials . . . . . . . . . . . . . . . . . . . . . . . . . .

142Analysis 09.03. Comparison 09 HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events - sensitivity

analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


the mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . . . . . .147Analysis 09.06. Comparison 09 HBIG versus placebo or no intervention, Outcome 06 Hepatitis B events according to

standard and rapid schedule of vaccines . . . . . . . . . . . . . . . . . . . . . . . . .

148Analysis 09.07. Comparison 09 HBIG versus placebo or no intervention, Outcome 07 Anti-HBs less than 10 IU/L .

149Analysis 09.08. Comparison 09 HBIG versus placebo or no intervention, Outcome 08 Anti-HBs level . . . . .

149Analysis 09.09. Comparison 09 HBIG versus placebo or no intervention, Outcome 09 Adverse events . . . . .

150Analysis 10.01. Comparison 10 Multiple HBIG plus PDV versus single HBIG plus PDV, Outcome 01 Hepatitis B

events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

150Analysis 11.01. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events


according to methodological quality of the trials . . . . . . . . . . . . . . . . . . . . . .

152Analysis 11.03. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events -

sensitivity analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

153Analysis 11.04. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 04 Hepatitis B eventsaccording to mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . .


according to time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . .

155Analysis 11.06. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 06 Adverse events . .




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Hepatitis B immunisation for newborn infants of hepatitis B

surface antigen-positive mothers (Review)

Lee C, Gong Y, Brok J, Boxall EH, Gluud C

This version first published online: 19 April 2006 in Issue 2,2006 ofThe Cochrane Library. LeeC, GongY, Brok J, Boxall EH, Gluud

C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database of Systematic

Reviews2007, Issue 2. Art. No.: CD004790. DOI: 10.1002/14651858.CD004790.pub2. Cochrane reviews are regularly updated as

new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the

review.

Date of most recent substantive amendment: 22 February 2006

A B S T R A C T

BackgroundHepatitis B vaccine and hepatitisB immunoglobulin are considered for newborn infants of HBsAg-positive mothers to prevent hepatitis

B infection.

Objectives

To assess the beneficial and harmful effects of hepatitis B vaccines and hepatitis B immunoglobulin in newborn infants of HBsAg-

positive mothers.

Search strategy

Trials were identified through The Cochrane Neonatal Group Controlled Trials Register, The Cochrane Hepato-Biliary Group Controlled

Trials Register, The Cochrane Central Register of Controlled Trialsin The Cochrane Library, MEDLINE, and EMBASE(until February

2004), authors of trials, and pharmaceutical companies.

Selection criteria

Randomised clinical trials comparing: plasma-derived vaccine (PDV) or recombinant vaccine (RV) versus no intervention, placebo, or

other active vaccines; hepatitis B immunoglobulin versus no intervention, placebo, or other control immunoglobulin; as well as PDV

or RV plus hepatitis B immunoglobulin versus no intervention, placebo, or other control vaccines or immunoglobulin.

Data collection and analysis

Outcomes are assessed at maximal follow-up. The primary outcome measure was hepatitis B occurrence, based on a blood specimen

positive for HBsAg, HBeAg, or antibody to hepatitis B core antigen (anti-HBc). Binary outcomes are reported as relative risks (RR)

with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality of the trial, mothers

HBe-Ag status, and time of immunisation after birth.

Main results

We identified 29randomised clinical trials, fiveof which were considered highquality. Only three trials reported inclusion of hepatitisB

e-antigennegative mothers.Comparedwithplacebo/no intervention, vaccine reduced hepatitis B occurrence (RR0.28,95% confidence

interval (CI) 0.20 to 0.40, 4 trials). No significant differences of hepatitis B occurrence were found comparing recombinant vaccine

(RV) versus plasma-derived vaccine (PDV) (RR 1.00, 95% CI 0.71 to 1.42, 4 trials) and high-dose versus low-dose vaccine (PDV:

RR 0.97, 95% CI 0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial). Compared with placebo/no intervention,

hepatitis B immunoglobulin or the combination of vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (hepatitis

B immunoglobulin: RR 0.50, 95% CI 0.41 to 0.60, 1 trial; PDV plus hepatitis B immunoglobulin: RR 0.08, 95% CI 0.03 to 0.17,

3 trials). Compared with vaccine, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (RR 0.54, 95% CI 0.41 to

0.73, 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported on adverse events.

Authors conclusions

Vaccine, hepatitis B immunoglobulin, and vaccine plus hepatitis B immunoglobulin prevent hepatitis B occurrence in newborn infants

of HBsAg positive mothers.




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P L A I N L A N G U A G E S U M M A R Y

Hepatitis B vaccine, hepatitis B immunoglobulin, and hepatitis B vaccine plus immunoglobulin prevent perinatal transmission

of hepatitis B

Hepatitis B vaccination and hepatitis B immunoglobulin are considered as preventive measures for newborn infants of HBsAg positive

mothers. When all the identified trials were combined, hepatitis B vaccine alone, hepatitis B immunoglobulin alone, and hepatitisB vaccine plus hepatitis B immunoglobulin reduced perinatal transmission of hepatitis B compared with placebo or no intervention.

Hepatitis B vaccine plus hepatitis B immunoglobulin were superior to hepatitis B vaccination alone. Adverse events were rare and

mostly non-serious.

B A C K G R O U N D

Hepatitis B virus is a global acute and chronic communicable dis-

ease that causes major hepatic disease, with an estimated 350 mil-

lion people infected (Beasley 1984). Mother to child transmission

occurs frequently either in uterus (when the baby is still in the

womb), through placental leakage, or through exposure to bloodor blood contaminated fluids at or around the time of birth. Such

perinatal transmission is believed to account for 35% to 50% of

hepatitis B carriers (Yao 1996). The risk of perinatal transmission

is associated with the HBeAg status of the mother. If the mother

is both HBsAg and HBeAg positive, 70% to 90% of the children

become chronically infected (Stevens 1975; Akhter 1992). If the

mother is HBsAg positive but HBeAg negative, the risk is signifi-

cantly reduced (Okada 1976; Beasley 1977;Beasley 1983b; Nayak

1987; Aggarwal 2004).

Two types of vaccines have been licensed. One is derived from

human plasma (plasma-derived vaccine (PDV)) and the other is

derived from DNA recombinant technology (recombinant vac-

cine (RV)) from yeastor mammalian cells (Assad 1999). Repeated

injections over months are required to mount an effective anti-

body response with vaccination. Hepatitis B immunoglobulin is

an immune globulin, which contains a high level of antibody to

hepatitis B surface antigen (anti-HBs). Hepatitis B immunoglob-

ulin is considered immediately effective and seems protective for

several months after which it wanes (Beasley 1983; Nair 1984).

We have been unable to identify meta-analyses or systematic re-

views on hepatitis B immunisation for newborn infants of HB-

sAg positive mothers. A narrative review regarding the efficacy of

hepatitis B vaccine in neonates (Andre 1994) and several interna-

tional guidelines (CDC 1999; WHO 2002) have been published.

However, they do not represent systematic reviews containing anassessment of the methodological quality of the trials and present-

ing original data.

O B J E C T I V E S

To assess the beneficial and harmful effects of hepatitis B vaccine

and hepatitis B immunoglobulin in newborn infants of HBsAg-

positive mothers.

C R I T E R I A F O R C O N S I D E R I N G

S T U D I E S F O R T H I S R E V I E W

Types of studies

We included randomised clinical trials, irrespective of blinding,

publication status, or language.

Types of participants

We included newborn infants of either gender born to HBsAg-

positive mothers. The immunisation should start within the first

month of life.

Types of intervention

The following analyses were performed:

PDV or RV versus placebo or no intervention.

Hepatitis B immunoglobulin versusplacebo or no intervention.

PDV or RV plus hepatitis B immunoglobulin versus placebo,

no intervention, PDV, or RV.

Types of outcome measures

All outcomes were assessed at maximal follow-up.

Primary outcome

(1) Hepatitis B occurrence: blood specimen positive for HBsAg,

HBeAg, or antibody to hepatitis B core antigen (anti-HBc).

Secondary outcomes

(2) Number of newborn infants with anti-HBs less than 10 IU/L,which is considered insufficient to prevent hepatitis B virus infec-

tion (Szmuness 1981; Hadler 1986).

(3) Anti-HBs, either expressed as geometric mean titre (GMT) or

mean titre.

(4)Systemicadverse events: adverse eventssuch as malaise, nausea,

fever, arthralgia, rash, after each injection of vaccine.

(5) Local adverse events: adverse events such as pain, redness,

swelling, and/or myalgia at the site after each injection of vaccine.




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(6) Any adverse events: adverse events including local adverse

events and/or systemic adverse events. The adverse events are di-

vided into severe and non-severe. A severe adverse event, accord-

ing to the International Committee on Harmonisation Guidelines

(ICH 1997) is any event that would increase mortality; is life-

threatening; requires inpatient hospitalisation; results in a persis-tentor significant disability; or anyimportantmedical eventwhich

may jeopardise the patient or requires intervention to prevent it.

All other adverse events are considered non-severe.

(7) Cost-effectiveness.

S E A R C H M E T H O D S F O R

I D E N T I F I C A T I O N O F S T U D I E S

See: Cochrane Hepato-Biliary Group methods used in reviews.

We searched The Cochrane Neonatal Group Controlled Trials Regis-

ter, The Cochrane Hepato-Biliary Group Controlled Trials Register,

The Cochrane Central Register of Controlled Trials(CENTRAL) inThe Cochrane Library, MEDLINE/PubMed, and EMBASE. The

searchstrategies andtimespanof thesearchesare specified inTable

01. We consulted with The Cochrane Vaccines Field to identify

furthertrials,butno reply was received.Weread thebibliographies

of retrieved articles to identify further trials. We checked the ref-

erence lists of relevant articles for any new trials. We wrote to the

principal authors of the identified trials and the pharmaceutical

companies (SmithKline Beecham and Merck, Sharp & Dohme;

GreenCross Vaccine; GlaxoSmithKline; Pasteur; and Abbott) in-

volved in the production of hepatitis B vaccines for missing infor-

mation and additional published or unpublished trials.

M E T H O D S O F T H E R E V I E W

Selection of trials for inclusion

CL made the decisions on which trials to be included, and the

selection was validated by YG, JB, and CG. We were unblinded

withregard to the namesof the authors, investigators, institutions,

and results. Excluded trials were identified and listed with the

reasons for exclusion.

Data extraction

CL, YG, and JB independently extracted the data from the in-

cluded randomised trials. We wrote to the authors of trials if data

were missing in the report.

We extracted: primary author; number of participants; inclusion

and exclusion criteria; HBeAg status of the mother; methodolog-

ical quality (see below); dosage and types of vaccines; site of injec-

tion; vaccination schedules; duration of follow-up; outcome mea-

sures; and number and type of adverse events in the intervention

and the control groups.

Methodological quality

Methodological quality is defined as the confidence that the de-

sign and report restrict bias in the intervention comparison (Mo-

her 1998; Kjaergard 2001). Due to the risk of overestimation of

intervention effects in randomised trials with inadequate method-

ological quality (Schultz1995; Moher 1998; Kjaergard2001), the

methodological quality was assessed by using the following crite-ria:

Generation of the allocation sequence

Adequate, if the allocation sequence was generated by a com-

puter or random number table. Drawing of lots, tossing of a

coin, shuffling of cards, or throwing dice was considered as ad-

equate if a person who was not otherwise involved in the re-

cruitment of participants performed the procedure.

Unclear, if the trial wasdescribedas randomised,butthemethod

used for the allocation sequence generation was not described.

Inadequate, if a system involving dates, names, or admittance

numbers were used for the allocation of patients. Such quasi-randomised studies were excluded.

Allocation concealment

Adequate, if the allocation of patients involved a central inde-

pendent unit, on-site locked computer, identically appearing

numbered drug bottles or containers prepared by an indepen-

dent pharmacist or investigator, or sealed envelopes.

Unclear, if the trial wasdescribedas randomised,butthemethod

used to conceal the allocation was not described.

Inadequate, if the allocation sequence was known to the inves-

tigators who assigned participants.

Blinding (or masking)

Adequate, if the trial was described as double blind and the

method of blinding involved identical placebo or active drugs.

Unclear, if the trial was described as double blind, but the

method of blinding was not described.

Not performed, if the trial was not double blind.

Follow-up

Adequate, if the numbers and reasons for dropouts and with-

drawals in all intervention groups were described or if it was

specified that there were no dropouts or withdrawals.

Unclear, if the report gave the impression that there had been

no dropouts or withdrawals, but this was not specifically stated.

Inadequate, if the number or reasons for dropouts and with-

drawals were not described.

We post hocdefined high-quality trials when at least two out of

the three quality components were adequate: generation of the

allocation sequence, allocation concealment, and blinding. This




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wasduetothefactthatonlyasingletrialhadhighqualityregarding

all three components.

Statistical methods

Review Manager 4.2. was used to perform meta-analyses. Data

were analysed by both a random-effects model (DerSimonian

1986) and a fixed-effect model (DeMets 1987). If the results of

both analyses gave the same overall results regarding significance,

only the results of the fixed-effect model analysis was reported.

We presented binary outcome measure as relative risks (RR) with

95% confidence interval (CI), and continuous outcome measure

as weightedmeandifference (WMD) with95%CI.Heterogeneity

was explored by chi-squared test with significance set at P < 0.10

and the quantity of heterogeneity was measured by I2 (Higgins

2002).

Meta-regression analysis was performed by STATAon hepatitis

B occurrence, when more than 10 trials were included. Meta-

regression analysis examined the intervention effect in relationto methodological quality of trials, dosage of hepatitis B im-

munoglobulin and vaccine, and time of immunisation.

Subgroup analyses were performed to compare the effects of vac-

cines in mothers with HBsAg (+)/HBeAg(+) compared to HB-

sAg (+)/HBeAg(-), doses (high-dose versus low-dose), as well as

methodological quality of the trials (high-quality versus low-qual-

ity). The difference between the estimates of two subgroups was

estimated according to Altman 2003.

Regarding the hepatitis B occurrence, we included newborn in-

fants with incomplete or missing data in the sensitivity analyses

by imputing them in the following analyses (the last four being

intention-to-treat analyses):

Available data analysis: data on only those whose results are

known, using the total number of patients who completed the

trial as denominator;

Assuming poor outcome: dropouts in both experimental and

control group had the primary outcome;

Assuming good outcome: none of the dropouts in the experi-

mental and control group had the primary outcome;

Extreme case favouring experimental intervention: none of the

dropouts in the experimental groupbut all in the control group

had the primary outcome;

Extreme case favouring control intervention: all dropouts from

the experimental group but no controls had primary outcome.

We used funnel plot to provide a visual assessment of whether

treatment estimates are associated with study size. We explored

publication bias and other bias according to Beggs and Eggers

methods (Begg 1994; Egger 1997).

D E S C R I P T I O N O F S T U D I E S

We identified 226 references, but 186 were clearly irrelevant refer-

ences. The remaining 40 references describing 29 randomised tri-

als were included. Twenty-eight trials were published as full paper

articles and one trial was published as an abstract. We were not

able to extract relevant data according to our outcome measures

from three trials (Yeoh 1986; Zhu 1987; Grosheide 1993). Ex-

cluded studies are listedunder Characteristics of excluded studies

withreasons for exclusion. The immunisation doses and schedules

in the included trials varied substantially as described below. The

capital letters in the references refer to the intervention arms of

the trial as described in Table of included studies.

Vaccine versus placebo or no intervention

The dose of vaccine used was 3 microgram (Ip 1989 CD), 16

microgram (Xu 1995 AD), or 20 microgram (Liu 1987 AB; Xu

1995 BD). The vaccination schedules were 0-1-6 months (Liu

1987 AB; Xu 1995 AD/Xu 1995 BD), 0-1-2-6 months (Ip 1989

CD), or 0-1-2-14 months (Khukhlovich 1996).

RV versus PDV

The dose of vaccines was 5 microgram (Lee 1995 AB/Lee 1995

CB), 10 microgram (Pongpipat 1989), or 20 microgram (Halli-

day 1992 AB; Zhu 1994). The vaccination schedules were 0-1-6

months (Pongpipat 1989; Halliday 1992 AB; Zhu 1994) or 0-1-

2-12 months (Lee 1995 AB/Lee 1995 CB).

High-dose vaccine versus low-dose vaccine

The doses of PDV were 10 microgram, 5 microgram, and 2 mi-

crogram (Oon 1986 AB, Oon 1986 CD, Pongpipat 1988; Thep-

pisai 1990). The doses of RV were 20 microgram and 10 micro-

gram (Halliday 1992 DC). The vaccination schedules were 0-1-6

months (Halliday 1992 DC), 0-1-2 months (Oon 1986 AB/Oon1986 CD), or 0-1-2-12 months (Pongpipat 1988).

Three-dose PDV plus hepatitis B immunoglobulin versus two-

dose PDV plus hepatitis B immunoglobulin

One trial assessed three-doses PDV plus hepatitis B immunoglob-

ulin versus two-doses PDV plus hepatitis B immunoglobulin (Pi-

azza 1985). Both groups were given hepatitis B immunoglobulin

50 IU at birth, then 5 microgram PDV within five days and at two

months. The experimental group was given an additional PDV at

one month.

PDV at birth versus PDV at one month

One trial assessed 20 microgram PDV at 0-1-6 months versus 20

microgram PDV at 1-2-7 months (Beasley 1983b). Both groupswere given hepatitis B immunoglobulin 145 IU at birth.

One type of PDV versus another type of PDV

One trial assessed different types of PDV (PDV1(NIAID) versus

PDV2 (BIVS) (Xu 1995 AB). The dose was 16 microgram of

PDV1 and 20 microgram of PDV2. The schedules were 0-1-6

months.

Four RV vaccinations versus three RV vaccinations




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One trial assessed four RV vaccinations (0-1-2-12 months) versus

three RV vaccinations (0-1-6 months) (Lolekha 2002). The dose

of each RV was 5 microgram.

One RV versus another RV with the same vaccination schedule

Two trials assessed differenttypesof RV (RV1(Beijing, China) ver-

sus RV2 (Institute of Preventive Medicine, China) (Kang 1995)

andonetrial assessedCuban versus Engerix-B(Galban1992). Two

trials assessed different types of RV plus hepatitis B immunoglob-

ulin (Hepavax-Gene versus Engerix-B (Hieu 2002) and HB-VAX

II versus Engerix-B (Lee 1995 CA/Lee 1995 DE). The doses of

RV were 5 versus 10 microgram (Lee 1995 CA/Lee 1995 DE),

10 versus 10 microgram (Hieu 2002), or 20 versus 20 microgram

(Kang 1995). The vaccination scheduleswere0-1-6months (Kang

1995; Hieu 2002) or 0-1-2-12 months (Lee 1995 CA/Lee 1995

DE).

Hepatitis B immunoglobulin versus placebo or no interven-

tion

The doses of hepatitis B immunoglobulin ranged from 90 to260 IU. HepatitisB immunoglobulin was administered within 12

hoursofbirth inseventrials (Beasley 1983aAB/Beasley 1983aCB;

Lo 1985 AB/Lo 1985 CB; Theppisai 1987; Ip 1989 AC/ Ip 1989

BC; Halliday 1992 CA; Xu 1995 CB; Poovorawan 1997), within

24 hours in three trials (Farmer 1987; Sehgal 1992; Assateerawatt

1993), or within 48 hours in one trial (Liu 1987 CA). The vacci-

nation schedules were 0-3-6 months (Beasley 1983a AB/Beasley

1983a CB), 0-6 weeks-6 months (Farmer 1987), 0-1-6 months

(Ip 1989 AC/Ip 1989 BC; Theppisai 1987; Xu 1995 CB), 0-1-2-

6 months ( Liu 1987 CA), 0-2-6-10 weeks (Lo 1985 AB/Lo 1985

CB), and 0-4-8 weeks (Sehgal 1992).

Multiple hepatitis B immunoglobulin versus single hepatitisB immunoglobulin

Onetrialcompared 5 microgram PDV at 2-6-10weeks plus 50 IU

hepatitis B immunoglobulin at birth with or without additional

hepatitis B immunoglobulin at 1 month (Lo 1985 CA). One trial

compared 3 microgram PDV at 1-2-6 months plus 200 IU hep-

atitis B immunoglobulin at birth with or without additional hep-

atitis B immunoglobulin at 1-2-3-4-5-6 months (Ip 1989 AB)

PDV plus hepatitis B immunoglobulin versus placebo or no

intervention

One trial compared 200 IU hepatitis B immunoglobulin at 0-1-2-

3-4-5-6 months plus 3 microgram PDV at 0-1-2-6 months versus

200 IU hepatitis B immunoglobulin at birth plus 3 microgramPDV at 0-1-2-6 months versus placebo (Ip 1989 AD/Ip 1989

BD). One trial compared 20 microgram PDV at 0-1-2-6 months

plus hepatitis B immunoglobulin at birth with placebo (Liu 1987

CB). One trial compared 20 microgram PDV at 0-1-6 months

plus 250 IU hepatitis B immunoglobulin at birth versus placebo

(Xu 1995 CD). Hepatitis B immunoglobulin was given within 12

hours (Ip 1989 AD/Ip 1989 BD), or within 24 hours (Xu 1995

CD), and within 48 hours (Liu 1987 CB).

A number of trials had several intervention arms. For details of

the included trials, we provided Table 02 by listing the relevant

comparisonsandwhich trials assessed this comparison.The capital

letters after years of publication in the references stands for the

comparison arms of the individual trial.

Mothers HBeAg statusEighteen trials included only mothers, who were HBeAg positive.

Three trials included mothers who were HBeAg positive or neg-

ative (Lee 1995 AB; Oon 1986 AB; Xu 1995 AB), and in eight

trials mothers HBeAg status was not reported.

Newborns birthweight

Ten trials reported exclusion of low-birth-weight newborn infants.

The limits for exclusion varied from 1600 to 3000 gram. The re-

maining 19 trials did not report any birth weight exclusion crite-

ria. The average duration of follow-up was 19 months (range 6 to

60 months).

M E T H O D O L O G I C A L Q U A L I T Y

Generation of the allocation sequence was adequate in six trials

(Piazza 1985; Oon 1986 AB/Oon 1986 CD; Farmer 1987; Hal-

liday 1992 AB/Halliday 1992 CA/Halliday 1992 DC; Assateer-

awatt 1993; Hieu 2002).

Treatment allocation was adequately concealed in six trials (Ip

1989 AD/Ip 1989 BD/Ip 1989CD; Piazza 1985;Liu1987AB/Liu

1987 CA/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/

Halliday 1992 DC; Grosheide 1993; Hieu 2002).

Adequate method of double blinding was reported in three trials

(Ip 1989 AD/Ip 1989 BD/Ip 1989 CD; Liu 1987 AB/Liu 1987

CA/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/Halliday

1992 DC).

According to our criteria, we classified five trials as high quality

trials (Ip 1989 AD/Ip 1989 BD/Ip 1989 CD; Piazza 1985; Liu

1987 AB/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/

Halliday 1992 DC; Hieu 2002).

The numbers and reasons for dropouts and withdrawals were ad-

equately reported in six trials (Beasley 1983a AB/Beasley 1983a

CB/Beasley 1983b; Piazza 1985; Theppisai 1987; Halliday 1992

AB/Halliday 1992 CA/Halliday 1992 DC; Grosheide 1993).

R E S U L T S

Hepatitis B vaccines versus placebo or no intervention (Com-

parison 01-01 to 01-05)

Compared with placebo/no intervention, hepatitis B vaccination

significantly decreased the riskof hepatitis B occurrence (RR 0.28,

95% CI 0.20 to 0.40, 4 trials). The analysis showed heterogeneity

(P=0.07,I2 = 54.2%). The results of sensitivity analyses regarding

dropouts were consistent. Analyses of PDV and RV individually




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showed that both vaccines significantly decreased the risk of hep-

atitis B occurrence.

Subgroup analyses did not find a significant difference between

high-and low-quality trials, the mothers HBeAg status, or time of

vaccine injection (testsof interaction, P= 0.25, 0.07, and 0.11, re-

spectively). Post hocsubgroup analysis according to vaccine sched-ules (0-1-6 months versus 0-1-2-6 or -12 months) showed no sig-

nificant difference (test of interaction, P = 0.75). No data on ad-

verse events were reported.

RV versus PDV (Comparison 02-01 to 02-05)

We found no significant difference between RV and PDV on hep-

atitis B occurrence (RR 1.00, 95% CI 0.70 to 1.42, 4 trials). Het-

erogeneity was moderate (I2 = 29.4%). The results of sensitiv-

ity analyses regarding dropouts confirmed the finding. Subgroup

analysesdidnotfinda significant difference regarding the method-

ological quality or the mothers HBeAg status (both tests of inter-

action, P = 0.21).

Significantly fewer newborn infants on RV compared to PDV had

anti-HBs less than 10 IU/L (RR 0.51, 95% CI 0.36 to 0.72, 3

trials).

High-dose versus low-dose vaccine (Comparison 03-01 to 03-

05)

We found no statistical difference on hepatitis B occurrence com-

paringhigh-dose versuslow-dosevaccine (PDV:RR0.97, 95%CI

0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial).

There was no significant difference between high-dose versus low-

dose vaccine on anti-HBs less than 10 IU/L (RR 1.02, 95% CI

0.82, 1.27, 2 trials).

Three-dose PDV versus two-dose PDV (Comparison 04-01 to

04-02)

Three-dose PDV plus hepatitis B immunoglobulin did not sig-

nificantly prevent hepatitis B occurrence compared with two-dose

PDV plus hepatitis B immunoglobulin (RR 0.50, 95% CI 0.05

to 5.28, 1 trial). However, three-dose PDV plus hepatitis B im-

munoglobulin resulted in significantly less newborn infants who

had anti-HBs less than 10 IU/L compared with two-dose PDV

plus hepatitis B immunoglobulin (RR0.05, 95% CI 0.00 to 0.78,

1 trial).

PDV at birth versus PDV at one month (Comparison 05-01)

PDV administered for the first time at birth did not significantly

differ from PDV administered for the first time at one month ofage regarding the number of newborn infants having hepatitis B

occurrence (RR 0.70, 95% CI 0.18 to 2.77, 1 trial).

One type of PDV versus another type of PDV (Comparison

06-01)

One trial compared two different types of PDV and no significant

difference was found in terms of hepatitis B occurrence (Xu 1995

AB).

Four-dose RV vaccination versus three-dose RV vaccination

(Comparison 07-01 to 07-02)

One trial (Lolekha 2002) compared one type of RV with four vac-

cinations (0-1-2-12 months) versus the same RV with three vacci-

nations (0-1-6 months). No significant differences were found on

hepatitis B occurrence (RR 1.49, 95% CI 0.51 to 4.37) or anti-HBs level less than 10 IU/L (RR 0.53, 95% CI 0.10 to 2.77).

One type of RV versus another type of RV with the same vac-

cination schedule (Comparison 08-01 to 08-02)

Different RV in terms of various manufacturers were assessed and

no significant differences were found on hepatitis B occurrence or

anti-HBs less than 10 IU/L.

Hepatitis B immunoglobulin versus placebo or no interven-

tion (Comparison 09-01 to 09-08)

Overall, hepatitis B immunoglobulin significantly decreased the

risk of hepatitis B occurrence in newborn infants (RR 0.52, 95%

CI 0.44 to 0.63, 11 trials). Compared with placebo/no interven-

tion, hepatitisB immunoglobulin alone significantly reduced hep-atitis B occurrence (RR 0.50, 95% CI 0.41 to 0.60, 1 trial). Com-

pared withvaccination, vaccination plus hepatitis B immunoglob-

ulin was likewise superior (RR 0.54, 95% CI 0.41 to 0.73, 10 tri-

als). The sensitivity analyses regarding dropouts were consistent,

indicating the robustness of the findings. In the meta-regression

analyses, none of the trial characteristics (methodological qual-

ity, dosage of hepatitis B immunoglobulin, or time of hepatitis B

immunoglobulin injection) was significantly associated with the

effect of hepatitis B immunoglobulin (P = 0.92, 0.67, and 0.79,

respectively). Subgroup analyses did not find a significant differ-

ence between high- and low-quality trials, the mothers HBeAg

status, or time of hepatitis B immunoglobulin injection (tests of

interaction, P = 0.70, 0.62, and 0.63, respectively).

Hepatitis B immunoglobulinhad no significant effecton the num-

ber of newborn infants with anti-HBs level less than 10 IU/L (RR

1.55, 95% CI 0.89 to 2.73, 4 trials).

Few trials reported adverse events. If reported, the authors did not

specify in which intervention group these events occurred. There-

fore we were notable to perform a meta-analysis on adverse events.

In one trial (Beasley 1983a AB/Beasley 1983a CB), one infant

receiving hepatitis B immunoglobulin died. The death appeared

unrelated to hepatitis B immunoglobulin.

Neither the Eggers nor the Beggs graphs and their corresponding

tests on hepatitis B occurrence provided evidence for asymmetry(Eggers test, P = 0.31; Beggs test, P = 0.23).

Multiple hepatitis B immunoglobulin versus single hepatitis

B immunoglobulin administration (Comparison 10-01)

Multiple hepatitis B immunoglobulin plusPDVversus single hep-

atitis B immunoglobulin plus PDV did not significantly reduced

the risk of hepatitis B occurrence (RR 0.87, 95% CI 0.30 to 2.47,

2 trials) with no heterogeneity (I2 = 0%).




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PDV plus hepatitis B immunoglobulin versus placebo or no

intervention (Comparison 11-01 to 11-06)

Compared with placebo/no intervention, PDV plus hepatitis B

immunoglobulin significantly reduced hepatitis B occurrence (RR

0.08, 95% CI 0.03 to 0.17, 3 trials). The sensitivity analyses con-

firmed the robustness of the finding. Subgroup analyses did notfind a significant difference between high- and low-quality trials,

the mothers HBeAg status, or time of hepatitis B immunoglob-

ulin injection (tests of interaction, P = 0.13, 0.28, and 0.22, re-

spectively).

Onetrial reportedthe numberof adverse events: 3 out of71 infants

given vaccination versus 5 out of 34 in control group (Ip 1989

AD/Ip 1989 BD). The results showed no significant difference

(0.29, 0.07 to 1.13)

D I S C U S S I O N

Our systematic review demonstrates that hepatitis B vaccine, hep-atitis B immunoglobulin, or the combination of vaccine plus hep-

atitis B immunoglobulin given to newborn infants of HBsAg-pos-

itive mothers prevent hepatitis B occurrence. Further, the combi-

nation of vaccine plus hepatitis B immunoglobulin was superior

to vaccine alone. These benefits were not significantly associated

with the methodological quality of the trials, the mothers HBeAg

status, time of immunisation, or the number of infants dropping

out.

Our review has several potential limitations. First, some analyses

include few trials and a smallnumber ofnewborn infants. Second,

most trials had low methodological quality. However, we did not

find strong association between the methodological quality andthe trial results. This supports the robustness of our results, but

doesnot exclude thepossibility ofbiasaffecting ourresults (Schultz

1995; Moher 1998; Kjaergard 2001; Als-Nielsen 2004). Third,

although we did not find funnel plot asymmetries, we cannot ex-

clude publication bias. Fourth, only few investigators responded

to our request for further information and often the information

was that the details were lost. Fifth, most trials only reported sur-

rogate outcomes (HBsAg status or anti-HBs level) and not long-

term clinical outcomes. Of note is the fact that one trial with long-

term follow-up found more patients with chronic hepatitis in the

PDV plus hepatitis B immunoglobulin group compared with the

PDV group (Ip 1989 AC). Such an increase of chronic hepatitis

could be due to contamination of hepatitis B immunoglobulinwith hepatitis C virus.

Our results convincingly demonstrate that hepatitis B vaccination

reduces hepatitis B infection in newborn infants of hepatitis B

surface antigen-positive mothers. We found no significant differ-

ence between RV and PDV on hepatitis B infections (RR 1.00,

95% CI 0.70 to 1.42). However, a greater number of newborn

infants on PDV did not achieve anti-HBs level above 10 IU/L

(RR 1.96, 95% CI 1.39 to 2.78). The advantage of RV might be

due to the difference in chemical and physical characteristics of

the antigens components of the vaccines (Heijtink 2002). RV is

the vaccine used in high-income countries due to the fear of hu-

man immuno-deficiency virus infection and other infections, in-

cluding transmissible spongiform encephalopathies (MacGregor2004). Our finding seems to support the introduction of RVs in

clinical practice.

The recommended prevention regimen for immune prophylaxis

varies among countries (David 1996; CDC 1999). Similarly in

our included trials, the reported doses and schedules varied sub-

stantially (Table 02). In general, we were unable to demonstrate

significant differences among different doses, different schedules,

and different forms of PDV and RV on hepatitis B occurrence.

Furthermore, our subgroup analyses did not show strong associa-

tions between timing of injection (within 12, 24, or48 hours) and

magnitude of effects. The number of newborn infants evaluated in

these comparisons was small. Therefore, future trials ought to be

much larger before equivalence or non-inferiority can be claimed.

Our meta-analyses demonstrated that hepatitis B immunoglobu-

lin alone or when added to hepatitis B vaccine significantly de-

creased the risk of hepatitis B infection (RR 0.52, 95% CI 0.44

to 0.63). A recent non-randomised study reported no benefit of

adding hepatitis B immunoglobulin to vaccine in HBeAg-negative

mothers (Yang2003). Inour analysis,only onesmalltrialout of11

trials included newborn infants of HBeAg-negative mothers (Xu

1995 AB). Our subgroup analysis, not surprisingly, did not find

any statistically significant difference between newborn infants

of HBeAg-negative and of HBeAg-positive mothers. Accordingly,

more randomised trials on adding hepatitis B immunoglobulin

to vaccine for newborn infants of HBeAg-negative mothers seemwarranted. It should be noticed that hepatitis B immunoglobulin,

as PDV, has the potential of transmitting blood-borne infections

(CDC 1991).

Few trials reported on adverse events. According to what has

been reported, hepatitis B vaccine and hepatitis B immunoglob-

ulin seem safe. These results are in accordance with two recent

Cochrane reviews on hepatitis B vaccination for dialysis patients

and health-care workers (Niu 1996; Chen 2005). Furthermore,

several cohort studies found that hepatitis B vaccination is well

tolerated and severe adverse eventsare rare (ICH 1997; Niu1999;

DuVernoy 2000; Kojouharova 2001; Lewis 2001; Bohlke 2003;

Deeks 2003). However, one cohort study found that vaccine in-

creased the risk of chronic arthritis and acute ear infections (Fisher

2001).Weare unableto determine if this is a reliablefinding dueto

the methodological weakness of cohort studies (CDC 1999). On

the other hand, randomised clinical trials may overlook adverse

events due to relatively low numbers of participants and/or poor

reporting of adverse events (Hayashi 1996; Ioannidis 2001; Etmi-

nan 2004). Further trials ought to focus on these adverse events

following ICH-GCP (ICH 1997).




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The risk of perinatal transmission from HBeAg-negative moth-

ers is considered much lower than in HBeAg-positive mothers

(Okada 1976). If infected, the newborn infants of HBeAg-neg-

ative mothers often clear an asymptomatic infection (Dusheiko

1998). Our findings are mainly based on immune prophylaxis for

newborn infants of mothers being HBsAg and HBeAg positive.Evidence from randomised clinical trials is insufficient to either

support or refute immune prophylaxis for infants of hepatitis B

e antigen negative mothers. The applicability of our findings to

mothers negative for HBeAg, which are of high proportions in eg,

the States and northern Europe, is therefore limited (Funk 2002).

Cost-effectiveness studies indicate that hepatitis B vaccination

for newborn infants of HBsAg-positive mothers are cost effec-

tive in countries with low (Bloom 1993; Tormans 1993; Da Villa

1999; Harris 2001), intermediate, and high prevalence of hep-

atitis B (Hall 1993; Liu 1995; Margolis 1995; Sriprakash 1997).

We identified no cost-effectiveness studies assessing the effects of

adding hepatitis B immunoglobulin to vaccine. As hepatitis B im-

munoglobulin seems able to reduce the risk of hepatitis B infec-tion, the need to perform cost-effectiveness studies based on ran-

domised trials seems justified.

Two trials examined a new way to prevent vertical transmission

of hepatitis B, which could not be included according to our in-

clusion criteria (Lee 2004). The two trials randomised pregnant

women positive for hepatitis B surface antigen to hepatitis B im-

munoglobulin versus no intervention before delivery (Zhu 1997;

Li 2003). In the group receiving immunoglobulin, fewer infants

were positive for hepatitis B surface antigen at follow-up. The

methodological quality of the two trials was low. Furthermore, the

mothers are at risk of developing immune complex disease due to

hepatitis B immunoglobulin reacting with their own circulatinghepatitis B surface antigens. More trials are therefore needed be-

fore this intervention should be adopted.

A U T H O R S C O N C L U S I O N S

Implications for practice

HBsAg positive mothers who are HBeAg positive

Evidence suggests that hepatitis B vaccine, hepatitis B im-

munoglobulin, and the combination of hepatitis B vaccine and

hepatitis B immunoglobulin reduce the risk of perinatal transmis-

sion of hepatitis B in newborn infants of HBsAg positive motherswho are also positive for HBeAg. However, the optimal treatment

regimen remains unclear.

HBsAg positive mothers who are HBeAg negative

There is insufficientevidenceto support or refutethe useof hepati-

tis B vaccine, hepatitis B immunoglobulin, and the combination

of hepatitis B vaccine and immunoglobulin in newborn infants

of HBsAg postive mother who are HBeAg negative. The number

needed to treat to prevent a hepatitis B event is probably much

larger than in mothers who are both HBsAg and HBeAg positive.

Implications for research

The potential adverse events related to hepatitis B prophylaxis

should be studied further, especially the risk for ear infection and

chronic arthritis. The new way of preventing hepatitis B prophy-

laxis in newborn infants - the hepatitis B immunoglobulin ad-

ministration to the pregnant mother - need to be examined in

randomised clinical trials of high quality. The cost-effectiveness

of hepatitis B vaccination and hepatitis B immunoglobulin ought

to be further evaluated based on results from randomised clini-

cal trials. Further trials need to examine the effects of hepatitis B

vaccine and hepatitis B immunoglobulin in newborn infants of

HBsAg positive mothers who are HBsAg negative. Further trials

need to examine the effects of hepatitis B vaccine and hepatitis B

immunoglobulin in preterm infants and low birth-weight infants

of HBsAg-positive mothers. Further trials need to examine if hep-

atitis B vaccine plus multiple hepatitis B immunoglobulin doses

is superior to hepatitis B vaccine plus a single dose of hepatitis B

immunoglobulin.

N O T E S

1. A protocol for a systematic review on this topic was first pub-

lished in Issue 2, 1998 of The Cochrane Library and continued to

be published until Issue 1, 2004 with a title Vaccines for prevent-

ing hepatitis B in high risk newborn infants. The authors, Jeffer-

son TO, Pratt M, Buttery J, and El-Shukri N, have abandoned

the systematic review. This necessitated an update of the protocol

and the conduct of the review be performed by a new team of

reviewers who now consists of Lee C, Gong Y, Brok J, Boxall EH,

and Gluud C.

2. We modified the definition of hepatitis B occurence as shown

in the present review.

3. In our protocol we demanded that each trial had to assess sero-

logical outcome in two and more consecutive blood specimens.

We realized that this requirement was not detainable in themajor-

ity of the trials. We therefore decided to delete this requirement.

P O T E N T I A L C O N F L I C T O F

I N T E R E S T

None known.

A C K N O W L E D G E M E N T S

We thank TO Jefferson, M Pratt, J Buttery, and N El-Shukri who

participated in the formulation of the first Cochrane protocol on

this topic. D Nikolova, The Cochrane Hepato-Biliary Group, is




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thanked for translating a Russian trial and retrieving articles. We

thank D Haughton, The Cochrane Neonatal Review Group, for

retrieving articles. We thank Y Poovorawan and M Piazza who

clarified information on their trials. We thank A Dutta, MM Has-

san, and SD Lee for providing assistance in our work to identify

trial authors, and JUOlsen, GlaxoSmithKline, Denmark, for pro-viding information regarding randomised clinical trials.

S O U R C E S O F S U P P O R T

External sources of support

S.C. Van Foundation DENMARK

Internal sources of support

Public Health Laboratory Service UK

Tri-Service General Hospital TAIWAN

Copenhagen Trial Unit, Centre for Clinical Intervention Re-

search, H:S Rigshospitalet DENMARK

R E F E R E N C E S

References to studies included in this reviewAssateerawatt 1993 {published data only}

Assateerawatt A, Tanphaichitr VS, Suvatte V, Yodthong S. Immuno-

genicityand efficacy ofa recombinant DNAhepatitis B vaccine, Gen-

Hevac B Pasteur in high risk neonates, school children and healthy

adults. Asian Pacific Journal of Allergy Immunology 1993;11(1):8591.

Beasley 1983a AB {published data only} Beasley RP, Hwang LY, Stevens CE,Lin CC, Hsieh FJ,Wang KY, etal. Efficacy ofhepatitisB immune globulin forprevention ofperinatal

transmission of the hepatitis B virus carrier state: final report of a

randomized double-blind, placebo-controlled trial. Hepatology1983;3(2):13541.

Beasley RP, Hwang LY, Szmuness W, Stevens CE, Lin CC, Hsieh FJ,

et al. HBIGprophylaxis for perinatal HBV infections - final report of

the Taiwan trial. Developmental Biology Standard1983;54:36375.

Beasley 1983a CB {published data only} Beasley RP, Hwang LY, Stevens CE,Lin CC, Hsieh FJ,Wang KY, et

al. Efficacy ofhepatitisB immune globulin forprevention ofperinatal

transmission of the hepatitis B virus carrier state: final report of a

randomized double-blind, placebo-controlled trial. Hepatology1983;

3(2):13541.

Beasley RP, Hwang LY, Szmuness W, Stevens CE, Lin CC, Hsieh FJ,

et al. HBIGprophylaxis for perinatal HBV infections - final report of

the Taiwan trial. Developmental Biology Standard1983;54:36375.

Beasley 1983b {published data only}

Beasley RP, Hwang LY, Lee GC, Lan CC, Roan CH, Huang FY, et

al. Prevention of perinatally transmitted hepatitis B virus infections

with hepatitis B virus infections with hepatitis B immune globulin

and hepatitis B vaccine. Lancet1983;2(8359):1099102.

Farmer 1987 {published data only}

Farmer K, Gunn T, Woodfield DG. A combination of hepatitis B

vaccine and immunoglobulin does not protect all infants born to

hepatitis B e antigen positive mothers. New Zealand Medical Journal

1987;100(827):4124.

Garcia 1992 {published data only}

Garcia EG, Gonzalez JRB, Guillot CC, Curbelo GT, Griego AG,

Gonzalez MGD. [Field trial of the Cuban recombinant vaccine

against hepatitisB (Heberbiovac HB).Study in newborn infantsbornto AgsHB+ mothers]. Revista Cubana de Medicina Tropical1992;44

(2):14957.

Grosheide 1993 {published data only} Grosheide PM, del Canho R, Heijtink RA, Nuijten AS, Zwijnen-

berg J, Banffer JR, et al. Passive-active immunization in infants of

hepatitis Be antigen-positive mothers. Comparison of the efficacy of

early and delayed active immunization. American Journal of Diseasesof Children 1993;147(12):131620.

MazelJA, SchalmSW, deGastBC, NuijtenAS, HeijtinkRA, Botman

MJ, et al. Passive-active immunisation of neonates of HBsAgpositive

carrier mothers: preliminary observations. British Medical Journal

(Clinical Research Ed.) 1984;288(6416):5135.

Halliday 1992 AB {published data only}Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH,

et al.An efficacy trial of a mammalian cell-derived recombinant DNA

hepatitis B vaccine in infants born to mothers positive for HBsAg, in

Shanghai, China. International Journal of Epidemiology1992;21(3):

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Halliday 1992 CA {published data only}

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Halliday 1992 DC {published data only}

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ficacy, safety and immunogenicity of Hepavax-Gene and Engerix-

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Ip 1989 AB {published data only} Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention

ofhepatitisB viruscarrier state in infantsaccordingto maternalserum

levels of HBV DNA. Lancet1989;1(8635):40610.

IpHM, WongVC, Lelie PN,Reesink HW, SchaasbergW, Yeung CY,et al. Hepatitis B infection in infants after neonatal immunization.

Acta Paediatric Japanese1989;31(6):6548.

Ip 1989 AC {published data only} Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention

ofhepatitisB viruscarrier state in infantsaccordingto maternalserum


IpHM, WongVC, Lelie PN,Reesink HW, SchaasbergW, Yeung CY,

et al. Hepatitis B infection in infants after neonatal immunization.


Ip 1989 AD {published data only}IpHM,Lelie PN,WongVC, Kuhns MC,ReesinkHW. Preventionof

hepatitis B virus carrier state in infants according to maternal serum





Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE,

Yeung CY, et al.Preventionof the HBsAg carrier state in newborn in-

fantsofmotherswhoarechroniccarriersofHBsAgandHBeAgbyad-

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Ip 1989 BD {published data only}

IpHM,Lelie PN,WongVC, Kuhns MC,ReesinkHW. Preventionof



IpHM, WongVC, Lelie PN,Reesink HW, Schaasberg W, Yeung CY,




Yeung CY, et al.Prevention of the HBsAg carrierstate in newborn in-

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Kang 1995 {published data only} Kang P, Shen XM, Yu HM. [Study on the efficacy of genetically

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Khukhlovich 1996 {published data only}

Khukhlovich PA, Shakhgildian IV, Narkevich MI, Ananev VA,

Kuzin SN, Sergeeva NA, et al. [The vaccinal prophylaxis of hepatitis

B among children born to mothers with persistent HBs-antigene-

mia]. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii1996;2:559.

Kuru 1995 AB {published data only}Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated

infants born to HBsAg-positive mothers with different hepatitis B

vaccines and doses. The Turkish Journal of Pediatrics1995;37(2):93

102.

Kuru 1995 AC {published data only}

Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated


vaccines and doses. The Turkish Journal of Pediatrics1995;37(2):93102.

Kuru 1995 BC {published data only}Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated


vaccines and doses. The Turkish Journal of Pediatrics1995;37(2):93

102.Lee 1995 AB {published data only}

Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The

protective efficacy of recombinant hepatitis B vaccine in newborn

infants of hepatitis B e antigen-positive-hepatitis B surface antigen

carrier mothers. The Pediatric infectious Disease Journal1991;10(4):

299303.

Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-

combinant hepatitis B vaccine and risk of natural infection in infants




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born to mothers with hepatitis B e antigen. The Journal of Pediatrics1995;126(5 Pt 1):71621.

Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up

studyof combinedvaccination withplasma-derived andrecombinant

hepatitis B vaccines in infants. Vaccine1995;13(17):16859.

Lee 1995 CA {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The



carrier mothers. The Pediatric infectious Disease Journal1991;10(4):299303.



born to mothers with hepatitis B e antigen. The Journal of Pediatrics

1995;126(5 Pt 1):71621.




Lee 1995 CB {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The




299303.



born to mothers with hepatitis B e antigen. The Journal of Pediatrics1995;126(5 Pt 1):71621.




Lee 1995 DE {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The




299303.



born to mothers with hepatitis B e antigen. The Journal of Pediatrics

1995;126(5 Pt 1):71621.




Liu 1987 AB {published data only}

Liu LH. [Comparative study of the efficacy of hepatitis B virus

(HBV) vaccine combined with hepatitis B immunoglobulin(HBIG)

versus vaccine alone in the interruption of the perinatal transmission

of HBV carrier state]. Zhonghua Liu Xing Bing Xue Za Zhi1987;8

(6):3258.

Liu 1987 CA {published data only}

Liu LH. [Comparative study of the efficacy of hepatitis B virus




(6):3258.

Liu 1987 CB {published data only}Liu LH. [Comparative study of the efficacy of hepatitis B virus




(6):3258.

Lo 1985 AB {published data only}

Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et al.

Prevention of hepatitis B virus infection in children born to HBsAg

positive/HBeAg positive mothers. Preliminary results of active and

passive-active immunization. Developmental Biology Standard1983;54:399404.

Lo KJ, TsaiYT, LeeSD, Yeh CL, Wang JY, Chiang BN, et al. Com-

bined passive and active immunization for interruption of perinatal

transmission of hepatitis B virus in Taiwan. Hepatogastroenterology

1985;32(2):658.

Lo 1985 CA {published data only}Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et al.


positive/HBeAg positive mothers. Preliminary results of active and

passive-active immunization. Developmental Biology Standard1983;54:399404.

Lo KJ, TsaiYT, LeeSD, Yeh CL, Wang JY, Chiang BN, et al. Com-



1985;32(2):658.

Lo 1985 CB {published data only}Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et al.


positive/HBeAg positive mothers. Preliminary results of active andpassive-active immunization. Developmental Biology Standard1983;54:399404.

Lo KJ, TsaiYT,Lee SD,Yeh CL, Wang JY, Chiang BN, et al. Com-



1985;32(2):658.

Lolekha 2002 {published data only}

LolekhaS, WarachitB, HirunyachoteA, Bowonkiratikachorn P, West

DJ, Poerschke G. Protective efficacy of hepatitis B vaccine without

HBIG in infants of HBeAg-positive carrier mothers in Thailand.

Vaccine2002;20(31-32):373943.

Oon 1986 AB {published data only}

Oon CJ, Tan KL, Goh KT, Wong-Yong L, Viegas O, McCarthy T,et al. Evaluation of a low dose of hepatitis B vaccine given within

a childhood immunisation programme in Singapore. The Journal ofInfection 1986;13(3):25567.

Oon 1986 CD {published data only}

Oon CJ, Tan KL, Goh KT, Wong-Yong L, Viegas O, McCarthy T,

et al. Evaluation of a low dose of hepatitis B vaccine given within

a childhood immunisation programme in Singapore. The Journal ofInfection 1986;13(3):25567.




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Piazza 1985 {published data only}Piazza M, Picciotto L, Villari R, Guadagnino V, Orlando R, Isabella

L, et al. Hepatitis B immunisation with a reduced number of doses

in newborn babies and children. Lancet1985;1(8435):94951.

Pongpipat 1986 {published data only}Pongpipat D, Suvatte V, Assateerawatts A. Efficacy of hepatitis-B

immunoglobulinand hepatitis-Bvaccinein prevention of the HBsAg

carrier state in newborn infants of mothers who are chronic carriers

of HBsAg and HBeAg. Asian Pacific Journal of Allergy Immunology1986;4(1):336.

Pongpipat 1988 {published data only}

PongpipatD, Suvatte V, AssateerawattsA. Hepatitis B immunization

in high risk neonates born from HBsAg andHBeAgpositive mothers:

comparison of standard and low dose regimens. Asian Pacific Journalof Allergy Immunology1988;6(2):10710.

Pongpipat 1989 {published data only}PongpipatD, Suvatte V, AssateerawattsA. Hepatitis B immunization

in highrisk neonatesborn fromHBsAg positivemothers:comparison

between plasma derived and recombinant DNAvaccine.Asian Pacific

Journal of Allergy Immunology1989;7(1):3740.

Poovorawan 1997 {published data only} PoovorawanY, Sanpavat S, Chumdermpadetsuk S, Safary A. Long-

term hepatitis B vaccine in infants born to hepatitis B e antigen

positive mothers. Archives of Disease in Childhood.Fetal and Neonatal

Edition 1997;77(1):F47F51.

Poovorawan Y,Sanpavat S, Pongpunglert W, Chumdermpadetsuk S,

Sentrakul P, Vandepapeliere P, et al. Long term efficacy of hepatitis

B vaccine in infants born to hepatitis B e antigen-positive mothers.

The Pediatric Infectious Disease Journal1992;11(10):81621.

Sehgal 1992 {published data only}

Sehgal A, Gupta I, Sehgal R, GangulyNK. Hepatitis B vaccine alone

or in combination with anti-HBs immunoglobulin in the perinatal

prophylaxis of babies born to HBsAgcarrier mothers. Acta Virologica1992;36(4):35966.

Sehgal A, Sehgal R, Gupta I, Bhakoo ON, Ganguly NK. Use of

hepatitis B vaccine alone or in combination with hepatitis B im-

munoglobulin for immunoprophylaxis of perinatal hepatitis B infec-

tion. Journal of Tropical Pediatrics1992;38(5):24751.

Theppisai 1987 {published data only}

Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P. A compar-

ison between the efficacy of passive-active and active immunization

for prevention of perinatal transmission of hepatitis B virus. Journalof Medical Association, Thailand1987;70(8):45962.

Theppisai 1990 {published data only}Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P. Prevention

of hepatitis B infection in infants born to hepatitis B carrier moth-

ers: low dosage vaccination. International Journal of Gynaecology and

Obstetrics1990;32(4):3537.

Xu 1995 AB {published data only}Xu ZY, Duan SC,MargolisHS, Purcell RH,Ou-YangPY,Coleman

PJ, et al. Long-term efficacy of active postexposure immunization of

infants for prevention of hepatitis B virus infection. United States-

Peoples Republic of China Study Group on Hepatitis B. The Journalof Infectious Diseases1995;171(1):5460.

Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et

al. Prevention of hepatitis B virus carriage of infants using HBV

vaccine in Shanghai. Preliminary report of a randomized double-

blind placebo-controlled trial. Chinese Medical Journal1985;98(9):

6236.

Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, 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. Pediatrics1985;76(5):7138.

Xu 1995 AD {published data only}XuZY,Duan SC,Margolis HS,Purcell RH,Ou-YangPY,Coleman








6236.





Xu 1995 BD {published data only}XuZY,Duan SC,Margolis HS,Purcell RH,Ou-YangPY,Coleman






vaccine in Shanghai. Preliminary report of a randomized double-blind placebo-controlled trial. Chinese Medical Journal1985;98(9):6236.





Xu 1995 CB {published data only}XuZY,Duan SC,Margolis HS,Purcell RH,Ou-YangPY,Coleman



Peoples Republic of China Study Group on Hepatitis B. The Journal

of Infectious Diseases1995;171(1):5460.

Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, etal. Prevention of hepatitis B virus carriage of infants using HBV



6236.








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Xu 1995 CD {published data only}Xu ZY, Duan SC,MargolisHS, Purcell RH,Ou-YangPY,Coleman




XuZY, FrancisDP, LiuCB,PurcellRH, Duan SC,et al.Preventionof

hepatitis B virus carriage of infants using HBV vaccine in Shanghai.

Preliminary report of a randomized double-blind placebo-controlled

trial. Chinese Medical Journal1985;98(9):6236.





Yeoh 1986 {published data only}

Yeoh EK, Chang WK, IpP, Chan KH, Chan E, Fung C. Efficacyand

safety of recombinant hepatitis B vaccine in infants born to HBsAg-

positive mothers. The Journal of Infection 1986;13 Suppl A:158.

Zhu 1987 {published data only}

Zhu Q-Y, Radvan GH. A randomized controlled trial of hepatitis

B vaccine in high risk newborn infants in China. Australian & New

Zealand Journal of Medicine1987;17:498.

Zhu 1994 {published data only}

Zhu QR, Gu XH, Duan SC, Xu HF. Long-term immunogenicity

and efficacy of recombinant yeast derived hepatitis B vaccine for in-

terruptionof mother-infant transmissionof hepatitisB virus.ChineseMedical Journal1994;107(12):9158.

References to studies excluded from this reviewChung 1988

ChungWK. Persistenceandboostingresponseof antibodyto HBsAg

induced by vaccine treatment. Tropical Gastroenterology1988;9(1):

2630.

Chung 1988 BChung WK, Choi KY, Shim KS, Chung JW, Sun HS, Chung KW,

et al. Safety, immunogenicity, and efficacy of a new heat-inactivated

hepatitis B vaccine in the newborn. Viral Hepatitis and Liver Disease1988:10146.

Coursaget 1984

Coursaget P, Deciron F, Tortey E, Barin F, Chiron JP, Yvonnet B, et

al. Immune response to hepatitis B vaccine in infants and newborns:

control trial in an endemic area (Senegal). International Agency for

Research on Cancer1984;63:31935.

Da 1995

Da Villa G, Picciottoc L, Elia S, Peluso F, Montanaro F, Maisto T.

HepatitisB vaccination: universal vaccinationof newborn babies and

children at 12 years of age versus high risk groups. A comparison in

the field. Vaccine1995;13(13):12403.

Delage 1993

Delage G, Remy-Prince S, Montplaisir S. Combined active-passive

immunization against the hepatitis B virus: five-year follow-up of

children born to hepatitis B surface antigen-positive mothers. The

Pediatric Infectious Disease Journal1993;12(2):12630.

Esteban 1986

Esteban JI, Genesca J, Esteban R, Hernandez JM, Seijo G, Buti M,

et al. Immunoprophylaxis of perinatal transmission of the hepatitis

B virus: efficacy of hepatitis B immune globulin and hepatitis B

vaccine in a low-prevalence area. Journal of Medical Virology 1986;

18(4):38191.

Goh 1992

Goh KT, Tan KL, Kong KH, Oon CJ, Chan SH.Comparison of the

immune response of four different dosages of a yeast-recombinant

hepatitisB vaccine in Singaporechildren: a four-year follow-up study.

Bulletin of the World Health Organization 1992;70(2):2339.

Kang 1986

Kang Y. Efficacy of domestic hepatitis B viral vaccines in preventing

transmissionof e antigenfrom mothersto newborn infants.ZhonghuaLiu Xing Bing Xue Za Zhi1986;7(2):813.

Lai 1986

Lai CL, Yeoh EK, Chang WK, Lo VW, Ng LN. Use of the hepatitis

B recombinant DNA yeast vaccine (H-B-VAX II) in children: two

doses vs. three doses of 5 micrograms regime; an interim report. TheJournal of Infection 1986;13 Suppl A:1925.

Lai 1993

Lai CL, Wong BC, Yeoh EK, Lim WL, Chang WK, Lin HJ. Five-yearfollow-up ofa prospectiverandomized trial of hepatitis B recom-

binant DNA yeast vaccine vs. plasma-derived vaccine in children:

immunogenicity and anamnestic responses. Hepatology1993;18(4):

7637.

Laille 1988

Laille M, Brethes B, Moreau JP, Pillot J. [Trial of hepatitis B pro-

phylaxis in children born to mothers carrying HBs antigen in New

Caledonia].Bulletin de la Societede Pathologie Exotique et de sesFiliales

1988;81(4):6738.

Lin 1987

Lin KH, Twu SJ, Chen DS, Su S, Lee CJ. Efficacy of the national

hepatitis B vaccination program in the Republic of China: prelim-

inary observations from Taoyuan area. Taiwan Yi Xue Hui Za Zhi1987;86(8):86972.

Linder 2000

Linder N, w-up.5Tf-24.9p97 0 Tdf-14.7601 Td0.63989en70.5Tf-8iS5599j6.95991 0 Td8 0 0 Td(F)Tjobser5998 0 Td(oh9 Td(Yi)Tj9.47inh.11.87993 0 T/R1it3R101 7.j8.75986.759HBsthe23.15979.47in


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Nair 1984

Nair PV, Weissman JY, Tong MJ, Thursby MW, Paul RH, Henne-

man CE. Efficacy of hepatitis B immune globulin in prevention of

perinatal transmission of the hepatitis B virus.Gastroenterology1984;

87(2):2938.

Okoth 1994

Okoth FA, Kobayashi M, Takayanagi N, Kapttich DC, Kaiguri PM,

Tukei PM. Efficacy of hepatitis B vaccine in a rural community in

Muranga, Kenya. East

hepatitis b immunisation for

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