hepatitis b immunisation for newborn infants of hepatitis

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 and published in The Cochrane Library2008, Issue 3

http://www.thecochranelibrary.com

1Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

http://www.thecochranelibrary.com

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

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .

3SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .

3METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .

8ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42Table 01. Search strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44Table 02. Intervention by group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47Comparison 01. Vaccine versus placebo or no intervention . . . . . . . . . . . . . . . . . . . .

47Comparison 02. RV versus PDV . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47Comparison 03. High-dose versus low-dose vaccine . . . . . . . . . . . . . . . . . . . . . . .

48Comparison 04. Three-dose PDV plus HBIG versus two-dose PDV plus HBIG . . . . . . . . . . . . .

48Comparison 05. PDV at birth versus PDV at one month . . . . . . . . . . . . . . . . . . . . .

48Comparison 06. One type of PDV versus another type of PDV . . . . . . . . . . . . . . . . . . .

48Comparison 07. Four RV vaccinations versus three RV vaccinations . . . . . . . . . . . . . . . . .

48Comparison 08. One type of RV versus another type of RV with the same vaccination schedule . . . . . . . .

48Comparison 09. HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . . . . . .

49Comparison 10. Multiple HBIG plus PDV versus single HBIG plus PDV . . . . . . . . . . . . . . .

49Comparison 11. PDV plus HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . .

49INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51Analysis 01.01. Comparison 01 Vaccine versus placebo or no intervention, Outcome 01 Hepatitis B events according to

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


methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events - Sensitivity

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


the mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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

57Analysis 02.01. Comparison 02 RV versus PDV, Outcome 01 Hepatitis B events . . . . . . . . . . . . .

58Analysis 02.02. Comparison 02 RV versus PDV, Outcome 02 Hepatitis B events according to methodological quality

59Analysis 02.03. Comparison 02 RV versus PDV, Outcome 03 Hepatitis B events - sensitivity analyses . . . . . .

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


61Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mother’s HBeAg status

62Analysis 02.05. Comparison 02 RV versus PDV, Outcome 05 Anti-HBs less than 10 IU/L . . . . . . . . .

62Analysis 03.01. Comparison 03 High-dose versus low-dose vaccine, Outcome 01 Hepatitis B events . . . . . .

63Analysis 03.02. Comparison 03 High-dose versus low-dose vaccine, Outcome 02 Hepatitis B events according to

methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events - sensitivity analyses

66Analysis 03.04. Comparison 03 High-dose versus low-dose vaccine, Outcome 04 Hepatitis B events according to the

mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67Analysis 03.05. Comparison 03 High-dose versus low-dose vaccine, Outcome 05 Anti-HBs less than 10 IU/L . . .

67Analysis 04.01. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 01 Hepatitis

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

68Analysis 04.02. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 02 Anti-HBs

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

68Analysis 05.01. Comparison 05 PDV at birth versus PDV at one month, Outcome 01 Hepatitis B events . . . .

69Analysis 06.01. Comparison 06 One type of PDV versus another type of PDV, Outcome 01 Hepatitis B events . .

69Analysis 07.01. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 01 Hepatitis B events .

70Analysis 07.02. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 02 Anti-HBs level less

than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

70Analysis 08.01. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule, Outcome

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

71Analysis 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71Analysis 09.01. Comparison 09 HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events . . . .

73Analysis 09.02. Comparison 09 HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events according to

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

74Analysis 09.03. Comparison 09 HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events - sensitivity

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


the mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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

80Analysis 09.07. Comparison 09 HBIG versus placebo or no intervention, Outcome 07 Anti-HBs less than 10 IU/L .

81Analysis 09.08. Comparison 09 HBIG versus placebo or no intervention, Outcome 08 Anti-HBs level . . . . .

81Analysis 09.09. Comparison 09 HBIG versus placebo or no intervention, Outcome 09 Adverse events . . . . .

82Analysis 10.01. Comparison 10 Multiple HBIG plus PDV versus single HBIG plus PDV, Outcome 01 Hepatitis B

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

82Analysis 11.01. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events


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

84Analysis 11.03. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events -

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


according to mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . .


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

87Analysis 11.06. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 06 Adverse events . .

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


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

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

This record should be cited as:

Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive

mothers. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD004790. DOI: 10.1002/14651858.CD004790.pub2.

This version first published online: 19 April 2006 in Issue 2, 2006.

Date of most recent substantive amendment: 22 February 2006

A B S T R A C T

Background

Hepatitis B vaccine and hepatitis B 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 ControlledTrials Register, The Cochrane Central Register of Controlled Trials in 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, mother’s

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

Main results

We identified 29 randomised clinical trials, five of which were considered high quality. Only three trials reported inclusion of hepatitis B

e-antigen negative mothers. Compared with placebo/no intervention, vaccine reduced hepatitis B occurrence (RR 0.28, 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.



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 hepatitis

B 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 blood

or 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 yeast or 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 an

assessment 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 versus placebo 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) Systemic adverse events: adverse events such 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.



(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-

tent or significant disability; or any important medical event which

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 TrialsRegister, The Cochrane Hepato-Biliary Group ControlledTrials Register, The Cochrane Central Register of ControlledTrials(CENTRAL) in The Cochrane Library, MEDLINE/PubMed,

and EMBASE. The search strategies and time span of the

searches are specified in Table 01. We consulted with The

Cochrane Vaccines Field to identify further trials, but no reply

was received. We read the bibliographies of retrieved articles

to identify further trials. We checked the reference 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) involved in the

production of hepatitis B vaccines for missing information 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

with regard to the names of 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

included 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;

methodological quality (see below); dosage and types of vaccines;

site of injection; vaccination schedules; duration of follow-up;

outcome measures; 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

design and report restrict bias in the intervention comparison

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

of intervention effects in randomised trials with inadequate

methodological quality (Schultz 1995; Moher 1998; Kjaergard

2001), the methodological quality was assessed by using the

following criteria:

Generation of the allocation sequence

• Adequate, if the allocation sequence was generated by a

computer or random number table. Drawing of lots, tossing

of a coin, shuffling of cards, or throwing dice was considered

as adequate if a person who was not otherwise involved in the

recruitment of participants performed the procedure.

• Unclear, if the trial was described as randomised, but the method

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

independent unit, on-site locked computer, identically

appearing numbered drug bottles or containers prepared by an

independent pharmacist or investigator, or sealed envelopes.

• Unclear, if the trial was described as randomised, but the method

used to conceal the allocation was not described.

• Inadequate, if the allocation sequence was known to the

investigators 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

withdrawals 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

withdrawals were not described.

We post hoc defined 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

was due to the fact that only a single trial had high quality regarding

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 weighted mean difference (WMD) with 95% 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 STATA®on hepatitis

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

regression analysis examined the intervention effect in relation

to methodological quality of trials, dosage of hepatitis B

immunoglobulin and vaccine, and time of immunisation.

Subgroup analyses were performed to compare the effects of

vaccines in mothers with HBsAg (+)/HBeAg(+) compared to

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

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

quality). The difference between the estimates of two subgroups

was estimated according to Altman 2003.

Regarding the hepatitis B occurrence, we included newborn

infants 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

experimental and control group had the primary outcome;

• Extreme case favouring experimental intervention: none of the

dropouts in the experimental group but 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 Begg’s and Egger’s

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 listed under ’Characteristics of excluded studies’

with reasons 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/Oon

1986 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 groups

were 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



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 different types of RV (RV1(Beijing, China) ver-

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

and one trial assessed Cuban versus Engerix-B (Galban 1992). 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 schedules were 0-1-6 months (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 to

260 IU. Hepatitis B immunoglobulin was administered within 12

hours of birth in seven trials (Beasley 1983a AB/Beasley 1983a CB;

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 hepatitis

B immunoglobulin

One trial compared 5 microgram PDV at 2-6-10 weeks 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 microgram

PDV 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

comparisons and which trials assessed this comparison. The capital

letters after years of publication in the references stands for the

comparison arms of the individual trial.

Mother’s HBeAg status

Eighteen 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 mother’s HBeAg status was not reported.

Newborn’s 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 1989 CD; Piazza 1985; Liu 1987

AB/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 tri-

als (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 risk of 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



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 mother’s HBeAg status, or time of

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

spectively). Post hoc subgroup 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

analyses did not find a significant difference regarding the method-

ological quality or the mother’s 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-

paring 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).

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 (RR 0.05, 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 of

age 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, hepatitis B immunoglobulin alone significantly reduced hep-

atitis B occurrence (RR 0.50, 95% CI 0.41 to 0.60, 1 trial). Com-

pared with vaccination, 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 mother’s HBeAg

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

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

Hepatitis B immunoglobulin had no significant effect on 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 not able 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 Egger’s nor the Begg’s graphs and their corresponding

tests on hepatitis B occurrence provided evidence for asymmetry

(Egger’s test, P = 0.31; Begg’s test, P = 0.23).

Multiple hepatitis B immunoglobulin versus single hepatitis

B immunoglobulin administration (Comparison 10-01)

Multiple hepatitis B immunoglobulin plus PDV versus 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%).



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 not

find a significant difference between high- and low-quality trials,

the mother’s HBeAg status, or time of hepatitis B immunoglob-

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

spectively).

One trial reported the number of adverse events: 3 out of 71 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 mother’s 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 small number of newborn infants. Second,

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

find strong association between the methodological quality and

the trial results. This supports the robustness of our results, but

does not exclude the possibility of bias affecting our results (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 immunoglobulin

with 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 (MacGregor

2004). 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, or 48 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 (Yang 2003). In our analysis, only one small trial out of 11

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 seem

warranted. 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 events are rare (ICH 1997; Niu 1999;

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). We are unable to determine if this is a reliable finding due to

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).



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 circulating

hepatitis 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 mothers

who are also positive for HBeAg. However, the optimal treatment

regimen remains unclear.

HBsAg positive mothers who are HBeAg negative

There is insufficient evidence to support or refute the use of 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 the major-

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



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 JU Olsen, 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

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

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

randomized double-blind, placebo-controlled trial. Hepatology 1983;

3(2):135–41.

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

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the Taiwan trial. Developmental Biology Standard 1983;54:363–75.

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

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

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

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

fants of mothers who are chronic carriers of HBsAg and HBeAg by ad-

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born to mothers with hepatitis B e antigen. The Journal of Pediatrics1995;126(5 Pt 1):716–21.




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 Zhi 1987;8

(6):325–8.

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




(6):325–8.

Liu 1987 CB {published data only}

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




(6):325–8.

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 Standard 1983;

54:399–404.

∗Lo KJ, Tsai YT, Lee SD, Yeh CL, Wang JY, Chiang BN, et

al.Combined passive and active immunization for interruption of

perinatal transmission of hepatitis B virus in Taiwan. Hepatogastroen-

terology 1985;32(2):65–8.

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




54:399–404.



perinatal transmission of hepatitis B virus in Taiwan. Hepatogastroen-terology 1985;32(2):65–8.

Lo 1985 CB {published data only}

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




54:399–404.



perinatal transmission of hepatitis B virus in Taiwan. Hepatogastroen-

terology 1985;32(2):65–8.

Lolekha 2002 {published data only}

Lolekha S, Warachit B, Hirunyachote A, Bowonkiratikachorn P, West

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

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

Vaccine 2002;20(31-32):3739–43.

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):255–67.

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 of

Infection 1986;13(3):255–67.



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. Lancet 1985;1(8435):949–51.

Pongpipat 1986 {published data only}

Pongpipat D, Suvatte V, Assateerawatts A. Efficacy of hepatitis-B

immunoglobulin and hepatitis-B vaccine in prevention of the HBsAg

carrier state in newborn infants of mothers who are chronic carriers

of HBsAg and HBeAg. Asian Pacific Journal of Allergy Immunology

1986;4(1):33–6.

Pongpipat 1988 {published data only}Pongpipat D, Suvatte V, Assateerawatts A. Hepatitis B immunization

in high risk neonates born from HBsAg and HBeAg positive mothers:

comparison of standard and low dose regimens. Asian Pacific Journal

of Allergy Immunology 1988;6(2):107–10.

Pongpipat 1989 {published data only}

Pongpipat D, Suvatte V, Assateerawatts A. Hepatitis B immunization

in high risk neonates born from HBsAg positive mothers: comparison

between plasma derived and recombinant DNA vaccine. Asian PacificJournal of Allergy Immunology 1989;7(1):37–40.

Poovorawan 1997 {published data only}∗Poovorawan Y, 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):F47–F51.

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 Journal 1992;11(10):816–21.

Sehgal 1992 {published data only}

Sehgal A, Gupta I, Sehgal R, Ganguly NK. Hepatitis B vaccine alone

or in combination with anti-HBs immunoglobulin in the perinatal

prophylaxis of babies born to HBsAg carrier mothers. Acta Virologica1992;36(4):359–66.

∗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 Pediatrics 1992;38(5):247–51.

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. Journal

of Medical Association, Thailand 1987;70(8):459–62.

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 andObstetrics 1990;32(4):353–7.

Xu 1995 AB {published data only}∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman

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

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

People’s Republic of China Study Group on Hepatitis B. The Journal

of Infectious Diseases 1995;171(1):54–60.

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

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

cine in Shanghai. Preliminary report of a randomized double-blind

placebo-controlled trial. Chinese Medical Journal 1985;98(9):623–6.

Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC,

et al.Prevention of perinatal acquisition of hepatitis B virus car-

riage using vaccine: preliminary report of a randomized, double-

blind placebo-controlled and comparative trial. Pediatrics 1985;76

(5):713–8.

Xu 1995 AD {published data only}∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman













(5):713–8.

Xu 1995 BD {published data only}∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman













(5):713–8.

Xu 1995 CB {published data only}∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman













(5):713–8.



Xu 1995 CD {published data only}∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman





Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, 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 Journal 1985;98(9):623–6.





(5):713–8.

Yeoh 1986 {published data only}

Yeoh EK, Chang WK, Ip P, Chan KH, Chan E, Fung C. Efficacy and

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

positive mothers. The Journal of Infection 1986;13 Suppl A:15–8.

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 & NewZealand Journal of Medicine 1987;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-

terruption of mother-infant transmission of hepatitis B virus. ChineseMedical Journal 1994;107(12):915–8.

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Chung WK. Persistence and boosting response of antibody to HBsAg

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Sriprakash I, Anil T. Routine prenatal screening of Indian women

for HBsAg: benefits derived versus cost. Tropical Doctor 1997;27(3):

176–7.

Stevens 1975

Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of

hepatitis B antigen in Taiwan. The New England Journal of Medicine

1975;292(15):771–4.

Szmuness 1981

Szmuness W, Stevens CE, Zang EA, Harley EJ, Kellner AA. A con-

trolled clinical trial of the efficacy of the hepatitis B vaccine: a final

report. Hepatology 1981;1(5):377–85. [MEDLINE: 7030902].

Tormans 1993

Tormans G, Van Damme P, Carrin G, Clara R, Eylenbosch W. Cost-

effectiveness analysis of prenatal screening and vaccination against

hepatitis B virus - the case of Belgium. Social Society of Medicine 1993;

37(2):173–81.

WHO 2002

World Health Organization Department of Communicable Disease

Surveillance and Response.

Hepatitis B. http://www.who.int/csr/disease/hepatitis/HepatitisB_

whocdscsrlyo2002_2.pdf (Accessed 7 February 2006).

Yang 2003

Yang Y, Liu C, Chen T, Lee M, Chen S, Shi H, et al.Role of hepatitis

B immunoglobulin in infants born to hepatitis B e antigen-negative

carrier mothers in Taiwan. Pediatrics Infection Disease Journal 2003;

22(7):584–8.



Yao 1996

Yao JL. Perinatal transmission of hepatitis B virus infection and vac-

cination in China. Gut 1996;38 Suppl 2:S37–S38.

Zhu 1997

Zhu Q, Lu Q, Gu X, Xu H, Duan S. A preliminary study on in-

terruption of HBV transmission in uterus. Chinese Medical Journal

1997;110(2):145–7.

∗Indicates the major publication for the study

T A B L E S

Characteristics of included studies

Study Assateerawatt 1993

Methods Generation of allocation sequence: adequate - random permutation table.

Allocation concealment: unclear - not described.

Blinding: not performed.

Follow-up: inadequate - only number of dropouts reported in each group, the reasons not described.

Participants Country: Thailand.

Publication language: English.

Inclusion criteria:

HBsAg and HBeAg positive mothers.

Interventions Group A: HBIG 100 IU at birth and GenHevac (RV) 20 microgram at birth, 1, 2 and 12 months.

Group B: GenHevac (RV) 20 microgram at birth, 1, 2 and 12 months.

Outcomes HBsAg

Anti-HBs

Anti-HBc

Notes Follow-up time: 14, 18 or 30 months.

Adverse events: there were no serious reactions to the vaccine, and the adverse effects observed were mild and

transient. Local swelling and erythema were observed in 3.3% of neonates.

Allocation concealment B – Unclear

Study Beasley 1983a AB

Methods Generation of allocation sequence: unclear - not described.


Blinding: unclear - described as double blind, but method of blinding not described.

Follow-up: adequate - number and reasons reported.

Participants Country: Taiwan.


Inclusion criteria:

HBsAg- and HBeAg-positive mothers.

Infant birth weight over 2500 gm with Apgar scores > 8 at 1 minute.

Exclusion criteria:



Characteristics of included studies (Continued )

HBeAg negative mother.

Participants:

(1) Group A (control group)

received no prophylaxis against HBV. 23 were infants born in the same hospital and 61 were those randomised

blind to receive placebo in another HBIG prophylaxis trial.

Birth weight: (3239+-407) gram

Older siblings (mean number): 0.5+-0.6

Cord blood positive (%): 29.5%

Age 1st treatment (minutes): 36.0+-76.8

Age 2nd treatment (minutes): 98.4+-9.0

Age 3rd treatment (minutes): 190.1+-8.8

Mother’s mean age: 24.8+-3.1

HBsAg titer: 12.1+-1.7

Drop-out: 12

(2) Group B









Drop-out: 9

(3) Group C









Drop-out: 6

Interventions Group A: HBIG 1.0 mL (180 mIU, Abbott) at birth and saline at 3 and 6 months.

Group B: saline at birth, 3 and 6 months.

Group C: given HBIG 0.5 mL (90 mIU, Abbott) diluted in 0.5 mL of immune serum globulin at birth, 3

and 6 months.

The mean administration time of HBIG was within 36 minutes of birth: 95% were treated within an hour;

all were treated within 30 hours.

Outcomes Hepatitis events at 15 months follow-up. HBsAg, Anti-HBs, Anti-HBc, and HBeAg.

Notes Follow-up time: 15 months.

Adverse events: One infant died, but the death appeared unrelated to HBIG.

12 dropouts in Group A, including 10 refuse and 2 lost; 9 in Group B, including 7 refuse and 2 lost; 6

dropouts in Group C, all because of refusal.





Study Beasley 1983a CB

Methods This trial is the same as Beasley 1983a BA, but has been entered with its own identifier due to technical

limits of RevMan in order to make data comparison.

Participants

Interventions

Outcomes

Notes


Study Beasley 1983b



Blinding: unclear - described as double blind but the method of blinding was not described.

Follow-up: adequate - no dropouts.



Inclusion criteria:


infant birth weight over 3000 gm and one-minute Apgar scores >= 9.

Participants:

(1) Control group

received no prophylaxis against HBV. 23 were infants born in the same hospital and 61 were those randomised

blind to receive placebo in another HBIG prophylaxis trial.

Birth weight (mean +- SD): (3185+-438 gram)

Sex ratio (% male): 50.7

Apgar score: 9.9+-0.1

Age initial HBIG (min): not reported.

Mother’s age: 25.1+-3.3

(2) Group A




Age initial HBIG (min): 65+-186


(3) Group B


Sex ratio (% male): 56




(4) Group C






Interventions Control group: saline at birth (mean and SD = 2.1+-4.8 h), 3 and 6 months (from previous study).




Group A: HBIG 0.5 mL (145 IU, Abbott) at birth, a second dose at 3 months of age, at which time

vaccination (20 microgram, Merck Sharp and Dohme) is initiated (88.6+-14.5 days). Followed by boosters

a month and 6 month later.

Group B: HBIG 0.5 mL at birth only and vaccination was initiated when they were 4 to 7 days old (6.3+-

1.5). Followed by boosters a month and 6 month later.

Group C: HBIG 0.5 mL only and vaccination was initiated when they were approximately 1 month old

(30.2+-4.3 days). Followed by boosters a month and 6 month later.

Outcomes Hepatitis events at maximum HBsAg, anti-HBs.


Adverse events:

The data in control group (84 infants) were obtained from another trial (Beasley, 1983)


Study Farmer 1987

Methods Generation of allocation sequence: adequate - random number list.



Follow-up: inadequate - not specified in the each groups.

Participants Country: New Zealand.


Inclusion criteria:

Both HBsAg and HBeAg positive mothers.

infant birth weight over 2500 gm with Apgar scores > 8 at 1 minute.

Exclusion criteria:

not reported.

Participants:

(1) Group A

(3) Group B

Interventions Group A: 0.25 mL (5 microgram) Hepavax (PDV, Merck Sharp and Dohme) I.M. at birth, 6 weeks and 6

months.

Group B: 0.25 mL (5 microgram) Hepavax (PDV, Merck Sharp and Dohme) I.M. plus HBIG 0.25 mL (25

IU/kg) at birth then Hepavax + HBIG 0.25 mL (25 IU/kg) at 6 weeks. Finally, another Hepavax vaccine in

6 months.

Outcomes Hepatitis events at maximum follow-up.

HBsAg. HBeAg and anti-HBs.


Adverse events: not reported.

Four infants were lost to follow-up.


Study Garcia 1992



Blinding: unclear - described as double blind but the method of blinding was not described.




Follow-up: inadequate - not described.

Participants Country: Cuba.

Publication language: Spanish.

Inclusion criteria:

HBsAg positive mothers.

Interventions Group A (Cuban): RV 10 microgram at birth, 1 and 2 months.

Group B (SK): RV 10 microgram at birth, 1, and 2 months.

Outcomes Anti-HBs, HBsAg, Anti-HBc.

Notes Follow up time: 6 months.



Study Grosheide 1993

Methods Generation of allocation sequence: unclear - described as randomised, but the method not described.

Allocation concealment: adequate - sealed envelops.


Follow-up: adequate - number and reasons for dropouts described.

Participants Country: Netherlands


Inclusion criteria:


Exclusion criteria:

Participants:

Group A:

Mother median age: 23 (19;33)

Country of birth, No. (%)

The Netherlands +other: 3 (8.6)

Mediterranean: 15 (42.9)

Surinam: 5 (14.3)

Asia: 12 (34.3)

Group B:

Mother median age: 24 (17;38)

Country of birth, No. (%)

The Netherlands +other: 2 (5.4)

Mediterranean: 16 (43.2)

Surinam: 7 (18.9)

Asia: 12 (32.4)

Eight infants (schedule A, three infants; schedule B, five infants) were excluded from further analysis.

Interventions Group A: HBIG (0.5 mL/kg body weight) given within 2 hours of birth and PDV 10 microgram 2 days

after birth, 1, 2, and 11 months.

Group B: HBIG (0.5 mL/kg body weight) and PDV 10 microgram at 3, 4, 5 and 11 months (with diphtheria,

pertussis, tetanus, poliomyelitis concomitantly. HBIG (0.5 mL/kg body weight) was given at the age of 3

months.

Outcomes Number of HBsAg positive children in each group.

Anti-HBs level.





Adverse events: no side-effect were observed after neither passive or active immunisation (data from Mazel

et al, 1984, a duplication publication). The data in this trial were not usable because the PDV vaccination

schedule were different.

Allocation concealment A – Adequate

Study Halliday 1992 AB

Methods Generation of allocation sequence: adequate - random code.

Allocation concealment: adequate - by independent unit.

Blinding: adequate - injection was administered by a doctor who was not part of the research team. No one

on the research team, or in the laboratory that performed the HBV marker tests, knew which vaccine was

administered or whether the infant received HBIG.

Follow-up: adequate - number and reasons described in each groups.

Participants Country: China.


Inclusion criteria:


infant weight equal to or greater than 2500 gm and a 5-minute Apgar score equal to or greater than 7

or infant weights less than 2500 gm but greater than 1600 gm and a 5-minute Apgar score of at least 9.

Exclusion criteria:

not reported.

Participants:

(1) Group A

(2) Group B

(3) Group C

(4) Group D

Interventions Group A: Betagen (20 microgram, RV) at birth, and 1 and 6 months.

Group B: Lanzhou (20 microgram, PDV) at birth, and 1 and 6 months.

Group C: HBIG (260 IU) at birth and RV (10 microgram) at birth, and 1 and 6 months.

Group D: HBIG (260 IU) at birth and RV (20 microgram) at birth, and 1 and 6 months.

Outcomes Percentage of infants with HBsAg at maxim (12 months) follow-up.

Percentage of infants with HBsAg, by mother’s HBsAg/HBeAg status.

Geometric mean titre of anti-HBs in each group.

Percentage of infants in each group with anti-HBsAg level higher than 10 mIU/mL.


Reasons not to entering the trial:

living too far to travel for follow-up visits

too many blood tests

did not want the baby to be hurt

did not think vaccination was necessary

would be going away.


Study Halliday 1992 CA

Methods This trial is the same as Halliday 1992 BA, but has been entered with its own identifier due to technical





Participants

Interventions

Outcomes

Notes


Study Halliday 1992 DC

Methods This trial is the same as Halliday 1992 BA, but has been entered with its own identifier due to technical


Participants

Interventions

Outcomes

Notes


Study Hieu 2002

Methods Generation of allocation sequence: adequate - sequence generated by a computer program.

Allocation concealment: adequate - sealed envelopes.



Participants Country: Vietnam.


Inclusion criteria:


birth weight more than 2500 gm.

Apgar score at least 8 at 1 minute.

gestational age >= 37 completed weeks.

In good general health as determined by birth history and physical examination.

Exclusion criteria:

Fever or significant malnutrition.

confirmed HIV positive individuals.

Evidence of significant haematological, cardiovascular or neoplastic disease.

Participants:

(1) Hepavax-Gene Group (n = 53)

Mother’s mean age: 26.8

(2) Engerix-B Group (n = 51)

Mother’s mean age: 27.9

Interventions Hepavax-Gene Group : HBIG 100 microgram+ Hepavax 10 microgram I.M. at birth, then Hepavax at 30

days and 180 days of age.

Engerix-B Group: HBIG 100 microgram+ Engerix-B 10 microgram I.M. at birth, then Engerix-B at 30 days

and 180 days of age.

Outcomes Number of infants with HBsAg during the follow-up period.

Anti-HBs

Anti-HBs titer

GMT of Anti-HBs

Number of anti-HBc positive infants.




Notes Follow-up times: 30-60-180-210-360 days and 2 years.

Adverse events:

The majority of AEs were mild fever of less than 38 C degree.

One infant had mild hyperexcitability (excessive crying).


Study Ip 1989 AB




Follow-up: inadequate - not described in each group.

Participants Country: HongKong, China.


Inclusion criteria:

HBeAg positive mothers.

Participants:

(1) Group A:

(2) Group B:

(3) Group C:

(4) Group D: (control)

Interventions Group A: received four 3 microgram of PDV at birth and at the age of 1, 2, and 6 months, respectively. Also,

received HBIG 200 IU at birth, and 100 IU at monthly intervals during the first 6 months after birth.

Group B: received four 3 microgram of PDV at birth and at the age of 1, 2, and 6 months. Also, received

HBIG 200 IU at birth.

Group C: received four 3 microgram of PDV at birth and at the age of 1, 2, and 6 months.

Group D: control group (not randomised).

Outcomes HBsAg

HBeAg, HBV DNA



The code was broken in Oct, 1983. After that no new babies entered the placebo group and eligible babies

were only randomly allocated to one of the first three intervention groups. Part of the infants of the Ip 1989

trial originated from the Wong 1984 trial.


Study Ip 1989 AC

Methods This trial is the same as Ip 1989 AB, but has been entered with its own identifier due to technical limits of

RevMan in order to make data comparison.

Participants

Interventions

Outcomes

Notes





Study Ip 1989 AD


Allocation concealment: adequate.

Blinding: adequate.

Follow-up: inadequate - reasons for dropouts described only, number was not reported.



Inclusion criteria:


Exclusion criteria:

Infants birthweight less than 2500 gm, gestational age less than 37 weeks, Apgar score less than 7, or in

whom there were gross congenital abnormalities.

Participants:

Group A (n = 36):

Mothers:

age (yr): 26.0+-4.3

number of pregnancies: 1.7+-1.1

parity: 0.6+-0.1

duration of labour (minutes): 371+-268

mode of delivery:

normal: 64%

forceps: 8%

lower section caesarean section: 8%

induction of labour: 28%

Infants:

males: 47%

birthweight (gm): 3112+-307

maturity (weeks): 40+-1

breastfed: 18%

Group B (n = 35):

Mothers:

age (yr): 24.20+-3.6


parity: 0.5+-1.0


mode of delivery:

normal: 51%

forceps: 23%



Infants:

males: 60%


maturity(weeks): 40+-1

breastfed: 18%

Group C (n = 35):

Mothers:

age (yr): 25.6+-4.1





parity: 0.5+-0.8


mode of delivery:

normal: 60%

forceps: 23%



Infants:

males: 57%



breastfed: 21%

Group D (n = 34):

Mothers:

age (yr): 24.6+-3.8


parity: 0.3+-0.6


mode of delivery:

normal: 56%

forceps: 12%



Infants:

males: 47%



breastfed: 21%.

Interventions Group A: HBIG 200 IU and PDV 3 microgram were given at birth. Then HBIG 100 IU was given at 1, 2,

3, 4, 5, and 6 months. PDV 3 microgram were given at 1, 2, and 6 months.

Group B: HBIG 200 IU was given at birth. Placebo B was given at 1, 2, 3, 4, 5 and 6 months. PDV 3

microgram was given at birth, 1, 2 and 6 months.

Group C: PDV 3 microgram was given at birth, 1, 2 and 6 months. Placebo B was given at birth, 1, 2, 3, 4,

5 and 6 months.

Group D: placebo B was given at birth, 1, 2, 3, 4, 5, and 6 months. Placebo A was given at birth, 1, 2, and

6 months.

Outcomes HBsAg HBeAg Anti-HBs Anti-HBe IgM-anti-HBc


Adverse events:

No serious side-effects from the injections were noticed. Six mothers observed a small swelling at the site of

injection for 1 day; 6 babies had low-grade fever for 1 day; and 2 babies had low-grade fever for 1 day.

Definition of persistent HBsAg antigenemia: all babies having been HBsAg-positive for over 6 months. The

Wong 1984 trial constituted part of the infants in the Ip 1989 trial.





Study Ip 1989 BC

Methods This trial is the same as Ip 1989 AB, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Ip 1989 BD

Methods This trial is the same as Ip 1989 AD, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Ip 1989 CD

Methods This trial is the same as Ip 1989 AD, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Kang 1995






Publication language: Chinese.

Inclusion criteria:

HBsAg+ HBeAg positive mothers.

Participants:

(1) Group A:

(2) Group B:

(3) Group C:

Interventions Group A: received 20 microgram of RV at birth and at the age of 1 and 6 months, respectively.

Group B: received 20 microgram of genetic engineering vaccine at birth and at the age of 1 and 6 months.

Group C: received 10 microgram of genetic engineering vaccine and HBIG 200 IU at birth and 10 microgram

doses of genetic engineering vaccine at the age of 1 and 6 months.

Outcomes HBsAg, Anti-HBs




Anti-HBc

Notes Follow-up time: 7 months

1% soap solution was applied to avoid contamination by mothers’ faeces.

No adverse events was reported. Data was comparable for Group A and Group B.


Study Khukhlovich 1996





Participants Country: Uzbekistan and Moldova (former Soviet Union).

Publication language: Russian.

Inclusion criteria:

HBsAg positive carrier mothers.

The children were healthy without any contraindications.

Interventions Treatment Group: Engerix B 1 mL was given at birth, 1, 2, and 14 months.

Control Group: no vaccines.

Outcomes Anti-HBs, HBsAg.

Notes Follow-up time:2 years.

Adverse events: skin reactions, weak pain, little swollen of the injection site (transient reactions, disappeared

within 1-3 days). Rare adverse events: without good sleep, over excited, dyspepsia, subfebrile temperature.

After the vaccination, no other adverse event was observed.


Study Kuru 1995 AB




Follow-up: unclear.

Participants Country: Turkey.


Inclusion criteria:


Participants:

(1) Group A (Hevac B 0.5 mL)

(2) Group B (Hevac B 1 mL)

(3) Group C (Engerix B).

Interventions Group A (Hevac B 0.5 mL): received 2.5 microgram of vaccine and HBIG 200 IU at birth and vaccine at

the age of 1, 2, and 12 months, respectively.

Group B (Hevac B 1 mL): received 5 microgram of vaccine and HBIG 200 IU at birth and vaccine at the

age of 1, 2, and 12 months respectively.

Group C (Engerix B 0.5 mL): received 10 microgram of vaccine and HBIG 200 IU at birth and vaccine at

the age of 1, 2, and 12 months, respectively.

Outcomes HBsAg,




Anti-HBs (geometric mean titer, GMT),

HBeAg, Anti-HBe.

Notes Follow-up time:13 months

without the primary outcome defined in the protocol, which is Hepatitis B events at maximum follow-up.

Adverse events: no side effects in the infants after the vaccination.


Study Kuru 1995 AC

Methods This trial is the same as Kuru 1995 AB, but has been entered with its own identifier due to technical limits

of RevMan in order to make data comparison.

Participants

Interventions

Outcomes

Notes


Study Kuru 1995 BC

Methods This trial is the same as Kuru 1995 AB, but has been entered with its own identifier due to technical limits


Participants

Interventions

Outcomes

Notes


Study Lee 1995 AB



Blinding: Not performed.

Follow-up: inadequate - number of dropouts reported, but reasons not described.

Participants Country: Taiwan. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive/negative

mothers.

Interventions Group A (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ Engerix-B 10 microgram (1)+

Engerix-B 10 microgram (2)+ Engerix-B 10 microgram (12)

Group B (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ PDV 5 microgram (1)+ PDV 5

microgram (2)+ PDV 5 microgram (12)

Group C (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ H-B-VAX II 5 microgram (1)+ H-

B-VAX II 5 microgram (2)+ H-B-VAX II 5 microgram (12)

Group D (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ PDV 5 microgram (1)+ H-B-VAX

II 5 microgram (2)+ H-B-VAX II 5 microgram (12)

Group E (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ PDV 5 microgram (1)+ Engerix-

B 10 microgram (2)+ Engerix 10 microgram (12)

Group F (HBeAg- mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ Engerix-B 10 microgram (2)+

Engerix-B 10 microgram (6)




Group G (HBeAg- mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ H-B-VAX II 5 microgram(2)+ H-

B-VAX II 5 microgram(6)

Outcomes HBsAg, HBeAg,

Anti-HBs by radioimmunoassay.

Notes Follow-up time: 6, 14, and 30 months (high risk infants).

Adverse events: there was no significant adverse reaction in any of the children during the study period.


Study Lee 1995 CA

Methods This trial is the same as Lee 1995 A1C, but has been entered with its own identifier due to technical limits


Participants

Interventions

Outcomes

Notes


Study Lee 1995 CB



Participants

Interventions

Outcomes

Notes


Study Lee 1995 DE



Participants

Interventions

Outcomes

Notes


Study Liu 1987 AB



Blinding: adequate - with placebo.



Publication language: Chinese.

Inclusion criteria:

HBsAg+ HBeAg positive mothers or HBsAg titre >= 1:512.

Interventions Group A: received 20 microgram of vaccine at birth and at the age of 1, 2, and 6 months, respectively.




Group B: placebo (normal saline) at birth and at the age of 1, 2, and 6 months, respectively.

Group C: received 20 microgram of vaccine and HBIG 1: 1600,000 to 1: 3200,000 (RIA) at birth and

vaccine at the age of 1, 2, and 6 months respectively.

Outcomes Overall number of HBsAg newborns in each tests.

Anti-HBs, Anti-HBc (RIA)

Notes Follow-up time: 6-9-12 months.

The numbers of HBsAg newborns were the sum of number of HBsAg positive newborns detected in 6, 9

and 12 months, not only in 12 months follow-up.

Adverse events: no systemic reaction and serious local events. Some infants had local swollen and red, but all

disappeared in 1 to 2 days.


Study Liu 1987 CA

Methods This trial is the same as Liu 1987 AC, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Liu 1987 CB

Methods This trial is the same as Liu 1987 AC, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Lo 1985 AB




Follow-up: unclear.



Inclusion criteria:

HBsAg+ HBeAg positive mothers.

Mother age: 20 to 36 years, mean 27 years old.

Interventions Group A: received HBIG 50 IU at birth, then Hevac-B 5 microgram at 2 weeks, 6 weeks, and 10 weeks.

Group B: received Hevac-B 5 microgram at 2 weeks, 6 weeks, and 10 weeks.

Group C: received Hevac-B 5 microgram at 2 weeks, 6 weeks, and 10 weeks. Plus HBIG 50 IU at birth and

one month of age.




Group D: control group (refused vaccination).

Outcomes The status of HBsAg and HBeAg in infants

Number of infants with HBsAg positive in 6 weeks, 10 weeks and 6 months of age.

The incidence of persistent HBsAg carrier state.

A summary of adverse events of HBV vaccination.

Notes Follow-up time: 6 weeks- 10 weeks- 6 months (all with number of infants HBsAg (+)).

Adverse events:

Fever: 2.8%

Diarrhoea: 0.5%

Swelling erythema: 6.6%

Restlessness: 22.2%

Two infants in Group 3 had an ALT rise. One was considered to be related to the use of traditional herbal

drug. The other could not be accounted for. Both children returned to normal ALT within the follow-up

period.


Study Lo 1985 CA

Methods This trial is the same as Lo 1985 BA, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Lo 1985 CB

Methods This trial is the same as Lo 1985 BA, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Lolekha 2002







Inclusion criteria:


Infant birth weight >= 2000 gram, Apgar score >= 7 at 5 minutes

Participants:

(1) Group A




Male (%): 52

Female (%): 48

Birth weight (kg)

Range: 2.15-4.26

Mean: 3.1

Median: 3.05

(2) Group B

Male (%): 51

Female (%): 49

Birth weight (kg)

Range: 2.34-4.25

Mean: 3.04

Median: 3.02

Interventions Group A: received 5 microgram of vaccine at birth (0 to 3 days) and at the age of 1 and 6 months, respectively.

Group B: received 5 microgram of vaccine at birth (0 to 3 days) and at the age of 1, 2, and 12 months,

respectively.

Outcomes HBsAg

HBeAg

Anti-HBc

Anti-HBs


Adverse events: None of the vaccines had a serious adverse experience and none withdrew from the study

because of a vaccine related adverse experience.


Study Oon 1986 AB

Methods Generation of allocation sequence: adequate - by lottery or the use of coded numbers.




Participants Country: Singapore


Inclusion criteria:

HBsAg positive and negative mothers.

Participants:

Group A: HBsAg (-) mothers (n = 28)

Group B: HBeAg (-)/HBsAg (+) mothers (n = 188)

Group C: HBeAg (+)/HBsAg (+) mothers (n = 99)

Group D: HBsAg (-) mothers (n = 39)

Group E: HBeAg (-)/HBsAg (+) mothers (n = 205)

Group F: HBeAg (+)/HBsAg (+) mothers (n = 103)

Interventions Group A: 10 microgram PDV at birth, 1 and 2 months.

Group B: 5 microgram PDV at birth, 1 and 2 months.

Group C: HBIG 100 IU and 10 microgram PDV at birth and 10 microgram PDV at 1 and 2 months.

Group D: HBIG 0.5 mL (100 IU) and 5 microgram PDV at birth and 5 microgram PDV at 1 and 2 months.

Group E: 5 microgram PDV at birth, 1 and 2 months.




Group F: 10 microgram PDV at birth, 1 and 2 months.

Outcomes HBsAg

HBeAg

Anti-HBs


Adverse effects: none was observed during the surveillance period.


Study Oon 1986 CD

Methods This trial is the same as Oon 1986 EB, but has been entered with its own identifier due to technical limits


Participants

Interventions

Outcomes

Notes


Study Piazza 1985

Methods Generation of allocation sequence: adequate - random number.


Blinding: unclear.

Follow-up: adequate - reasons and numbers described.

Participants Country: Italy.


Inclusion criteria:

HBsAg-positive mothers. Mothers with HBsAg, anti-HBs, anti-HBc negative were also included in this study

with different comparison groups.

Participants: (partly included, some children were not infants)

Group A: 2 withdrawn by their parents.

Group B: 1 withdrawn by their parents.

Group C: 5 withdrawn by their parents.

Group D: 5 withdrawn by their parents.

Interventions Group A: HBIG 50 IU at birth, PDV 5 microgram within 5 days after birth and at 2 months.

Group B: HBIG 50 IU at birth, PDV 5 microgram within 5 days after birth and at 1 and 2 months.

Group C: PDV 5 microgram within 5 days after birth and at 2 months.

Group D: PDV 5 microgram within 5 days after birth and at 1 and 2 months.

Outcomes HBsAg

Anti-HBc


Adverse events: 2 children reported a sore arm after the 2nd dose of vaccine, and in both the complaint

resolved a few hours later. There were no other adverse reactions.





Study Pongpipat 1986




Follow-up: inadequate - reasons not described.



Inclusion criteria:


Interventions Group A: HBIG (Gamma-protect) 200 IU (at birth) + Havac B 5 microgram (birth-1-2 months).

Group B: HBIG (Hepatect) 100 IU (0)+ HB vax (PDV) 10 microgram (birth-1-6 months).

Outcomes HBsAg

Anti-HBc


Adverse events: neither local nor systemic reactions were observed after immunisation.






Follow-up: inadequate - number reported only.



Inclusion criteria:


Participants:

Group A:

Group B:

Interventions Group A (HBIG+ Hevac B): received 5 microgram of vaccine and HBIG 100 IU at birth and vaccine at the

age of 1, 2, and 12 months, respectively.

Group B (HBIG+ Hevac B): received 2 microgram of vaccine and HBIG 100 IU at birth and vaccine at the

age of 1, 2, and 12 months respectively.

Outcomes GMT (anti-HBs)

seroconversion rate

HBsAg

Anti-PreS2

Anti-HBc

Notes Follow-up time: 4, 6, 12, and 13 months.

Adverse events: neither local nor systemic reactions were observed after immunization with HBIG and

hepatitis B vaccine.









Follow-up: inadequate - number for dropouts described only.



Inclusion criteria:


Participants:

Group A:

Group B:

Interventions Group A (HBIG+ HBVax): received 10 microgram of PDV and HBIG 100 IU (0.5mL) at birth and vaccine

at the age of 1, 2, and 12 months, respectively.

Group B (HBIG+ HBVax II): received 5 microgram of RV and HBIG 100 IU (0.5mL) at birth and vaccine

at the age of 1, 2, and 12 months respectively.

Outcomes GMT (anti-HBs)

seroconversion rate (definition: higher than 5 mIU/mL after vaccination) HBsAg.


Adverse events: neither local nor systemic reactions were observed after immunization with HBIG and both

kinds of hepatitis B vaccine.


Study Poovorawan 1997




Follow-up: inadequate - reasons for dropouts described only, number was not reported.



Inclusion criteria:


Weight of 2 kg or more at birth and with a 5 minute Apgar score of 7 or higher.

Interventions Open design without randomisation

Group A: were vaccinated with Engerix-B (RV) 10 microgram at birth and subsequently at 1, 2, and 12

months of age.

Group B: were vaccinated with Engerix-B (RV) 10 microgram and HBIG 100 IU at birth and Engerix-B

(RV) 10 microgram and Engerix-B 10 microgram subsequently at 1, 2, and 12 months of age.

Randomised groups:

Group C: were vaccinated with Engerix-B (RV) 10 microgram at birth and subsequently at 1 and 6 months

of age.

Group D: were vaccinated with Engerix-B (RV) 10 microgram and HBIG 100 IU at birth and Engerix-B

10 microgram subsequently at 1 and 6 months of age. A booster was administered at 60 months for Group

C and Group D.

Outcomes HBsAg

GMT (Anti-HBs)

Anti-HBc





Adverse events: not reported. Only the data in Group C and D were used for analysis.


Study Sehgal 1992




Follow-up: inadequate.

Participants Country: India.


Inclusion criteria:


Interventions Group A: 10 microgram PDV within 24 hours of birth, 4 and 8 weeks.

Group B: HBIG and 10 microgram PDV within 24 hours of birth, and PDV given at 4 and 8 weeks.

Group C (control group): not vaccinated.

Outcomes HBsAg

HBeAg

Anti-HBe

Anti-HBs

Notes Follow-up time: 3 and 6 months.



Study Theppisai 1987




Follow-up: adequate - no dropouts.



Inclusion criteria:


Interventions Group A: 10 microgram PDV given at 21 to 72 minutes of birth and the age of 1 and 6 months.

Group B: HBIG 200 IU and 10 microgram PDV given at 21-72 minutes (average 67 minutes) of birth and

10 microgram PDV given the age of 1 and 6 months.

Outcomes HBsAg

HBeAg

Anti-HBs

Anti-HBe

Notes Follow-up time: 3 and 6 months.

Adverse events: not reported





Study Theppisai 1990




Follow-up: inadequate - number reported, but the reasons for dropouts not described.



Inclusion criteria:


Historical control group.

Interventions Group A: HBIG 200 IU administered within 3 hours of birth, and 5 microgram PDV given at the age of 2

days, 1, 2, and 12 months.

Group B: HBIG 200 IU administered within 3 hours of birth, and 2 microgram PDV given at the age of 2

days, 1, 2, and 12 months.

Control group (historical control): no vaccination.

Outcomes HBsAg

Anti-HBs

GMT

seroconversion rate.

Notes Follow-up time: 4, 6, 12 and 13 months



Study Xu 1995 AB




Follow-up: inadequate - number for dropouts described only, reasons was not reported.



Inclusion criteria:

HBsAg and HBeAg positive/negative mothers.

Exclusion criteria

Infants birthweight less than 2500 gm, gestational age less than 37 weeks, Apgar score less than 7, or whom

there were gross congenital abnormalities.

Interventions Group A: NIAID vaccine (PDV produced by the U.S.) vaccine 16 microgram at birth, 1 and 6 months.

Group B: BIVS vaccine (PDV produced by China) vaccine 20 microgram at birth, 1, and 6 months.

Group C: randomisation into Group C was not begun until later in the trial): HBIG 250 IU at birth and

BIVS vaccine 20 microgram at birth, 1, and 6 months.

Group D (placebo): vaccine diluent plus adjuvant at birth, 1, and 6 months.

Outcomes HBsAg Anti-HBs Anti-HBc

Notes Follow-up time: 60 months, but due to the poor reporting, data on 6th month were extracted.

Adverse events: not reported

HBsAg event was defined as HBsAg positive at any time >= 1 month of age.




Chronic HBsAg was defined as HBsAg positive for >= 6 months.


Study Xu 1995 AD

Methods This trial is the same as Xu 1995 AB, but has been entered with its own identifier due to technical limits of


Participants

Interventions

Outcomes

Notes


Study Xu 1995 BD



Participants

Interventions

Outcomes

Notes


Study Xu 1995 CB



Participants

Interventions

Outcomes

Notes


Study Xu 1995 CD



Participants

Interventions

Outcomes

Notes


Study Yeoh 1986










Inclusion criteria:

HBsAg-positive mothers.

Infants birthweight over 2000 gm. Apgar score >= 7 at 5 minutes.

Interventions HBsAg(+)/ HBeAg(+) mothers (150 infants):

Group A: HBIG 0.5 mL at birth and PDV 10 microgram were administered at birth, 1, and 6 months.

Group B: HBIG 0.5 mL at birth and RV 5 microgram were administered at birth, 1, and 6 months.

HBsAg(+)/ HBeAg(-) mothers (150 infants).

Group C: HBIG 0.5 mL at birth and PDV 10 microgram were administered at birth, 1, and 6 months.

Group D: HBIG 0.5 mL at birth and RV 5 microgram were administered at birth, 1, and 6 months.

Outcomes HBsAg

HBeAg

Anti-HBs

Anti-HBc

Anti-HBe

Notes This trial was published as an abstract. We were not able to extract any relevant data from this abstract.

Follow-up time: 6 and 9 months.

Adverse events were few and minor, and no serious side-effects were attributable to either vaccine.


Study Zhu 1987





Participants Country: China


Inclusion criteria:


Interventions Treatment group: 16 microgram vaccine (PDV or RV ?) was given at birth, 1, and 6 months.

Control group (n = 57): buffer of HBV at the same interval.

Outcomes Transaminase abnormalities and hepatitis markers.

Notes This trial was published as an abstract. We were not able to extract relevant data from this abstract.

Follow-up time: 24 months.



Study Zhu 1994




Follow-up: inadequate - number for dropouts described only, reasons was not reported.





Inclusion criteria:


Participants:

Group 1 (RV):

Birth weight: (mean+-SD): 3290+- 312

Apgar score: 9.3

No of male infants (%): 28 (52%)

No of caesarean births (%): 9 (17%)

Group 2 (PDV):

Birth weight: (mean+-SD): 3301+- 347

Apgar score: 9.1

No of male infants (%): 26 (50%)

No of caesarean births (%): 7 (14%)

Interventions Group A: RV 20 microgram was administered at birth, 1 and 6 months.

Group B: PDV 20 microgram was administered at birth, 1, and 6 months.

Outcomes HBsAg

Anti-HBs

Notes Follow-up time: 6, 12, 24, 36, 48 and 60 months.

Adverse events: These recipients of RV have no side effects and the vaccine is safe.

Regarding Table 2 and 3. We considered ” negative” patients as having no anti-HBs despite it is unclear in

the report.


Characteristics of excluded studies

Study Reason for exclusion

Chung 1988 Non-randomised clinical study.

Chung 1988 B Not newborns of HBsAg-positive mothers.

Coursaget 1984 Non-randomised clinical study.

Da 1995 Non-randomised clinical study.

Delage 1993 Non-randomised clinical study.

Esteban 1986 Non-randomised clinical study.

Goh 1992 The study population were not newborns but 1-12 year-old children.

Kang 1986 Non-randomised clinical study.

Lai 1986 The study population were not newborns but 3 months to 11 year-old children and the mothers were negative

for all hepatitis B viral markers.

Lai 1993 The study population were not newborns but 3 months to 11 year-old children.

Laille 1988 Non-randomised clinical study.

Lin 1987 Non-randomised clinical study.

Linder 2000 The study population were not high-risk newborns.

Milne 1989 The study population were healthy newborns, not high-risk newborns of HBsAg-positive mothers.

Mittal 1994 Non-randomised clinical study.

Moulia-Pelat 1994 The study population were healthy newborns, not high-risk newborns of HBsAg-positive mothers.



Characteristics of excluded studies (Continued )

Nair 1984 Non-randomised clinical study.

Okoth 1994 The study population was not newborns of HBsAg-positive mothers.

Perrin 1986 The study population in this study was not newborns of HBsAg-positive mothers.

Pongpipat 1984 Non-randomised clinical study.

Poovorawan 1989 Non-randomised clinical study.

Poovorawan 1990 Non-randomised clinical study.

Shikata 1984 Non-randomised clinical study.

Stevens 1987 Non-randomised clinical study.




Surya 1996 Non-randomised clinical study.

Suwignyo 1994 Non-randomised clinical study.

Theppisai 1988 Non-randomised clinical study.

Theppisai 1989 Non-randomised clinical study.

Wheeley 1991 Non-randomised clinical study.

Young 2003 Non-randomised clinical study.

Yuen 1999 The study population was not newborns of HBsAg-positive mothers.

Zanetti 1986 Non-randomised clinical study.

Zhu 2003 The study population was not exclusively newborns of HBsAg-positive mothers.

A D D I T I O N A L T A B L E S

Table 01. Search strategies

Database Period Search strategy

The Cochrane Hepato-Biliary Group Controlled

Trials Register

Until February 2004 vaccin* AND ’hepatitis B’ AND (newborn* OR

infant* OR child* OR baby OR babies) AND

’high risk’

The Cochrane Neonatal Group Controlled

Trials Register

20 February 2004 A request for search on the Neonatal Group

Controlled Trials Register was made (20 Feb,

2004)

The Cochrane Vaccines Field Controlled Trials

Register

Not obtained A request for search on the Vaccine Field

Controlled Trials Register was made (20 Feb,

2004). But no reply were obtained.

The Cochrane Central Register of Controlled

Trials (CENTRAL/CCTR) in The Cochrane

Library

Until February 2004 vaccin* AND ’hepatitis B’ AND (newborn* OR

infant* OR child* OR baby OR babies) AND

’high risk’

PubMed Until February 2004 #1 explode “Vaccination”/ all subheadings

#2 explode “Hepatitis-B-Vaccines”/ all

subheadings



Table 01. Search strategies (Continued )


#3 explode “Vaccines”/ all subheadings

#4 vaccin*

#5 PDV

#6 YDV

#7 #1 or #2 or #3 or #4 or #5 or #6

#8 explode “Hepatitis-B”/ all subheadings

#9 hepatitis B

#10 #8 or #9

#11 explode “Infant-Newborn”/ all subheadings

#12 newborn* or infant* or child* or baby or

babies

#13 #11 or #12

#14 #13 and high risk

#15 #7 and #10 and #14

#16 random* or blind* or placebo* or meta-

analysis

#17 #15 and #16

#18 (DTP-HB or Hib-HB or Comvax or

Pediarix)

MEDLINE January 1966 to February 2004 #1 explode “Vaccination”/ all subheadings

#2 explode “Hepatitis-B-Vaccines”/ all

subheadings

#3 explode “Vaccines”/ all subheadings

#4 vaccin*

#5 PDV

#6 YDV

#7 #1 or #2 or #3 or #4 or #5 or #6

#8 explode “Hepatitis-B”/ all subheadings

#9 hepatitis B

#10 #8 or #9

#11 explode “Infant-Newborn”/ all subheadings


babies

#13 #11 or #12


#15 #7 and #10 and #14


analysis

#17 #15 and #16


Pediarix)

EMBASE January 1980 to February 2004 #1 explode “vaccination”/ all subheadings

#2 explode “hepatitis-B-vaccine”/ all

subheadings

#3 explode “hepatitis-vaccine”/ all subheadings

#4 explode “vaccine”/ all subheadings

#5 vaccin*

#6 PDV



Table 01. Search strategies (Continued )


#7 YDV

#8 #1 or #2 or #3 or #4 or #5 or #6 or #7

#9 explode “hepatitis-B”/ all subheadings

#10 hepatitis B

#11 #9 or #10

#12 explode “infant”/ all subheadings

#13 explode “newborn”/ all subheadings

#14 explode “newborn-hepatitis”/ all

subheadings

#15 explode “baby”/ all subheadings

#16 #12 or #13 or #14 or #15


babies

#18 #16 or #17


#20 #8 and #11 and #19


analysis

#22 #20 and #21


Pediarix)

Table 02. Intervention by group

Trial Intervention group Control group

Assateerawatt 1993 A*: HBIG 100 IU at birth and RV 20

microgram at birth and at 1, 2, and 12

months.

B: RV 20 microgram at birth and at 1, 2,

and 12 months.

Beasley 1983a A: HBIG 1.0 ml (180 IU) at birth and

saline at 3 and 6 months. C: HBIG 0.5

ml (90 IU) diluted in 0.5 ml of immune

serum globulin at birth and 3 and 6

months.

B: saline at birth and 3 and 6 months.

Beasley 1983b A: HBIG 0.5 ml (145 IU) at birth and

PDV 20 microgram at 4-7 days. Followed

by boosters 1 and 6 months later.

B: HBIG 0.5 ml (145 IU) and PDV

20 microgram at 1 month. Followed by

boosters 1 and 6 months later.

Farmer 1987 A: PDV 0.25 ml (5 microgram) + HBIG

0.25 ml (25 IU/kg) at birth then PDV +

HBIG 0.25 ml (25 IU/kg) at 6 weeks and

PDV at 6 months.

B: PDV 0.25 ml (5 microgram) at birth

and at 6 weeks and 6 months.

Garcia 1992 A: 10 microgram RV-1 at birth and at 1

and 2 months.

B: 10 microgram RV-2 at birth and at 1

and 2 months.

Grosheide 1993 A: HBIG 0.5 ml/kg body weight at birth

and PDV 10 microgram at 2 days and at

1, 2, and 11 months.

B: HBIG 0.5 ml/kg body weight and PDV

10 microgram at 3, 4, 5, and 11 months

(with diphtheria, pertussis, tetanus,



Table 02. Intervention by group (Continued )


poliomyelitis concomitantly). HBIG 0.5

ml/kg body weight at 3 months.

Halliday 1992 A: RV 20 microgram at birth and at 1 and

6 months. C: HBIG 260 IU at birth and

RV 20 microgram at birth and at 1 and 6

months.

B: PDV 20 microgram at birth and at 1

and 6 months. D: HBIG 260 IU at birth

and RV 10 microgram at birth and at 1

and 6 months.

Hieu 2002 A: HBIG 100 microgram + 10 microgram

RV-1 at birth and Hepavax at 30 and 180

days.

B: HBIG 100 microgram + 10 microgram

RV-2 at birth and Engerix-B at 30 and

180 days.

Ip 1989 A: PDV 3 microgram at birth and at 1,

2, and 6 months. Also, HBIG 200 IU

at birth, and HBIG 100 IU at monthly

intervals during the first 6 months after

birth. C: PDV 3 microgram at birth and

at 1, 2, and 6 months.

B: PDV 3 microgram at birth and at 1, 2,

and 6 months + HBIG 200 IU at birth.

D: placebo.

Kang 1995 A: 20 microgram RV-1 at birth and at 1

and 6 months.

B: 20 microgram RV-2 at birth and at 1

and 6 months.

Khukhlovich 1996 A: RV 1 ml at birth and at 1, 2, and 14

months.

B: No vaccines.

Kuru 1995 A: PDV 0.5 ml (2.5 microgram) and

HBIG 200 IU at birth and PDV at 1,

2, and 12 months. C: RV 0.5 ml (10

microgram) and HBIG 200 IU at birth

and RV at 1, 2, and 12 months.

B: PDV 1 ml (5 microgram) and HBIG

200 IU at birth and PDV at 1, 2, and 12

months.

Lee 1995 * A: HBIG 145 IU at birth + PDV 5

microgram at birth + 10 microgram RV-1


C: HBIG 145 IU at birth + PDV 5

microgram at birth + 5 microgram RV-2


E: HBIG 145 IU at birth + PDV 5

microgram at birth and 1 month + 10

microgram RV-1 at 2 and 12 months.

G: HBIG 145 IU at birth + PDV 5

microgram at birth and RV-2 at 2 and 6

months.

B: HBIG 145 IU at birth + PDV 5

microgram at birth + PDV 5 microgram at

1, 2, and 12 months.

D: HBIG 145 IU at birth + PDV 5

microgram at birth and 1 month + 5

microgram RV-2 at 2 and 12 months.

F: HBIG 145 IU at birth + PDV 5

microgram at birth and RV-1 at 2 and 6

months.

Liu 1987 A: PDV 20 microgram at birth and at 1, 2,

and 6 months. C: PDV 20 microgram at

birth and at 1, 2, and 6 months and HBIG

at birth.

B: placebo (normal saline) at birth and at

1, 2, and 6 months.

Lo 1985 A: HBIG 50 IU at birth, then PDV 5

microgram at 2, 6, and 10 weeks. C: PDV

5 microgram at 2, 6, and 10 weeks +

HBIG 50 IU at birth and 1 month.

B: PDV 5 microgram at 2, 6, and 10

weeks.





Lolekha 2002 A: RV 5 microgram at birth and at 1 and 6

months.

B: RV 5 microgram at birth and at 1, 2,

and 12 months.

Oon 1986 A: PDV 10 microgram at birth and at

1 and 2 months. C: HBIG 100 IU and

PDV 10 microgram at birth and PDV 10

microgram at 1 and 2 months.

B: PDV 5 microgram at birth and at 1 and

2 months. D: HBIG 100 IU and PDV 5

microgram at birth and PDV 5 microgram

at 1 and 2 months.

Piazza 1985 A: PDV 5 microgram and HBIG 50 IU at

birth and PDV at 1 and 2 months.

B:PDV 5 microgram and HBIG 50 IU at

birth and PDV at 2 months.

Pongpipat 1986 A: 200 IU HBIG-1 at birth + 5 microgram

PDV1 at birth and at 1 and 6 months.

B: 100 IU HBIG-2 at birth + 10

microgram PDV2 at birth and at 1 and 6

months.

Pongpipat 1988 A: PDV 5 microgram and HBIG 100 IU

at birth + PDV at 1, 2, and 12 months.

B:PDV 2 microgram and HBIG 100 IU at

birth + PDV at 1, 2, and 12 months.

Pongpipat 1989 A: RV 5 microgram and HBIG 100 IU at

birth and RV at 1, 2, and 12 months.

B: PDV 10 microgram and HBIG 100 IU

at birth and PDV at 1, 2, and 12 months.

Poovorawan 1997 A: RV 10 microgram and HBIG 100 IU

at birth and RV 10 microgram at 1 and 6

months. A booster was administered at 60

months.

B: RV 10 microgram at birth and at 1 and

6 months. A booster was administered at

60 months.

Sehgal 1992 A: HBIG 0.5 ml and PDV 10 microgram

at birth, and PDV at 4 and 8 weeks.


and 8 weeks.

Theppisai 1987 A: HBIG 200 IU and PDV 10 microgram

at birth and PDV 10 microgram at 1 and

6 months.


and 6 months.

Theppisai 1990 A: HBIG 200 IU at birth and PDV 5

microgram at the age of 2 days, 1, 2, and

12 months.

B: HBIG 200 IU at birth and PDV 2

microgram at the age of 2 days, 1, 2, and

12 months.

Xu 1995 A: 16 microgram PDV-1 at birth and at 1

and 6 months. C: HBIG 250 IU at birth

and 20 microgram PDV2 at birth and at 1

and 6 months.

B: 20 microgram PDV-2 at birth and at

1 and 6 months. D: vaccine diluent plus

adjuvant at birth and at 1 and 6 months.

Yeoh 1986 A: HBsAg(+)/ HBeAg(+) mothers (150

infants): HBIG 0.5 ml at birth and PDV

10 microgram at birth and at 1 and 6

months. C: HBsAg(+)/ HBeAg(-) mothers

(150 infants). HBIG 0.5 ml at birth and

PDV 10 microgram at birth and at 1 and

6 months.

B: HBsAg(+)/ HBeAg(+) mothers (150

infants): HBIG 0.5 ml at birth and RV 5

microgram at birth and at 1 and 6 months.

D: HBsAg(+)/ HBeAg(-) mothers (150

infants). HBIG 0.5 ml at birth and RV 5

microgram at birth and at 1 and 6 months.

Zhu 1987 A: 16 microgram vaccine given at birth, 1

and 6 months.

B: buffer of HBV given at birth, 1 and 6

months

Zhu 1994 A: RV 20 microgram at birth and at 1 and

6 months.


and 6 months.

* HBeAg-positive mothers in A to E





groups.

HBeAg-negative mothers in F and G

group.

A N A L Y S E S

Comparison 01. Vaccine versus placebo or no intervention

Outcome titleNo. of

studies

No. of

participants Statistical method Effect size

01 Hepatitis B events according to

type of vaccine

5 403 Relative Risk (Fixed) 95% CI 0.28 [0.20, 0.40]


methodological quality


03 Hepatitis B events - Sensitivity

analyses

Relative Risk (Fixed) 95% CI Subtotals only


the mother’s HBeAg status


05 Hepatitis B events according

to first time of vaccine

administration


Comparison 02. RV versus PDV

Outcome titleNo. of

studies

No. of


01 Hepatitis B events 5 382 Relative Risk (Fixed) 95% CI 1.00 [0.70, 1.42]




03 Hepatitis B events - sensitivity

analyses





05 Anti-HBs less than 10 IU/L 4 256 Relative Risk (Fixed) 95% CI 0.51 [0.36, 0.72]

Comparison 03. High-dose versus low-dose vaccine

Outcome titleNo. of

studies

No. of







analyses








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

Outcome titleNo. of

studies

No. of




Comparison 05. PDV at birth versus PDV at one month

Outcome titleNo. of

studies

No. of



Comparison 06. One type of PDV versus another type of PDV

Outcome titleNo. of

studies

No. of



Comparison 07. Four RV vaccinations versus three RV vaccinations

Outcome titleNo. of

studies

No. of



02 Anti-HBs level less than 10

IU/L


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

Outcome titleNo. of

studies

No. of


01 Hepatitis B events Relative Risk (Fixed) 95% CI Subtotals only

02 Anti-HBs less than 10 IU/L Relative Risk (Fixed) 95% CI Subtotals only

Comparison 09. HBIG versus placebo or no intervention

Outcome titleNo. of

studies

No. of




methodological quality of the

trials



analyses






time of HBIG administration



standard and rapid schedule of

vaccines





08 Anti-HBs level Weighted Mean Difference (Fixed) 95% CI Subtotals only

09 Adverse events 1 136 Relative Risk (Fixed) 95% CI 3.47 [0.14, 83.67]

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

Outcome titleNo. of

studies

No. of



Comparison 11. PDV plus HBIG versus placebo or no intervention

Outcome titleNo. of

studies

No. of




methodological quality of the

trials



analyses



mother’s HBeAg status



time of HBIG administration


06 Adverse events 2 105 Relative Risk (Fixed) 95% CI 0.29 [0.07, 1.13]

I N D E X T E R M S

Medical Subject Headings (MeSH)

Hepatitis B [immunology; ∗prevention & control]; Hepatitis B Antibodies [∗ therapeutic use]; Hepatitis B e Antigens [∗blood]; Hepatitis

B Vaccines [∗therapeutic use]; Infant, Newborn; Randomized Controlled Trials as Topic

MeSH check words

Female; Humans

C O V E R S H E E T

Title Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive moth-

ers

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

Contribution of author(s) CL developed the search strategy, identified trials, extracted data, carried out the statistical

analyses, and drafted parts of the review.

YG extracted data, carried out the statistical analyses, drafted parts of the review, and revised

the review. YG is the guarantor.

JB validated the assessment of methodological quality of the included trials, validated data

from six randomly selected trials, drafted parts of the review, and revised the review.

EHB has research experience in this topic. She provided trials for this review, validated data

extraction, and revised the review.

CG coordinated the review, functioned as an adjudicator in cases of disagreement, drafted

parts of the review, and revised the review.



Issue protocol first published 2004/2

Review first published 2006/2

Date of most recent amendment 22 February 2006

Date of most recent

SUBSTANTIVE amendment

22 February 2006

What’s New Information not supplied by author

Date new studies sought but

none found

Information not supplied by author

Date new studies found but not

yet included/excluded


Date new studies found and

included/excluded

01 February 2004

Date authors’ conclusions

section amended


Contact address Dr Yan Gong

Copenhagen Trial Unit

Centre for Clinical Intervention Research, Copenhagen University Hospital

Dept. 7102, Blegdamsvej 9

H:S Rigshospitalet

Copenhagen

DK-2100

DENMARK

E-mail: [email protected]

Tel: +45 3545 7161

Fax: +45 3545 7101

DOI 10.1002/14651858.CD004790.pub2

Cochrane Library number CD004790

Editorial group Cochrane Hepato-Biliary Group

Editorial group code HM-LIVER



G R A P H S A N D O T H E R T A B L E S

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

according to type of vaccine

Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers

Comparison: 01 Vaccine versus placebo or no intervention

Outcome: 01 Hepatitis B events according to type of vaccine

Study Vaccine Control Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 PDV versus placebo or no intervention

Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

Liu 1987 AB 3/27 21/26 24.0 0.14 [ 0.05, 0.41 ]

Xu 1995 AD 7/60 12/30 17.9 0.29 [ 0.13, 0.66 ]

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ]

Subtotal (95% CI) 182 120 86.0 0.31 [ 0.21, 0.45 ]

Total events: 31 (Vaccine), 68 (Control)

Test for heterogeneity chi-square=6.00 df=3 p=0.11 I² =50.0%

Test for overall effect z=6.03 p<0.00001

02 RV versus no intervention

Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ]

Subtotal (95% CI) 70 31 14.0 0.10 [ 0.02, 0.43 ]


Test for heterogeneity: not applicable

Test for overall effect z=3.09 p=0.002

Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ]




0.01 0.1 1 10 100

Vaccine better Control better




according to methodological quality



Outcome: 02 Hepatitis B events according to methodological quality


n/N n/N 95% CI (%) 95% CI

01 High-quality trials

Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

Liu 1987 AB 3/27 21/26 24.0 0.14 [ 0.05, 0.41 ]

Subtotal (95% CI) 62 60 50.1 0.22 [ 0.12, 0.40 ]




02 Low-quality trials

Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ]

Xu 1995 AD 7/60 12/30 17.9 0.29 [ 0.13, 0.66 ]

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ]

Subtotal (95% CI) 190 91 49.9 0.34 [ 0.22, 0.54 ]




Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ]




0.01 0.1 1 10 100




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

Sensitivity analyses



Outcome: 03 Hepatitis B events - Sensitivity analyses


n/N n/N 95% CI (%) 95% CI

01 Available patients’ course analysis

Ip 1989 CD 7/35 23/34 28.2 0.30 [ 0.15, 0.60 ]

Khukhlovich 1996 2/70 9/31 15.1 0.10 [ 0.02, 0.43 ]

Liu 1987 AB 3/27 21/26 25.9 0.14 [ 0.05, 0.41 ]

Xu 1995 AD 2/55 9/27 14.6 0.11 [ 0.03, 0.47 ]

Xu 1995 BD 10/56 10/28 16.1 0.50 [ 0.24, 1.06 ]

Subtotal (95% CI) 243 146 100.0 0.23 [ 0.15, 0.35 ]




02 Assuming poor outcome

Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ]

Liu 1987 AB 3/27 21/26 24.0 0.14 [ 0.05, 0.41 ]

Xu 1995 AD 7/60 12/30 17.9 0.29 [ 0.13, 0.66 ]

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ]

Subtotal (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ]




03 Assuming good outcome

Ip 1989 CD 7/35 23/34 28.3 0.30 [ 0.15, 0.60 ]

Khukhlovich 1996 2/70 9/31 15.1 0.10 [ 0.02, 0.43 ]

Liu 1987 AB 3/27 21/26 25.9 0.14 [ 0.05, 0.41 ]

Xu 1995 AD 2/60 9/30 14.5 0.11 [ 0.03, 0.48 ]

Xu 1995 BD 10/60 10/30 16.2 0.50 [ 0.23, 1.07 ]

Subtotal (95% CI) 252 151 100.0 0.23 [ 0.15, 0.35 ]




0.01 0.1 1 10 100

Vaccine better Control better (Continued . . . )



(. . . Continued)


n/N n/N 95% CI (%) 95% CI

04 Extreme case favouring vaccine

Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ]

Liu 1987 AB 3/27 21/26 24.0 0.14 [ 0.05, 0.41 ]

Xu 1995 AD 2/60 12/30 17.9 0.08 [ 0.02, 0.35 ]

Xu 1995 BD 10/60 12/30 17.9 0.42 [ 0.20, 0.85 ]

Subtotal (95% CI) 252 151 100.0 0.21 [ 0.14, 0.32 ]




05 Extreme case favouring control

Ip 1989 CD 7/35 23/34 28.3 0.30 [ 0.15, 0.60 ]

Khukhlovich 1996 2/70 9/31 15.1 0.10 [ 0.02, 0.43 ]

Liu 1987 AB 3/27 21/26 25.9 0.14 [ 0.05, 0.41 ]

Xu 1995 AD 7/60 9/30 14.5 0.39 [ 0.16, 0.94 ]

Xu 1995 BD 14/60 10/30 16.2 0.70 [ 0.35, 1.39 ]

Subtotal (95% CI) 252 151 100.0 0.30 [ 0.21, 0.44 ]




0.01 0.1 1 10 100





according to the mother’s HBeAg status



Outcome: 04 Hepatitis B events according to the mother’s HBeAg status


n/N n/N 95% CI (%) 95% CI

01 HBeAg positive

Ip 1989 CD 7/35 23/34 26.3 0.30 [ 0.15, 0.60 ]

Liu 1987 AB 3/27 21/26 24.1 0.14 [ 0.05, 0.41 ]

Xu 1995 AD 5/30 10/15 15.0 0.25 [ 0.10, 0.60 ]

Xu 1995 BD 9/29 11/16 16.0 0.45 [ 0.24, 0.85 ]

Subtotal (95% CI) 121 91 81.4 0.27 [ 0.18, 0.40 ]




02 HBeAg unknown

Khukhlovich 1996 2/70 9/31 14.1 0.10 [ 0.02, 0.43 ]

Subtotal (95% CI) 70 31 14.1 0.10 [ 0.02, 0.43 ]




03 HBeAg negative

Xu 1995 AD 2/30 1/14 1.5 0.93 [ 0.09, 9.45 ]

Xu 1995 BD 5/31 2/15 3.0 1.21 [ 0.26, 5.53 ]

Subtotal (95% CI) 61 29 4.6 1.12 [ 0.31, 3.97 ]




Total (95% CI) 252 151 100.0 0.29 [ 0.20, 0.41 ]




0.01 0.1 1 10 100





according to first time of vaccine administration



Outcome: 05 Hepatitis B events according to first time of vaccine administration


n/N n/N 95% CI (%) 95% CI

01 Vaccine administered within 12 hours of birth

Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ]

Subtotal (95% CI) 105 65 40.1 0.23 [ 0.12, 0.42 ]





Xu 1995 AD 7/60 12/30 17.9 0.29 [ 0.13, 0.66 ]

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ]

Subtotal (95% CI) 120 60 35.9 0.44 [ 0.27, 0.72 ]





Liu 1987 AB 3/27 21/26 24.0 0.14 [ 0.05, 0.41 ]

Subtotal (95% CI) 27 26 24.0 0.14 [ 0.05, 0.41 ]




Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ]




0.01 0.1 1 10 100




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


Comparison: 02 RV versus PDV

Outcome: 01 Hepatitis B events

Study RV PDV Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 RV versus PDV

Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ]

Zhu 1994 17/54 21/52 45.9 0.78 [ 0.47, 1.30 ]

Subtotal (95% CI) 109 107 84.5 0.75 [ 0.51, 1.12 ]

Total events: 30 (RV), 39 (PDV)



02 RV plus HBIG versus PDV plus HBIG

Lee 1995 AB 15/51 2/14 6.7 2.06 [ 0.53, 7.96 ]

Lee 1995 CB 16/47 2/14 6.6 2.38 [ 0.62, 9.13 ]

Pongpipat 1989 3/20 1/20 2.1 3.00 [ 0.34, 26.45 ]

Subtotal (95% CI) 118 48 15.5 2.33 [ 0.97, 5.56 ]




Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ]



Test for overall effect z=0.02 p=1

0.01 0.1 1 10 100

RV better PDV better



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

quality





n/N n/N 95% CI (%) 95% CI


Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ]

Subtotal (95% CI) 55 55 38.6 0.72 [ 0.39, 1.33 ]





Lee 1995 AB 15/51 2/14 6.7 2.06 [ 0.53, 7.96 ]

Lee 1995 CB 16/47 2/14 6.6 2.38 [ 0.62, 9.13 ]

Pongpipat 1989 3/20 1/20 2.1 3.00 [ 0.34, 26.45 ]

Zhu 1994 17/54 21/52 45.9 0.78 [ 0.47, 1.30 ]

Subtotal (95% CI) 172 100 61.4 1.17 [ 0.75, 1.82 ]




Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ]




0.01 0.1 1 10 100




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



Outcome: 03 Hepatitis B events - sensitivity analyses


n/N n/N 95% CI (%) 95% CI


Halliday 1992 AB 4/46 12/49 42.0 0.36 [ 0.12, 1.02 ]

Lee 1995 AB 2/38 2/14 10.6 0.37 [ 0.06, 2.37 ]

Lee 1995 CB 3/34 2/14 10.2 0.62 [ 0.12, 3.31 ]

Pongpipat 1989 2/19 1/20 3.5 2.11 [ 0.21, 21.36 ]

Zhu 1994 6/43 9/40 33.7 0.62 [ 0.24, 1.59 ]

Subtotal (95% CI) 180 137 100.0 0.53 [ 0.30, 0.95 ]





Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ]

Lee 1995 AB 15/51 2/14 6.7 2.06 [ 0.53, 7.96 ]

Lee 1995 CB 16/47 2/14 6.6 2.38 [ 0.62, 9.13 ]

Pongpipat 1989 3/20 1/20 2.1 3.00 [ 0.34, 26.45 ]

Zhu 1994 17/54 21/52 45.9 0.78 [ 0.47, 1.30 ]

Subtotal (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ]





Halliday 1992 AB 4/55 12/55 42.3 0.33 [ 0.11, 0.97 ]

Lee 1995 AB 2/51 2/14 11.1 0.27 [ 0.04, 1.78 ]

Lee 1995 CB 3/47 2/14 10.9 0.45 [ 0.08, 2.41 ]

Pongpipat 1989 2/20 1/20 3.5 2.00 [ 0.20, 20.33 ]

Zhu 1994 6/54 9/52 32.3 0.64 [ 0.25, 1.68 ]

Subtotal (95% CI) 227 155 100.0 0.50 [ 0.28, 0.89 ]




0.01 0.1 1 10 100

RV better PDV better (Continued . . . )



(. . . Continued)


n/N n/N 95% CI (%) 95% CI

04 Extreme case favouring RV

Halliday 1992 AB 4/55 18/55 38.6 0.22 [ 0.08, 0.61 ]

Lee 1995 AB 2/51 2/14 6.7 0.27 [ 0.04, 1.78 ]

Lee 1995 CB 3/47 2/14 6.6 0.45 [ 0.08, 2.41 ]

Pongpipat 1989 2/20 1/20 2.1 2.00 [ 0.20, 20.33 ]

Zhu 1994 6/54 21/52 45.9 0.28 [ 0.12, 0.63 ]

Subtotal (95% CI) 227 155 100.0 0.30 [ 0.18, 0.52 ]




05 Extreme case favouring PDV

Halliday 1992 AB 13/55 12/55 42.3 1.08 [ 0.54, 2.16 ]

Lee 1995 AB 15/51 2/14 11.1 2.06 [ 0.53, 7.96 ]

Lee 1995 CB 16/47 2/14 10.9 2.38 [ 0.62, 9.13 ]

Pongpipat 1989 3/20 1/20 3.5 3.00 [ 0.34, 26.45 ]

Zhu 1994 17/54 9/52 32.3 1.82 [ 0.89, 3.71 ]

Subtotal (95% CI) 227 155 100.0 1.64 [ 1.07, 2.52 ]




0.01 0.1 1 10 100




Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mother’s

HBeAg status





n/N n/N 95% CI (%) 95% CI

01 HBeAg positive

Lee 1995 AB 15/51 2/14 6.7 2.06 [ 0.53, 7.96 ]

Lee 1995 CB 16/47 2/14 6.6 2.38 [ 0.62, 9.13 ]

Pongpipat 1989 3/20 1/20 2.1 3.00 [ 0.34, 26.45 ]

Zhu 1994 17/54 21/52 45.9 0.78 [ 0.47, 1.30 ]

Subtotal (95% CI) 172 100 61.4 1.17 [ 0.75, 1.82 ]




02 HBeAg unknown

Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ]

Subtotal (95% CI) 55 55 38.6 0.72 [ 0.39, 1.33 ]




03 HBeAg negative

Subtotal (95% CI) 0 0 0.0 Not estimable



Test for overall effect: not applicable

Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ]




0.01 0.1 1 10 100




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



Outcome: 05 Anti-HBs less than 10 IU/L


n/N n/N 95% CI (%) 95% CI

Halliday 1992 AB 6/46 16/49 30.9 0.40 [ 0.17, 0.93 ]

Kuru 1995 AC 0/5 0/25 0.0 Not estimable

Kuru 1995 BC 0/6 1/42 0.8 2.05 [ 0.09, 45.42 ]

Zhu 1994 19/43 33/40 68.2 0.54 [ 0.37, 0.77 ]

Total (95% CI) 100 156 100.0 0.51 [ 0.36, 0.72 ]




0.01 0.1 1 10 100


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


Comparison: 03 High-dose versus low-dose vaccine


Study High dose Low dose Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 High-dose PDV versus low-dose PDV

Oon 1986 AB 0/141 0/102 0.0 Not estimable


Total events: 0 (High dose), 0 (Low dose)



02 High-dose PDV plus HBIG versus low-dose PDV plus HBIG

Oon 1986 CD 10/70 10/59 36.4 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 3/20 6/20 20.1 0.50 [ 0.14, 1.73 ]

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ]

Subtotal (95% CI) 120 109 69.9 0.97 [ 0.55, 1.68 ]




0.01 0.1 1 10 100

High dose better Low dose better (Continued . . . )



(. . . Continued)

Study High dose Low dose Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

03 High-dose RV plus HBIG versus low-dose RV plus HBIG

Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ]

Subtotal (95% CI) 55 55 30.1 0.78 [ 0.31, 1.94 ]




Total (95% CI) 316 266 100.0 0.91 [ 0.57, 1.46 ]




0.01 0.1 1 10 100

High dose better Low dose better

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

to methodological quality




Study High-dose vaccine Low-dose vaccine Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI


Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ]

Subtotal (95% CI) 55 55 30.1 0.78 [ 0.31, 1.94 ]

Total events: 7 (High-dose vaccine), 9 (Low-dose vaccine)





Oon 1986 CD 10/70 10/59 36.4 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 3/20 6/20 20.1 0.50 [ 0.14, 1.73 ]

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ]

Subtotal (95% CI) 261 211 69.9 0.97 [ 0.55, 1.68 ]




Total (95% CI) 316 266 100.0 0.91 [ 0.57, 1.46 ]

0.01 0.1 1 10 100




(. . . Continued)


n/N n/N 95% CI (%) 95% CI




0.01 0.1 1 10 100


Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events -

sensitivity analyses





n/N n/N 95% CI (%) 95% CI


Halliday 1992 DC 2/50 3/49 18.0 0.65 [ 0.11, 3.74 ]


Oon 1986 CD 10/70 10/59 64.5 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 1/18 1/15 6.5 0.83 [ 0.06, 12.22 ]

Theppisai 1990 2/24 2/28 11.0 1.17 [ 0.18, 7.67 ]

Subtotal (95% CI) 303 253 100.0 0.84 [ 0.44, 1.63 ]




02 Assuming poor oucome

Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ]


Oon 1986 CD 10/70 10/59 36.4 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 3/20 6/20 20.1 0.50 [ 0.14, 1.73 ]

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ]

Subtotal (95% CI) 316 266 100.0 0.91 [ 0.57, 1.46 ]





0.01 0.1 1 10 100




(. . . Continued)


n/N n/N 95% CI (%) 95% CI

Halliday 1992 DC 2/55 3/55 17.8 0.67 [ 0.12, 3.84 ]


Oon 1986 CD 10/70 10/59 64.4 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 1/20 1/20 5.9 1.00 [ 0.07, 14.90 ]

Theppisai 1990 2/30 2/30 11.9 1.00 [ 0.15, 6.64 ]

Subtotal (95% CI) 316 266 100.0 0.84 [ 0.43, 1.63 ]




04 Extreme case favouring high-dose vaccine

Halliday 1992 DC 2/55 9/55 32.3 0.22 [ 0.05, 0.98 ]


Oon 1986 CD 10/70 10/59 39.0 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 1/20 6/20 21.5 0.17 [ 0.02, 1.26 ]

Theppisai 1990 8/30 2/30 7.2 4.00 [ 0.92, 17.30 ]

Subtotal (95% CI) 316 266 100.0 0.72 [ 0.42, 1.24 ]




05 Extreme case favouring low-dose vaccine

Halliday 1992 DC 7/55 3/55 15.9 2.33 [ 0.64, 8.56 ]


Oon 1986 CD 10/70 10/59 57.6 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 3/20 1/20 5.3 3.00 [ 0.34, 26.45 ]

Theppisai 1990 8/30 4/30 21.2 2.00 [ 0.67, 5.94 ]

Subtotal (95% CI) 316 266 100.0 1.44 [ 0.84, 2.48 ]




0.01 0.1 1 10 100




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

to the mother’s HBeAg status





n/N n/N 95% CI (%) 95% CI

01 HBeAg positive

Oon 1986 CD 10/70 10/59 36.4 0.84 [ 0.38, 1.89 ]

Pongpipat 1988 3/20 6/20 20.1 0.50 [ 0.14, 1.73 ]

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ]

Subtotal (95% CI) 120 109 69.9 0.97 [ 0.55, 1.68 ]




02 HBeAg unknown

Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ]

Subtotal (95% CI) 55 55 30.1 0.78 [ 0.31, 1.94 ]




03 HBeAg negative






Total (95% CI) 277 305 100.0 0.91 [ 0.57, 1.46 ]




0.01 0.1 1 10 100




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





n/N n/N 95% CI (%) 95% CI

01 High dose PDV versus low dose PDV

Kuru 1995 AB 1/42 0/25 1.6 1.81 [ 0.08, 42.90 ]

Subtotal (95% CI) 42 25 1.6 1.81 [ 0.08, 42.90 ]




02 High dose RV versus low dose RV

Halliday 1992 DC 39/50 38/49 98.4 1.01 [ 0.81, 1.24 ]

Subtotal (95% CI) 50 49 98.4 1.01 [ 0.81, 1.24 ]




Total (95% CI) 92 74 100.0 1.02 [ 0.82, 1.27 ]




0.001 0.01 0.1 1 10 100 1000


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

Hepatitis B events


Comparison: 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG


Study Three doses Two doses Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Piazza 1985 1/37 2/37 100.0 0.50 [ 0.05, 5.28 ]

Total (95% CI) 37 37 100.0 0.50 [ 0.05, 5.28 ]

Total events: 1 (Three doses), 2 (Two doses)



0.01 0.1 1 10 100

Three doses better Two doses better



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

Anti-HBs less than 10 IU/L


Comparison: 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG


Study Three doses Two doses Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Piazza 1985 0/37 10/37 100.0 0.05 [ 0.00, 0.78 ]

Total (95% CI) 37 37 100.0 0.05 [ 0.00, 0.78 ]

Total events: 0 (Three doses), 10 (Two doses)



0.001 0.01 0.1 1 10 100 1000

Three doses better Two doses better

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


Comparison: 05 PDV at birth versus PDV at one month


Study At birth At one month Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Beasley 1983b 3/50 5/58 100.0 0.70 [ 0.18, 2.77 ]

Total (95% CI) 50 58 100.0 0.70 [ 0.18, 2.77 ]

Total events: 3 (At birth), 5 (At one month)



0.01 0.1 1 10 100

At birth better One month better



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


Comparison: 06 One type of PDV versus another type of PDV


Study NIAID BIVS Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 NIAID versus BIVS

Xu 1995 AB 7/60 14/60 100.0 0.50 [ 0.22, 1.15 ]

Total (95% CI) 60 60 100.0 0.50 [ 0.22, 1.15 ]

Total events: 7 (NIAID), 14 (BIVS)



0.01 0.1 1 10 100

NIAID better BIVS better

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

events


Comparison: 07 Four RV vaccinations versus three RV vaccinations


Study 0-1-2-12 schedule 0-1-6 schedule Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Lolekha 2002 7/47 5/50 100.0 1.49 [ 0.51, 4.37 ]

Total (95% CI) 47 50 100.0 1.49 [ 0.51, 4.37 ]

Total events: 7 (0-1-2-12 schedule), 5 (0-1-6 schedule)



0.01 0.1 1 10 100

0-1-2-12 better 0-1-6 better



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

level less than 10 IU/L


Comparison: 07 Four RV vaccinations versus three RV vaccinations

Outcome: 02 Anti-HBs level less than 10 IU/L

Study 0-1-2-12 schedule 0-1-6 schedule Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Lolekha 2002 2/47 4/50 100.0 0.53 [ 0.10, 2.77 ]

Total (95% CI) 47 50 100.0 0.53 [ 0.10, 2.77 ]

Total events: 2 (0-1-2-12 schedule), 4 (0-1-6 schedule)



0.01 0.1 1 10 100

0-1-2-12 better 0-1-6 better

Analysis 08.01. Comparison 08 One type of RV versus another type of RV with the same vaccination

schedule, Outcome 01 Hepatitis B events


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


Study RV1 RV2 Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Hepavax-Gene plus HBIG versus Engerix-B plus HBIG

Hieu 2002 1/53 2/52 100.0 0.49 [ 0.05, 5.25 ]

Subtotal (95% CI) 53 52 100.0 0.49 [ 0.05, 5.25 ]

Total events: 1 (RV1), 2 (RV2)



02 HB VAX II plus HBIG versus Engerix-B plus HBIG

Lee 1995 CA 3/34 2/38 31.8 1.68 [ 0.30, 9.44 ]

Lee 1995 DE 3/36 4/35 68.2 0.73 [ 0.18, 3.03 ]

Subtotal (95% CI) 70 73 100.0 1.03 [ 0.35, 3.02 ]




03 RV1 (Beijing, China) versus RV2 (Institute of Preventive Medicine, China )

Kang 1995 9/57 5/41 100.0 1.29 [ 0.47, 3.58 ]

Subtotal (95% CI) 57 41 100.0 1.29 [ 0.47, 3.58 ]




0.01 0.1 1 10 100

RV1 better RV2 better



Analysis 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


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


Study RV Engerix-B Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Hepavax-Gene versus Engerix-B

Hieu 2002 4/53 5/52 100.0 0.78 [ 0.22, 2.76 ]

Subtotal (95% CI) 53 52 100.0 0.78 [ 0.22, 2.76 ]

Total events: 4 (RV), 5 (Engerix-B)



02 Cuban versus Engerix-B

Garcia 1992 0/54 1/24 100.0 0.15 [ 0.01, 3.59 ]

Subtotal (95% CI) 54 24 100.0 0.15 [ 0.01, 3.59 ]

Total events: 0 (RV), 1 (Engerix-B)



0.001 0.01 0.1 1 10 100 1000

RV better Engerix-B better

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


Comparison: 09 HBIG versus placebo or no intervention


Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 HBIG versus placebo or no intervention

Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ]

Subtotal (95% CI) 139 73 46.9 0.50 [ 0.41, 0.60 ]

Total events: 66 (HBIG), 68 (Control)



02 HBIG plus PDV versus PDV

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

0.001 0.01 0.1 1 10 100 1000

HBIG better Control better (Continued . . . )



(. . . Continued)


n/N n/N 95% CI (%) 95% CI

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ]

Subtotal (95% CI) 328 249 29.0 0.49 [ 0.32, 0.74 ]




03 HBIG plus RV versus RV

Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Subtotal (95% CI) 148 149 24.1 0.61 [ 0.41, 0.92 ]




Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]




0.001 0.01 0.1 1 10 100 1000

HBIG better Control better




according to methodological quality of the trials



Outcome: 02 Hepatitis B events according to methodological quality of the trials


n/N n/N 95% CI (%) 95% CI


Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Subtotal (95% CI) 82 82 8.7 0.45 [ 0.20, 1.01 ]





Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ]

Subtotal (95% CI) 533 389 91.3 0.53 [ 0.44, 0.64 ]




Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]




0.001 0.01 0.1 1 10 100 1000




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

sensitivity analyses





n/N n/N 95% CI (%) 95% CI


Assateerawatt 1993 1/25 3/22 2.5 0.29 [ 0.03, 2.62 ]

Beasley 1983a AB 36/67 28/30 29.9 0.58 [ 0.45, 0.73 ]

Beasley 1983a CB 15/57 28/31 28.1 0.29 [ 0.19, 0.46 ]

Farmer 1987 3/21 4/18 3.3 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 2/50 4/46 3.2 0.46 [ 0.09, 2.39 ]

Ip 1989 AC 5/60 7/32 7.1 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 8.3 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 2.7 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 4.1 0.53 [ 0.15, 1.88 ]

Poovorawan 1997 0/48 3/45 2.8 0.13 [ 0.01, 2.53 ]

Sehgal 1992 3/24 1/21 0.8 2.63 [ 0.29, 23.36 ]

Theppisai 1987 0/25 2/18 2.2 0.15 [ 0.01, 2.87 ]

Xu 1995 CB 1/27 10/56 5.0 0.21 [ 0.03, 1.54 ]

Subtotal (95% CI) 531 397 100.0 0.44 [ 0.35, 0.55 ]





Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

0.001 0.01 0.1 1 10 100 1000




(. . . Continued)


n/N n/N 95% CI (%) 95% CI

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ]

Subtotal (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]





Assateerawatt 1993 1/30 3/30 2.2 0.33 [ 0.04, 3.03 ]

Beasley 1983a AB 36/76 28/36 28.4 0.61 [ 0.45, 0.82 ]

Beasley 1983a CB 15/63 28/37 26.4 0.31 [ 0.20, 0.51 ]

Farmer 1987 3/21 4/18 3.2 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 2/55 4/55 3.0 0.50 [ 0.10, 2.62 ]

Ip 1989 AC 5/60 7/32 6.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 8.0 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 2.6 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 3.9 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 5.0 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 0/63 3/64 2.6 0.15 [ 0.01, 2.75 ]

Sehgal 1992 3/27 1/24 0.8 2.67 [ 0.30, 23.96 ]

Theppisai 1987 0/27 2/18 2.2 0.14 [ 0.01, 2.67 ]

Xu 1995 CB 1/28 10/60 4.8 0.21 [ 0.03, 1.59 ]

Subtotal (95% CI) 615 471 100.0 0.44 [ 0.35, 0.56 ]




04 Extreme case favouring HBIG

Assateerawatt 1993 1/30 11/30 5.8 0.09 [ 0.01, 0.66 ]

Beasley 1983a AB 36/76 34/36 24.5 0.50 [ 0.39, 0.64 ]

Beasley 1983a CB 15/63 34/37 22.7 0.26 [ 0.16, 0.41 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 2/55 13/55 6.9 0.15 [ 0.04, 0.65 ]

0.001 0.01 0.1 1 10 100 1000




(. . . Continued)


n/N n/N 95% CI (%) 95% CI

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.7 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.9 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 0/63 22/64 11.9 0.02 [ 0.00, 0.36 ]

Sehgal 1992 3/27 4/24 2.2 0.67 [ 0.17, 2.68 ]

Theppisai 1987 0/27 2/18 1.6 0.14 [ 0.01, 2.67 ]

Xu 1995 CB 2/28 10/60 3.4 0.43 [ 0.10, 1.83 ]

Subtotal (95% CI) 615 471 100.0 0.32 [ 0.26, 0.40 ]





Assateerawatt 1993 6/30 3/30 2.2 2.00 [ 0.55, 7.27 ]

Beasley 1983a AB 45/76 28/36 28.1 0.76 [ 0.59, 0.98 ]

Beasley 1983a CB 21/63 28/37 26.1 0.44 [ 0.30, 0.65 ]

Farmer 1987 3/21 4/18 3.2 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 7/55 4/55 3.0 1.75 [ 0.54, 5.64 ]

Ip 1989 AC 5/60 7/32 6.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 7.9 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 2.6 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 3.9 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 4.9 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 3/64 2.2 5.08 [ 1.55, 16.69 ]

Sehgal 1992 6/27 1/24 0.8 5.33 [ 0.69, 41.20 ]

Theppisai 1987 2/27 2/18 1.8 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 1/28 14/60 6.6 0.15 [ 0.02, 1.11 ]

Subtotal (95% CI) 615 471 100.0 0.73 [ 0.59, 0.89 ]




0.001 0.01 0.1 1 10 100 1000





according to the mother’s HBeAg status





n/N n/N 95% CI (%) 95% CI

01 HBeAg positive

Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Beasley 1983a AB 45/76 34/36 24.2 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.5 0.36 [ 0.25, 0.52 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.7 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/17 9/29 3.5 0.38 [ 0.09, 1.55 ]

Subtotal (95% CI) 522 361 89.4 0.51 [ 0.42, 0.61 ]




02 HBeAg unknown

Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Subtotal (95% CI) 82 79 9.0 0.73 [ 0.38, 1.42 ]




03 HBeAg negative

Xu 1995 CB 0/11 5/31 1.6 0.24 [ 0.01, 4.06 ]

Subtotal (95% CI) 11 31 1.6 0.24 [ 0.01, 4.06 ]




0.001 0.01 0.1 1 10 100 1000




(. . . Continued)


n/N n/N 95% CI (%) 95% CI

Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]




0.001 0.01 0.1 1 10 100 1000



according to time of HBIG administration



Outcome: 05 Hepatitis B events according to time of HBIG administration


n/N n/N 95% CI (%) 95% CI

01 HBIG administered within 12 hours of birth

Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ]

Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Subtotal (95% CI) 482 312 83.2 0.52 [ 0.43, 0.62 ]





Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ]

0.001 0.01 0.1 1 10 100 1000




(. . . Continued)


n/N n/N 95% CI (%) 95% CI

Subtotal (95% CI) 106 132 15.0 0.60 [ 0.35, 1.05 ]





Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Subtotal (95% CI) 27 27 1.8 0.14 [ 0.01, 2.64 ]




Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]




0.001 0.01 0.1 1 10 100 1000



according to standard and rapid schedule of vaccines



Outcome: 06 Hepatitis B events according to standard and rapid schedule of vaccines

Study HBIG+vaccine Vaccine Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

01 Standard schedule (0-1-6 months)

Farmer 1987 3/21 4/18 5.1 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 7/55 13/55 15.3 0.54 [ 0.23, 1.25 ]

Theppisai 1987 2/27 2/18 2.8 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 10.5 0.31 [ 0.07, 1.26 ]

Subtotal (95% CI) 131 151 33.8 0.49 [ 0.27, 0.90 ]

Total events: 14 (HBIG+vaccine), 33 (Vaccine)



02 Rapid schedule (0-1-2-6 or 0-1-2-12 months)

Assateerawatt 1993 6/30 11/30 13.0 0.55 [ 0.23, 1.28 ]

0.001 0.01 0.1 1 10 100 1000




(. . . Continued)

Study HBIG+vaccine Vaccine Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Ip 1989 AC 5/60 7/32 10.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 12.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 4.1 0.14 [ 0.01, 2.64 ]

Poovorawan 1997 15/63 22/64 25.8 0.69 [ 0.40, 1.21 ]

Subtotal (95% CI) 244 185 66.2 0.55 [ 0.38, 0.81 ]




Total (95% CI) 375 336 100.0 0.53 [ 0.39, 0.74 ]




0.001 0.01 0.1 1 10 100 1000


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

IU/L





n/N n/N 95% CI (%) 95% CI

01 HBIG plus PDV versus PDV

Sehgal 1992 6/27 4/24 24.6 1.33 [ 0.43, 4.17 ]

Subtotal (95% CI) 27 24 24.6 1.33 [ 0.43, 4.17 ]




02 HBIG plus RV versus RV

Assateerawatt 1993 1/30 1/30 5.8 1.00 [ 0.07, 15.26 ]

Halliday 1992 CA 11/55 6/55 34.9 1.83 [ 0.73, 4.61 ]

Poovorawan 1997 9/63 6/64 34.6 1.52 [ 0.58, 4.03 ]

Subtotal (95% CI) 148 149 75.4 1.63 [ 0.85, 3.11 ]



0.01 0.1 1 10 100




(. . . Continued)


n/N n/N 95% CI (%) 95% CI


Total (95% CI) 175 173 100.0 1.55 [ 0.89, 2.73 ]




0.01 0.1 1 10 100


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



Outcome: 08 Anti-HBs level

Study HBIG Control Weighted Mean Difference (Fixed) Weight Weighted Mean Difference (Fixed)

N Mean(SD) N Mean(SD) 95% CI (%) 95% CI

Poovorawan 1997 45 3.64 (1.44) 48 3.74 (1.43) 100.0 -0.10 [ -0.68, 0.48 ]

Subtotal (95% CI) 45 48 100.0 -0.10 [ -0.68, 0.48 ]



-10 -5 0 5 10


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



Outcome: 09 Adverse events


n/N n/N 95% CI (%) 95% CI

Beasley 1983a CB 1/63 0/73 100.0 3.47 [ 0.14, 83.67 ]

Total (95% CI) 63 73 100.0 3.47 [ 0.14, 83.67 ]




0.01 0.1 1 10 100




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

B events


Comparison: 10 Multiple HBIG plus PDV versus single HBIG plus PDV


Study Multiple HBIG Single HBIG Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Ip 1989 AB 4/60 3/64 41.4 1.42 [ 0.33, 6.09 ]

Lo 1985 CA 2/38 4/36 58.6 0.47 [ 0.09, 2.43 ]

Total (95% CI) 98 100 100.0 0.87 [ 0.30, 2.47 ]

Total events: 6 (Multiple HBIG), 7 (Single HBIG)



0.1 0.2 0.5 1 2 5 10

Mutliple HBIG better Single HBIG better

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

events


Comparison: 11 PDV plus HBIG versus placebo or no intervention


Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ]

Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ]

Total events: 5 (PDV + HBIG), 68 (Control)



0.001 0.01 0.1 1 10 100 1000

PDV + HBIG better Control better




events according to methodological quality of the trials



Outcome: 02 Hepatitis B events according to methodological quality of the trials


n/N n/N 95% CI (%) 95% CI


Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Subtotal (95% CI) 98 60 77.6 0.05 [ 0.02, 0.14 ]





Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ]

Subtotal (95% CI) 28 60 22.4 0.18 [ 0.05, 0.70 ]




Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ]




0.001 0.01 0.1 1 10 100 1000





events - sensitivity analyses





n/N n/N 95% CI (%) 95% CI


Ip 1989 AD 1/36 12/17 24.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 22.6 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 33.4 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 1/27 19/55 19.1 0.11 [ 0.02, 0.76 ]

Subtotal (95% CI) 125 115 100.0 0.06 [ 0.02, 0.15 ]





Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ]

Subtotal (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ]





Ip 1989 AD 1/36 12/17 25.0 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 22.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 33.6 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 1/28 19/60 18.6 0.11 [ 0.02, 0.80 ]

Subtotal (95% CI) 126 120 100.0 0.06 [ 0.02, 0.15 ]




04 Extreme case favouring PDV plus HBIG

Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

0.001 0.01 0.1 1 10 100 1000

PDV + HBIG better Control better (Continued . . . )



(. . . Continued)


n/N n/N 95% CI (%) 95% CI

Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 1/28 24/60 22.4 0.09 [ 0.01, 0.63 ]

Subtotal (95% CI) 126 120 100.0 0.06 [ 0.02, 0.15 ]





Ip 1989 AD 1/36 12/17 25.0 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 22.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 33.6 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/28 19/60 18.6 0.23 [ 0.06, 0.90 ]

Subtotal (95% CI) 126 120 100.0 0.08 [ 0.04, 0.18 ]




0.001 0.01 0.1 1 10 100 1000



events according to mother’s HBeAg status



Outcome: 04 Hepatitis B events according to mother’s HBeAg status


n/N n/N 95% CI (%) 95% CI

01 HBeAg positive

Ip 1989 AD 1/36 12/17 23.3 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.2 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 31.3 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/17 21/31 21.3 0.17 [ 0.05, 0.65 ]

Subtotal (95% CI) 115 91 97.1 0.07 [ 0.03, 0.17 ]




0.001 0.01 0.1 1 10 100 1000

PDV + HBIG better Control better (Continued . . . )



(. . . Continued)


n/N n/N 95% CI (%) 95% CI

02 HBeAg unknown





03 HBeAg negative

Xu 1995 CD 0/11 3/29 2.9 0.36 [ 0.02, 6.40 ]

Subtotal (95% CI) 11 29 2.9 0.36 [ 0.02, 6.40 ]




Total (95% CI) 126 120 100.0 0.08 [ 0.04, 0.18 ]




0.001 0.01 0.1 1 10 100 1000



events according to time of HBIG administration



Outcome: 05 Hepatitis B events according to time of HBIG administration


n/N n/N 95% CI (%) 95% CI


Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

Subtotal (95% CI) 71 34 45.6 0.06 [ 0.02, 0.19 ]





Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ]

Subtotal (95% CI) 28 60 22.4 0.18 [ 0.05, 0.70 ]


0.001 0.01 0.1 1 10 100 1000

PDV + HBIG Control better (Continued . . . )



(. . . Continued)


n/N n/N 95% CI (%) 95% CI




Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Subtotal (95% CI) 27 26 32.1 0.02 [ 0.00, 0.35 ]




Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ]




0.001 0.01 0.1 1 10 100 1000

PDV + HBIG Control better

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

events



Outcome: 06 Adverse events

Study PDV+HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)

n/N n/N 95% CI (%) 95% CI

Ip 1989 AD 1/36 2/17 40.2 0.24 [ 0.02, 2.43 ]

Ip 1989 BD 2/35 3/17 59.8 0.32 [ 0.06, 1.76 ]

Total (95% CI) 71 34 100.0 0.29 [ 0.07, 1.13 ]

Total events: 3 (PDV+HBIG), 5 (Control)



0.01 0.1 1 10 100

PDV+HBIG better Control better



hepatitis b immunisation for newborn infants of hepatitis

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