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Hepatitis B immunisation for newborn infants of hepatitis B
surface antigen-positive mothers (Review)
Lee C, Gong Y, Brok J, Boxall EH, Gluud C
This 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
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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52Analysis 01.02. Comparison 01 Vaccine versus placebo or no intervention, Outcome 02 Hepatitis B events according to
methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events - Sensitivity
analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55Analysis 01.04. Comparison 01 Vaccine versus placebo or no intervention, Outcome 04 Hepatitis B events according to
the mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56Analysis 01.05. Comparison 01 Vaccine versus placebo or no intervention, Outcome 05 Hepatitis B events according to
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 . . . . . .
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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77Analysis 09.04. Comparison 09 HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events according to
the mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78Analysis 09.05. Comparison 09 HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events according to
time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . . . . . .
79Analysis 09.06. Comparison 09 HBIG versus placebo or no intervention, Outcome 06 Hepatitis B events according to
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
83Analysis 11.02. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 02 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85Analysis 11.04. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events
according to mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . .
86Analysis 11.05. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events
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)
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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.
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P L A I N L A N G U A G E S U M M A R Y
Hepatitis B vaccine, hepatitis B immunoglobulin, and hepatitis B vaccine plus immunoglobulin prevent perinatal transmission
of hepatitis B
Hepatitis B vaccination and hepatitis B immunoglobulin are considered as preventive measures for newborn infants of HBsAg positive
mothers. When all the identified trials were combined, hepatitis B vaccine alone, hepatitis B immunoglobulin alone, and 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.
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(6) Any adverse events: adverse events including local adverse
events and/or systemic adverse events. The adverse events are di-
vided into severe and non-severe. A severe adverse event, accord-
ing to the International Committee on Harmonisation Guidelines
(ICH 1997) is any event that would increase mortality; is life-
threatening; requires inpatient hospitalisation; results in a persis-
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
3Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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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
4Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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One trial assessed four RV vaccinations (0-1-2-12 months) versus
three RV vaccinations (0-1-6 months) (Lolekha 2002). The dose
of each RV was 5 microgram.
One RV versus another RV with the same vaccination schedule
Two trials assessed 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
5Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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showed that both vaccines significantly decreased the risk of hep-
atitis B occurrence.
Subgroup analyses did not find a significant difference between
high- and low-quality trials, the 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%).
6Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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PDV plus hepatitis B immunoglobulin versus placebo or no
intervention (Comparison 11-01 to 11-06)
Compared with placebo/no intervention, PDV plus hepatitis B
immunoglobulin significantly reduced hepatitis B occurrence (RR
0.08, 95% CI 0.03 to 0.17, 3 trials). The sensitivity analyses con-
firmed the robustness of the finding. Subgroup analyses did 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).
7Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 11
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
8Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 12
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
References to studies included in this reviewAssateerawatt 1993 {published data only}
Assateerawatt A, Tanphaichitr VS, Suvatte V, Yodthong S. Immuno-
genicity and efficacy of a recombinant DNA hepatitis B vaccine, Gen-
Hevac B Pasteur in high risk neonates, school children and healthy
adults. Asian Pacific Journal of Allergy Immunology 1993;11(1):85–
91.
Beasley 1983a AB {published data only}∗Beasley RP, Hwang LY, Stevens CE, Lin CC, Hsieh FJ, Wang KY, et
al.Efficacy of hepatitis B immune globulin for prevention of perinatal
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,
et al.HBIG prophylaxis for perinatal HBV infections - final report of
the Taiwan trial. Developmental Biology Standard 1983;54:363–75.
Beasley 1983a CB {published data only}∗Beasley RP, Hwang LY, Stevens CE, Lin CC, Hsieh FJ, Wang KY, et
al.Efficacy of hepatitis B immune globulin for prevention of perinatal
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,
et al.HBIG prophylaxis for perinatal HBV infections - final report of
the Taiwan trial. Developmental Biology Standard 1983;54:363–75.
Beasley 1983b {published data only}Beasley RP, Hwang LY, Lee GC, Lan CC, Roan CH, Huang FY, et
al.Prevention of perinatally transmitted hepatitis B virus infections
with hepatitis B virus infections with hepatitis B immune globulin
and hepatitis B vaccine. Lancet 1983;2(8359):1099–102.
Farmer 1987 {published data only}
Farmer K, Gunn T, Woodfield DG. A combination of hepatitis B
vaccine and immunoglobulin does not protect all infants born to
hepatitis B e antigen positive mothers. New Zealand Medical Journal1987;100(827):412–4.
Garcia 1992 {published data only}Garcia EG, Gonzalez JRB, Guillot CC, Curbelo GT, Griego AG,
Gonzalez MGD. [Field trial of the Cuban recombinant vaccine
against hepatitis B (Heberbiovac HB). Study in newborn infants born
to AgsHB+ mothers]. Revista Cubana de Medicina Tropical 1992;44
(2):149–57.
Grosheide 1993 {published data only}∗Grosheide PM, del Canho R, Heijtink RA, Nuijten AS, Zwijnenberg
J, Banffer JR, et al.Passive-active immunization in infants of hepatitis
Be antigen-positive mothers. Comparison of the efficacy of early and
delayed active immunization. American Journal of Diseases of Children
1993;147(12):1316–20.
Mazel JA, Schalm SW, de Gast BC, Nuijten AS, Heijtink RA, Botman
MJ, et al.Passive-active immunisation of neonates of HBsAg positive
carrier mothers: preliminary observations. British Medical Journal(Clinical Research Ed.) 1984;288(6416):513–5.
Halliday 1992 AB {published data only}Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH,
et al.An efficacy trial of a mammalian cell-derived recombinant DNA
hepatitis B vaccine in infants born to mothers positive for HBsAg, in
Shanghai, China. International Journal of Epidemiology 1992;21(3):
564–73.
Halliday 1992 CA {published data only}Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH,
et al.An efficacy trial of a mammalian cell-derived recombinant DNA
9Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 13
hepatitis B vaccine in infants born to mothers positive for HBsAg, in
Shanghai, China. International Journal of Epidemiology 1992;21(3):
564–73.
Halliday 1992 DC {published data only}Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH,
et al.An efficacy trial of a mammalian cell-derived recombinant DNA
hepatitis B vaccine in infants born to mothers positive for HBsAg, in
Shanghai, China. International Journal of Epidemiology 1992;21(3):
564–73.
Hieu 2002 {published data only}Hieu NT, Kim KH, Janowicz Z, Timmermans I. Comparative ef-
ficacy, safety and immunogenicity of Hepavax-Gene and Engerix-
B, recombinant hepatitis B vaccines, in infants born to HBsAg and
HBeAg positive mothers in Vietnam: an assessment at 2 years. Vac-cine 2002;20(13-14):1803–8.
Ip 1989 AB {published data only}∗Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention
of hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet 1989;1(8635):406–10.
Ip HM, Wong VC, Lelie PN, Reesink HW, Schaasberg W, Yeung CY,
et al.Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese 1989;31(6):654–8.
Ip 1989 AC {published data only}∗Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention
of hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet 1989;1(8635):406–10.
Ip HM, Wong VC, Lelie PN, Reesink HW, Schaasberg W, Yeung CY,
et al.Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese 1989;31(6):654–8.
Ip 1989 AD {published data only}
Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention of
hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet 1989;1(8635):406–10.
Ip HM, Wong VC, Lelie PN, Reesink HW, Schaasberg W, Yeung CY,
et al.Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese 1989;31(6):654–8.
∗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-
ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin.
Double-blind randomised placebo-controlled study. Lancet 1984;1
(8383):921–6.
Ip 1989 BC {published data only}∗Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention
of hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet 1989;1(8635):406–10.
Ip HM, Wong VC, Lelie PN, Reesink HW, Schaasberg W, Yeung CY,
et al.Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese 1989;31(6):654–8.
Ip 1989 BD {published data only}
Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention of
hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet 1989;1(8635):406–10.
Ip HM, Wong VC, Lelie PN, Reesink HW, Schaasberg W, Yeung CY,
et al.Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese 1989;31(6):654–8.
∗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-
ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin.
Double-blind randomised placebo-controlled study. Lancet 1984;1
(8383):921–6.
Ip 1989 CD {published data only}
Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention of
hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet 1989;1(8635):406–10.
Ip HM, Wong VC, Lelie PN, Reesink HW, Schaasberg W, Yeung CY,
et al.Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese 1989;31(6):654–8.
∗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-
ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin.
Double-blind randomised placebo-controlled study. Lancet 1984;1
(8383):921–6.
Kang 1995 {published data only}∗Kang P, Shen XM, Yu HM. [Study on the efficacy of genetically
engineered vaccines against hepatitis B for interruption of perinatal
transmission]. Zhonghua Hu Li Za Zhi 1995;30(7):390–2.
Khukhlovich 1996 {published data only}Khukhlovich PA, Shakhgil’dian IV, Narkevich MI, Anan’ev VA,
Kuzin SN, Sergeeva NA, et al.[The vaccinal prophylaxis of hepatitis
B among children born to mothers with persistent HBs-antigene-
mia]. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 1996;
2:55–9.
Kuru 1995 AB {published data only}
Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated
infants born to HBsAg-positive mothers with different hepatitis B
vaccines and doses. The Turkish Journal of Pediatrics 1995;37(2):93–
102.
Kuru 1995 AC {published data only}Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated
infants born to HBsAg-positive mothers with different hepatitis B
vaccines and doses. The Turkish Journal of Pediatrics 1995;37(2):93–
102.
Kuru 1995 BC {published data only}
Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated
infants born to HBsAg-positive mothers with different hepatitis B
vaccines and doses. The Turkish Journal of Pediatrics 1995;37(2):93–
102.
Lee 1995 AB {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, Sung JL, et al.The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal 1991;10(4):
299–303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
10Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 14
born to mothers with hepatitis B e antigen. The Journal of Pediatrics
1995;126(5 Pt 1):716–21.
∗Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
study of combined vaccination with plasma-derived and recombinant
hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9.
Lee 1995 CA {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, Sung JL, et al.The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal 1991;10(4):
299–303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
born to mothers with hepatitis B e antigen. The Journal of Pediatrics1995;126(5 Pt 1):716–21.
∗Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
study of combined vaccination with plasma-derived and recombinant
hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9.
Lee 1995 CB {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, Sung JL, et al.The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal 1991;10(4):
299–303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
born to mothers with hepatitis B e antigen. The Journal of Pediatrics
1995;126(5 Pt 1):716–21.
∗Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
study of combined vaccination with plasma-derived and recombinant
hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9.
Lee 1995 DE {published data only}
Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, Sung JL, et al.The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal 1991;10(4):
299–303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
born to mothers with hepatitis B e antigen. The Journal of Pediatrics1995;126(5 Pt 1):716–21.
∗Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
study of combined vaccination with plasma-derived and recombinant
hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9.
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
(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 CB {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.
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
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 CB {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.
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.
11Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 15
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
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 BD {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 CB {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.
12Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 16
Xu 1995 CD {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, 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.
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.
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.
References to studies excluded from this review
Chung 1988
Chung WK. Persistence and boosting response of antibody to HBsAg
induced by vaccine treatment. Tropical Gastroenterology 1988;9(1):
26–30.
Chung 1988 B
Chung WK, Choi KY, Shim KS, Chung JW, Sun HS, Chung KW,
et al.Safety, immunogenicity, and efficacy of a new heat-inactivated
hepatitis B vaccine in the newborn. Viral Hepatitis and Liver Disease
1988:1014–6.
Coursaget 1984
Coursaget P, Deciron F, Tortey E, Barin F, Chiron JP, Yvonnet B, et
al.Immune response to hepatitis B vaccine in infants and newborns:
control trial in an endemic area (Senegal). International Agency forResearch on Cancer 1984;63:319–35.
Da 1995
Da Villa G, Picciottoc L, Elia S, Peluso F, Montanaro F, Maisto T.
Hepatitis B vaccination: universal vaccination of newborn babies and
children at 12 years of age versus high risk groups. A comparison in
the field. Vaccine 1995;13(13):1240–3.
Delage 1993
Delage G, Remy-Prince S, Montplaisir S. Combined active-passive
immunization against the hepatitis B virus: five-year follow-up of
children born to hepatitis B surface antigen-positive mothers. The
Pediatric Infectious Disease Journal 1993;12(2):126–30.
Esteban 1986
Esteban JI, Genesca J, Esteban R, Hernandez JM, Seijo G, Buti M,
et al.Immunoprophylaxis of perinatal transmission of the hepatitis B
virus: efficacy of hepatitis B immune globulin and hepatitis B vaccine
in a low-prevalence area. Journal of Medical Virology 1986;18(4):381–
91.
Goh 1992
Goh KT, Tan KL, Kong KH, Oon CJ, Chan SH. Comparison of the
immune response of four different dosages of a yeast-recombinant
hepatitis B vaccine in Singapore children: a four-year follow-up study.
Bulletin of the World Health Organization 1992;70(2):233–9.
Kang 1986
Kang Y. Efficacy of domestic hepatitis B viral vaccines in preventing
transmission of e antigen from mothers to newborn infants. Zhonghua
Liu Xing Bing Xue Za Zhi 1986;7(2):81–3.
Lai 1986
Lai CL, Yeoh EK, Chang WK, Lo VW, Ng LN. Use of the hepatitis
B recombinant DNA yeast vaccine (H-B-VAX II) in children: two
doses vs. three doses of 5 micrograms regime; an interim report. TheJournal of Infection 1986;13 Suppl A:19–25.
Lai 1993
Lai CL, Wong BC, Yeoh EK, Lim WL, Chang WK, Lin HJ. Five-
year follow-up of a prospective randomized trial of hepatitis B recom-
binant DNA yeast vaccine vs. plasma-derived vaccine in children:
immunogenicity and anamnestic responses. Hepatology 1993;18(4):
763–7.
Laille 1988
Laille M, Brethes B, Moreau JP, Pillot J. [Trial of hepatitis B pro-
phylaxis in children born to mothers carrying HBs antigen in New
Caledonia]. Bulletin de la Societe de Pathologie Exotique et de ses Filiales
1988;81(4):673–8.
Lin 1987
Lin KH, Twu SJ, Chen DS, Su S, Lee CJ. Efficacy of the national
hepatitis B vaccination program in the Republic of China: prelim-
inary observations from Taoyuan area. Taiwan Yi Xue Hui Za Zhi1987;86(8):869–72.
Linder 2000
Linder N, Handsher R, German B, Sirota L, Bachman M, Zinger
S, et al.Controlled trial of immune response of preterm infants to
recombinant hepatitis B and inactivated poliovirus vaccines adminis-
tered simultaneously shortly after birth. Archives of Disease in Child-hood. Fetal and neonatal edition 2000;83(1):F24–F27.
Milne 1989
Milne A, Heydon JL, Hindle RC, Pearce NE. Prevalence of hepatitis B
in children in a high risk New Zealand community, and control using
recombinant DNA vaccine. New Zealand Medical Journal 1989;102
(866):182–4.
Mittal 1994
Mittal SK, Rao S, Kumari S, Aggarwal V, Prakash C, Thirupuram S.
Simultaneous administration of hepatitis B vaccine with other E.P.I.
vaccines. Indian Journal of Pediatrics 1994;61(2):183–8.
Moulia-Pelat 1994
Moulia-Pelat JP, Spiegel A, Martin PM, Cardines R, Boutin JP, Roux
JF, et al.A 5-year immunization field trial against hepatitis B using a
Chinese hamster ovary cell recombinant vaccine in French Polynesian
newborns: results at 3 years. Vaccine 1994;12(6):499–502.
13Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 17
Nair 1984
Nair PV, Weissman JY, Tong MJ, Thursby MW, Paul RH, Henne-
man CE. Efficacy of hepatitis B immune globulin in prevention of
perinatal transmission of the hepatitis B virus. Gastroenterology 1984;
87(2):293–8.
Okoth 1994
Okoth FA, Kobayashi M, Takayanagi N, Kapttich DC, Kaiguri PM,
Tukei PM. Efficacy of hepatitis B vaccine in a rural community in
Muranga, Kenya. East African Medical Journal 1994;71(4):250–2.
Perrin 1986
Perrin J, Coursaget P, Ntareme F, Chiron JP. Hepatitis B immuniza-
tion of newborns according to a two dose protocol. Vaccine 1986;4
(4):241–4.
Pongpipat 1984
Pongpipat D, Suvatte V, Assateerawatts A. Vaccination against hep-
atitis B virus infection in neonates. Helvetica Paediatrica Acta 1984;
39(3):231–6.
Poovorawan 1989
Poovorawan Y, Sanpavat S, Pongpunlert W, Chumdermpadetsuk S,
Sentrakul P, Safary A. Protective efficacy of a recombinant DNA
hepatitis B vaccine in neonates of HBe antigen-positive mothers. TheJournal of the American Medical Association 1989;261(22):3278–81.
Poovorawan 1990
Poovorawan Y, Sanpavat S, Pongpunlert W, Chumdermpadetsuk S,
Sentrakul P, Chitinand S, et al.Comparison of a recombinant DNA
hepatitis B vaccine alone or in combination with hepatitis B immune
globulin for the prevention of perinatal acquisition of hepatitis B
carriage. Vaccine 1990;8 Suppl:S56-S59; discussion S60-S62.
Shikata 1984
Shikata T, Yano M, Shiraki K, Oda T. Efficacy trial of HBIG and
hepatitis B vaccine for the prevention of perinatal HBV transmission.
Viral Hepatitis and Liver Disease 1984:596–7.
Stevens 1987
Stevens CE, Taylor PE, Tong MJ, Toy PT, Vyas GN, Nair PV, et
al.Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B
immune globulin in prevention of perinatal hepatitis B virus trans-
mission. The Journal of the American Medical Association 1987;257
(19):2612–6.
Stevens 1988
Stevens CE, Taylor PE, Tong MJ, Toy PT, Vyas GN, Zang EA, et
al.Prevention of perinatal hepatitis B virus infection with hepatitis B
immune globulin and hepatitis B vaccine. Viral Hepatitis and Liver
Disease 1988:982–8.
Stevens 1990
Stevens CE, Taylor PE, Tong MJ, Toy PT. Hepatitis B immune glob-
ulin and yeast-recombinant hepatitis B vaccine in prevention of peri-
natal HBV infection in the USA. Viral Hepatits and HepatocellularCarcinoma 1990:377–84.
Stevens 1992
Stevens CE, Toy PT, Taylor PE, Lee T, Yip HY. Prospects for control
of hepatitis B virus infection: implications of childhood vaccination
and long-term protection. Pediatrics 1992;90(1 Pt 2):170–3.
Surya 1996
Surya IGP, Kishimoto S, Sudaryat S, Tsuda F, Hamid A, Takahashi K,
et al.Prevention of mother-to-infant transmission of hepatitis B virus
with use of a preS2-containing vaccine in Bali, Indonesia. Vaccine
Research 1996;5(4):203–12.
Suwignyo 1994
Suwignyo S, Surya IGP, Mulyanto, Montessori, Domoto K, Tsuda
F, et al.The use of a PreS2-containing recombinant vaccine for the
prevention of maternal transmission of hepatitis B virus in Indonesian
neonates. Viral Hepatitis and Liver Disease 1994:536–9.
Theppisai 1988
Theppisai U, Thanuntaseh C, Chiewsilp P, Siripoonya P. Two-year
study of passive-active immunization for prevention of hepatitis B
infection in newborns. Journal of the Medical Association of Thailand
1988;71(8):413–6.
Theppisai 1989
Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P. Long-term
immunoprophylaxis of hepatitis B surface antigen carrier in infants
born to hepatitis B surface antigen positive mothers using plasma
derived vaccine. Asia Oceania Journal of Obstetrics and Gynaecology
1989;15(2):111–5.
Wheeley 1991
Wheeley SM, Jackson PT, Boxall EH, Tarlow MJ, Gatrad AR, An-
derson J, et al.Prevention of perinatal transmission of hepatitis B
virus (HBV): a comparison of two prophylactic schedules. Journal of
Medical Virology 1991;35(3):212–5.
Young 2003
Young BW, Lee SS, Lim WL, Yeoh EK. The long-term efficacy of
plasma-derived hepatitis B vaccine in babies born to carrier mothers.
Journal of Viral Hepatitis 2003;10(1):23–30.
Yuen 1999
Yuen MF, Lim WL, Cheng CC, Lam SK, Lai CL. Twelve-year follow-
up of a prospective randomized trial of hepatitis B recombinant DNA
yeast vaccine versus plasma-derived vaccine without booster doses in
children. Hepatology 1999;29(3):924–7.
Zanetti 1986
Zanetti AR, Dentico P, Del Vecchio Blanco C, Sagnelli E, Villa E,
Ferroni P, et al.Multicenter trial on the efficacy of HBIG and vaccine
in preventing perinatal hepatitis B. Final report. Journal of Medical
Virology 1986;18(4):327–34.
Zhu 2003
Zhu Q, Yu G, Yu H, Lu Q, Gu X, Dong Z, et al.A randomized
control trial on interruption of HBV transmission in uterus. ChineseMedical Journal 2003;116(5):685–7.
Additional references
Aggarwal 2004
Aggarwal R, Ranjan P. Preventing and treating hepatitis B infection.
BMJ (Clinical Research Ed.) 2004;329(7474):1080–6.
Akhter 1992
Akhter S, Talukder MQ, Bhuiyan N, Chowdhury TA, Islam MN,
Begum S. Hepatitis B virus infection in pregnant mothers and its
transmission to infants. Indian Journal of Pediatrics 1992;59(4):411–
5.
Als-Nielsen 2004
Als-Nielsen B, Gluud LL, Gluud C. Methodological quality and
treatment effects in randomised trials - a review of six empirical stud-
ies (abstract). Cochrane Colloquium 2004, Ottawa, Canada. 2004.
14Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 18
Altman 2003
Altman DG, Bland JM. Interaction revisited: the difference between
two estimates. BMJ (Clinical Research Ed.) 2003;326:219.
Andre 1994
Andre FE, Zuckerman AJ. Review: protective efficacy of hepatitis B
vaccines in neonates. Journal of Medical Virology 1994;44(2):144–
51.
Assad 1999
Assad S, Francis A. Over a decade of experience with a yeast recom-
binant hepatitis B vaccine. Vaccine 1999;18(1-2):57–67.
Beasley 1977
Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and
vertical transmission of hepatitis B surface antigen. American Journal
of Epidemiology 1977;105(2):94–8.
Beasley 1983
Beasley RP, Hwang LY. Postnatal infectivity of hepatitis B surface
antigen-carrier mothers. Journal of Infectious Diseases 1983;147(2):
185–90.
Beasley 1984
Beasley RP, Hwang LY. Hepatocellular carcinoma and hepatitis B
virus. Seminars in Liver Disease 1984;4(2):113–21.
Begg 1994
Begg CB, Mazumdar M. Operating characteristics of a rank correla-
tion test for publication bias. Biometrics 1994;50(4):1088–101.
Bloom 1993
Bloom BS, Hillman AL, Fendrick AM, Schwartz JS. A reappraisal of
hepatitis B virus vaccination strategies using cost-effectiveness anal-
ysis. Annals of Internal Medicine 1993;118(4):298–306.
Bohlke 2003
Bohlke K, Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB,
et al.Risk of anaphylaxis after vaccination of children and adolescents.
Pediatrics 2003;112(4):815–20.
CDC 1991
Centers for Disease Control and Prevention. Hepatitis B virus: a
comprehensive strategy for eliminating transmission in the United
States through universal childhood vaccination: recommendations of
the Immunization Practices Advisory Committee (ACIP). Morbidityand Mortality Weekly Report. Recommendations and Reports/Centers for
Disease Control 1991;40:1–19.
CDC 1999
Centers for Disease Control and Prevention. Notice to readers up-
date: recommendations to prevent hepatitis B virus transmission -
United States-updated. Morbidity and Mortality Weekly Report 1999;
48(2):33–4.
Chen 2005
Chen W, Gluud C. Vaccines for preventing hepatitis B
in health-care workers. The Cochrane Database of System-
atic Reviews 2005, Issue 4. Art. No.: CD000100. DOI:
10.1002/14651858.CD000100.pub3.
Da Villa 1999
Da Villa G, Sepe A. Immunization programme against hepatitis B
virus infection in Italy: Cost-effectiveness. Vaccine 1999;17(13-14):
1734–8.
David 1996
David MS, Norman TB. Immunisation against Infectious Disease.London: HMSO, 1996.
Deeks 2003
Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F,
et al.Evaluating non-randomised intervention studies. Health Tech-
nology Assessment 2003;7(27):1–173.
DeMets 1987
DeMets DL. Methods for combining randomized clinical trials:
strengths and limitations. Statistics in Medicine 1987;6(3):341–50.
[MEDLINE: 3616287].
DerSimonian 1986
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled
Clinical Trials 1986;7(3):177–88. [MEDLINE: 3802833].
Dusheiko 1998
Dusheiko G. Hepatitis B. In: BircherJ, BenhamouJP, McIntyreN,
RizzettoM, RodésJ editor(s). Oxford Textbook of Clinical Hepatology.Oxford, UK: Oxford Medical Publications, 1998:876–96.
DuVernoy 2000
DuVernoy TS, Braun MM. Hypotonic-hyporesponsive episodes re-
ported to the Vaccine Adverse Event Reporting System (VAERS),
1996-1998. Pediatrics 2000;106(4):E52.
Egger 1997
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-
analysis detected by a simple graphical test. BMJ (Clinical Research
Ed.) 1997;315(7109):629–34. [MEDLINE: 9310563].
Etminan 2004
Etminan M, Carleton B, Rochon PA. Quantifying adverse drug
events: Are systematic reviews the answer?. Drug Safety 2004;27(11):
757–61.
Fisher 2001
Fisher MA, Eklund SA, James SA, Lin X. Adverse events associated
with hepatitis B vaccine in U.S. children less than six years of age,
1993 and 1994. Annals of Epidemiology 2001;11(1):13–21.
Funk 2002
Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of
HBeAg-negative chronic hepatitis B and associated precore and core
promoter variants. Journal of Viral Hepatitis 2002;9:52–61.
Hadler 1986
Hadler SC, Francis DP, Maynard JE, Thompson SE, Judson FN,
Echenberg DF, et al.Long-term immunogenicity and efficacy of hep-
atitis B vaccine in homosexual men. The New England Journal of
Medicine 1986;315(4):209–14. [MEDLINE: 2941687].
Hall 1993
Hall AJ, Robertson RL, Crivelli PE, Lowe Y, Inskip H, Snow SK, et
al.Cost-effectiveness of hepatitis B vaccine in the Gambia. Transac-tions of the Royal Society of Tropical Medicine and Hygiene 1993;87
(3):333–6.
Harris 2001
Harris A, Yong K, Kermode M. An economic evaluation of univer-
sal infant vaccination against hepatitis B virus using a combination
vaccine (Hib-HepB): a decision analytic approach to cost effective-
ness. Australian and New Zealand Journal of Public Health 2001;25
(3):222–9.
15Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 19
Hayashi 1996
Hayashi K, Walker AM. Japanese and American reports of random-
ized trials: Differences in the reporting of adverse effects. Controlled
Clinical Trials 1996;17(2):99–110.
Heijtink 2002
Heijtink RA, Kruining J, van Bergen P, de Rave S, van Hattum J,
Schutten M, et al.Characterization of a human monoclonal antibody
obtained after immunization with plasma vaccine and a booster with
recombinant-DNA hepatitis B vaccine. Journal of Medical Virology2002;66(3):304–11. [MEDLINE: 11793381].
Higgins 2002
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-
analysis. Statistics in Medicine 2002;21:1539–58.
ICH 1997
International Conference on Harmonisation Expert Working Group.
Code of Federal Regulations & International Conference on Harmoniza-
tion Guidelines. Media: Parexel Barnett, 1997.
Ioannidis 2001
Ioannidis JP, Lau J. Completeness of safety reporting in randomized
trials: an evaluation of 7 medical areas. JAMA 2001;285(4):437–43.
Kjaergard 2001
Kjaergard LL, Villumsen J, Gluud C. Reported methodological qual-
ity and discrepancies between large and small randomized trials
in meta-analyses. Annals of Internal Medicine 2001;135(11):982–9.
[MEDLINE: 11730399].
Kojouharova 2001
Kojouharova M, Teoharov P, Bahtchevanova T, Maeva I, Eginlian A,
Deneva M. Safety and immunogenicity of a yeast-derived recombi-
nant hepatitis B vaccine in Bulgarian newborns. Infection 2001;29
(6):342–4.
Lee 2004
Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B prophy-
laxis for newborns of hepatitis B surface antigen-positive mothers.
(Protocol) The Cochrane Database of Systematic Reviews 2004, Is-
sue 2. Art. No.: CD004790. DOI: 10.1002/14651858.CD004790.
Lewis 2001
Lewis E, Shinefield HR, Woodruff BA, Black SB, Destefano F, Chen
RT, et al.Safety of neonatal hepatitis B vaccine administration. ThePediatric Infectious Disease Journal 2001;20(11):1049–54.
Li 2003
Li XM, Yang YB, Hou HY, Shi ZJ, Shen HM, Teng BQ, et
al.Interruption of HBV intrauterine transmission: a clinical study.
World Journal of Gastroenterology 2003;9:1501–3.
Liu 1995
Liu ZG, Zhao SL, Zhang YX. Cost-benefit analysis on immuniza-
tion of newborns with hepatitis B vaccine in Jinan City (Chinese).
Zhonghua Liu Xing Bing Xue Za Zhi 1995;16(2):81–4.
MacGregor 2004
MacGregor IR. Screening assays for transmissible spongiform en-
cephalopathies (TSEs). Vox Sanguinis 2004;87 Suppl 2:3–6.
Margolis 1995
Margolis H, Coleman P, Brown R, Mast E, Sheingold S, Arevalo J.
Prevention of hepatitis B virus transmission by immunization. An
economic analysis of current recommendations. JAMA 1995;274
(15):1201–8.
Moher 1998
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al.Does
quality of reports of randomised trials affect estimates of intervention
efficacy reported in meta-analyses. Lancet 1998;352(9128):609–13.
[MEDLINE: 9746022].
Nayak 1987
Nayak NC, Panda SK, Zuckerman AJ, Bhan MK, Guha DK. Dy-
namics and impact of perinatal transmission of hepatitis B virus in
north India. Journal of Medical Virology 1987;21(2):137–45.
Niu 1996
Niu MT, Davis DM, Ellenberg S. Recombinant hepatitis B vacci-
nation of neonates and infants: emerging safety data from the Vac-
cine Adverse Event Reporting System. The Pediatric Infectious DiseaseJournal 1996;15(9):771–6.
Niu 1999
Niu MT, Salive ME, Ellenberg SS. Neonatal deaths after hepatitis
B vaccine: the vaccine adverse event reporting system, 1991-1998.
Archives of Pediatrics & Adolescent Medicine 1999;153(12):1279–82.
Okada 1976
Okada K, Kamiyama I, Inomata M, Imai M, Miyakawa Y. E antigen
and anti-e in the serum of asymptomatic carrier mothers as indicators
of positive and negative transmission of hepatitis B virus to their
infants. New England Journal of Medicine 1976;294(14):746–9.
Schultz 1995
Schultz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of
methodological quality associated with estimates of treatment effects
in controlled trials. The Journal of the American Medical Association
1995;273:408–12.
Sriprakash 1997
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.
16Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 20
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.
Allocation concealment: 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.
Publication language: English.
Inclusion criteria:
HBsAg- and HBeAg-positive mothers.
Infant birth weight over 2500 gm with Apgar scores > 8 at 1 minute.
Exclusion criteria:
17Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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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
Birth weight: (3209+-308) gram
Older siblings (mean number): 0.7+-0.6
Cord blood positive (%): 23.9%
Age 1st treatment (minutes): 20.5+-20.4
Age 2nd treatment (minutes): 97.1+-7.9
Age 3rd treatment (minutes): 186.8+-10.3
Mother’s mean age: 26.3+-3.7
HBsAg titer: 11.9+-1.8
Drop-out: 9
(3) Group C
Birth weight: (3232+-372) gram
Older siblings (mean number): 0.6+-0.7
Cord blood positive (%): 22.8%
Age 1st treatment (minutes): 35.8+-135.1
Age 2nd treatment (minutes): 98.0+-8.0
Age 3rd treatment (minutes): 189.0+-9.5
Mother’s mean age: 25.5+-3.3
HBsAg titer: 12.0+-1.9
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.
Allocation concealment B – Unclear
18Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 22
Characteristics of included studies (Continued )
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
Allocation concealment B – Unclear
Study Beasley 1983b
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: unclear - described as double blind but the method of blinding was not described.
Follow-up: adequate - no dropouts.
Participants Country: Taiwan.
Publication language: English.
Inclusion criteria:
HBsAg- and HBeAg-positive mothers.
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
Birth weight (mean +- SD): (3392+-399 gram)
Sex ratio (% male): 60.8
Apgar score: 9.9+-0.4
Age initial HBIG (min): 65+-186
Mother’s age: 26.1+-4.1
(3) Group B
Birth weight (mean +- SD): (3288+-264 gram)
Sex ratio (% male): 56
Apgar score: 9.9+-0.3
Age initial HBIG (min): 171+-328
Mother’s age: 25.4+-2.6
(4) Group C
Birth weight (mean +- SD): (3192+-367 gram)
Sex ratio (% male): 53.4
Apgar score: 9.7+-0.8
Age initial HBIG (min): 145+-312
Mother’s age: 26.3+-3.4
Interventions Control group: saline at birth (mean and SD = 2.1+-4.8 h), 3 and 6 months (from previous study).
19Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 23
Characteristics of included studies (Continued )
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.
Notes Follow-up time: 9 months.
Adverse events:
The data in control group (84 infants) were obtained from another trial (Beasley, 1983)
Allocation concealment B – Unclear
Study Farmer 1987
Methods Generation of allocation sequence: adequate - random number list.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - not specified in the each groups.
Participants Country: New Zealand.
Publication language: English.
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.
Notes Follow-up time: 12 months.
Adverse events: not reported.
Four infants were lost to follow-up.
Allocation concealment B – Unclear
Study Garcia 1992
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: unclear - described as double blind but the method of blinding was not described.
20Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 24
Characteristics of included studies (Continued )
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.
Adverse events: not reported.
Allocation concealment B – Unclear
Study Grosheide 1993
Methods Generation of allocation sequence: unclear - described as randomised, but the method not described.
Allocation concealment: adequate - sealed envelops.
Blinding: not performed.
Follow-up: adequate - number and reasons for dropouts described.
Participants Country: Netherlands
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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.
Notes Follow-up time: 12 months.
21Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 25
Characteristics of included studies (Continued )
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.
Publication language: English.
Inclusion criteria:
HBsAg positive mothers.
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.
Notes Follow-up time: 12 months.
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.
Allocation concealment A – Adequate
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
limits of RevMan in order to make data comparison.
22Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 26
Characteristics of included studies (Continued )
Participants
Interventions
Outcomes
Notes
Allocation concealment A – Adequate
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
limits of RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment A – Adequate
Study Hieu 2002
Methods Generation of allocation sequence: adequate - sequence generated by a computer program.
Allocation concealment: adequate - sealed envelopes.
Blinding: not performed.
Follow-up: inadequate - not described.
Participants Country: Vietnam.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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.
23Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 27
Characteristics of included studies (Continued )
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).
Allocation concealment A – Adequate
Study Ip 1989 AB
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: unclear - described as double blind, but method of blinding not described.
Follow-up: inadequate - not described in each group.
Participants Country: HongKong, China.
Publication language: English.
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
Notes Follow-up time: 36 months.
Adverse events: not reported.
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.
Allocation concealment B – Unclear
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
Allocation concealment B – Unclear
24Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Characteristics of included studies (Continued )
Study Ip 1989 AD
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: adequate.
Blinding: adequate.
Follow-up: inadequate - reasons for dropouts described only, number was not reported.
Participants Country: China.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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
number of pregnancies: 1.4+-0.8
parity: 0.5+-1.0
duration of labour (minutes): 452+-252
mode of delivery:
normal: 51%
forceps: 23%
lower section caesarean section: 26%
induction of labour: 21%
Infants:
males: 60%
birthweight (gm): 3204+-341
maturity(weeks): 40+-1
breastfed: 18%
Group C (n = 35):
Mothers:
age (yr): 25.6+-4.1
25Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Characteristics of included studies (Continued )
number of pregnancies: 1.5+-1.0
parity: 0.5+-0.8
duration of labour (minutes): 396+-243
mode of delivery:
normal: 60%
forceps: 23%
lower section caesarean section: 17%
induction of labour: 20%
Infants:
males: 57%
birthweight (gm): 3107+-393
maturity(weeks): 40+-2
breastfed: 21%
Group D (n = 34):
Mothers:
age (yr): 24.6+-3.8
number of pregnancies: 1.4+-0.6
parity: 0.3+-0.6
duration of labour (minutes): 430+-231
mode of delivery:
normal: 56%
forceps: 12%
lower section caesarean section: 32%
induction of labour: 24%
Infants:
males: 47%
birthweight (gm): 3231+-362
maturity(weeks): 40+-2
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
Notes Follow-up time: 12 months.
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.
Allocation concealment A – Adequate
26Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Characteristics of included studies (Continued )
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment A – Adequate
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment A – Adequate
Study Kang 1995
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - not described.
Participants Country: China.
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
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Characteristics of included studies (Continued )
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.
Allocation concealment B – Unclear
Study Khukhlovich 1996
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: unclear - described as double blind, but method of blinding not described.
Follow-up: inadequate - not described.
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.
Allocation concealment B – Unclear
Study Kuru 1995 AB
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: unclear.
Participants Country: Turkey.
Publication language: English.
Inclusion criteria:
HBsAg positive mothers.
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,
28Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Characteristics of included studies (Continued )
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.
Allocation concealment B – Unclear
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
Allocation concealment B – Unclear
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
of RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
Study Lee 1995 AB
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
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)
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Characteristics of included studies (Continued )
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.
Allocation concealment B – Unclear
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
of RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
Study Lee 1995 CB
Methods This trial is the same as Lee 1995 A1C, but has been entered with its own identifier due to technical limits
of RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
Study Lee 1995 DE
Methods This trial is the same as Lee 1995 A1C, but has been entered with its own identifier due to technical limits
of RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
Study Liu 1987 AB
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: adequate - sealed envelopes.
Blinding: adequate - with placebo.
Follow-up: inadequate - not described.
Participants Country: China.
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.
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Characteristics of included studies (Continued )
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.
Allocation concealment A – Adequate
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment A – Adequate
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment A – Adequate
Study Lo 1985 AB
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: unclear.
Participants Country: Taiwan.
Publication language: English.
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.
31Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Characteristics of included studies (Continued )
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.
Allocation concealment B – Unclear
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
Study Lolekha 2002
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - not described.
Participants Country: Thailand.
Publication language: English.
Inclusion criteria:
HBsAg- and HBeAg-positive mothers.
Infant birth weight >= 2000 gram, Apgar score >= 7 at 5 minutes
Participants:
(1) Group A
32Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Characteristics of included studies (Continued )
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
Notes Follow-up time: 13 months.
Adverse events: None of the vaccines had a serious adverse experience and none withdrew from the study
because of a vaccine related adverse experience.
Allocation concealment B – Unclear
Study Oon 1986 AB
Methods Generation of allocation sequence: adequate - by lottery or the use of coded numbers.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - not described.
Participants Country: Singapore
Publication language: English.
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.
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Characteristics of included studies (Continued )
Group F: 10 microgram PDV at birth, 1 and 2 months.
Outcomes HBsAg
HBeAg
Anti-HBs
Notes Follow-up time: 12 months.
Adverse effects: none was observed during the surveillance period.
Allocation concealment B – Unclear
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
of RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
Study Piazza 1985
Methods Generation of allocation sequence: adequate - random number.
Allocation concealment: adequate - sealed envelopes.
Blinding: unclear.
Follow-up: adequate - reasons and numbers described.
Participants Country: Italy.
Publication language: English.
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
Notes Follow-up time: 6 months.
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.
Allocation concealment A – Adequate
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Characteristics of included studies (Continued )
Study Pongpipat 1986
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - reasons not described.
Participants Country: Thailand.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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
Notes Follow-up time: 12 months.
Adverse events: neither local nor systemic reactions were observed after immunisation.
Allocation concealment B – Unclear
Study Pongpipat 1988
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - number reported only.
Participants Country: Thailand.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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.
Allocation concealment B – Unclear
Study Pongpipat 1989
Methods Generation of allocation sequence: unclear - not described.
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Characteristics of included studies (Continued )
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - number for dropouts described only.
Participants Country: Thailand.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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.
Notes Follow-up time: 12 months.
Adverse events: neither local nor systemic reactions were observed after immunization with HBIG and both
kinds of hepatitis B vaccine.
Allocation concealment B – Unclear
Study Poovorawan 1997
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - reasons for dropouts described only, number was not reported.
Participants Country: Thailand.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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
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Characteristics of included studies (Continued )
Notes Follow-up time: 60 months.
Adverse events: not reported. Only the data in Group C and D were used for analysis.
Allocation concealment B – Unclear
Study Sehgal 1992
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate.
Participants Country: India.
Publication language: English.
Inclusion criteria:
HBsAg positive mothers.
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.
Adverse events: not reported.
Allocation concealment B – Unclear
Study Theppisai 1987
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: adequate - no dropouts.
Participants Country: Thailand.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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
Allocation concealment B – Unclear
37Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Characteristics of included studies (Continued )
Study Theppisai 1990
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - number reported, but the reasons for dropouts not described.
Participants Country: Thailand.
Publication language: English.
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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
Adverse events: not reported.
Allocation concealment B – Unclear
Study Xu 1995 AB
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: unclear - described as double blind, but method of blinding not described.
Follow-up: inadequate - number for dropouts described only, reasons was not reported.
Participants Country: China.
Publication language: English.
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.
38Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 42
Characteristics of included studies (Continued )
Chronic HBsAg was defined as HBsAg positive for >= 6 months.
Allocation concealment B – Unclear
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
RevMan in order to make data comparison.
Participants
Interventions
Outcomes
Notes
Allocation concealment B – Unclear
Study Xu 1995 BD
Methods This trial is the same as Xu 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
Allocation concealment B – Unclear
Study Xu 1995 CB
Methods This trial is the same as Xu 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
Allocation concealment B – Unclear
Study Xu 1995 CD
Methods This trial is the same as Xu 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
Allocation concealment B – Unclear
Study Yeoh 1986
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate.
Participants Country: China.
Publication language: English.
39Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 43
Characteristics of included studies (Continued )
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.
Allocation concealment B – Unclear
Study Zhu 1987
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: unclear - described as double blind, but method of blinding not described.
Follow-up: inadequate.
Participants Country: China
Publication language: English.
Inclusion criteria:
HBsAg positive mothers.
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.
Adverse events: not reported.
Allocation concealment B – Unclear
Study Zhu 1994
Methods Generation of allocation sequence: unclear - not described.
Allocation concealment: unclear - not described.
Blinding: not performed.
Follow-up: inadequate - number for dropouts described only, reasons was not reported.
Participants Country: China.
Publication language: English.
40Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 44
Inclusion criteria:
HBsAg and HBeAg positive mothers.
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.
Allocation concealment B – Unclear
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.
41Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 45
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.
Stevens 1988 Non-randomised clinical study.
Stevens 1990 Non-randomised clinical study.
Stevens 1992 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
42Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 46
Table 01. Search strategies (Continued )
Database Period Search strategy
#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
#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)
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
43Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 47
Table 01. Search strategies (Continued )
Database Period Search strategy
#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
#17 newborn* or infant* or child* or baby or
babies
#18 #16 or #17
#19 #18 and high risk
#20 #8 and #11 and #19
#21 random* or blind* or placebo* or meta-
analysis
#22 #20 and #21
#23 (DTP-HB or Hib-HB or Comvax or
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,
44Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 48
Table 02. Intervention by group (Continued )
Trial Intervention group Control group
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
at 1, 2, and 12 months.
C: HBIG 145 IU at birth + PDV 5
microgram at birth + 5 microgram RV-2
at 1, 2, and 12 months.
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.
45Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 49
Table 02. Intervention by group (Continued )
Trial Intervention group Control group
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.
B: PDV 10 microgram at birth and at 4
and 8 weeks.
Theppisai 1987 A: HBIG 200 IU and PDV 10 microgram
at birth and PDV 10 microgram at 1 and
6 months.
B: PDV 10 microgram at birth and at 1
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.
B: PDV 20 microgram at birth and at 1
and 6 months.
* HBeAg-positive mothers in A to E
46Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 50
Table 02. Intervention by group (Continued )
Trial Intervention group Control group
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]
02 Hepatitis B events according to
methodological quality
5 403 Relative Risk (Fixed) 95% CI 0.28 [0.20, 0.40]
03 Hepatitis B events - Sensitivity
analyses
Relative Risk (Fixed) 95% CI Subtotals only
04 Hepatitis B events according to
the mother’s HBeAg status
7 403 Relative Risk (Fixed) 95% CI 0.29 [0.20, 0.41]
05 Hepatitis B events according
to first time of vaccine
administration
5 403 Relative Risk (Fixed) 95% CI 0.28 [0.20, 0.40]
Comparison 02. RV versus PDV
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Hepatitis B events 5 382 Relative Risk (Fixed) 95% CI 1.00 [0.70, 1.42]
02 Hepatitis B events according to
methodological quality
5 382 Relative Risk (Fixed) 95% CI 1.00 [0.70, 1.42]
03 Hepatitis B events - sensitivity
analyses
Relative Risk (Fixed) 95% CI Subtotals only
04 Hepatitis B events according to
the mother’s HBeAg status
5 382 Relative Risk (Fixed) 95% CI 1.00 [0.70, 1.42]
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
participants Statistical method Effect size
01 Hepatitis B events 5 582 Relative Risk (Fixed) 95% CI 0.91 [0.57, 1.46]
02 Hepatitis B events according to
methodological quality
5 582 Relative Risk (Fixed) 95% CI 0.91 [0.57, 1.46]
03 Hepatitis B events - sensitivity
analyses
Relative Risk (Fixed) 95% CI Subtotals only
04 Hepatitis B events according to
the mother’s HBeAg status
5 582 Relative Risk (Fixed) 95% CI 0.91 [0.57, 1.46]
47Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 51
05 Anti-HBs less than 10 IU/L 2 166 Relative Risk (Fixed) 95% CI 1.02 [0.82, 1.27]
Comparison 04. Three-dose PDV plus HBIG versus two-dose PDV plus HBIG
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Hepatitis B events 1 74 Relative Risk (Fixed) 95% CI 0.50 [0.05, 5.28]
02 Anti-HBs less than 10 IU/L 1 74 Relative Risk (Fixed) 95% CI 0.05 [0.00, 0.78]
Comparison 05. PDV at birth versus PDV at one month
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Hepatitis B events 1 108 Relative Risk (Fixed) 95% CI 0.70 [0.18, 2.77]
Comparison 06. One type of PDV versus another type of PDV
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Hepatitis B events 1 120 Relative Risk (Fixed) 95% CI 0.50 [0.22, 1.15]
Comparison 07. Four RV vaccinations versus three RV vaccinations
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Hepatitis B events 1 97 Relative Risk (Fixed) 95% CI 1.49 [0.51, 4.37]
02 Anti-HBs level less than 10
IU/L
1 97 Relative Risk (Fixed) 95% CI 0.53 [0.10, 2.77]
Comparison 08. One type of RV versus another type of RV with the same vaccination schedule
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
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
participants Statistical method Effect size
01 Hepatitis B events 14 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63]
02 Hepatitis B events according to
methodological quality of the
trials
14 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63]
03 Hepatitis B events - sensitivity
analyses
Relative Risk (Fixed) 95% CI Subtotals only
04 Hepatitis B events according to
the mother’s HBeAg status
15 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63]
05 Hepatitis B events according to
time of HBIG administration
14 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63]
06 Hepatitis B events according to
standard and rapid schedule of
vaccines
9 711 Relative Risk (Fixed) 95% CI 0.53 [0.39, 0.74]
48Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Page 52
07 Anti-HBs less than 10 IU/L 4 348 Relative Risk (Fixed) 95% CI 1.55 [0.89, 2.73]
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
participants Statistical method Effect size
01 Hepatitis B events 2 198 Relative Risk (Fixed) 95% CI 0.87 [0.30, 2.47]
Comparison 11. PDV plus HBIG versus placebo or no intervention
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Hepatitis B events 4 246 Relative Risk (Fixed) 95% CI 0.08 [0.03, 0.17]
02 Hepatitis B events according to
methodological quality of the
trials
4 246 Relative Risk (Fixed) 95% CI 0.08 [0.03, 0.17]
03 Hepatitis B events - sensitivity
analyses
Relative Risk (Fixed) 95% CI Subtotals only
04 Hepatitis B events according to
mother’s HBeAg status
5 246 Relative Risk (Fixed) 95% CI 0.08 [0.04, 0.18]
05 Hepatitis B events according to
time of HBIG administration
4 246 Relative Risk (Fixed) 95% CI 0.08 [0.03, 0.17]
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.
49Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
Page 53
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
Information not supplied by author
Date new studies found and
included/excluded
01 February 2004
Date authors’ conclusions
section amended
Information not supplied by author
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
50Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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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 ]
Total events: 2 (Vaccine), 9 (Control)
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 ]
Total events: 33 (Vaccine), 77 (Control)
Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2%
Test for overall effect z=6.83 p<0.00001
0.01 0.1 1 10 100
Vaccine better Control better
51Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 01.02. Comparison 01 Vaccine versus placebo or no intervention, Outcome 02 Hepatitis B events
according to methodological quality
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 01 Vaccine versus placebo or no intervention
Outcome: 02 Hepatitis B events according to methodological quality
Study Vaccine Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 10 (Vaccine), 44 (Control)
Test for heterogeneity chi-square=1.40 df=1 p=0.24 I² =28.7%
Test for overall effect z=5.03 p<0.00001
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 events: 23 (Vaccine), 33 (Control)
Test for heterogeneity chi-square=5.61 df=2 p=0.06 I² =64.3%
Test for overall effect z=4.56 p<0.00001
Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ]
Total events: 33 (Vaccine), 77 (Control)
Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2%
Test for overall effect z=6.83 p<0.00001
0.01 0.1 1 10 100
Vaccine better Control better
52Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events -
Sensitivity analyses
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 01 Vaccine versus placebo or no intervention
Outcome: 03 Hepatitis B events - Sensitivity analyses
Study Vaccine Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 24 (Vaccine), 72 (Control)
Test for heterogeneity chi-square=7.74 df=4 p=0.10 I² =48.3%
Test for overall effect z=6.94 p<0.00001
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 ]
Total events: 33 (Vaccine), 77 (Control)
Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2%
Test for overall effect z=6.83 p<0.00001
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 ]
Total events: 24 (Vaccine), 72 (Control)
Test for heterogeneity chi-square=7.57 df=4 p=0.11 I² =47.2%
Test for overall effect z=6.91 p<0.00001
0.01 0.1 1 10 100
Vaccine better Control better (Continued . . . )
53Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study Vaccine Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 24 (Vaccine), 77 (Control)
Test for heterogeneity chi-square=7.53 df=4 p=0.11 I² =46.8%
Test for overall effect z=7.39 p<0.00001
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 ]
Total events: 33 (Vaccine), 72 (Control)
Test for heterogeneity chi-square=10.35 df=4 p=0.03 I² =61.4%
Test for overall effect z=6.26 p<0.00001
0.01 0.1 1 10 100
Vaccine better Control better
54Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 01.04. Comparison 01 Vaccine versus placebo or no intervention, Outcome 04 Hepatitis B events
according to the mother’s HBeAg status
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 01 Vaccine versus placebo or no intervention
Outcome: 04 Hepatitis B events according to the mother’s HBeAg status
Study Vaccine Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 24 (Vaccine), 65 (Control)
Test for heterogeneity chi-square=4.08 df=3 p=0.25 I² =26.4%
Test for overall effect z=6.43 p<0.00001
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 ]
Total events: 2 (Vaccine), 9 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=3.09 p=0.002
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 events: 7 (Vaccine), 3 (Control)
Test for heterogeneity chi-square=0.03 df=1 p=0.85 I² =0.0%
Test for overall effect z=0.17 p=0.9
Total (95% CI) 252 151 100.0 0.29 [ 0.20, 0.41 ]
Total events: 33 (Vaccine), 77 (Control)
Test for heterogeneity chi-square=10.33 df=6 p=0.11 I² =41.9%
Test for overall effect z=6.88 p<0.00001
0.01 0.1 1 10 100
Vaccine better Control better
55Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 01.05. Comparison 01 Vaccine versus placebo or no intervention, Outcome 05 Hepatitis B events
according to first time of vaccine administration
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 01 Vaccine versus placebo or no intervention
Outcome: 05 Hepatitis B events according to first time of vaccine administration
Study Vaccine Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 9 (Vaccine), 32 (Control)
Test for heterogeneity chi-square=1.78 df=1 p=0.18 I² =43.9%
Test for overall effect z=4.67 p<0.00001
02 Vaccine administered within 24 hours of birth
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 ]
Total events: 21 (Vaccine), 24 (Control)
Test for heterogeneity chi-square=1.72 df=1 p=0.19 I² =42.0%
Test for overall effect z=3.26 p=0.001
03 Vaccine administered within 48 hours of birth
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 events: 3 (Vaccine), 21 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=3.59 p=0.0003
Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ]
Total events: 33 (Vaccine), 77 (Control)
Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2%
Test for overall effect z=6.83 p<0.00001
0.01 0.1 1 10 100
Vaccine better Control better
56Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 02.01. Comparison 02 RV versus PDV, Outcome 01 Hepatitis B events
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
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)
Test for heterogeneity chi-square=0.04 df=1 p=0.85 I² =0.0%
Test for overall effect z=1.41 p=0.2
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 events: 34 (RV), 5 (PDV)
Test for heterogeneity chi-square=0.09 df=2 p=0.96 I² =0.0%
Test for overall effect z=1.90 p=0.06
Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ]
Total events: 64 (RV), 44 (PDV)
Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4%
Test for overall effect z=0.02 p=1
0.01 0.1 1 10 100
RV better PDV better
57Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 02.02. Comparison 02 RV versus PDV, Outcome 02 Hepatitis B events according to methodological
quality
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 02 RV versus PDV
Outcome: 02 Hepatitis B events according to methodological quality
Study RV PDV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 High-quality trials
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 ]
Total events: 13 (RV), 18 (PDV)
Test for heterogeneity: not applicable
Test for overall effect z=1.05 p=0.3
02 Low-quality trials
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 events: 51 (RV), 26 (PDV)
Test for heterogeneity chi-square=4.87 df=3 p=0.18 I² =38.4%
Test for overall effect z=0.70 p=0.5
Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ]
Total events: 64 (RV), 44 (PDV)
Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4%
Test for overall effect z=0.02 p=1
0.01 0.1 1 10 100
RV better PDV better
58Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 02.03. Comparison 02 RV versus PDV, Outcome 03 Hepatitis B events - sensitivity analyses
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 02 RV versus PDV
Outcome: 03 Hepatitis B events - sensitivity analyses
Study RV PDV Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 Available patients’ course analysis
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 ]
Total events: 17 (RV), 26 (PDV)
Test for heterogeneity chi-square=2.20 df=4 p=0.70 I² =0.0%
Test for overall effect z=2.13 p=0.03
02 Assuming poor outcome
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 ]
Total events: 64 (RV), 44 (PDV)
Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4%
Test for overall effect z=0.02 p=1
03 Assuming good outcome
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 ]
Total events: 17 (RV), 26 (PDV)
Test for heterogeneity chi-square=2.60 df=4 p=0.63 I² =0.0%
Test for overall effect z=2.34 p=0.02
0.01 0.1 1 10 100
RV better PDV better (Continued . . . )
59Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study RV PDV Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 17 (RV), 44 (PDV)
Test for heterogeneity chi-square=3.17 df=4 p=0.53 I² =0.0%
Test for overall effect z=4.33 p=0.00001
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 ]
Total events: 64 (RV), 26 (PDV)
Test for heterogeneity chi-square=2.17 df=4 p=0.70 I² =0.0%
Test for overall effect z=2.25 p=0.02
0.01 0.1 1 10 100
RV better PDV better
60Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mother’s
HBeAg status
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 02 RV versus PDV
Outcome: 04 Hepatitis B events according to the mother’s HBeAg status
Study RV PDV Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 51 (RV), 26 (PDV)
Test for heterogeneity chi-square=4.87 df=3 p=0.18 I² =38.4%
Test for overall effect z=0.70 p=0.5
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 ]
Total events: 13 (RV), 18 (PDV)
Test for heterogeneity: not applicable
Test for overall effect z=1.05 p=0.3
03 HBeAg negative
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (RV), 0 (PDV)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ]
Total events: 64 (RV), 44 (PDV)
Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4%
Test for overall effect z=0.02 p=1
0.01 0.1 1 10 100
RV better PDV better
61Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 02.05. Comparison 02 RV versus PDV, Outcome 05 Anti-HBs less than 10 IU/L
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 02 RV versus PDV
Outcome: 05 Anti-HBs less than 10 IU/L
Study RV PDV Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 25 (RV), 50 (PDV)
Test for heterogeneity chi-square=1.17 df=2 p=0.56 I² =0.0%
Test for overall effect z=3.81 p=0.0001
0.01 0.1 1 10 100
RV better PDV better
Analysis 03.01. Comparison 03 High-dose versus low-dose vaccine, Outcome 01 Hepatitis B events
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 03 High-dose versus low-dose vaccine
Outcome: 01 Hepatitis B events
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
Subtotal (95% CI) 141 102 0.0 Not estimable
Total events: 0 (High dose), 0 (Low dose)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
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 ]
Total events: 21 (High dose), 20 (Low dose)
Test for heterogeneity chi-square=2.91 df=2 p=0.23 I² =31.3%
Test for overall effect z=0.12 p=0.9
0.01 0.1 1 10 100
High dose better Low dose better (Continued . . . )
62Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . 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 events: 7 (High dose), 9 (Low dose)
Test for heterogeneity: not applicable
Test for overall effect z=0.54 p=0.6
Total (95% CI) 316 266 100.0 0.91 [ 0.57, 1.46 ]
Total events: 28 (High dose), 29 (Low dose)
Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8%
Test for overall effect z=0.39 p=0.7
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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
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
01 High-quality trials
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)
Test for heterogeneity: not applicable
Test for overall effect z=0.54 p=0.6
02 Low-quality trials
Oon 1986 AB 0/141 0/102 0.0 Not estimable
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 events: 21 (High-dose vaccine), 20 (Low-dose vaccine)
Test for heterogeneity chi-square=2.91 df=2 p=0.23 I² =31.3%
Test for overall effect z=0.12 p=0.9
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 (Continued . . . )
63Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study High-dose vaccine Low-dose vaccine Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
Total events: 28 (High-dose vaccine), 29 (Low-dose vaccine)
Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8%
Test for overall effect z=0.39 p=0.7
0.01 0.1 1 10 100
High dose better Low dose better
Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events -
sensitivity analyses
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 03 High-dose versus low-dose vaccine
Outcome: 03 Hepatitis B events - sensitivity analyses
Study High-dose vaccine Low-dose vaccine Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 Available patients’ course analysis
Halliday 1992 DC 2/50 3/49 18.0 0.65 [ 0.11, 3.74 ]
Oon 1986 AB 0/141 0/102 0.0 Not estimable
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 ]
Total events: 15 (High-dose vaccine), 16 (Low-dose vaccine)
Test for heterogeneity chi-square=0.20 df=3 p=0.98 I² =0.0%
Test for overall effect z=0.51 p=0.6
02 Assuming poor oucome
Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ]
Oon 1986 AB 0/141 0/102 0.0 Not estimable
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 ]
Total events: 28 (High-dose vaccine), 29 (Low-dose vaccine)
Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8%
Test for overall effect z=0.39 p=0.7
03 Assuming good outcome
0.01 0.1 1 10 100
High dose better Low dose better (Continued . . . )
64Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
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 2/55 3/55 17.8 0.67 [ 0.12, 3.84 ]
Oon 1986 AB 0/141 0/102 0.0 Not estimable
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 ]
Total events: 15 (High-dose vaccine), 16 (Low-dose vaccine)
Test for heterogeneity chi-square=0.12 df=3 p=0.99 I² =0.0%
Test for overall effect z=0.52 p=0.6
04 Extreme case favouring high-dose vaccine
Halliday 1992 DC 2/55 9/55 32.3 0.22 [ 0.05, 0.98 ]
Oon 1986 AB 0/141 0/102 0.0 Not estimable
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 ]
Total events: 21 (High-dose vaccine), 27 (Low-dose vaccine)
Test for heterogeneity chi-square=9.82 df=3 p=0.02 I² =69.5%
Test for overall effect z=1.18 p=0.2
05 Extreme case favouring low-dose vaccine
Halliday 1992 DC 7/55 3/55 15.9 2.33 [ 0.64, 8.56 ]
Oon 1986 AB 0/141 0/102 0.0 Not estimable
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 ]
Total events: 28 (High-dose vaccine), 18 (Low-dose vaccine)
Test for heterogeneity chi-square=3.02 df=3 p=0.39 I² =0.5%
Test for overall effect z=1.31 p=0.2
0.01 0.1 1 10 100
High dose better Low dose better
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Analysis 03.04. Comparison 03 High-dose versus low-dose vaccine, Outcome 04 Hepatitis B events according
to the mother’s HBeAg status
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 03 High-dose versus low-dose vaccine
Outcome: 04 Hepatitis B events according to the mother’s HBeAg status
Study High-dose vaccine Low-dose vaccine Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 21 (High-dose vaccine), 20 (Low-dose vaccine)
Test for heterogeneity chi-square=2.91 df=2 p=0.23 I² =31.3%
Test for overall effect z=0.12 p=0.9
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 ]
Total events: 7 (High-dose vaccine), 9 (Low-dose vaccine)
Test for heterogeneity: not applicable
Test for overall effect z=0.54 p=0.6
03 HBeAg negative
Oon 1986 AB 0/102 0/141 0.0 Not estimable
Subtotal (95% CI) 102 141 0.0 Not estimable
Total events: 0 (High-dose vaccine), 0 (Low-dose vaccine)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
Total (95% CI) 277 305 100.0 0.91 [ 0.57, 1.46 ]
Total events: 28 (High-dose vaccine), 29 (Low-dose vaccine)
Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8%
Test for overall effect z=0.39 p=0.7
0.01 0.1 1 10 100
High dose better Low dose better
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Analysis 03.05. Comparison 03 High-dose versus low-dose vaccine, Outcome 05 Anti-HBs less than 10 IU/L
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 03 High-dose versus low-dose vaccine
Outcome: 05 Anti-HBs less than 10 IU/L
Study High-dose vaccine Low-dose vaccine Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 1 (High-dose vaccine), 0 (Low-dose vaccine)
Test for heterogeneity: not applicable
Test for overall effect z=0.37 p=0.7
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 events: 39 (High-dose vaccine), 38 (Low-dose vaccine)
Test for heterogeneity: not applicable
Test for overall effect z=0.05 p=1
Total (95% CI) 92 74 100.0 1.02 [ 0.82, 1.27 ]
Total events: 40 (High-dose vaccine), 38 (Low-dose vaccine)
Test for heterogeneity chi-square=0.14 df=1 p=0.71 I² =0.0%
Test for overall effect z=0.17 p=0.9
0.001 0.01 0.1 1 10 100 1000
High dose better Low dose better
Analysis 04.01. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 01
Hepatitis B events
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG
Outcome: 01 Hepatitis B events
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)
Test for heterogeneity: not applicable
Test for overall effect z=0.58 p=0.6
0.01 0.1 1 10 100
Three doses better Two doses better
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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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG
Outcome: 02 Anti-HBs less than 10 IU/L
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)
Test for heterogeneity: not applicable
Test for overall effect z=2.13 p=0.03
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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 05 PDV at birth versus PDV at one month
Outcome: 01 Hepatitis B events
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)
Test for heterogeneity: not applicable
Test for overall effect z=0.51 p=0.6
0.01 0.1 1 10 100
At birth better One month better
68Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 06.01. Comparison 06 One type of PDV versus another type of PDV, Outcome 01 Hepatitis B events
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 06 One type of PDV versus another type of PDV
Outcome: 01 Hepatitis B events
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)
Test for heterogeneity: not applicable
Test for overall effect z=1.63 p=0.1
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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 07 Four RV vaccinations versus three RV vaccinations
Outcome: 01 Hepatitis B events
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)
Test for heterogeneity: not applicable
Test for overall effect z=0.73 p=0.5
0.01 0.1 1 10 100
0-1-2-12 better 0-1-6 better
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Analysis 07.02. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 02 Anti-HBs
level less than 10 IU/L
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
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)
Test for heterogeneity: not applicable
Test for overall effect z=0.75 p=0.5
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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 08 One type of RV versus another type of RV with the same vaccination schedule
Outcome: 01 Hepatitis B events
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)
Test for heterogeneity: not applicable
Test for overall effect z=0.59 p=0.6
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 ]
Total events: 6 (RV1), 6 (RV2)
Test for heterogeneity chi-square=0.53 df=1 p=0.47 I² =0.0%
Test for overall effect z=0.05 p=1
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 ]
Total events: 9 (RV1), 5 (RV2)
Test for heterogeneity: not applicable
Test for overall effect z=0.50 p=0.6
0.01 0.1 1 10 100
RV1 better RV2 better
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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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
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
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)
Test for heterogeneity: not applicable
Test for overall effect z=0.38 p=0.7
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)
Test for heterogeneity: not applicable
Test for overall effect z=1.17 p=0.2
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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
Outcome: 01 Hepatitis B events
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)
Test for heterogeneity chi-square=7.81 df=1 p=0.005 I² =87.2%
Test for overall effect z=7.17 p<0.00001
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 . . . )
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(. . . Continued)
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 33 (HBIG), 51 (Control)
Test for heterogeneity chi-square=5.97 df=8 p=0.65 I² =0.0%
Test for overall effect z=3.38 p=0.0007
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 events: 28 (HBIG), 46 (Control)
Test for heterogeneity chi-square=0.35 df=2 p=0.84 I² =0.0%
Test for overall effect z=2.35 p=0.02
Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]
Total events: 127 (HBIG), 165 (Control)
Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3%
Test for overall effect z=7.03 p<0.00001
0.001 0.01 0.1 1 10 100 1000
HBIG better Control better
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Analysis 09.02. Comparison 09 HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events
according to methodological quality of the trials
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
Outcome: 02 Hepatitis B events according to methodological quality of the trials
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 High-quality trials
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 ]
Total events: 7 (HBIG), 16 (Control)
Test for heterogeneity chi-square=0.76 df=1 p=0.38 I² =0.0%
Test for overall effect z=1.93 p=0.05
02 Low-quality trials
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 events: 120 (HBIG), 149 (Control)
Test for heterogeneity chi-square=12.89 df=11 p=0.30 I² =14.7%
Test for overall effect z=6.79 p<0.00001
Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]
Total events: 127 (HBIG), 165 (Control)
Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3%
Test for overall effect z=7.03 p<0.00001
0.001 0.01 0.1 1 10 100 1000
HBIG better Control better
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Analysis 09.03. Comparison 09 HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events -
sensitivity analyses
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
Outcome: 03 Hepatitis B events - sensitivity analyses
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 Available patients’ course analysis
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 ]
Total events: 79 (HBIG), 105 (Control)
Test for heterogeneity chi-square=13.95 df=12 p=0.30 I² =14.0%
Test for overall effect z=7.11 p<0.00001
02 Assuming poor outcome
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
HBIG better Control better (Continued . . . )
74Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 127 (HBIG), 165 (Control)
Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3%
Test for overall effect z=7.03 p<0.00001
03 Assuming good outcome
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 ]
Total events: 81 (HBIG), 110 (Control)
Test for heterogeneity chi-square=13.12 df=13 p=0.44 I² =0.9%
Test for overall effect z=6.76 p<0.00001
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
HBIG better Control better (Continued . . . )
75Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 82 (HBIG), 161 (Control)
Test for heterogeneity chi-square=24.65 df=13 p=0.03 I² =47.3%
Test for overall effect z=9.85 p<0.00001
05 Extreme case favouring control
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 ]
Total events: 126 (HBIG), 114 (Control)
Test for heterogeneity chi-square=33.05 df=13 p=0.002 I² =60.7%
Test for overall effect z=3.12 p=0.002
0.001 0.01 0.1 1 10 100 1000
HBIG better Control better
76Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 09.04. Comparison 09 HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events
according to the mother’s HBeAg status
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
Outcome: 04 Hepatitis B events according to the mother’s HBeAg status
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 114 (HBIG), 143 (Control)
Test for heterogeneity chi-square=11.50 df=11 p=0.40 I² =4.4%
Test for overall effect z=7.18 p<0.00001
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 ]
Total events: 13 (HBIG), 17 (Control)
Test for heterogeneity chi-square=1.58 df=1 p=0.21 I² =36.6%
Test for overall effect z=0.92 p=0.4
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 ]
Total events: 0 (HBIG), 5 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=0.99 p=0.3
0.001 0.01 0.1 1 10 100 1000
HBIG better Control better (Continued . . . )
77Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]
Total events: 127 (HBIG), 165 (Control)
Test for heterogeneity chi-square=13.79 df=14 p=0.47 I² =0.0%
Test for overall effect z=7.04 p<0.00001
0.001 0.01 0.1 1 10 100 1000
HBIG better Control better
Analysis 09.05. Comparison 09 HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events
according to time of HBIG administration
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
Outcome: 05 Hepatitis B events according to time of HBIG administration
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 110 (HBIG), 129 (Control)
Test for heterogeneity chi-square=10.07 df=8 p=0.26 I² =20.6%
Test for overall effect z=6.92 p<0.00001
02 HBIG administered within 24 hours of birth
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
HBIG better Control better (Continued . . . )
78Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
Subtotal (95% CI) 106 132 15.0 0.60 [ 0.35, 1.05 ]
Total events: 17 (HBIG), 33 (Control)
Test for heterogeneity chi-square=2.81 df=3 p=0.42 I² =0.0%
Test for overall effect z=1.79 p=0.07
03 HBIG administered within 48 hours of birth
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 events: 0 (HBIG), 3 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=1.31 p=0.2
Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ]
Total events: 127 (HBIG), 165 (Control)
Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3%
Test for overall effect z=7.03 p<0.00001
0.001 0.01 0.1 1 10 100 1000
HBIG better Control better
Analysis 09.06. Comparison 09 HBIG versus placebo or no intervention, Outcome 06 Hepatitis B events
according to standard and rapid schedule of vaccines
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
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)
Test for heterogeneity chi-square=0.73 df=3 p=0.87 I² =0.0%
Test for overall effect z=2.29 p=0.02
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
HBIG better Control better (Continued . . . )
79Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . 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 events: 35 (HBIG+vaccine), 51 (Vaccine)
Test for heterogeneity chi-square=1.93 df=4 p=0.75 I² =0.0%
Test for overall effect z=3.07 p=0.002
Total (95% CI) 375 336 100.0 0.53 [ 0.39, 0.74 ]
Total events: 49 (HBIG+vaccine), 84 (Vaccine)
Test for heterogeneity chi-square=2.75 df=8 p=0.95 I² =0.0%
Test for overall effect z=3.83 p=0.0001
0.001 0.01 0.1 1 10 100 1000
HBIG better Control better
Analysis 09.07. Comparison 09 HBIG versus placebo or no intervention, Outcome 07 Anti-HBs less than 10
IU/L
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
Outcome: 07 Anti-HBs less than 10 IU/L
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 6 (HBIG), 4 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=0.49 p=0.6
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 ]
Total events: 21 (HBIG), 13 (Control)
Test for heterogeneity chi-square=0.20 df=2 p=0.90 I² =0.0%
0.01 0.1 1 10 100
HBIG better Control better (Continued . . . )
80Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
Test for overall effect z=1.47 p=0.1
Total (95% CI) 175 173 100.0 1.55 [ 0.89, 2.73 ]
Total events: 27 (HBIG), 17 (Control)
Test for heterogeneity chi-square=0.30 df=3 p=0.96 I² =0.0%
Test for overall effect z=1.54 p=0.1
0.01 0.1 1 10 100
HBIG better Control better
Analysis 09.08. Comparison 09 HBIG versus placebo or no intervention, Outcome 08 Anti-HBs level
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
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 ]
Test for heterogeneity: not applicable
Test for overall effect z=0.34 p=0.7
-10 -5 0 5 10
HBIG better Control better
Analysis 09.09. Comparison 09 HBIG versus placebo or no intervention, Outcome 09 Adverse events
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 09 HBIG versus placebo or no intervention
Outcome: 09 Adverse events
Study HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 1 (HBIG), 0 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=0.77 p=0.4
0.01 0.1 1 10 100
HBIG better Control better
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Analysis 10.01. Comparison 10 Multiple HBIG plus PDV versus single HBIG plus PDV, Outcome 01 Hepatitis
B events
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 10 Multiple HBIG plus PDV versus single HBIG plus PDV
Outcome: 01 Hepatitis B events
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)
Test for heterogeneity chi-square=0.97 df=1 p=0.32 I² =0.0%
Test for overall effect z=0.27 p=0.8
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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 11 PDV plus HBIG versus placebo or no intervention
Outcome: 01 Hepatitis B 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 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)
Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0%
Test for overall effect z=6.17 p<0.00001
0.001 0.01 0.1 1 10 100 1000
PDV + HBIG better Control better
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Analysis 11.02. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 02 Hepatitis B
events according to methodological quality of the trials
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 11 PDV plus HBIG versus placebo or no intervention
Outcome: 02 Hepatitis B events according to methodological quality of the trials
Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 High-quality trials
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 ]
Total events: 3 (PDV + HBIG), 44 (Control)
Test for heterogeneity chi-square=1.13 df=2 p=0.57 I² =0.0%
Test for overall effect z=5.44 p<0.00001
02 Low-quality trials
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 events: 2 (PDV + HBIG), 24 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=2.46 p=0.01
Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ]
Total events: 5 (PDV + HBIG), 68 (Control)
Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0%
Test for overall effect z=6.17 p<0.00001
0.001 0.01 0.1 1 10 100 1000
PDV + HBIG better Control better
83Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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Analysis 11.03. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 03 Hepatitis B
events - sensitivity analyses
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 11 PDV plus HBIG versus placebo or no intervention
Outcome: 03 Hepatitis B events - sensitivity analyses
Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 Available patients’ course analysis
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 ]
Total events: 4 (PDV + HBIG), 63 (Control)
Test for heterogeneity chi-square=1.34 df=3 p=0.72 I² =0.0%
Test for overall effect z=5.89 p<0.00001
02 Assuming poor outcome
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 ]
Total events: 5 (PDV + HBIG), 68 (Control)
Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0%
Test for overall effect z=6.17 p<0.00001
03 Assuming good outcome
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 ]
Total events: 4 (PDV + HBIG), 63 (Control)
Test for heterogeneity chi-square=1.39 df=3 p=0.71 I² =0.0%
Test for overall effect z=5.87 p<0.00001
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 . . . )
84Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 4 (PDV + HBIG), 68 (Control)
Test for heterogeneity chi-square=1.19 df=3 p=0.76 I² =0.0%
Test for overall effect z=5.91 p<0.00001
05 Extreme case favouring control
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 ]
Total events: 5 (PDV + HBIG), 63 (Control)
Test for heterogeneity chi-square=3.51 df=3 p=0.32 I² =14.4%
Test for overall effect z=6.11 p<0.00001
0.001 0.01 0.1 1 10 100 1000
PDV + HBIG better Control better
Analysis 11.04. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 04 Hepatitis B
events according to mother’s HBeAg status
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 11 PDV plus HBIG versus placebo or no intervention
Outcome: 04 Hepatitis B events according to mother’s HBeAg status
Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
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 ]
Total events: 5 (PDV + HBIG), 65 (Control)
Test for heterogeneity chi-square=2.78 df=3 p=0.43 I² =0.0%
Test for overall effect z=6.26 p<0.00001
0.001 0.01 0.1 1 10 100 1000
PDV + HBIG better Control better (Continued . . . )
85Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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(. . . Continued)
Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
02 HBeAg unknown
Subtotal (95% CI) 0 0 0.0 Not estimable
Total events: 0 (PDV + HBIG), 0 (Control)
Test for heterogeneity: not applicable
Test for overall effect: not applicable
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 events: 0 (PDV + HBIG), 3 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=0.70 p=0.5
Total (95% CI) 126 120 100.0 0.08 [ 0.04, 0.18 ]
Total events: 5 (PDV + HBIG), 68 (Control)
Test for heterogeneity chi-square=3.63 df=4 p=0.46 I² =0.0%
Test for overall effect z=6.36 p<0.00001
0.001 0.01 0.1 1 10 100 1000
PDV + HBIG better Control better
Analysis 11.05. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 05 Hepatitis B
events according to time of HBIG administration
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 11 PDV plus HBIG versus placebo or no intervention
Outcome: 05 Hepatitis B events according to time of HBIG administration
Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
01 HBIG administered within 12 hours of birth
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 ]
Total events: 3 (PDV + HBIG), 23 (Control)
Test for heterogeneity chi-square=0.45 df=1 p=0.50 I² =0.0%
Test for overall effect z=4.80 p<0.00001
02 HBIG administered within 24 hours of birth
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 events: 2 (PDV + HBIG), 24 (Control)
0.001 0.01 0.1 1 10 100 1000
PDV + HBIG Control better (Continued . . . )
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(. . . Continued)
Study PDV + HBIG Control Relative Risk (Fixed) Weight Relative Risk (Fixed)
n/N n/N 95% CI (%) 95% CI
Test for heterogeneity: not applicable
Test for overall effect z=2.46 p=0.01
03 HBIG administered within 48 hours of birth
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 events: 0 (PDV + HBIG), 21 (Control)
Test for heterogeneity: not applicable
Test for overall effect z=2.70 p=0.007
Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ]
Total events: 5 (PDV + HBIG), 68 (Control)
Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0%
Test for overall effect z=6.17 p<0.00001
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
Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers
Comparison: 11 PDV plus HBIG versus placebo or no intervention
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)
Test for heterogeneity chi-square=0.05 df=1 p=0.83 I² =0.0%
Test for overall effect z=1.78 p=0.07
0.01 0.1 1 10 100
PDV+HBIG better Control better
87Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
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