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EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL
Evid.-Based Child Health 2: 67155 (2007)
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ebch.120
Hepatitis B immunisation for newborn infants of hepatitis B
surface antigen-positive mothers (Review)
Lee C, Gong Y, Brok J, Boxall EH, Gluud C
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration, first published in The Cochrane
Library 2007, Issue 1
http://www.thecochranelibrary.com
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T A B L E O F C O N T E N T S
70ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .
72SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .
72METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
73DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
76DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .
77ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
110Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
111ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
111Table 01. Search strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
113Table 02. Intervention by group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
115ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
115Comparison 01. Vaccine versus placebo or no intervention . . . . . . . . . . . . . . . . . . . .
116Comparison 02. RV versus PDV . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
116Comparison 03. High-dose versus low-dose vaccine . . . . . . . . . . . . . . . . . . . . . . .
116Comparison 04. Three-dose PDV plus HBIG versus two-dose PDV plus HBIG . . . . . . . . . . . . .
116Comparison 05. PDV at birth versus PDV at one month . . . . . . . . . . . . . . . . . . . . .
116Comparison 06. One type of PDV versus another type of PDV . . . . . . . . . . . . . . . . . . .117Comparison 07. Four RV vaccinations versus three RV vaccinations . . . . . . . . . . . . . . . . .
117Comparison 08. One type of RV versus another type of RV with the same vaccination schedule . . . . . . . .
117Comparison 09. HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . . . . . .
117Comparison 10. Multiple HBIG plus PDV versus single HBIG plus PDV . . . . . . . . . . . . . . .
117Comparison 11. PDV plus HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . .
118INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
119GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
119Analysis 01.01. Comparison 01 Vaccine versus placebo or no intervention, Outcome 01 Hepatitis B events according
to type of vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
120Analysis 01.02. Comparison 01 Vaccine versus placebo or no intervention, Outcome 02 Hepatitis B events according
to methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
121Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events - Sensitivityanalyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
123Analysis 01.04. Comparison 01 Vaccine versus placebo or no intervention, Outcome 04 Hepatitis B events according
to the mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . .
124Analysis 01.05. Comparison 01 Vaccine versus placebo or no intervention, Outcome 05 Hepatitis B events according
to first time of vaccine administration . . . . . . . . . . . . . . . . . . . . . . . . .
125 Analysis 02.01. Comparison 02 RV versus PDV, Outcome 01 Hepatitis B events . . . . . . . . . . . . .
126Analysis 02.02. Comparison 02 RV versus PDV, Outcome 02 Hepatitis B events according to methodological quality
127Analysis 02.03. Comparison 02 RV versus PDV, Outcome 03 Hepatitis B events - sensitivity analyses . . . . . .
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129Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mothers HBeAg
status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
130 Analysis 02.05. Comparison 02 RV versus PDV, Outcome 05 Anti-HBs less than 10 IU/L . . . . . . . . .
130Analysis 03.01. Comparison 03 High-dose versus low-dose vaccine, Outcome 01 Hepatitis B events . . . . . .
131Analysis 03.02. Comparison 03 High-dose versus low-dose vaccine, Outcome 02 Hepatitis B events according to
methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events - sensitivity analyses
134Analysis 03.04. Comparison 03 High-dose versus low-dose vaccine, Outcome 04 Hepatitis B events according to the
mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
135Analysis 03.05. Comparison 03 High-dose versus low-dose vaccine, Outcome 05 Anti-HBs less than 10 IU/L . . .
135Analysis 04.01. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 01 Hepatitis
B events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
136Analysis 04.02. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 02 Anti-
HBs less than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
136Analysis 05.01. Comparison 05 PDV at birth versus PDV at one month, Outcome 01 Hepatitis B events . . . .
137Analysis 06.01. Comparison 06 One type of PDV versus another type of PDV, Outcome 01 Hepatitis B events . .
137Analysis 07.01. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 01 Hepatitis B events .
138Analysis 07.02. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 02 Anti-HBs level less
than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Analysis 08.01. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule,
Outcome 01 Hepatitis B events . . . . . . . . . . . . . . . . . . . . . . . . . . . .
139Analysis 08.02. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule,
Outcome 02 Anti-HBs less than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . .
139Analysis 09.01. Comparison 09 HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events . . . .
141Analysis 09.02. Comparison 09 HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events according to
methodological quality of the trials . . . . . . . . . . . . . . . . . . . . . . . . . .
142Analysis 09.03. Comparison 09 HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events - sensitivity
analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
145Analysis 09.04. Comparison 09 HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events according to
the mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
146Analysis 09.05. Comparison 09 HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events according to
time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . . . . . .147Analysis 09.06. Comparison 09 HBIG versus placebo or no intervention, Outcome 06 Hepatitis B events according to
standard and rapid schedule of vaccines . . . . . . . . . . . . . . . . . . . . . . . . .
148Analysis 09.07. Comparison 09 HBIG versus placebo or no intervention, Outcome 07 Anti-HBs less than 10 IU/L .
149Analysis 09.08. Comparison 09 HBIG versus placebo or no intervention, Outcome 08 Anti-HBs level . . . . .
149Analysis 09.09. Comparison 09 HBIG versus placebo or no intervention, Outcome 09 Adverse events . . . . .
150Analysis 10.01. Comparison 10 Multiple HBIG plus PDV versus single HBIG plus PDV, Outcome 01 Hepatitis B
events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
150Analysis 11.01. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events
151Analysis 11.02. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events
according to methodological quality of the trials . . . . . . . . . . . . . . . . . . . . . .
152Analysis 11.03. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events -
sensitivity analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
153Analysis 11.04. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 04 Hepatitis B eventsaccording to mothers HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . .
154Analysis 11.05. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events
according to time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . .
155Analysis 11.06. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 06 Adverse events . .
69Hepatitis 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 B
surface antigen-positive mothers (Review)
Lee C, Gong Y, Brok J, Boxall EH, Gluud C
This version first published online: 19 April 2006 in Issue 2,2006 ofThe Cochrane Library. LeeC, GongY, Brok J, Boxall EH, Gluud
C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database of Systematic
Reviews2007, Issue 2. Art. No.: CD004790. DOI: 10.1002/14651858.CD004790.pub2. Cochrane reviews are regularly updated as
new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the
review.
Date of most recent substantive amendment: 22 February 2006
A B S T R A C T
BackgroundHepatitis B vaccine and hepatitisB immunoglobulin are considered for newborn infants of HBsAg-positive mothers to prevent hepatitis
B infection.
Objectives
To assess the beneficial and harmful effects of hepatitis B vaccines and hepatitis B immunoglobulin in newborn infants of HBsAg-
positive mothers.
Search strategy
Trials were identified through The Cochrane Neonatal Group Controlled Trials Register, The Cochrane Hepato-Biliary Group Controlled
Trials Register, The Cochrane Central Register of Controlled Trialsin The Cochrane Library, MEDLINE, and EMBASE(until February
2004), authors of trials, and pharmaceutical companies.
Selection criteria
Randomised clinical trials comparing: plasma-derived vaccine (PDV) or recombinant vaccine (RV) versus no intervention, placebo, or
other active vaccines; hepatitis B immunoglobulin versus no intervention, placebo, or other control immunoglobulin; as well as PDV
or RV plus hepatitis B immunoglobulin versus no intervention, placebo, or other control vaccines or immunoglobulin.
Data collection and analysis
Outcomes are assessed at maximal follow-up. The primary outcome measure was hepatitis B occurrence, based on a blood specimen
positive for HBsAg, HBeAg, or antibody to hepatitis B core antigen (anti-HBc). Binary outcomes are reported as relative risks (RR)
with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality of the trial, mothers
HBe-Ag status, and time of immunisation after birth.
Main results
We identified 29randomised clinical trials, fiveof which were considered highquality. Only three trials reported inclusion of hepatitisB
e-antigennegative mothers.Comparedwithplacebo/no intervention, vaccine reduced hepatitis B occurrence (RR0.28,95% confidence
interval (CI) 0.20 to 0.40, 4 trials). No significant differences of hepatitis B occurrence were found comparing recombinant vaccine
(RV) versus plasma-derived vaccine (PDV) (RR 1.00, 95% CI 0.71 to 1.42, 4 trials) and high-dose versus low-dose vaccine (PDV:
RR 0.97, 95% CI 0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial). Compared with placebo/no intervention,
hepatitis B immunoglobulin or the combination of vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (hepatitis
B immunoglobulin: RR 0.50, 95% CI 0.41 to 0.60, 1 trial; PDV plus hepatitis B immunoglobulin: RR 0.08, 95% CI 0.03 to 0.17,
3 trials). Compared with vaccine, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (RR 0.54, 95% CI 0.41 to
0.73, 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported on adverse events.
Authors conclusions
Vaccine, hepatitis B immunoglobulin, and vaccine plus hepatitis B immunoglobulin prevent hepatitis B occurrence in newborn infants
of HBsAg positive mothers.
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P L A I N L A N G U A G E S U M M A R Y
Hepatitis B vaccine, hepatitis B immunoglobulin, and hepatitis B vaccine plus immunoglobulin prevent perinatal transmission
of hepatitis B
Hepatitis B vaccination and hepatitis B immunoglobulin are considered as preventive measures for newborn infants of HBsAg positive
mothers. When all the identified trials were combined, hepatitis B vaccine alone, hepatitis B immunoglobulin alone, and hepatitisB vaccine plus hepatitis B immunoglobulin reduced perinatal transmission of hepatitis B compared with placebo or no intervention.
Hepatitis B vaccine plus hepatitis B immunoglobulin were superior to hepatitis B vaccination alone. Adverse events were rare and
mostly non-serious.
B A C K G R O U N D
Hepatitis B virus is a global acute and chronic communicable dis-
ease that causes major hepatic disease, with an estimated 350 mil-
lion people infected (Beasley 1984). Mother to child transmission
occurs frequently either in uterus (when the baby is still in the
womb), through placental leakage, or through exposure to bloodor blood contaminated fluids at or around the time of birth. Such
perinatal transmission is believed to account for 35% to 50% of
hepatitis B carriers (Yao 1996). The risk of perinatal transmission
is associated with the HBeAg status of the mother. If the mother
is both HBsAg and HBeAg positive, 70% to 90% of the children
become chronically infected (Stevens 1975; Akhter 1992). If the
mother is HBsAg positive but HBeAg negative, the risk is signifi-
cantly reduced (Okada 1976; Beasley 1977;Beasley 1983b; Nayak
1987; Aggarwal 2004).
Two types of vaccines have been licensed. One is derived from
human plasma (plasma-derived vaccine (PDV)) and the other is
derived from DNA recombinant technology (recombinant vac-
cine (RV)) from yeastor mammalian cells (Assad 1999). Repeated
injections over months are required to mount an effective anti-
body response with vaccination. Hepatitis B immunoglobulin is
an immune globulin, which contains a high level of antibody to
hepatitis B surface antigen (anti-HBs). Hepatitis B immunoglob-
ulin is considered immediately effective and seems protective for
several months after which it wanes (Beasley 1983; Nair 1984).
We have been unable to identify meta-analyses or systematic re-
views on hepatitis B immunisation for newborn infants of HB-
sAg positive mothers. A narrative review regarding the efficacy of
hepatitis B vaccine in neonates (Andre 1994) and several interna-
tional guidelines (CDC 1999; WHO 2002) have been published.
However, they do not represent systematic reviews containing anassessment of the methodological quality of the trials and present-
ing original data.
O B J E C T I V E S
To assess the beneficial and harmful effects of hepatitis B vaccine
and hepatitis B immunoglobulin in newborn infants of HBsAg-
positive mothers.
C R I T E R I A F O R C O N S I D E R I N G
S T U D I E S F O R T H I S R E V I E W
Types of studies
We included randomised clinical trials, irrespective of blinding,
publication status, or language.
Types of participants
We included newborn infants of either gender born to HBsAg-
positive mothers. The immunisation should start within the first
month of life.
Types of intervention
The following analyses were performed:
PDV or RV versus placebo or no intervention.
Hepatitis B immunoglobulin versusplacebo or no intervention.
PDV or RV plus hepatitis B immunoglobulin versus placebo,
no intervention, PDV, or RV.
Types of outcome measures
All outcomes were assessed at maximal follow-up.
Primary outcome
(1) Hepatitis B occurrence: blood specimen positive for HBsAg,
HBeAg, or antibody to hepatitis B core antigen (anti-HBc).
Secondary outcomes
(2) Number of newborn infants with anti-HBs less than 10 IU/L,which is considered insufficient to prevent hepatitis B virus infec-
tion (Szmuness 1981; Hadler 1986).
(3) Anti-HBs, either expressed as geometric mean titre (GMT) or
mean titre.
(4)Systemicadverse events: adverse eventssuch as malaise, nausea,
fever, arthralgia, rash, after each injection of vaccine.
(5) Local adverse events: adverse events such as pain, redness,
swelling, and/or myalgia at the site after each injection of vaccine.
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(6) Any adverse events: adverse events including local adverse
events and/or systemic adverse events. The adverse events are di-
vided into severe and non-severe. A severe adverse event, accord-
ing to the International Committee on Harmonisation Guidelines
(ICH 1997) is any event that would increase mortality; is life-
threatening; requires inpatient hospitalisation; results in a persis-tentor significant disability; or anyimportantmedical eventwhich
may jeopardise the patient or requires intervention to prevent it.
All other adverse events are considered non-severe.
(7) Cost-effectiveness.
S E A R C H M E T H O D S F O R
I D E N T I F I C A T I O N O F S T U D I E S
See: Cochrane Hepato-Biliary Group methods used in reviews.
We searched The Cochrane Neonatal Group Controlled Trials Regis-
ter, The Cochrane Hepato-Biliary Group Controlled Trials Register,
The Cochrane Central Register of Controlled Trials(CENTRAL) inThe Cochrane Library, MEDLINE/PubMed, and EMBASE. The
searchstrategies andtimespanof thesearchesare specified inTable
01. We consulted with The Cochrane Vaccines Field to identify
furthertrials,butno reply was received.Weread thebibliographies
of retrieved articles to identify further trials. We checked the ref-
erence lists of relevant articles for any new trials. We wrote to the
principal authors of the identified trials and the pharmaceutical
companies (SmithKline Beecham and Merck, Sharp & Dohme;
GreenCross Vaccine; GlaxoSmithKline; Pasteur; and Abbott) in-
volved in the production of hepatitis B vaccines for missing infor-
mation and additional published or unpublished trials.
M E T H O D S O F T H E R E V I E W
Selection of trials for inclusion
CL made the decisions on which trials to be included, and the
selection was validated by YG, JB, and CG. We were unblinded
withregard to the namesof the authors, investigators, institutions,
and results. Excluded trials were identified and listed with the
reasons for exclusion.
Data extraction
CL, YG, and JB independently extracted the data from the in-
cluded randomised trials. We wrote to the authors of trials if data
were missing in the report.
We extracted: primary author; number of participants; inclusion
and exclusion criteria; HBeAg status of the mother; methodolog-
ical quality (see below); dosage and types of vaccines; site of injec-
tion; vaccination schedules; duration of follow-up; outcome mea-
sures; and number and type of adverse events in the intervention
and the control groups.
Methodological quality
Methodological quality is defined as the confidence that the de-
sign and report restrict bias in the intervention comparison (Mo-
her 1998; Kjaergard 2001). Due to the risk of overestimation of
intervention effects in randomised trials with inadequate method-
ological quality (Schultz1995; Moher 1998; Kjaergard2001), the
methodological quality was assessed by using the following crite-ria:
Generation of the allocation sequence
Adequate, if the allocation sequence was generated by a com-
puter or random number table. Drawing of lots, tossing of a
coin, shuffling of cards, or throwing dice was considered as ad-
equate if a person who was not otherwise involved in the re-
cruitment of participants performed the procedure.
Unclear, if the trial wasdescribedas randomised,butthemethod
used for the allocation sequence generation was not described.
Inadequate, if a system involving dates, names, or admittance
numbers were used for the allocation of patients. Such quasi-randomised studies were excluded.
Allocation concealment
Adequate, if the allocation of patients involved a central inde-
pendent unit, on-site locked computer, identically appearing
numbered drug bottles or containers prepared by an indepen-
dent pharmacist or investigator, or sealed envelopes.
Unclear, if the trial wasdescribedas randomised,butthemethod
used to conceal the allocation was not described.
Inadequate, if the allocation sequence was known to the inves-
tigators who assigned participants.
Blinding (or masking)
Adequate, if the trial was described as double blind and the
method of blinding involved identical placebo or active drugs.
Unclear, if the trial was described as double blind, but the
method of blinding was not described.
Not performed, if the trial was not double blind.
Follow-up
Adequate, if the numbers and reasons for dropouts and with-
drawals in all intervention groups were described or if it was
specified that there were no dropouts or withdrawals.
Unclear, if the report gave the impression that there had been
no dropouts or withdrawals, but this was not specifically stated.
Inadequate, if the number or reasons for dropouts and with-
drawals were not described.
We post hocdefined high-quality trials when at least two out of
the three quality components were adequate: generation of the
allocation sequence, allocation concealment, and blinding. This
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wasduetothefactthatonlyasingletrialhadhighqualityregarding
all three components.
Statistical methods
Review Manager 4.2. was used to perform meta-analyses. Data
were analysed by both a random-effects model (DerSimonian
1986) and a fixed-effect model (DeMets 1987). If the results of
both analyses gave the same overall results regarding significance,
only the results of the fixed-effect model analysis was reported.
We presented binary outcome measure as relative risks (RR) with
95% confidence interval (CI), and continuous outcome measure
as weightedmeandifference (WMD) with95%CI.Heterogeneity
was explored by chi-squared test with significance set at P < 0.10
and the quantity of heterogeneity was measured by I2 (Higgins
2002).
Meta-regression analysis was performed by STATAon hepatitis
B occurrence, when more than 10 trials were included. Meta-
regression analysis examined the intervention effect in relationto methodological quality of trials, dosage of hepatitis B im-
munoglobulin and vaccine, and time of immunisation.
Subgroup analyses were performed to compare the effects of vac-
cines in mothers with HBsAg (+)/HBeAg(+) compared to HB-
sAg (+)/HBeAg(-), doses (high-dose versus low-dose), as well as
methodological quality of the trials (high-quality versus low-qual-
ity). The difference between the estimates of two subgroups was
estimated according to Altman 2003.
Regarding the hepatitis B occurrence, we included newborn in-
fants with incomplete or missing data in the sensitivity analyses
by imputing them in the following analyses (the last four being
intention-to-treat analyses):
Available data analysis: data on only those whose results are
known, using the total number of patients who completed the
trial as denominator;
Assuming poor outcome: dropouts in both experimental and
control group had the primary outcome;
Assuming good outcome: none of the dropouts in the experi-
mental and control group had the primary outcome;
Extreme case favouring experimental intervention: none of the
dropouts in the experimental groupbut all in the control group
had the primary outcome;
Extreme case favouring control intervention: all dropouts from
the experimental group but no controls had primary outcome.
We used funnel plot to provide a visual assessment of whether
treatment estimates are associated with study size. We explored
publication bias and other bias according to Beggs and Eggers
methods (Begg 1994; Egger 1997).
D E S C R I P T I O N O F S T U D I E S
We identified 226 references, but 186 were clearly irrelevant refer-
ences. The remaining 40 references describing 29 randomised tri-
als were included. Twenty-eight trials were published as full paper
articles and one trial was published as an abstract. We were not
able to extract relevant data according to our outcome measures
from three trials (Yeoh 1986; Zhu 1987; Grosheide 1993). Ex-
cluded studies are listedunder Characteristics of excluded studies
withreasons for exclusion. The immunisation doses and schedules
in the included trials varied substantially as described below. The
capital letters in the references refer to the intervention arms of
the trial as described in Table of included studies.
Vaccine versus placebo or no intervention
The dose of vaccine used was 3 microgram (Ip 1989 CD), 16
microgram (Xu 1995 AD), or 20 microgram (Liu 1987 AB; Xu
1995 BD). The vaccination schedules were 0-1-6 months (Liu
1987 AB; Xu 1995 AD/Xu 1995 BD), 0-1-2-6 months (Ip 1989
CD), or 0-1-2-14 months (Khukhlovich 1996).
RV versus PDV
The dose of vaccines was 5 microgram (Lee 1995 AB/Lee 1995
CB), 10 microgram (Pongpipat 1989), or 20 microgram (Halli-
day 1992 AB; Zhu 1994). The vaccination schedules were 0-1-6
months (Pongpipat 1989; Halliday 1992 AB; Zhu 1994) or 0-1-
2-12 months (Lee 1995 AB/Lee 1995 CB).
High-dose vaccine versus low-dose vaccine
The doses of PDV were 10 microgram, 5 microgram, and 2 mi-
crogram (Oon 1986 AB, Oon 1986 CD, Pongpipat 1988; Thep-
pisai 1990). The doses of RV were 20 microgram and 10 micro-
gram (Halliday 1992 DC). The vaccination schedules were 0-1-6
months (Halliday 1992 DC), 0-1-2 months (Oon 1986 AB/Oon1986 CD), or 0-1-2-12 months (Pongpipat 1988).
Three-dose PDV plus hepatitis B immunoglobulin versus two-
dose PDV plus hepatitis B immunoglobulin
One trial assessed three-doses PDV plus hepatitis B immunoglob-
ulin versus two-doses PDV plus hepatitis B immunoglobulin (Pi-
azza 1985). Both groups were given hepatitis B immunoglobulin
50 IU at birth, then 5 microgram PDV within five days and at two
months. The experimental group was given an additional PDV at
one month.
PDV at birth versus PDV at one month
One trial assessed 20 microgram PDV at 0-1-6 months versus 20
microgram PDV at 1-2-7 months (Beasley 1983b). Both groupswere given hepatitis B immunoglobulin 145 IU at birth.
One type of PDV versus another type of PDV
One trial assessed different types of PDV (PDV1(NIAID) versus
PDV2 (BIVS) (Xu 1995 AB). The dose was 16 microgram of
PDV1 and 20 microgram of PDV2. The schedules were 0-1-6
months.
Four RV vaccinations versus three RV vaccinations
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One trial assessed four RV vaccinations (0-1-2-12 months) versus
three RV vaccinations (0-1-6 months) (Lolekha 2002). The dose
of each RV was 5 microgram.
One RV versus another RV with the same vaccination schedule
Two trials assessed differenttypesof RV (RV1(Beijing, China) ver-
sus RV2 (Institute of Preventive Medicine, China) (Kang 1995)
andonetrial assessedCuban versus Engerix-B(Galban1992). Two
trials assessed different types of RV plus hepatitis B immunoglob-
ulin (Hepavax-Gene versus Engerix-B (Hieu 2002) and HB-VAX
II versus Engerix-B (Lee 1995 CA/Lee 1995 DE). The doses of
RV were 5 versus 10 microgram (Lee 1995 CA/Lee 1995 DE),
10 versus 10 microgram (Hieu 2002), or 20 versus 20 microgram
(Kang 1995). The vaccination scheduleswere0-1-6months (Kang
1995; Hieu 2002) or 0-1-2-12 months (Lee 1995 CA/Lee 1995
DE).
Hepatitis B immunoglobulin versus placebo or no interven-
tion
The doses of hepatitis B immunoglobulin ranged from 90 to260 IU. HepatitisB immunoglobulin was administered within 12
hoursofbirth inseventrials (Beasley 1983aAB/Beasley 1983aCB;
Lo 1985 AB/Lo 1985 CB; Theppisai 1987; Ip 1989 AC/ Ip 1989
BC; Halliday 1992 CA; Xu 1995 CB; Poovorawan 1997), within
24 hours in three trials (Farmer 1987; Sehgal 1992; Assateerawatt
1993), or within 48 hours in one trial (Liu 1987 CA). The vacci-
nation schedules were 0-3-6 months (Beasley 1983a AB/Beasley
1983a CB), 0-6 weeks-6 months (Farmer 1987), 0-1-6 months
(Ip 1989 AC/Ip 1989 BC; Theppisai 1987; Xu 1995 CB), 0-1-2-
6 months ( Liu 1987 CA), 0-2-6-10 weeks (Lo 1985 AB/Lo 1985
CB), and 0-4-8 weeks (Sehgal 1992).
Multiple hepatitis B immunoglobulin versus single hepatitisB immunoglobulin
Onetrialcompared 5 microgram PDV at 2-6-10weeks plus 50 IU
hepatitis B immunoglobulin at birth with or without additional
hepatitis B immunoglobulin at 1 month (Lo 1985 CA). One trial
compared 3 microgram PDV at 1-2-6 months plus 200 IU hep-
atitis B immunoglobulin at birth with or without additional hep-
atitis B immunoglobulin at 1-2-3-4-5-6 months (Ip 1989 AB)
PDV plus hepatitis B immunoglobulin versus placebo or no
intervention
One trial compared 200 IU hepatitis B immunoglobulin at 0-1-2-
3-4-5-6 months plus 3 microgram PDV at 0-1-2-6 months versus
200 IU hepatitis B immunoglobulin at birth plus 3 microgramPDV at 0-1-2-6 months versus placebo (Ip 1989 AD/Ip 1989
BD). One trial compared 20 microgram PDV at 0-1-2-6 months
plus hepatitis B immunoglobulin at birth with placebo (Liu 1987
CB). One trial compared 20 microgram PDV at 0-1-6 months
plus 250 IU hepatitis B immunoglobulin at birth versus placebo
(Xu 1995 CD). Hepatitis B immunoglobulin was given within 12
hours (Ip 1989 AD/Ip 1989 BD), or within 24 hours (Xu 1995
CD), and within 48 hours (Liu 1987 CB).
A number of trials had several intervention arms. For details of
the included trials, we provided Table 02 by listing the relevant
comparisonsandwhich trials assessed this comparison.The capital
letters after years of publication in the references stands for the
comparison arms of the individual trial.
Mothers HBeAg statusEighteen trials included only mothers, who were HBeAg positive.
Three trials included mothers who were HBeAg positive or neg-
ative (Lee 1995 AB; Oon 1986 AB; Xu 1995 AB), and in eight
trials mothers HBeAg status was not reported.
Newborns birthweight
Ten trials reported exclusion of low-birth-weight newborn infants.
The limits for exclusion varied from 1600 to 3000 gram. The re-
maining 19 trials did not report any birth weight exclusion crite-
ria. The average duration of follow-up was 19 months (range 6 to
60 months).
M E T H O D O L O G I C A L Q U A L I T Y
Generation of the allocation sequence was adequate in six trials
(Piazza 1985; Oon 1986 AB/Oon 1986 CD; Farmer 1987; Hal-
liday 1992 AB/Halliday 1992 CA/Halliday 1992 DC; Assateer-
awatt 1993; Hieu 2002).
Treatment allocation was adequately concealed in six trials (Ip
1989 AD/Ip 1989 BD/Ip 1989CD; Piazza 1985;Liu1987AB/Liu
1987 CA/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/
Halliday 1992 DC; Grosheide 1993; Hieu 2002).
Adequate method of double blinding was reported in three trials
(Ip 1989 AD/Ip 1989 BD/Ip 1989 CD; Liu 1987 AB/Liu 1987
CA/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/Halliday
1992 DC).
According to our criteria, we classified five trials as high quality
trials (Ip 1989 AD/Ip 1989 BD/Ip 1989 CD; Piazza 1985; Liu
1987 AB/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/
Halliday 1992 DC; Hieu 2002).
The numbers and reasons for dropouts and withdrawals were ad-
equately reported in six trials (Beasley 1983a AB/Beasley 1983a
CB/Beasley 1983b; Piazza 1985; Theppisai 1987; Halliday 1992
AB/Halliday 1992 CA/Halliday 1992 DC; Grosheide 1993).
R E S U L T S
Hepatitis B vaccines versus placebo or no intervention (Com-
parison 01-01 to 01-05)
Compared with placebo/no intervention, hepatitis B vaccination
significantly decreased the riskof hepatitis B occurrence (RR 0.28,
95% CI 0.20 to 0.40, 4 trials). The analysis showed heterogeneity
(P=0.07,I2 = 54.2%). The results of sensitivity analyses regarding
dropouts were consistent. Analyses of PDV and RV individually
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showed that both vaccines significantly decreased the risk of hep-
atitis B occurrence.
Subgroup analyses did not find a significant difference between
high-and low-quality trials, the mothers HBeAg status, or time of
vaccine injection (testsof interaction, P= 0.25, 0.07, and 0.11, re-
spectively). Post hocsubgroup analysis according to vaccine sched-ules (0-1-6 months versus 0-1-2-6 or -12 months) showed no sig-
nificant difference (test of interaction, P = 0.75). No data on ad-
verse events were reported.
RV versus PDV (Comparison 02-01 to 02-05)
We found no significant difference between RV and PDV on hep-
atitis B occurrence (RR 1.00, 95% CI 0.70 to 1.42, 4 trials). Het-
erogeneity was moderate (I2 = 29.4%). The results of sensitiv-
ity analyses regarding dropouts confirmed the finding. Subgroup
analysesdidnotfinda significant difference regarding the method-
ological quality or the mothers HBeAg status (both tests of inter-
action, P = 0.21).
Significantly fewer newborn infants on RV compared to PDV had
anti-HBs less than 10 IU/L (RR 0.51, 95% CI 0.36 to 0.72, 3
trials).
High-dose versus low-dose vaccine (Comparison 03-01 to 03-
05)
We found no statistical difference on hepatitis B occurrence com-
paringhigh-dose versuslow-dosevaccine (PDV:RR0.97, 95%CI
0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial).
There was no significant difference between high-dose versus low-
dose vaccine on anti-HBs less than 10 IU/L (RR 1.02, 95% CI
0.82, 1.27, 2 trials).
Three-dose PDV versus two-dose PDV (Comparison 04-01 to
04-02)
Three-dose PDV plus hepatitis B immunoglobulin did not sig-
nificantly prevent hepatitis B occurrence compared with two-dose
PDV plus hepatitis B immunoglobulin (RR 0.50, 95% CI 0.05
to 5.28, 1 trial). However, three-dose PDV plus hepatitis B im-
munoglobulin resulted in significantly less newborn infants who
had anti-HBs less than 10 IU/L compared with two-dose PDV
plus hepatitis B immunoglobulin (RR0.05, 95% CI 0.00 to 0.78,
1 trial).
PDV at birth versus PDV at one month (Comparison 05-01)
PDV administered for the first time at birth did not significantly
differ from PDV administered for the first time at one month ofage regarding the number of newborn infants having hepatitis B
occurrence (RR 0.70, 95% CI 0.18 to 2.77, 1 trial).
One type of PDV versus another type of PDV (Comparison
06-01)
One trial compared two different types of PDV and no significant
difference was found in terms of hepatitis B occurrence (Xu 1995
AB).
Four-dose RV vaccination versus three-dose RV vaccination
(Comparison 07-01 to 07-02)
One trial (Lolekha 2002) compared one type of RV with four vac-
cinations (0-1-2-12 months) versus the same RV with three vacci-
nations (0-1-6 months). No significant differences were found on
hepatitis B occurrence (RR 1.49, 95% CI 0.51 to 4.37) or anti-HBs level less than 10 IU/L (RR 0.53, 95% CI 0.10 to 2.77).
One type of RV versus another type of RV with the same vac-
cination schedule (Comparison 08-01 to 08-02)
Different RV in terms of various manufacturers were assessed and
no significant differences were found on hepatitis B occurrence or
anti-HBs less than 10 IU/L.
Hepatitis B immunoglobulin versus placebo or no interven-
tion (Comparison 09-01 to 09-08)
Overall, hepatitis B immunoglobulin significantly decreased the
risk of hepatitis B occurrence in newborn infants (RR 0.52, 95%
CI 0.44 to 0.63, 11 trials). Compared with placebo/no interven-
tion, hepatitisB immunoglobulin alone significantly reduced hep-atitis B occurrence (RR 0.50, 95% CI 0.41 to 0.60, 1 trial). Com-
pared withvaccination, vaccination plus hepatitis B immunoglob-
ulin was likewise superior (RR 0.54, 95% CI 0.41 to 0.73, 10 tri-
als). The sensitivity analyses regarding dropouts were consistent,
indicating the robustness of the findings. In the meta-regression
analyses, none of the trial characteristics (methodological qual-
ity, dosage of hepatitis B immunoglobulin, or time of hepatitis B
immunoglobulin injection) was significantly associated with the
effect of hepatitis B immunoglobulin (P = 0.92, 0.67, and 0.79,
respectively). Subgroup analyses did not find a significant differ-
ence between high- and low-quality trials, the mothers HBeAg
status, or time of hepatitis B immunoglobulin injection (tests of
interaction, P = 0.70, 0.62, and 0.63, respectively).
Hepatitis B immunoglobulinhad no significant effecton the num-
ber of newborn infants with anti-HBs level less than 10 IU/L (RR
1.55, 95% CI 0.89 to 2.73, 4 trials).
Few trials reported adverse events. If reported, the authors did not
specify in which intervention group these events occurred. There-
fore we were notable to perform a meta-analysis on adverse events.
In one trial (Beasley 1983a AB/Beasley 1983a CB), one infant
receiving hepatitis B immunoglobulin died. The death appeared
unrelated to hepatitis B immunoglobulin.
Neither the Eggers nor the Beggs graphs and their corresponding
tests on hepatitis B occurrence provided evidence for asymmetry(Eggers test, P = 0.31; Beggs test, P = 0.23).
Multiple hepatitis B immunoglobulin versus single hepatitis
B immunoglobulin administration (Comparison 10-01)
Multiple hepatitis B immunoglobulin plusPDVversus single hep-
atitis B immunoglobulin plus PDV did not significantly reduced
the risk of hepatitis B occurrence (RR 0.87, 95% CI 0.30 to 2.47,
2 trials) with no heterogeneity (I2 = 0%).
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PDV plus hepatitis B immunoglobulin versus placebo or no
intervention (Comparison 11-01 to 11-06)
Compared with placebo/no intervention, PDV plus hepatitis B
immunoglobulin significantly reduced hepatitis B occurrence (RR
0.08, 95% CI 0.03 to 0.17, 3 trials). The sensitivity analyses con-
firmed the robustness of the finding. Subgroup analyses did notfind a significant difference between high- and low-quality trials,
the mothers HBeAg status, or time of hepatitis B immunoglob-
ulin injection (tests of interaction, P = 0.13, 0.28, and 0.22, re-
spectively).
Onetrial reportedthe numberof adverse events: 3 out of71 infants
given vaccination versus 5 out of 34 in control group (Ip 1989
AD/Ip 1989 BD). The results showed no significant difference
(0.29, 0.07 to 1.13)
D I S C U S S I O N
Our systematic review demonstrates that hepatitis B vaccine, hep-atitis B immunoglobulin, or the combination of vaccine plus hep-
atitis B immunoglobulin given to newborn infants of HBsAg-pos-
itive mothers prevent hepatitis B occurrence. Further, the combi-
nation of vaccine plus hepatitis B immunoglobulin was superior
to vaccine alone. These benefits were not significantly associated
with the methodological quality of the trials, the mothers HBeAg
status, time of immunisation, or the number of infants dropping
out.
Our review has several potential limitations. First, some analyses
include few trials and a smallnumber ofnewborn infants. Second,
most trials had low methodological quality. However, we did not
find strong association between the methodological quality andthe trial results. This supports the robustness of our results, but
doesnot exclude thepossibility ofbiasaffecting ourresults (Schultz
1995; Moher 1998; Kjaergard 2001; Als-Nielsen 2004). Third,
although we did not find funnel plot asymmetries, we cannot ex-
clude publication bias. Fourth, only few investigators responded
to our request for further information and often the information
was that the details were lost. Fifth, most trials only reported sur-
rogate outcomes (HBsAg status or anti-HBs level) and not long-
term clinical outcomes. Of note is the fact that one trial with long-
term follow-up found more patients with chronic hepatitis in the
PDV plus hepatitis B immunoglobulin group compared with the
PDV group (Ip 1989 AC). Such an increase of chronic hepatitis
could be due to contamination of hepatitis B immunoglobulinwith hepatitis C virus.
Our results convincingly demonstrate that hepatitis B vaccination
reduces hepatitis B infection in newborn infants of hepatitis B
surface antigen-positive mothers. We found no significant differ-
ence between RV and PDV on hepatitis B infections (RR 1.00,
95% CI 0.70 to 1.42). However, a greater number of newborn
infants on PDV did not achieve anti-HBs level above 10 IU/L
(RR 1.96, 95% CI 1.39 to 2.78). The advantage of RV might be
due to the difference in chemical and physical characteristics of
the antigens components of the vaccines (Heijtink 2002). RV is
the vaccine used in high-income countries due to the fear of hu-
man immuno-deficiency virus infection and other infections, in-
cluding transmissible spongiform encephalopathies (MacGregor2004). Our finding seems to support the introduction of RVs in
clinical practice.
The recommended prevention regimen for immune prophylaxis
varies among countries (David 1996; CDC 1999). Similarly in
our included trials, the reported doses and schedules varied sub-
stantially (Table 02). In general, we were unable to demonstrate
significant differences among different doses, different schedules,
and different forms of PDV and RV on hepatitis B occurrence.
Furthermore, our subgroup analyses did not show strong associa-
tions between timing of injection (within 12, 24, or48 hours) and
magnitude of effects. The number of newborn infants evaluated in
these comparisons was small. Therefore, future trials ought to be
much larger before equivalence or non-inferiority can be claimed.
Our meta-analyses demonstrated that hepatitis B immunoglobu-
lin alone or when added to hepatitis B vaccine significantly de-
creased the risk of hepatitis B infection (RR 0.52, 95% CI 0.44
to 0.63). A recent non-randomised study reported no benefit of
adding hepatitis B immunoglobulin to vaccine in HBeAg-negative
mothers (Yang2003). Inour analysis,only onesmalltrialout of11
trials included newborn infants of HBeAg-negative mothers (Xu
1995 AB). Our subgroup analysis, not surprisingly, did not find
any statistically significant difference between newborn infants
of HBeAg-negative and of HBeAg-positive mothers. Accordingly,
more randomised trials on adding hepatitis B immunoglobulin
to vaccine for newborn infants of HBeAg-negative mothers seemwarranted. It should be noticed that hepatitis B immunoglobulin,
as PDV, has the potential of transmitting blood-borne infections
(CDC 1991).
Few trials reported on adverse events. According to what has
been reported, hepatitis B vaccine and hepatitis B immunoglob-
ulin seem safe. These results are in accordance with two recent
Cochrane reviews on hepatitis B vaccination for dialysis patients
and health-care workers (Niu 1996; Chen 2005). Furthermore,
several cohort studies found that hepatitis B vaccination is well
tolerated and severe adverse eventsare rare (ICH 1997; Niu1999;
DuVernoy 2000; Kojouharova 2001; Lewis 2001; Bohlke 2003;
Deeks 2003). However, one cohort study found that vaccine in-
creased the risk of chronic arthritis and acute ear infections (Fisher
2001).Weare unableto determine if this is a reliablefinding dueto
the methodological weakness of cohort studies (CDC 1999). On
the other hand, randomised clinical trials may overlook adverse
events due to relatively low numbers of participants and/or poor
reporting of adverse events (Hayashi 1996; Ioannidis 2001; Etmi-
nan 2004). Further trials ought to focus on these adverse events
following ICH-GCP (ICH 1997).
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The risk of perinatal transmission from HBeAg-negative moth-
ers is considered much lower than in HBeAg-positive mothers
(Okada 1976). If infected, the newborn infants of HBeAg-neg-
ative mothers often clear an asymptomatic infection (Dusheiko
1998). Our findings are mainly based on immune prophylaxis for
newborn infants of mothers being HBsAg and HBeAg positive.Evidence from randomised clinical trials is insufficient to either
support or refute immune prophylaxis for infants of hepatitis B
e antigen negative mothers. The applicability of our findings to
mothers negative for HBeAg, which are of high proportions in eg,
the States and northern Europe, is therefore limited (Funk 2002).
Cost-effectiveness studies indicate that hepatitis B vaccination
for newborn infants of HBsAg-positive mothers are cost effec-
tive in countries with low (Bloom 1993; Tormans 1993; Da Villa
1999; Harris 2001), intermediate, and high prevalence of hep-
atitis B (Hall 1993; Liu 1995; Margolis 1995; Sriprakash 1997).
We identified no cost-effectiveness studies assessing the effects of
adding hepatitis B immunoglobulin to vaccine. As hepatitis B im-
munoglobulin seems able to reduce the risk of hepatitis B infec-tion, the need to perform cost-effectiveness studies based on ran-
domised trials seems justified.
Two trials examined a new way to prevent vertical transmission
of hepatitis B, which could not be included according to our in-
clusion criteria (Lee 2004). The two trials randomised pregnant
women positive for hepatitis B surface antigen to hepatitis B im-
munoglobulin versus no intervention before delivery (Zhu 1997;
Li 2003). In the group receiving immunoglobulin, fewer infants
were positive for hepatitis B surface antigen at follow-up. The
methodological quality of the two trials was low. Furthermore, the
mothers are at risk of developing immune complex disease due to
hepatitis B immunoglobulin reacting with their own circulatinghepatitis B surface antigens. More trials are therefore needed be-
fore this intervention should be adopted.
A U T H O R S C O N C L U S I O N S
Implications for practice
HBsAg positive mothers who are HBeAg positive
Evidence suggests that hepatitis B vaccine, hepatitis B im-
munoglobulin, and the combination of hepatitis B vaccine and
hepatitis B immunoglobulin reduce the risk of perinatal transmis-
sion of hepatitis B in newborn infants of HBsAg positive motherswho are also positive for HBeAg. However, the optimal treatment
regimen remains unclear.
HBsAg positive mothers who are HBeAg negative
There is insufficientevidenceto support or refutethe useof hepati-
tis B vaccine, hepatitis B immunoglobulin, and the combination
of hepatitis B vaccine and immunoglobulin in newborn infants
of HBsAg postive mother who are HBeAg negative. The number
needed to treat to prevent a hepatitis B event is probably much
larger than in mothers who are both HBsAg and HBeAg positive.
Implications for research
The potential adverse events related to hepatitis B prophylaxis
should be studied further, especially the risk for ear infection and
chronic arthritis. The new way of preventing hepatitis B prophy-
laxis in newborn infants - the hepatitis B immunoglobulin ad-
ministration to the pregnant mother - need to be examined in
randomised clinical trials of high quality. The cost-effectiveness
of hepatitis B vaccination and hepatitis B immunoglobulin ought
to be further evaluated based on results from randomised clini-
cal trials. Further trials need to examine the effects of hepatitis B
vaccine and hepatitis B immunoglobulin in newborn infants of
HBsAg positive mothers who are HBsAg negative. Further trials
need to examine the effects of hepatitis B vaccine and hepatitis B
immunoglobulin in preterm infants and low birth-weight infants
of HBsAg-positive mothers. Further trials need to examine if hep-
atitis B vaccine plus multiple hepatitis B immunoglobulin doses
is superior to hepatitis B vaccine plus a single dose of hepatitis B
immunoglobulin.
N O T E S
1. A protocol for a systematic review on this topic was first pub-
lished in Issue 2, 1998 of The Cochrane Library and continued to
be published until Issue 1, 2004 with a title Vaccines for prevent-
ing hepatitis B in high risk newborn infants. The authors, Jeffer-
son TO, Pratt M, Buttery J, and El-Shukri N, have abandoned
the systematic review. This necessitated an update of the protocol
and the conduct of the review be performed by a new team of
reviewers who now consists of Lee C, Gong Y, Brok J, Boxall EH,
and Gluud C.
2. We modified the definition of hepatitis B occurence as shown
in the present review.
3. In our protocol we demanded that each trial had to assess sero-
logical outcome in two and more consecutive blood specimens.
We realized that this requirement was not detainable in themajor-
ity of the trials. We therefore decided to delete this requirement.
P O T E N T I A L C O N F L I C T O F
I N T E R E S T
None known.
A C K N O W L E D G E M E N T S
We thank TO Jefferson, M Pratt, J Buttery, and N El-Shukri who
participated in the formulation of the first Cochrane protocol on
this topic. D Nikolova, The Cochrane Hepato-Biliary Group, is
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thanked for translating a Russian trial and retrieving articles. We
thank D Haughton, The Cochrane Neonatal Review Group, for
retrieving articles. We thank Y Poovorawan and M Piazza who
clarified information on their trials. We thank A Dutta, MM Has-
san, and SD Lee for providing assistance in our work to identify
trial authors, and JUOlsen, GlaxoSmithKline, Denmark, for pro-viding information regarding randomised clinical trials.
S O U R C E S O F S U P P O R T
External sources of support
S.C. Van Foundation DENMARK
Internal sources of support
Public Health Laboratory Service UK
Tri-Service General Hospital TAIWAN
Copenhagen Trial Unit, Centre for Clinical Intervention Re-
search, H:S Rigshospitalet DENMARK
R E F E R E N C E S
References to studies included in this reviewAssateerawatt 1993 {published data only}
Assateerawatt A, Tanphaichitr VS, Suvatte V, Yodthong S. Immuno-
genicityand efficacy ofa recombinant DNAhepatitis B vaccine, Gen-
Hevac B Pasteur in high risk neonates, school children and healthy
adults. Asian Pacific Journal of Allergy Immunology 1993;11(1):8591.
Beasley 1983a AB {published data only} Beasley RP, Hwang LY, Stevens CE,Lin CC, Hsieh FJ,Wang KY, etal. Efficacy ofhepatitisB immune globulin forprevention ofperinatal
transmission of the hepatitis B virus carrier state: final report of a
randomized double-blind, placebo-controlled trial. Hepatology1983;3(2):13541.
Beasley RP, Hwang LY, Szmuness W, Stevens CE, Lin CC, Hsieh FJ,
et al. HBIGprophylaxis for perinatal HBV infections - final report of
the Taiwan trial. Developmental Biology Standard1983;54:36375.
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al. Efficacy ofhepatitisB immune globulin forprevention ofperinatal
transmission of the hepatitis B virus carrier state: final report of a
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Beasley RP, Hwang LY, Szmuness W, Stevens CE, Lin CC, Hsieh FJ,
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and hepatitis B vaccine. Lancet1983;2(8359):1099102.
Farmer 1987 {published data only}
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vaccine and immunoglobulin does not protect all infants born to
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Gonzalez MGD. [Field trial of the Cuban recombinant vaccine
against hepatitisB (Heberbiovac HB).Study in newborn infantsbornto AgsHB+ mothers]. Revista Cubana de Medicina Tropical1992;44
(2):14957.
Grosheide 1993 {published data only} Grosheide PM, del Canho R, Heijtink RA, Nuijten AS, Zwijnen-
berg J, Banffer JR, et al. Passive-active immunization in infants of
hepatitis Be antigen-positive mothers. Comparison of the efficacy of
early and delayed active immunization. American Journal of Diseasesof Children 1993;147(12):131620.
MazelJA, SchalmSW, deGastBC, NuijtenAS, HeijtinkRA, Botman
MJ, et al. Passive-active immunisation of neonates of HBsAgpositive
carrier mothers: preliminary observations. British Medical Journal
(Clinical Research Ed.) 1984;288(6416):5135.
Halliday 1992 AB {published data only}Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH,
et al.An efficacy trial of a mammalian cell-derived recombinant DNA
hepatitis B vaccine in infants born to mothers positive for HBsAg, in
Shanghai, China. International Journal of Epidemiology1992;21(3):
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Halliday 1992 CA {published data only}
Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH,
et al.An efficacy trial of a mammalian cell-derived recombinant DNA
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hepatitis B vaccine in infants born to mothers positive for HBsAg, in
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Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH,
et al. An efficacy trial of a mammalian cell-derived recombinant DNA
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56473.
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-
cine2002;20(13-14):18038.
Ip 1989 AB {published data only} Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention
ofhepatitisB viruscarrier state in infantsaccordingto maternalserum
levels of HBV DNA. Lancet1989;1(8635):40610.
IpHM, WongVC, Lelie PN,Reesink HW, SchaasbergW, Yeung CY,et al. Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese1989;31(6):6548.
Ip 1989 AC {published data only} Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention
ofhepatitisB viruscarrier state in infantsaccordingto maternalserum
levels of HBV DNA. Lancet1989;1(8635):40610.
IpHM, WongVC, Lelie PN,Reesink HW, SchaasbergW, Yeung CY,
et al. Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese1989;31(6):6548.
Ip 1989 AD {published data only}IpHM,Lelie PN,WongVC, Kuhns MC,ReesinkHW. Preventionof
hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet1989;1(8635):40610.
IpHM, WongVC, Lelie PN,Reesink HW, SchaasbergW, Yeung CY,
et al. Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese1989;31(6):6548.
Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE,
Yeung CY, et al.Preventionof the HBsAg carrier state in newborn in-
fantsofmotherswhoarechroniccarriersofHBsAgandHBeAgbyad-
ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin.
Double-blind randomised placebo-controlled study. Lancet1984;1
(8383):9216.
Ip 1989 BC {published data only} Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention
ofhepatitisB viruscarrier state in infantsaccordingto maternalserumlevels of HBV DNA. Lancet1989;1(8635):40610.
IpHM, WongVC, Lelie PN,Reesink HW, SchaasbergW, Yeung CY,
et al. Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese1989;31(6):6548.
Ip 1989 BD {published data only}
IpHM,Lelie PN,WongVC, Kuhns MC,ReesinkHW. Preventionof
hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet1989;1(8635):40610.
IpHM, WongVC, Lelie PN,Reesink HW, Schaasberg W, Yeung CY,
et al. Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese1989;31(6):6548.
Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE,
Yeung CY, et al.Prevention of the HBsAg carrierstate in newborn in-
fantsof mothers whoarechroniccarriersof HBsAg andHBeAg byad-
ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin.
Double-blind randomised placebo-controlled study. Lancet1984;1(8383):9216.
Ip 1989 CD {published data only}IpHM, Lelie PN, WongVC,KuhnsMC,ReesinkHW. Preventionof
hepatitis B virus carrier state in infants according to maternal serum
levels of HBV DNA. Lancet1989;1(8635):40610.
IpHM, WongVC, Lelie PN,Reesink HW, Schaasberg W, Yeung CY,
et al. Hepatitis B infection in infants after neonatal immunization.
Acta Paediatric Japanese1989;31(6):6548.
Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE,
Yeung CY, et al.Prevention of the HBsAg carrierstate in newborn in-
fantsof mothers whoarechroniccarriersof HBsAg andHBeAg byad-
ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin.
Double-blind randomised placebo-controlled study. Lancet1984;1
(8383):9216.
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 Zhi1995;30(7):3902.
Khukhlovich 1996 {published data only}
Khukhlovich PA, Shakhgildian IV, Narkevich MI, Ananev VA,
Kuzin SN, Sergeeva NA, et al. [The vaccinal prophylaxis of hepatitis
B among children born to mothers with persistent HBs-antigene-
mia]. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii1996;2:559.
Kuru 1995 AB {published data only}Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated
infants born to HBsAg-positive mothers with different hepatitis B
vaccines and doses. The Turkish Journal of Pediatrics1995;37(2):93
102.
Kuru 1995 AC {published data only}
Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated
infants born to HBsAg-positive mothers with different hepatitis B
vaccines and doses. The Turkish Journal of Pediatrics1995;37(2):93102.
Kuru 1995 BC {published data only}Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated
infants born to HBsAg-positive mothers with different hepatitis B
vaccines and doses. The Turkish Journal of Pediatrics1995;37(2):93
102.Lee 1995 AB {published data only}
Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal1991;10(4):
299303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
79Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
8/2/2019 Hepatitis B Immunisation For
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Evid.-Based Child Health 2: 67155 (2007)
born to mothers with hepatitis B e antigen. The Journal of Pediatrics1995;126(5 Pt 1):71621.
Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
studyof combinedvaccination withplasma-derived andrecombinant
hepatitis B vaccines in infants. Vaccine1995;13(17):16859.
Lee 1995 CA {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal1991;10(4):299303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
born to mothers with hepatitis B e antigen. The Journal of Pediatrics
1995;126(5 Pt 1):71621.
Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
studyof combinedvaccination withplasma-derived andrecombinant
hepatitis B vaccines in infants. Vaccine1995;13(17):16859.
Lee 1995 CB {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal1991;10(4):
299303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
born to mothers with hepatitis B e antigen. The Journal of Pediatrics1995;126(5 Pt 1):71621.
Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
studyof combinedvaccination withplasma-derived andrecombinant
hepatitis B vaccines in infants. Vaccine1995;13(17):16859.
Lee 1995 DE {published data only}Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, SungJL, etal. The
protective efficacy of recombinant hepatitis B vaccine in newborn
infants of hepatitis B e antigen-positive-hepatitis B surface antigen
carrier mothers. The Pediatric infectious Disease Journal1991;10(4):
299303.
Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re-
combinant hepatitis B vaccine and risk of natural infection in infants
born to mothers with hepatitis B e antigen. The Journal of Pediatrics
1995;126(5 Pt 1):71621.
Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up
studyof combinedvaccination withplasma-derived andrecombinant
hepatitis B vaccines in infants. Vaccine1995;13(17):16859.
Liu 1987 AB {published data only}
Liu LH. [Comparative study of the efficacy of hepatitis B virus
(HBV) vaccine combined with hepatitis B immunoglobulin(HBIG)
versus vaccine alone in the interruption of the perinatal transmission
of HBV carrier state]. Zhonghua Liu Xing Bing Xue Za Zhi1987;8
(6):3258.
Liu 1987 CA {published data only}
Liu LH. [Comparative study of the efficacy of hepatitis B virus
(HBV) vaccine combined with hepatitis B immunoglobulin(HBIG)
versus vaccine alone in the interruption of the perinatal transmission
of HBV carrier state]. Zhonghua Liu Xing Bing Xue Za Zhi1987;8
(6):3258.
Liu 1987 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 Zhi1987;8
(6):3258.
Lo 1985 AB {published data only}
Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et al.
Prevention of hepatitis B virus infection in children born to HBsAg
positive/HBeAg positive mothers. Preliminary results of active and
passive-active immunization. Developmental Biology Standard1983;54:399404.
Lo KJ, TsaiYT, LeeSD, Yeh CL, Wang JY, Chiang BN, et al. Com-
bined passive and active immunization for interruption of perinatal
transmission of hepatitis B virus in Taiwan. Hepatogastroenterology
1985;32(2):658.
Lo 1985 CA {published data only}Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et al.
Prevention of hepatitis B virus infection in children born to HBsAg
positive/HBeAg positive mothers. Preliminary results of active and
passive-active immunization. Developmental Biology Standard1983;54:399404.
Lo KJ, TsaiYT, LeeSD, Yeh CL, Wang JY, Chiang BN, et al. Com-
bined passive and active immunization for interruption of perinatal
transmission of hepatitis B virus in Taiwan. Hepatogastroenterology
1985;32(2):658.
Lo 1985 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 andpassive-active immunization. Developmental Biology Standard1983;54:399404.
Lo KJ, TsaiYT,Lee SD,Yeh CL, Wang JY, Chiang BN, et al. Com-
bined passive and active immunization for interruption of perinatal
transmission of hepatitis B virus in Taiwan. Hepatogastroenterology
1985;32(2):658.
Lolekha 2002 {published data only}
LolekhaS, WarachitB, HirunyachoteA, Bowonkiratikachorn P, West
DJ, Poerschke G. Protective efficacy of hepatitis B vaccine without
HBIG in infants of HBeAg-positive carrier mothers in Thailand.
Vaccine2002;20(31-32):373943.
Oon 1986 AB {published data only}
Oon CJ, Tan KL, Goh KT, Wong-Yong L, Viegas O, McCarthy T,et al. Evaluation of a low dose of hepatitis B vaccine given within
a childhood immunisation programme in Singapore. The Journal ofInfection 1986;13(3):25567.
Oon 1986 CD {published data only}
Oon CJ, Tan KL, Goh KT, Wong-Yong L, Viegas O, McCarthy T,
et al. Evaluation of a low dose of hepatitis B vaccine given within
a childhood immunisation programme in Singapore. The Journal ofInfection 1986;13(3):25567.
80Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
8/2/2019 Hepatitis B Immunisation For
15/89
Evid.-Based Child Health 2: 67155 (2007)
Piazza 1985 {published data only}Piazza M, Picciotto L, Villari R, Guadagnino V, Orlando R, Isabella
L, et al. Hepatitis B immunisation with a reduced number of doses
in newborn babies and children. Lancet1985;1(8435):94951.
Pongpipat 1986 {published data only}Pongpipat D, Suvatte V, Assateerawatts A. Efficacy of hepatitis-B
immunoglobulinand hepatitis-Bvaccinein prevention of the HBsAg
carrier state in newborn infants of mothers who are chronic carriers
of HBsAg and HBeAg. Asian Pacific Journal of Allergy Immunology1986;4(1):336.
Pongpipat 1988 {published data only}
PongpipatD, Suvatte V, AssateerawattsA. Hepatitis B immunization
in high risk neonates born from HBsAg andHBeAgpositive mothers:
comparison of standard and low dose regimens. Asian Pacific Journalof Allergy Immunology1988;6(2):10710.
Pongpipat 1989 {published data only}PongpipatD, Suvatte V, AssateerawattsA. Hepatitis B immunization
in highrisk neonatesborn fromHBsAg positivemothers:comparison
between plasma derived and recombinant DNAvaccine.Asian Pacific
Journal of Allergy Immunology1989;7(1):3740.
Poovorawan 1997 {published data only} PoovorawanY, Sanpavat S, Chumdermpadetsuk S, Safary A. Long-
term hepatitis B vaccine in infants born to hepatitis B e antigen
positive mothers. Archives of Disease in Childhood.Fetal and Neonatal
Edition 1997;77(1):F47F51.
Poovorawan Y,Sanpavat S, Pongpunglert W, Chumdermpadetsuk S,
Sentrakul P, Vandepapeliere P, et al. Long term efficacy of hepatitis
B vaccine in infants born to hepatitis B e antigen-positive mothers.
The Pediatric Infectious Disease Journal1992;11(10):81621.
Sehgal 1992 {published data only}
Sehgal A, Gupta I, Sehgal R, GangulyNK. Hepatitis B vaccine alone
or in combination with anti-HBs immunoglobulin in the perinatal
prophylaxis of babies born to HBsAgcarrier mothers. Acta Virologica1992;36(4):35966.
Sehgal A, Sehgal R, Gupta I, Bhakoo ON, Ganguly NK. Use of
hepatitis B vaccine alone or in combination with hepatitis B im-
munoglobulin for immunoprophylaxis of perinatal hepatitis B infec-
tion. Journal of Tropical Pediatrics1992;38(5):24751.
Theppisai 1987 {published data only}
Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P. A compar-
ison between the efficacy of passive-active and active immunization
for prevention of perinatal transmission of hepatitis B virus. Journalof Medical Association, Thailand1987;70(8):45962.
Theppisai 1990 {published data only}Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P. Prevention
of hepatitis B infection in infants born to hepatitis B carrier moth-
ers: low dosage vaccination. International Journal of Gynaecology and
Obstetrics1990;32(4):3537.
Xu 1995 AB {published data only}Xu ZY, Duan SC,MargolisHS, Purcell RH,Ou-YangPY,Coleman
PJ, et al. Long-term efficacy of active postexposure immunization of
infants for prevention of hepatitis B virus infection. United States-
Peoples Republic of China Study Group on Hepatitis B. The Journalof Infectious Diseases1995;171(1):5460.
Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et
al. Prevention of hepatitis B virus carriage of infants using HBV
vaccine in Shanghai. Preliminary report of a randomized double-
blind placebo-controlled trial. Chinese Medical Journal1985;98(9):
6236.
Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, et al.
Prevention of perinatal acquisition of hepatitis B virus carriage using
vaccine: preliminary report of a randomized, double-blind placebo-
controlled and comparative trial. Pediatrics1985;76(5):7138.
Xu 1995 AD {published data only}XuZY,Duan SC,Margolis HS,Purcell RH,Ou-YangPY,Coleman
PJ, et al. Long-term efficacy of active postexposure immunization of
infants for prevention of hepatitis B virus infection. United States-
Peoples Republic of China Study Group on Hepatitis B. The Journalof Infectious Diseases1995;171(1):5460.
Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et
al. Prevention of hepatitis B virus carriage of infants using HBV
vaccine in Shanghai. Preliminary report of a randomized double-
blind placebo-controlled trial. Chinese Medical Journal1985;98(9):
6236.
Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, et al.
Prevention of perinatal acquisition of hepatitis B virus carriage using
vaccine: preliminary report of a randomized, double-blind placebo-
controlled and comparative trial. Pediatrics1985;76(5):7138.
Xu 1995 BD {published data only}XuZY,Duan SC,Margolis HS,Purcell RH,Ou-YangPY,Coleman
PJ, et al. Long-term efficacy of active postexposure immunization of
infants for prevention of hepatitis B virus infection. United States-
Peoples Republic of China Study Group on Hepatitis B. The Journalof Infectious Diseases1995;171(1):5460.
Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et
al. Prevention of hepatitis B virus carriage of infants using HBV
vaccine in Shanghai. Preliminary report of a randomized double-blind placebo-controlled trial. Chinese Medical Journal1985;98(9):6236.
Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, et al.
Prevention of perinatal acquisition of hepatitis B virus carriage using
vaccine: preliminary report of a randomized, double-blind placebo-
controlled and comparative trial. Pediatrics1985;76(5):7138.
Xu 1995 CB {published data only}XuZY,Duan SC,Margolis HS,Purcell RH,Ou-YangPY,Coleman
PJ, et al. Long-term efficacy of active postexposure immunization of
infants for prevention of hepatitis B virus infection. United States-
Peoples Republic of China Study Group on Hepatitis B. The Journal
of Infectious Diseases1995;171(1):5460.
Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, etal. Prevention of hepatitis B virus carriage of infants using HBV
vaccine in Shanghai. Preliminary report of a randomized double-
blind placebo-controlled trial. Chinese Medical Journal1985;98(9):
6236.
Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, et al.
Prevention of perinatal acquisition of hepatitis B virus carriage using
vaccine: preliminary report of a randomized, double-blind placebo-
controlled and comparative trial. Pediatrics1985;76(5):7138.
81Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review)
Copyright 2007 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
8/2/2019 Hepatitis B Immunisation For
16/89
Evid.-Based Child Health 2: 67155 (2007)
Xu 1995 CD {published data only}Xu ZY, Duan SC,MargolisHS, Purcell RH,Ou-YangPY,Coleman
PJ, et al. Long-term efficacy of active postexposure immunization of
infants for prevention of hepatitis B virus infection. United States-
Peoples Republic of China Study Group on Hepatitis B. The Journalof Infectious Diseases1995;171(1):5460.
XuZY, FrancisDP, LiuCB,PurcellRH, Duan SC,et al.Preventionof
hepatitis B virus carriage of infants using HBV vaccine in Shanghai.
Preliminary report of a randomized double-blind placebo-controlled
trial. Chinese Medical Journal1985;98(9):6236.
Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, et al.
Prevention of perinatal acquisition of hepatitis B virus carriage using
vaccine: preliminary report of a randomized, double-blind placebo-
controlled and comparative trial. Pediatrics1985;76(5):7138.
Yeoh 1986 {published data only}
Yeoh EK, Chang WK, IpP, Chan KH, Chan E, Fung C. Efficacyand
safety of recombinant hepatitis B vaccine in infants born to HBsAg-
positive mothers. The Journal of Infection 1986;13 Suppl A:158.
Zhu 1987 {published data only}
Zhu Q-Y, Radvan GH. A randomized controlled trial of hepatitis
B vaccine in high risk newborn infants in China. Australian & New
Zealand Journal of Medicine1987;17:498.
Zhu 1994 {published data only}
Zhu QR, Gu XH, Duan SC, Xu HF. Long-term immunogenicity
and efficacy of recombinant yeast derived hepatitis B vaccine for in-
terruptionof mother-infant transmissionof hepatitisB virus.ChineseMedical Journal1994;107(12):9158.
References to studies excluded from this reviewChung 1988
ChungWK. Persistenceandboostingresponseof antibodyto HBsAg
induced by vaccine treatment. Tropical Gastroenterology1988;9(1):
2630.
Chung 1988 BChung WK, Choi KY, Shim KS, Chung JW, Sun HS, Chung KW,
et al. Safety, immunogenicity, and efficacy of a new heat-inactivated
hepatitis B vaccine in the newborn. Viral Hepatitis and Liver Disease1988:10146.
Coursaget 1984
Coursaget P, Deciron F, Tortey E, Barin F, Chiron JP, Yvonnet B, et
al. Immune response to hepatitis B vaccine in infants and newborns:
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Da 1995
Da Villa G, Picciottoc L, Elia S, Peluso F, Montanaro F, Maisto T.
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children at 12 years of age versus high risk groups. A comparison in
the field. Vaccine1995;13(13):12403.
Delage 1993
Delage G, Remy-Prince S, Montplaisir S. Combined active-passive
immunization against the hepatitis B virus: five-year follow-up of
children born to hepatitis B surface antigen-positive mothers. The
Pediatric Infectious Disease Journal1993;12(2):12630.
Esteban 1986
Esteban JI, Genesca J, Esteban R, Hernandez JM, Seijo G, Buti M,
et al. Immunoprophylaxis of perinatal transmission of the hepatitis
B virus: efficacy of hepatitis B immune globulin and hepatitis B
vaccine in a low-prevalence area. Journal of Medical Virology 1986;
18(4):38191.
Goh 1992
Goh KT, Tan KL, Kong KH, Oon CJ, Chan SH.Comparison of the
immune response of four different dosages of a yeast-recombinant
hepatitisB vaccine in Singaporechildren: a four-year follow-up study.
Bulletin of the World Health Organization 1992;70(2):2339.
Kang 1986
Kang Y. Efficacy of domestic hepatitis B viral vaccines in preventing
transmissionof e antigenfrom mothersto newborn infants.ZhonghuaLiu Xing Bing Xue Za Zhi1986;7(2):813.
Lai 1986
Lai CL, Yeoh EK, Chang WK, Lo VW, Ng LN. Use of the hepatitis
B recombinant DNA yeast vaccine (H-B-VAX II) in children: two
doses vs. three doses of 5 micrograms regime; an interim report. TheJournal of Infection 1986;13 Suppl A:1925.
Lai 1993
Lai CL, Wong BC, Yeoh EK, Lim WL, Chang WK, Lin HJ. Five-yearfollow-up ofa prospectiverandomized trial of hepatitis B recom-
binant DNA yeast vaccine vs. plasma-derived vaccine in children:
immunogenicity and anamnestic responses. Hepatology1993;18(4):
7637.
Laille 1988
Laille M, Brethes B, Moreau JP, Pillot J. [Trial of hepatitis B pro-
phylaxis in children born to mothers carrying HBs antigen in New
Caledonia].Bulletin de la Societede Pathologie Exotique et de sesFiliales
1988;81(4):6738.
Lin 1987
Lin KH, Twu SJ, Chen DS, Su S, Lee CJ. Efficacy of the national
hepatitis B vaccination program in the Republic of China: prelim-
inary observations from Taoyuan area. Taiwan Yi Xue Hui Za Zhi1987;86(8):86972.
Linder 2000
Linder N, w-up.5Tf-24.9p97 0 Tdf-14.7601 Td0.63989en70.5Tf-8iS5599j6.95991 0 Td8 0 0 Td(F)Tjobser5998 0 Td(oh9 Td(Yi)Tj9.47inh.11.87993 0 T/R1it3R101 7.j8.75986.759HBsthe23.15979.47in
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Nair 1984
Nair PV, Weissman JY, Tong MJ, Thursby MW, Paul RH, Henne-
man CE. Efficacy of hepatitis B immune globulin in prevention of
perinatal transmission of the hepatitis B virus.Gastroenterology1984;
87(2):2938.
Okoth 1994
Okoth FA, Kobayashi M, Takayanagi N, Kapttich DC, Kaiguri PM,
Tukei PM. Efficacy of hepatitis B vaccine in a rural community in
Muranga, Kenya. East