Hepatitis B immunisation for newborn infants of hepatitis B surface ...

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 Library 2008, Issue 3 http://www.thecochranelibrary.com

Hepatitis 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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TABLE OF CONTENTS ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . . SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . . METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 01. Search strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 02. Intervention by group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison 01. Vaccine versus placebo or no intervention . . . . . . . . . . . . . . . . . . . . Comparison 02. RV versus PDV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison 03. High-dose versus low-dose vaccine . . . . . . . . . . . . . . . . . . . . . . . Comparison 04. Three-dose PDV plus HBIG versus two-dose PDV plus HBIG . . . . . . . . . . . . . Comparison 05. PDV at birth versus PDV at one month . . . . . . . . . . . . . . . . . . . . . Comparison 06. One type of PDV versus another type of PDV . . . . . . . . . . . . . . . . . . . Comparison 07. Four RV vaccinations versus three RV vaccinations . . . . . . . . . . . . . . . . . Comparison 08. One type of RV versus another type of RV with the same vaccination schedule . . . . . . . . Comparison 09. HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . . . . . . Comparison 10. Multiple HBIG plus PDV versus single HBIG plus PDV . . . . . . . . . . . . . . . Comparison 11. PDV plus HBIG versus placebo or no intervention . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 01.01. Comparison 01 Vaccine versus placebo or no intervention, Outcome 01 Hepatitis B events according to type of vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 01.02. Comparison 01 Vaccine versus placebo or no intervention, Outcome 02 Hepatitis B events according to methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events - Sensitivity analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 01.04. Comparison 01 Vaccine versus placebo or no intervention, Outcome 04 Hepatitis B events according to the mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 01.05. Comparison 01 Vaccine versus placebo or no intervention, Outcome 05 Hepatitis B events according to first time of vaccine administration . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 02.01. Comparison 02 RV versus PDV, Outcome 01 Hepatitis B events . . . . . . . . . . . . . Analysis 02.02. Comparison 02 RV versus PDV, Outcome 02 Hepatitis B events according to methodological quality Analysis 02.03. Comparison 02 RV versus PDV, Outcome 03 Hepatitis B events - sensitivity analyses . . . . . . Hepatitis 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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Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mother’s HBeAg status Analysis 02.05. Comparison 02 RV versus PDV, Outcome 05 Anti-HBs less than 10 IU/L . . . . . . . . . Analysis 03.01. Comparison 03 High-dose versus low-dose vaccine, Outcome 01 Hepatitis B events . . . . . . Analysis 03.02. Comparison 03 High-dose versus low-dose vaccine, Outcome 02 Hepatitis B events according to methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events - sensitivity analyses Analysis 03.04. Comparison 03 High-dose versus low-dose vaccine, Outcome 04 Hepatitis B events according to the mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 03.05. Comparison 03 High-dose versus low-dose vaccine, Outcome 05 Anti-HBs less than 10 IU/L . . . Analysis 04.01. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 01 Hepatitis B events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 05.01. Comparison 05 PDV at birth versus PDV at one month, Outcome 01 Hepatitis B events . . . . Analysis 06.01. Comparison 06 One type of PDV versus another type of PDV, Outcome 01 Hepatitis B events . . Analysis 07.01. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 01 Hepatitis B events . Analysis 07.02. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 02 Anti-HBs level less than 10 IU/L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 08.01. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule, Outcome 01 Hepatitis B events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 09.01. Comparison 09 HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events . . . . Analysis 09.02. Comparison 09 HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events according to methodological quality of the trials . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 09.03. Comparison 09 HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events - sensitivity analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 09.04. Comparison 09 HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events according to the mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 09.05. Comparison 09 HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events according to time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 09.06. Comparison 09 HBIG versus placebo or no intervention, Outcome 06 Hepatitis B events according to standard and rapid schedule of vaccines . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 09.07. Comparison 09 HBIG versus placebo or no intervention, Outcome 07 Anti-HBs less than 10 IU/L . Analysis 09.08. Comparison 09 HBIG versus placebo or no intervention, Outcome 08 Anti-HBs level . . . . . Analysis 09.09. Comparison 09 HBIG versus placebo or no intervention, Outcome 09 Adverse events . . . . . Analysis 10.01. Comparison 10 Multiple HBIG plus PDV versus single HBIG plus PDV, Outcome 01 Hepatitis B events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 11.01. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events 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 . . . . . . . . . . . . . . . . . . . . . . Analysis 11.03. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events sensitivity analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 11.04. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events according to mother’s HBeAg status . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 11.05. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events according to time of HBIG administration . . . . . . . . . . . . . . . . . . . . . . . . Analysis 11.06. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 06 Adverse events . .


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Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) Lee C, Gong Y, Brok J, Boxall EH, Gluud C This 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

ABSTRACT 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 HBsAgpositive 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 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. Hepatitis 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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PLAIN LANGUAGE SUMMARY 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.

BACKGROUND Hepatitis B virus is a global acute and chronic communicable disease that causes major hepatic disease, with an estimated 350 million 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 significantly 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 vaccine (RV)) from yeast or mammalian cells (Assad 1999). Repeated injections over months are required to mount an effective antibody 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 immunoglobulin 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 reviews on hepatitis B immunisation for newborn infants of HBsAg positive mothers. A narrative review regarding the efficacy of hepatitis B vaccine in neonates (Andre 1994) and several international 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 presenting original data.

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

positive mothers.

CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW 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 HBsAgpositive 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 infection (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 divided into severe and non-severe. A severe adverse event, according to the International Committee on Harmonisation Guidelines (ICH 1997) is any event that would increase mortality; is lifethreatening; requires inpatient hospitalisation; results in a persistent 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.

SEARCH METHODS FOR IDENTIFICATION OF STUDIES See: Cochrane Hepato-Biliary Group methods used in reviews. We searched The Cochrane Neonatal Group Controlled Trials Register, The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials(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.

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 quasirandomised 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)

METHODS OF THE REVIEW 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.

• 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


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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. Metaregression 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 lowquality). 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).

DESCRIPTION OF STUDIES We identified 226 references, but 186 were clearly irrelevant references. The remaining 40 references describing 29 randomised trials 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). Excluded 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 (Halliday 1992 AB; Zhu 1994). The vaccination schedules were 0-1-6 months (Pongpipat 1989; Halliday 1992 AB; Zhu 1994) or 0-12-12 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 microgram (Oon 1986 AB, Oon 1986 CD, Pongpipat 1988; Theppisai 1990). The doses of RV were 20 microgram and 10 microgram (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 twodose PDV plus hepatitis B immunoglobulin One trial assessed three-doses PDV plus hepatitis B immunoglobulin versus two-doses PDV plus hepatitis B immunoglobulin (Piazza 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


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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) versus 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 immunoglobulin (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 intervention 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 vaccination 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), 0-1-26 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 hepatitis B immunoglobulin at birth with or without additional hepatitis 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 0-1-23-4-5-6 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 negative (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 remaining 19 trials did not report any birth weight exclusion criteria. The average duration of follow-up was 19 months (range 6 to 60 months).

METHODOLOGICAL QUALITY Generation of the allocation sequence was adequate in six trials (Piazza 1985; Oon 1986 AB/Oon 1986 CD; Farmer 1987; Halliday 1992 AB/Halliday 1992 CA/Halliday 1992 DC; Assateerawatt 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 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 adequately 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).

RESULTS Hepatitis B vaccines versus placebo or no intervention (Comparison 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


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showed that both vaccines significantly decreased the risk of hepatitis 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, respectively). Post hoc subgroup analysis according to vaccine schedules (0-1-6 months versus 0-1-2-6 or -12 months) showed no significant difference (test of interaction, P = 0.75). No data on adverse events were reported. RV versus PDV (Comparison 02-01 to 02-05) We found no significant difference between RV and PDV on hepatitis B occurrence (RR 1.00, 95% CI 0.70 to 1.42, 4 trials). Heterogeneity was moderate (I2 = 29.4%). The results of sensitivity analyses regarding dropouts confirmed the finding. Subgroup analyses did not find a significant difference regarding the methodological quality or the mother’s HBeAg status (both tests of interaction, 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 0305) We found no statistical difference on hepatitis B occurrence comparing 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 lowdose 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 significantly 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 immunoglobulin 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 vaccinations (0-1-2-12 months) versus the same RV with three vaccinations (0-1-6 months). No significant differences were found on hepatitis B occurrence (RR 1.49, 95% CI 0.51 to 4.37) or antiHBs 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 vaccination 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 intervention (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 intervention, hepatitis B immunoglobulin alone significantly reduced hepatitis B occurrence (RR 0.50, 95% CI 0.41 to 0.60, 1 trial). Compared with vaccination, vaccination plus hepatitis B immunoglobulin was likewise superior (RR 0.54, 95% CI 0.41 to 0.73, 10 trials). The sensitivity analyses regarding dropouts were consistent, indicating the robustness of the findings. In the meta-regression analyses, none of the trial characteristics (methodological quality, 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 difference 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 number 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. Therefore 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 hepatitis 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 confirmed 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 immunoglobulin injection (tests of interaction, P = 0.13, 0.28, and 0.22, respectively). 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)

DISCUSSION Our systematic review demonstrates that hepatitis B vaccine, hepatitis B immunoglobulin, or the combination of vaccine plus hepatitis B immunoglobulin given to newborn infants of HBsAg-positive mothers prevent hepatitis B occurrence. Further, the combination 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 exclude 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 surrogate outcomes (HBsAg status or anti-HBs level) and not longterm clinical outcomes. Of note is the fact that one trial with longterm 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 difference 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 human immuno-deficiency virus infection and other infections, including 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 substantially (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 associations 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 immunoglobulin alone or when added to hepatitis B vaccine significantly decreased 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 immunoglobulin 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 increased 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; Etminan 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 mothers is considered much lower than in HBeAg-positive mothers (Okada 1976). If infected, the newborn infants of HBeAg-negative 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 effective in countries with low (Bloom 1993; Tormans 1993; Da Villa 1999; Harris 2001), intermediate, and high prevalence of hepatitis 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 immunoglobulin seems able to reduce the risk of hepatitis B infection, the need to perform cost-effectiveness studies based on randomised trials seems justified. Two trials examined a new way to prevent vertical transmission of hepatitis B, which could not be included according to our inclusion criteria (Lee 2004). The two trials randomised pregnant women positive for hepatitis B surface antigen to hepatitis B immunoglobulin 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 before this intervention should be adopted.

AUTHORS’ CONCLUSIONS Implications for practice HBsAg positive mothers who are HBeAg positive Evidence suggests that hepatitis B vaccine, hepatitis B immunoglobulin, and the combination of hepatitis B vaccine and hepatitis B immunoglobulin reduce the risk of perinatal transmission 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 hepatitis 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 prophylaxis in newborn infants - the hepatitis B immunoglobulin administration 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 clinical 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 hepatitis B vaccine plus multiple hepatitis B immunoglobulin doses is superior to hepatitis B vaccine plus a single dose of hepatitis B immunoglobulin.

NOTES 1. A protocol for a systematic review on this topic was first published in Issue 2, 1998 of The Cochrane Library and continued to be published until Issue 1, 2004 with a title ’Vaccines for preventing hepatitis B in high risk newborn infants’. The authors, Jefferson 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 serological outcome in two and more consecutive blood specimens. We realized that this requirement was not detainable in the majority of the trials. We therefore decided to delete this requirement.

POTENTIAL CONFLICT OF INTEREST None known.

ACKNOWLEDGEMENTS 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 Hassan, and SD Lee for providing assistance in our work to identify trial authors, and JU Olsen, GlaxoSmithKline, Denmark, for providing information regarding randomised clinical trials.

SOURCES OF SUPPORT 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 Research, H:S Rigshospitalet DENMARK

REFERENCES

References to studies included in this review Assateerawatt 1993 {published data only} Assateerawatt A, Tanphaichitr VS, Suvatte V, Yodthong S. Immunogenicity and efficacy of a recombinant DNA hepatitis B vaccine, GenHevac 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 Journal 1987;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


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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 efficacy, safety and immunogenicity of Hepavax-Gene and EngerixB, recombinant hepatitis B vaccines, in infants born to HBsAg and HBeAg positive mothers in Vietnam: an assessment at 2 years. Vaccine 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. Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE, Yeung CY, et al.Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration 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.

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 infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitis-B immunoglobulin. Double-blind randomised placebo-controlled study. Lancet 1984;1 (8383):921–6.

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.

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.

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.

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-antigenemia]. 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.

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 infants of mothers who are chronic carriers of HBsAg and HBeAg by administration 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.

∗

Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of recombinant hepatitis B vaccine and risk of natural infection in infants


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

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.

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.

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. Hepatogastroenterology 1985;32(2):65–8.

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.

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.

∗ ∗

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

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)

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. Hepatogastroenterology 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. Hepatogastroenterology 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 of Infection 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.


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Piazza 1985 {published data only} Piazza M, Picciotto L, Villari R, Guadagnino V, Orlando R, Isabella L, et al.Hepatitis B immunisation with a reduced number of doses in newborn babies and children. Lancet 1985;1(8435):949–51.

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 Journal 1985;98(9):623–6.

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.

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, doubleblind placebo-controlled and comparative trial. Pediatrics 1985;76 (5):713–8.

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 Pacific Journal of Allergy Immunology 1989;7(1):37–40. Poovorawan 1997 {published data only} ∗ Poovorawan Y, Sanpavat S, Chumdermpadetsuk S, Safary A. Longterm 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 Virologica 1992;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 immunoglobulin for immunoprophylaxis of perinatal hepatitis B infection. Journal of Tropical Pediatrics 1992;38(5):247–51. ∗

Theppisai 1987 {published data only} Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P. A comparison 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 mothers: low dosage vaccination. International Journal of Gynaecology and Obstetrics 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 StatesPeople’s Republic of China Study Group on Hepatitis B. The Journal of Infectious Diseases 1995;171(1):54–60.

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 StatesPeople’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 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 carriage using vaccine: preliminary report of a randomized, doubleblind 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 StatesPeople’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 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 carriage using vaccine: preliminary report of a randomized, doubleblind 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 StatesPeople’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 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 carriage using vaccine: preliminary report of a randomized, doubleblind placebo-controlled and comparative trial. Pediatrics 1985;76 (5):713–8.


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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 StatesPeople’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 carriage using vaccine: preliminary report of a randomized, doubleblind 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 HBsAgpositive 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 & New Zealand 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 interruption of mother-infant transmission of hepatitis B virus. Chinese Medical 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 for Research 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. The Journal of Infection 1986;13 Suppl A:19–25. Lai 1993 Lai CL, Wong BC, Yeoh EK, Lim WL, Chang WK, Lin HJ. Fiveyear follow-up of a prospective randomized trial of hepatitis B recombinant 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 prophylaxis 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: preliminary observations from Taoyuan area. Taiwan Yi Xue Hui Za Zhi 1987;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 administered simultaneously shortly after birth. Archives of Disease in Childhood. 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.


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Nair 1984 Nair PV, Weissman JY, Tong MJ, Thursby MW, Paul RH, Henneman 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 immunization of newborns according to a two dose protocol. Vaccine 1986;4 (4):241–4. Pongpipat 1984 Pongpipat D, Suvatte V, Assateerawatts A. Vaccination against hepatitis 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. The Journal 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 transmission. 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 globulin and yeast-recombinant hepatitis B vaccine in prevention of perinatal HBV infection in the USA. Viral Hepatits and Hepatocellular Carcinoma 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, Anderson 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 followup 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. Chinese Medical 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 studies (abstract). Cochrane Colloquium 2004, Ottawa, Canada. 2004.


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Altman 2003 Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ (Clinical Research Ed.) 2003;326:219.

David 1996 David MS, Norman TB. Immunisation against Infectious Disease. London: HMSO, 1996.

Andre 1994 Andre FE, Zuckerman AJ. Review: protective efficacy of hepatitis B vaccines in neonates. Journal of Medical Virology 1994;44(2):144– 51.

Deeks 2003 Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.Evaluating non-randomised intervention studies. Health Technology Assessment 2003;7(27):1–173.

Assad 1999 Assad S, Francis A. Over a decade of experience with a yeast recombinant hepatitis B vaccine. Vaccine 1999;18(1-2):57–67.

DeMets 1987 DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341–50. [MEDLINE: 3616287].

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.

DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177–88. [MEDLINE: 3802833].

Beasley 1983 Beasley RP, Hwang LY. Postnatal infectivity of hepatitis B surface antigen-carrier mothers. Journal of Infectious Diseases 1983;147(2): 185–90.

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.

Beasley 1984 Beasley RP, Hwang LY. Hepatocellular carcinoma and hepatitis B virus. Seminars in Liver Disease 1984;4(2):113–21.

DuVernoy 2000 DuVernoy TS, Braun MM. Hypotonic-hyporesponsive episodes reported to the Vaccine Adverse Event Reporting System (VAERS), 1996-1998. Pediatrics 2000;106(4):E52.

Begg 1994 Begg CB, Mazumdar M. Operating characteristics of a rank correlation 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 analysis. 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). Morbidity and 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 update: 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 Systematic 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.

Egger 1997 Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis 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 hepatitis 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. Transactions 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 universal infant vaccination against hepatitis B virus using a combination vaccine (Hib-HepB): a decision analytic approach to cost effectiveness. Australian and New Zealand Journal of Public Health 2001;25 (3):222–9.


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Hayashi 1996 Hayashi K, Walker AM. Japanese and American reports of randomized 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 Virology 2002;66(3):304–11. [MEDLINE: 11793381]. Higgins 2002 Higgins JPT, Thompson SG. Quantifying heterogeneity in a metaanalysis. Statistics in Medicine 2002;21:1539–58. ICH 1997 International Conference on Harmonisation Expert Working Group. Code of Federal Regulations & International Conference on Harmonization 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 quality 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 recombinant 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 prophylaxis for newborns of hepatitis B surface antigen-positive mothers. (Protocol) The Cochrane Database of Systematic Reviews 2004, Issue 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. The Pediatric 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 immunization of newborns with hepatitis B vaccine in Jinan City (Chinese). Zhonghua Liu Xing Bing Xue Za Zhi 1995;16(2):81–4.

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. Dynamics 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 vaccination of neonates and infants: emerging safety data from the Vaccine Adverse Event Reporting System. The Pediatric Infectious Disease Journal 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 controlled 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. Costeffectiveness analysis of prenatal screening and vaccination against hepatitis B virus - the case of Belgium. Social Society of Medicine 1993; 37(2):173–81.

MacGregor 2004 MacGregor IR. Screening assays for transmissible spongiform encephalopathies (TSEs). Vox Sanguinis 2004;87 Suppl 2:3–6.

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).

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.

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.


16

Yao 1996 Yao JL. Perinatal transmission of hepatitis B virus infection and vaccination 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 interruption of HBV transmission in uterus. Chinese Medical Journal 1997;110(2):145–7. ∗

Indicates the major publication for the study

TABLES

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

Notes

HBsAg Anti-HBs Anti-HBc 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:


17

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.


B – Unclear


18

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).


19

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)


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

Outcomes Notes

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. Hepatitis events at maximum follow-up. HBsAg. HBeAg and anti-HBs. Follow-up time: 12 months. Adverse events: not reported. Four infants were lost to follow-up.


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.


20

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.


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.

Adverse events: not reported.

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

Outcomes Notes

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. Number of HBsAg positive children in each group. Anti-HBs level. Follow-up time: 12 months.


21

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. 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.


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.


22

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.


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.


23

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).


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.


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.


B – Unclear


24


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


25

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.


A – Adequate


26


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.


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.


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.


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


27


Anti-HBc 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.


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.


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,


28

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.


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.


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.


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)+ HB-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)+ EngerixB 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)


29

Characteristics of included studies (Continued ) Group G (HBeAg- mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ H-B-VAX II 5 microgram(2)+ HB-VAX II 5 microgram(6) Outcomes

HBsAg, HBeAg, Anti-HBs by radioimmunoassay.

Notes

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


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.

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


B – Unclear

Study

Lee 1995 CB

Methods



B – Unclear

Study

Lee 1995 DE

Methods



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.


30

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.


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.


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.


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.


31

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.


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.


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.


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


32

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

Notes

HBsAg HBeAg Anti-HBc Anti-HBs 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.


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.


33

Characteristics of included studies (Continued ) Group F: 10 microgram PDV at birth, 1 and 2 months. Outcomes

Notes

HBsAg HBeAg Anti-HBs Follow-up time: 12 months. Adverse effects: none was observed during the surveillance period.


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.


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.


A – Adequate


34


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


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 Notes

HBsAg Anti-HBc Follow-up time: 12 months. Adverse events: neither local nor systemic reactions were observed after immunisation.


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

Notes

GMT (anti-HBs) seroconversion rate HBsAg Anti-PreS2 Anti-HBc 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.


B – Unclear

Study

Pongpipat 1989

Methods

Generation of allocation sequence: unclear - not described.


35

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.


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


36


Follow-up time: 60 months. Adverse events: not reported. Only the data in Group C and D were used for analysis.


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.


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


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.


B – Unclear

Adverse events: not reported


37


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

Notes

HBsAg Anti-HBs GMT seroconversion rate. Follow-up time: 4, 6, 12 and 13 months Adverse events: not reported.


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.


38

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.


B – Unclear

Study

Xu 1995 BD

Methods



B – Unclear

Study

Xu 1995 CB

Methods



B – Unclear

Study

Xu 1995 CD

Methods



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.


39

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

Notes

HBsAg HBeAg Anti-HBs Anti-HBc Anti-HBe 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.


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.


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.


40

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

Notes

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


Da 1995


Delage 1993


Esteban 1986


Goh 1992

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

Kang 1986


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


Lin 1987


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


Moulia-Pelat 1994

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


41

Characteristics of excluded studies (Continued ) Nair 1984


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


Poovorawan 1989


Poovorawan 1990


Shikata 1984


Stevens 1987


Stevens 1988


Stevens 1990


Stevens 1992


Surya 1996


Suwignyo 1994


Theppisai 1988


Theppisai 1989


Wheeley 1991


Young 2003


Yuen 1999

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

Zanetti 1986


Zhu 2003

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

ADDITIONAL TABLES

Table 01. Search strategies Database

Period

The Cochrane Hepato-Biliary Group Controlled Until February 2004 Trials Register

Search strategy 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


42

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 metaanalysis #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 metaanalysis #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


43

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 metaanalysis #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,


44

Table 02. Intervention by group Trial

(Continued ) 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.


45

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 Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

46

Table 02. Intervention by group

(Continued )

Trial

Intervention group

Control group

groups. HBeAg-negative mothers in F and G group.

ANALYSES

Comparison 01. Vaccine versus placebo or no intervention Outcome title

No. of studies

No. of participants

5

403

Relative Risk (Fixed) 95% CI

0.28 [0.20, 0.40]

5

403


0.28 [0.20, 0.40]


Subtotals only

01 Hepatitis B events according to type of vaccine 02 Hepatitis B events according to methodological quality 03 Hepatitis B events - Sensitivity analyses 04 Hepatitis B events according to the mother’s HBeAg status 05 Hepatitis B events according to first time of vaccine administration

Statistical method

Effect size

7

403


0.29 [0.20, 0.41]

5

403


0.28 [0.20, 0.40]

No. of studies

No. of participants

5 5

382 382

Comparison 02. RV versus PDV Outcome title 01 Hepatitis B events 02 Hepatitis B events according to methodological quality 03 Hepatitis B events - sensitivity analyses 04 Hepatitis B events according to the mother’s HBeAg status 05 Anti-HBs less than 10 IU/L

Statistical method

Effect size

Relative Risk (Fixed) 95% CI Relative Risk (Fixed) 95% CI

1.00 [0.70, 1.42] 1.00 [0.70, 1.42]


Subtotals only

5

382


1.00 [0.70, 1.42]

4

256


0.51 [0.36, 0.72]

Comparison 03. High-dose versus low-dose vaccine Outcome title 01 Hepatitis B events 02 Hepatitis B events according to methodological quality 03 Hepatitis B events - sensitivity analyses 04 Hepatitis B events according to the mother’s HBeAg status

No. of studies

No. of participants

5 5

582 582

5

582

Statistical method

Effect size


0.91 [0.57, 1.46] 0.91 [0.57, 1.46]


Subtotals only


0.91 [0.57, 1.46]


47

05 Anti-HBs less than 10 IU/L

2

166


1.02 [0.82, 1.27]

Comparison 04. Three-dose PDV plus HBIG versus two-dose PDV plus HBIG Outcome title 01 Hepatitis B events 02 Anti-HBs less than 10 IU/L

No. of studies 1 1

No. of participants 74 74

Statistical method Relative Risk (Fixed) 95% CI Relative Risk (Fixed) 95% CI

Effect size 0.50 [0.05, 5.28] 0.05 [0.00, 0.78]

Comparison 05. PDV at birth versus PDV at one month Outcome title 01 Hepatitis B events

No. of studies 1

No. of participants 108

Statistical method Relative Risk (Fixed) 95% CI

Effect size 0.70 [0.18, 2.77]

Comparison 06. One type of PDV versus another type of PDV Outcome title 01 Hepatitis B events

No. of studies 1



Effect size 0.50 [0.22, 1.15]

Comparison 07. Four RV vaccinations versus three RV vaccinations Outcome title 01 Hepatitis B events 02 Anti-HBs level less than 10 IU/L

No. of studies 1 1



Effect size 1.49 [0.51, 4.37] 0.53 [0.10, 2.77]

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

No. of studies

No. of participants

01 Hepatitis B events 02 Anti-HBs less than 10 IU/L


Effect size Subtotals only Subtotals only

Comparison 09. HBIG versus placebo or no intervention Outcome title 01 Hepatitis B events 02 Hepatitis B events according to methodological quality of the trials 03 Hepatitis B events - sensitivity analyses 04 Hepatitis B events according to the mother’s HBeAg status 05 Hepatitis B events according to time of HBIG administration 06 Hepatitis B events according to standard and rapid schedule of vaccines

No. of studies 14 14


Statistical method

Effect size


0.52 [0.44, 0.63] 0.52 [0.44, 0.63]


Subtotals only

15

1086


0.52 [0.44, 0.63]

14

1086


0.52 [0.44, 0.63]

9

711


0.53 [0.39, 0.74]


48

07 Anti-HBs less than 10 IU/L 08 Anti-HBs level 09 Adverse events

4

348

1

136

Relative Risk (Fixed) 95% CI Weighted Mean Difference (Fixed) 95% CI Relative Risk (Fixed) 95% CI

1.55 [0.89, 2.73] Subtotals only 3.47 [0.14, 83.67]

Comparison 10. Multiple HBIG plus PDV versus single HBIG plus PDV Outcome title 01 Hepatitis B events

No. of studies 2



Effect size 0.87 [0.30, 2.47]

Comparison 11. PDV plus HBIG versus placebo or no intervention Outcome title 01 Hepatitis B events 02 Hepatitis B events according to methodological quality of the trials 03 Hepatitis B events - sensitivity analyses 04 Hepatitis B events according to mother’s HBeAg status 05 Hepatitis B events according to time of HBIG administration 06 Adverse events

No. of studies 4 4


Statistical method

Effect size


0.08 [0.03, 0.17] 0.08 [0.03, 0.17]


Subtotals only

5

246


0.08 [0.04, 0.18]

4

246


0.08 [0.03, 0.17]

2

105


0.29 [0.07, 1.13]

INDEX TERMS 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

COVER SHEET Title

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

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.


49

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


Date new studies found but not yet included/excluded


Date new studies found and included/excluded

01 February 2004

Date authors’ conclusions section amended


Contact address

Dr Yan Gong Copenhagen Trial Unit Centre for Clinical Intervention Research, Copenhagen University Hospital Dept. 7102, Blegdamsvej 9 H:S Rigshospitalet Copenhagen DK-2100 DENMARK E-mail: [email protected] Tel: +45 3545 7161 Fax: +45 3545 7101

DOI

10.1002/14651858.CD004790.pub2

Cochrane Library number

CD004790

Editorial group

Cochrane Hepato-Biliary Group

Editorial group code

HM-LIVER


50

Analysis 01.01. Review:

GRAPHS AND OTHER TABLES Comparison 01 Vaccine versus placebo or no intervention, Outcome 01 Hepatitis B events according to type of vaccine

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 ]

182

120

Subtotal (95% CI)

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