Hepatitis B Immunisation for Newborn Infants of Hepatitis B Surface Antigen-Positive Mothers (Review)

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) 1 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd TABLE OF CONTENTS

ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 BACKGROUND ...... 2 OBJECTIVES ...... 2 CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW ...... 2 SEARCH METHODS FOR IDENTIFICATION OF STUDIES ...... 3 METHODSOFTHEREVIEW ...... 3 DESCRIPTIONOFSTUDIES ...... 4 METHODOLOGICALQUALITY ...... 5 RESULTS...... 5 DISCUSSION ...... 7 AUTHORS’CONCLUSIONS ...... 8 NOTES...... 8 POTENTIALCONFLICTOFINTEREST ...... 8 ACKNOWLEDGEMENTS ...... 8 SOURCESOFSUPPORT ...... 9 REFERENCES ...... 9 TABLES ...... 17 Characteristics of included studies ...... 17 Characteristics of excluded studies ...... 41 ADDITIONALTABLES...... 42 Table01.Searchstrategies...... 42 Table 02. Intervention by group ...... 44 ANALYSES ...... 47 Comparison 01. Vaccine versus placebo or no intervention ...... 47 Comparison02.RVversusPDV ...... 47 Comparison 03. High-dose versus low-dose vaccine ...... 47 Comparison 04. Three-dose PDV plus HBIG versus two-dose PDV plusHBIG ...... 48 Comparison 05. PDV at birth versus PDV at one month ...... 48 Comparison 06. One type of PDV versus another type of PDV ...... 48 Comparison 07. Four RV vaccinations versus three RV vaccinations ...... 48 Comparison 08. One type of RV versus another type of RV with the same vaccination schedule ...... 48 Comparison 09. HBIG versus placebo or no intervention ...... 48 Comparison 10. Multiple HBIG plus PDV versus single HBIG plusPDV ...... 49 Comparison 11. PDV plus HBIG versus placebo or no intervention ...... 49 INDEXTERMS ...... 49 COVERSHEET ...... 49 GRAPHSANDOTHERTABLES ...... 51 Analysis 01.01. Comparison 01 Vaccine versus placebo or no intervention, Outcome 01 Hepatitis B events according to 51 typeofvaccine ...... Analysis 01.02. Comparison 01 Vaccine versus placebo or no intervention, Outcome 02 Hepatitis B events according to 52 methodologicalquality...... Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events - Sensitivity 53 analyses...... Analysis 01.04. Comparison 01 Vaccine versus placebo or no intervention, Outcome 04 Hepatitis B events according to 55 themother’sHBeAgstatus ...... Analysis 01.05. Comparison 01 Vaccine versus placebo or no intervention, Outcome 05 Hepatitis B events according to 56 ﬁrst time of vaccine administration ...... Analysis 02.01. Comparison 02 RV versus PDV, Outcome 01 HepatitisBevents ...... 57 Analysis 02.02. Comparison 02 RV versus PDV, Outcome 02 Hepatitis B events according to methodological quality 58 Analysis 02.03. Comparison 02 RV versus PDV, Outcome 03 Hepatitis B events - sensitivity analyses ...... 59

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) i Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mother’s HBeAg status 61 Analysis 02.05. Comparison 02 RV versus PDV, Outcome 05 Anti-HBslessthan10IU/L ...... 62 Analysis 03.01. Comparison 03 High-dose versus low-dose vaccine, Outcome 01 Hepatitis B events ...... 62 Analysis 03.02. Comparison 03 High-dose versus low-dose vaccine, Outcome 02 Hepatitis B events according to 63 methodologicalquality...... Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events - sensitivity analyses 64 Analysis 03.04. Comparison 03 High-dose versus low-dose vaccine, Outcome 04 Hepatitis B events according to the 66 mother’sHBeAgstatus...... Analysis 03.05. Comparison 03 High-dose versus low-dose vaccine, Outcome 05 Anti-HBs less than 10 IU/L . . . 67 Analysis 04.01. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 01 Hepatitis 67 Bevents...... Analysis 04.02. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 02 Anti-HBs 68 lessthan10IU/L ...... Analysis 05.01. Comparison 05 PDV at birth versus PDV at one month, Outcome 01 Hepatitis B events . . . . 68 Analysis 06.01. Comparison 06 One type of PDV versus another type of PDV, Outcome 01 Hepatitis B events . . 69 Analysis 07.01. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 01 Hepatitis B events . 69 Analysis 07.02. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 02 Anti-HBs level less 70 than10IU/L...... Analysis 08.01. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule, Outcome 70 01HepatitisBevents ...... Analysis 08.02. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule, Outcome 71 02Anti-HBslessthan10IU/L...... Analysis 09.01. Comparison 09 HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events . . . . 71 Analysis 09.02. Comparison 09 HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events according to 73 methodological quality of the trials ...... Analysis 09.03. Comparison 09 HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events - sensitivity 74 analyses...... Analysis 09.04. Comparison 09 HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events according to 77 themother’sHBeAgstatus ...... Analysis 09.05. Comparison 09 HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events according to 78 time of HBIG administration ...... Analysis 09.06. Comparison 09 HBIG versus placebo or no intervention, Outcome 06 Hepatitis B events according to 79 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 . 80 Analysis 09.08. Comparison 09 HBIG versus placebo or no intervention, Outcome 08 Anti-HBs level . . . . . 81 Analysis 09.09. Comparison 09 HBIG versus placebo or no intervention, Outcome 09 Adverse events . . . . . 81 Analysis 10.01. Comparison 10 Multiple HBIG plus PDV versus single HBIG plus PDV, Outcome 01 Hepatitis B 82 events ...... Analysis 11.01. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events 82 Analysis 11.02. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events 83 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 - 84 sensitivityanalyses ...... Analysis 11.04. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events 85 according to mother’s HBeAg status ...... Analysis 11.05. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events 86 according to time of HBIG administration ...... Analysis 11.06. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 06 Adverse events . . 87

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) ii Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 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 HBsAg- positive mothers. Search strategy Trials were identified through The Cochrane Neonatal Group Controlled Trials Register, The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled 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 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 positive mothers.

Hepatitis B virus is a global acute and chronic communicable disease that causes major hepatic disease, with an estimated 350 mil- CRITERIAFORCONSIDERING lion people infected (Beasley 1984). Mother to child transmission STUDIESFORTHISREVIEW occurs frequently either in uterus (when the baby is still in the womb), through placental leakage, or through exposure to blood Types of studies or blood contaminated fluids at or around the time of birth. Such perinatal transmission is believed to account for 35% to 50% of We included randomised clinical trials, irrespective of blinding, hepatitis B carriers (Yao 1996). The risk of perinatal transmission publication status, or language. is associated with the HBeAg status of the mother. If the mother is both HBsAg and HBeAg positive, 70% to 90% of the children Types of participants become chronically infected (Stevens 1975; Akhter 1992). If the We included newborn infants of either gender born to HBsAg- mother is HBsAg positive but HBeAg negative, the risk is signifi- positive mothers. The immunisation should start within the first cantly reduced (Okada 1976; Beasley 1977; Beasley 1983b; Nayak month of life. 1987; Aggarwal 2004). Types of intervention Two types of vaccines have been licensed. One is derived from The following analyses were performed: human plasma (plasma-derived vaccine (PDV)) and the other is derived from DNA recombinant technology (recombinant vac- • PDV or RV versus placebo or no intervention. cine (RV)) from yeast or mammalian cells (Assad 1999). Repeated • injections over months are required to mount an effective anti- Hepatitis B immunoglobulin versus placebo or no intervention. body response with vaccination. Hepatitis B immunoglobulin is • PDV or RV plus hepatitis B immunoglobulin versus placebo, an immune globulin, which contains a high level of antibody to no intervention, PDV, or RV. hepatitis B surface antigen (anti-HBs). Hepatitis B immunoglobulin is considered immediately effective and seems protective for Types of outcome measures several months after which it wanes (Beasley 1983; Nair 1984). All outcomes were assessed at maximal follow-up.

We have been unable to identify meta-analyses or systematic re- Primary outcome views on hepatitis B immunisation for newborn infants of HB- (1) Hepatitis B occurrence: blood specimen positive for HBsAg, sAg positive mothers. A narrative review regarding the efficacy of HBeAg, or antibody to hepatitis B core antigen (anti-HBc). hepatitis B vaccine in neonates (Andre 1994) and several international guidelines (CDC 1999; WHO 2002) have been published. Secondary outcomes However, they do not represent systematic reviews containing an (2) Number of newborn infants with anti-HBs less than 10 IU/L, assessment of the methodological quality of the trials and present- which is considered insufficient to prevent hepatitis B virus infec- ing original data. tion (Szmuness 1981; Hadler 1986). (3) Anti-HBs, either expressed as geometric mean titre (GMT) or mean titre. OBJECTIVES (4) Systemic adverse events: adverse events such as malaise, nausea, fever, arthralgia, rash, after each injection of vaccine. To assess the beneficial and harmful effects of hepatitis B vaccine (5) Local adverse events: adverse events such as pain, redness, and hepatitis B immunoglobulin in newborn infants of HBsAg- swelling, and/or myalgia at the site after each injection of vaccine.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 2 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (6) Any adverse events: adverse events including local adverse Methodological quality events and/or systemic adverse events. The adverse events are di- Methodological quality is defined as the confidence that the vided into severe and non-severe. A severe adverse event, accord- design and report restrict bias in the intervention comparison ing to the International Committee on Harmonisation Guidelines (Moher 1998; Kjaergard 2001). Due to the risk of overestimation (ICH 1997) is any event that would increase mortality; is life- of intervention effects in randomised trials with inadequate threatening; requires inpatient hospitalisation; results in a persis- methodological quality (Schultz 1995; Moher 1998; Kjaergard tent or significant disability; or any important medical event which 2001), the methodological quality was assessed by using the may jeopardise the patient or requires intervention to prevent it. following criteria: All other adverse events are considered non-severe. Generation of the allocation sequence (7) Cost-effectiveness. • Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing SEARCH METHODS FOR of a coin, shuffling of cards, or throwing dice was considered IDENTIFICATIONOFSTUDIES as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure. See: Cochrane Hepato-Biliary Group methods used in reviews. • Unclear, if the trial was described as randomised, but the method We searched The Cochrane Neonatal Group Controlled Trials used for the allocation sequence generation was not described. Register, The Cochrane Hepato-Biliary Group Controlled • Inadequate, if a system involving dates, names, or admittance Trials Register, The Cochrane Central Register of Controlled numbers were used for the allocation of patients. Such quasi- Trials(CENTRAL) in The Cochrane Library, MEDLINE/PubMed, randomised studies were excluded. and EMBASE. The search strategies and time span of the searches are specified in Table 01. We consulted with The Allocation concealment Cochrane Vaccines Field to identify further trials, but no reply • Adequate, if the allocation of patients involved a central was received. We read the bibliographies of retrieved articles independent unit, on-site locked computer, identically to identify further trials. We checked the reference lists of appearing numbered drug bottles or containers prepared by an relevant articles for any new trials. We wrote to the principal independent pharmacist or investigator, or sealed envelopes. authors of the identified trials and the pharmaceutical companies (SmithKline Beecham and Merck, Sharp & Dohme; GreenCross • Unclear, if the trial was described as randomised, but the method Vaccine; GlaxoSmithKline; Pasteur; and Abbott) involved in the used to conceal the allocation was not described. production of hepatitis B vaccines for missing information and • Inadequate, if the allocation sequence was known to the additional published or unpublished trials. investigators who assigned participants. Blinding (or masking) METHODSOFTHEREVIEW • Adequate, if the trial was described as double blind and the method of blinding involved identical placebo or active drugs. Selection of trials for inclusion CL made the decisions on which trials to be included, and the • Unclear, if the trial was described as double blind, but the selection was validated by YG, JB, and CG. We were unblinded method of blinding was not described. with regard to the names of the authors, investigators, institutions, • Not performed, if the trial was not double blind. and results. Excluded trials were identified and listed with the reasons for exclusion. Follow-up Data extraction • Adequate, if the numbers and reasons for dropouts and CL, YG, and JB independently extracted the data from the withdrawals in all intervention groups were described or if it included randomised trials. We wrote to the authors of trials if was specified that there were no dropouts or withdrawals. data were missing in the report. • Unclear, if the report gave the impression that there had been We extracted: primary author; number of participants; no dropouts or withdrawals, but this was not specifically stated. inclusion and exclusion criteria; HBeAg status of the mother; • Inadequate, if the number or reasons for dropouts and methodological quality (see below); dosage and types of vaccines; withdrawals were not described. site of injection; vaccination schedules; duration of follow-up; outcome measures; and number and type of adverse events in the We post hoc defined high-quality trials when at least two out of intervention and the control groups. the three quality components were adequate: generation of the

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 3 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd allocation sequence, allocation concealment, and blinding. This DESCRIPTION OF STUDIES was due to the fact that only a single trial had high quality regarding all three components. We identified 226 references, but 186 were clearly irrelevant references. The remaining 40 references describing 29 randomised tri- Statistical methods als were included. Twenty-eight trials were published as full paper Review Manager 4.2. was used to perform meta-analyses. Data articles and one trial was published as an abstract. We were not were analysed by both a random-effects model (DerSimonian able to extract relevant data according to our outcome measures 1986) and a fixed-effect model (DeMets 1987). If the results of from three trials (Yeoh 1986; Zhu 1987; Grosheide 1993). Ex- both analyses gave the same overall results regarding significance, cluded studies are listed under ’Characteristics of excluded studies’ only the results of the fixed-effect model analysis was reported. with reasons for exclusion. The immunisation doses and schedules We presented binary outcome measure as relative risks (RR) with in the included trials varied substantially as described below. The 95% confidence interval (CI), and continuous outcome measure capital letters in the references refer to the intervention arms of as weighted mean difference (WMD) with 95% CI. Heterogeneity the trial as described in ’Table of included studies’. was explored by chi-squared test with significance set at P < 0.10 Vaccine versus placebo or no intervention and the quantity of heterogeneity was measured by I2 (Higgins The dose of vaccine used was 3 microgram (Ip 1989 CD), 16 2002). microgram (Xu 1995 AD), or 20 microgram (Liu 1987 AB; Xu 1995 BD). The vaccination schedules were 0-1-6 months (Liu Meta-regression analysis was performed by STATA®on hepatitis 1987 AB; Xu 1995 AD/Xu 1995 BD), 0-1-2-6 months (Ip 1989 B occurrence, when more than 10 trials were included. Meta- CD), or 0-1-2-14 months (Khukhlovich 1996). regression analysis examined the intervention effect in relation to methodological quality of trials, dosage of hepatitis B RV versus PDV immunoglobulin and vaccine, and time of immunisation. The dose of vaccines was 5 microgram (Lee 1995 AB/Lee 1995 CB), 10 microgram (Pongpipat 1989), or 20 microgram (Halli- Subgroup analyses were performed to compare the effects of day 1992 AB; Zhu 1994). The vaccination schedules were 0-1-6 vaccines in mothers with HBsAg (+)/HBeAg(+) compared to months (Pongpipat 1989; Halliday 1992 AB; Zhu 1994) or 0-1- HBsAg (+)/HBeAg(-), doses (high-dose versus low-dose), as well 2-12 months (Lee 1995 AB/Lee 1995 CB). as methodological quality of the trials (high-quality versus low- quality). The difference between the estimates of two subgroups High-dose vaccine versus low-dose vaccine was estimated according to Altman 2003. The doses of PDV were 10 microgram, 5 microgram, and 2 microgram (Oon 1986 AB, Oon 1986 CD, Pongpipat 1988; Thep- Regarding the hepatitis B occurrence, we included newborn pisai 1990). The doses of RV were 20 microgram and 10 micro- infants with incomplete or missing data in the sensitivity analyses gram (Halliday 1992 DC). The vaccination schedules were 0-1-6 by imputing them in the following analyses (the last four being months (Halliday 1992 DC), 0-1-2 months (Oon 1986 AB/Oon intention-to-treat analyses): 1986 CD), or 0-1-2-12 months (Pongpipat 1988).

• Available data analysis: data on only those whose results are Three-dose PDV plus hepatitis B immunoglobulin versus two- known, using the total number of patients who completed the dose PDV plus hepatitis B immunoglobulin trial as denominator; One trial assessed three-doses PDV plus hepatitis B immunoglobulin versus two-doses PDV plus hepatitis B immunoglobulin (Pi- • Assuming poor outcome: dropouts in both experimental and azza 1985). Both groups were given hepatitis B immunoglobulin control group had the primary outcome; 50 IU at birth, then 5 microgram PDV within ﬁve days and at two months. The experimental group was given an additional PDV at • Assuming good outcome: none of the dropouts in the one month. experimental and control group had the primary outcome; PDV at birth versus PDV at one month • Extreme case favouring experimental intervention: none of the One trial assessed 20 microgram PDV at 0-1-6 months versus 20 dropouts in the experimental group but all in the control group microgram PDV at 1-2-7 months (Beasley 1983b). Both groups had the primary outcome; were given hepatitis B immunoglobulin 145 IU at birth. • Extreme case favouring control intervention: all dropouts from One type of PDV versus another type of PDV the experimental group but no controls had primary outcome. One trial assessed different types of PDV (PDV1(NIAID) versus PDV2 (BIVS) (Xu 1995 AB). The dose was 16 microgram of We used funnel plot to provide a visual assessment of whether PDV1 and 20 microgram of PDV2. The schedules were 0-1-6 treatment estimates are associated with study size. We explored months. publication bias and other bias according to Begg’s and Egger’s methods (Begg 1994; Egger 1997). Four RV vaccinations versus three RV vaccinations

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 4 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd One trial assessed four RV vaccinations (0-1-2-12 months) versus A number of trials had several intervention arms. For details of three RV vaccinations (0-1-6 months) (Lolekha 2002). The dose the included trials, we provided Table 02 by listing the relevant of each RV was 5 microgram. comparisons and which trials assessed this comparison. The capital letters after years of publication in the references stands for the One RV versus another RV with the same vaccination schedule comparison arms of the individual trial. Two trials assessed different types of RV (RV1(Beijing, China) versus RV2 (Institute of Preventive Medicine, China) (Kang 1995) Mother’s HBeAg status and one trial assessed Cuban versus Engerix-B (Galban 1992). Two Eighteen trials included only mothers, who were HBeAg positive. trials assessed different types of RV plus hepatitis B immunoglob- Three trials included mothers who were HBeAg positive or neg- ulin (Hepavax-Gene versus Engerix-B (Hieu 2002) and HB-VAX ative (Lee 1995 AB; Oon 1986 AB; Xu 1995 AB), and in eight II versus Engerix-B (Lee 1995 CA/Lee 1995 DE). The doses of trials mother’s HBeAg status was not reported. RV were 5 versus 10 microgram (Lee 1995 CA/Lee 1995 DE), Newborn’s birthweight 10 versus 10 microgram (Hieu 2002), or 20 versus 20 microgram Ten trials reported exclusion of low-birth-weight newborn infants. (Kang 1995). The vaccination schedules were 0-1-6 months (Kang The limits for exclusion varied from 1600 to 3000 gram. The re- 1995; Hieu 2002) or 0-1-2-12 months (Lee 1995 CA/Lee 1995 maining 19 trials did not report any birth weight exclusion crite- DE). ria. The average duration of follow-up was 19 months (range 6 to Hepatitis B immunoglobulin versus placebo or no interven- 60 months). tion The doses of hepatitis B immunoglobulin ranged from 90 to 260 IU. Hepatitis B immunoglobulin was administered within 12 METHODOLOGICALQUALITY 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 Generation of the allocation sequence was adequate in six trials BC; Halliday 1992 CA; Xu 1995 CB; Poovorawan 1997), within (Piazza 1985; Oon 1986 AB/Oon 1986 CD; Farmer 1987; Hal- 24 hours in three trials (Farmer 1987; Sehgal 1992; Assateerawatt liday 1992 AB/Halliday 1992 CA/Halliday 1992 DC; Assateer- 1993), or within 48 hours in one trial (Liu 1987 CA). The vacci- awatt 1993; Hieu 2002). nation schedules were 0-3-6 months (Beasley 1983a AB/Beasley Treatment allocation was adequately concealed in six trials (Ip 1983a CB), 0-6 weeks-6 months (Farmer 1987), 0-1-6 months 1989 AD/Ip 1989 BD/Ip 1989 CD; Piazza 1985; Liu 1987 (Ip 1989 AC/Ip 1989 BC; Theppisai 1987; Xu 1995 CB), 0-1-2- AB/Liu 1987 CA/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 6 months ( Liu 1987 CA), 0-2-6-10 weeks (Lo 1985 AB/Lo 1985 CA/Halliday 1992 DC; Grosheide 1993; Hieu 2002). CB), and 0-4-8 weeks (Sehgal 1992). Adequate method of double blinding was reported in three trials (Ip 1989 AD/Ip 1989 BD/Ip 1989 CD; Liu 1987 AB/Liu 1987 Multiple hepatitis B immunoglobulin versus single hepatitis CA/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/Halliday B immunoglobulin 1992 DC). One trial compared 5 microgram PDV at 2-6-10 weeks plus 50 IU According to our criteria, we classified five trials as high quality tri- hepatitis B immunoglobulin at birth with or without additional als (Ip 1989 AD/Ip 1989 BD/Ip 1989 CD; Piazza 1985; Liu 1987 hepatitis B immunoglobulin at 1 month (Lo 1985 CA). One trial AB/Liu 1987 CB; Halliday 1992 AB/Halliday 1992 CA/Halliday compared 3 microgram PDV at 1-2-6 months plus 200 IU hep- 1992 DC; Hieu 2002). atitis B immunoglobulin at birth with or without additional hep- The numbers and reasons for dropouts and withdrawals were ad- atitis B immunoglobulin at 1-2-3-4-5-6 months (Ip 1989 AB) equately reported in six trials (Beasley 1983a AB/Beasley 1983a CB/Beasley 1983b; Piazza 1985; Theppisai 1987; Halliday 1992 PDV plus hepatitis B immunoglobulin versus placebo or no AB/Halliday 1992 CA/Halliday 1992 DC; Grosheide 1993). intervention One trial compared 200 IU hepatitis B immunoglobulin at 0-1-2- 3-4-5-6 months plus 3 microgram PDV at 0-1-2-6 months versus 200 IU hepatitis B immunoglobulin at birth plus 3 microgram RESULTS 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 Hepatitis B vaccines versus placebo or no intervention (Com- plus hepatitis B immunoglobulin at birth with placebo (Liu 1987 parison 01-01 to 01-05) CB). One trial compared 20 microgram PDV at 0-1-6 months Compared with placebo/no intervention, hepatitis B vaccination plus 250 IU hepatitis B immunoglobulin at birth versus placebo significantly decreased the risk of hepatitis B occurrence (RR 0.28, (Xu 1995 CD). Hepatitis B immunoglobulin was given within 12 95% CI 0.20 to 0.40, 4 trials). The analysis showed heterogeneity hours (Ip 1989 AD/Ip 1989 BD), or within 24 hours (Xu 1995 (P = 0.07, I2 = 54.2%). The results of sensitivity analyses regarding CD), and within 48 hours (Liu 1987 CB). dropouts were consistent. Analyses of PDV and RV individually

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 5 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd showed that both vaccines significantly decreased the risk of hep- Four-dose RV vaccination versus three-dose RV vaccination atitis B occurrence. (Comparison 07-01 to 07-02) One trial (Lolekha 2002) compared one type of RV with four vac- Subgroup analyses did not find a significant difference between cinations (0-1-2-12 months) versus the same RV with three vacci- high- and low-quality trials, the mother’s HBeAg status, or time of nations (0-1-6 months). No significant differences were found on vaccine injection (tests of interaction, P = 0.25, 0.07, and 0.11, re- hepatitis B occurrence (RR 1.49, 95% CI 0.51 to 4.37) or anti- spectively). Post hoc subgroup analysis according to vaccine sched- HBs level less than 10 IU/L (RR 0.53, 95% CI 0.10 to 2.77). ules (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 ad- One type of RV versus another type of RV with the same vac- verse events were reported. cination schedule (Comparison 08-01 to 08-02) Different RV in terms of various manufacturers were assessed and RV versus PDV (Comparison 02-01 to 02-05) no significant differences were found on hepatitis B occurrence or We found no significant difference between RV and PDV on hep- anti-HBs less than 10 IU/L. atitis B occurrence (RR 1.00, 95% CI 0.70 to 1.42, 4 trials). Het- erogeneity was moderate (I2 = 29.4%). The results of sensitiv- Hepatitis B immunoglobulin versus placebo or no interven- ity analyses regarding dropouts confirmed the finding. Subgroup tion (Comparison 09-01 to 09-08) analyses did not find a significant difference regarding the method- Overall, hepatitis B immunoglobulin significantly decreased the ological quality or the mother’s HBeAg status (both tests of inter- risk of hepatitis B occurrence in newborn infants (RR 0.52, 95% action, P = 0.21). CI 0.44 to 0.63, 11 trials). Compared with placebo/no intervention, hepatitis B immunoglobulin alone significantly reduced hep- Significantly fewer newborn infants on RV compared to PDV had atitis B occurrence (RR 0.50, 95% CI 0.41 to 0.60, 1 trial). Com- anti-HBs less than 10 IU/L (RR 0.51, 95% CI 0.36 to 0.72, 3 pared with vaccination, vaccination plus hepatitis B immunoglob- trials). ulin was likewise superior (RR 0.54, 95% CI 0.41 to 0.73, 10 trials). The sensitivity analyses regarding dropouts were consistent, High-dose versus low-dose vaccine (Comparison 03-01 to 03- indicating the robustness of the findings. In the meta-regression 05) analyses, none of the trial characteristics (methodological qual- We found no statistical difference on hepatitis B occurrence com- ity, dosage of hepatitis B immunoglobulin, or time of hepatitis B paring high-dose versus low-dose vaccine (PDV: RR 0.97, 95% CI immunoglobulin injection) was significantly associated with the 0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial). effect of hepatitis B immunoglobulin (P = 0.92, 0.67, and 0.79, There was no significant difference between high-dose versus low- respectively). Subgroup analyses did not find a significant differ- dose vaccine on anti-HBs less than 10 IU/L (RR 1.02, 95% CI ence between high- and low-quality trials, the mother’s HBeAg 0.82, 1.27, 2 trials). status, or time of hepatitis B immunoglobulin injection (tests of Three-dose PDV versus two-dose PDV (Comparison 04-01 to interaction, P = 0.70, 0.62, and 0.63, respectively). 04-02) Hepatitis B immunoglobulin had no significant effect on the num- Three-dose PDV plus hepatitis B immunoglobulin did not sig- ber of newborn infants with anti-HBs level less than 10 IU/L (RR nificantly prevent hepatitis B occurrence compared with two-dose 1.55, 95% CI 0.89 to 2.73, 4 trials). PDV plus hepatitis B immunoglobulin (RR 0.50, 95% CI 0.05 to 5.28, 1 trial). However, three-dose PDV plus hepatitis B im- Few trials reported adverse events. If reported, the authors did not munoglobulin resulted in significantly less newborn infants who specify in which intervention group these events occurred. There- had anti-HBs less than 10 IU/L compared with two-dose PDV fore we were not able to perform a meta-analysis on adverse events. plus hepatitis B immunoglobulin (RR 0.05, 95% CI 0.00 to 0.78, In one trial (Beasley 1983a AB/Beasley 1983a CB), one infant 1 trial). receiving hepatitis B immunoglobulin died. The death appeared unrelated to hepatitis B immunoglobulin. PDV at birth versus PDV at one month (Comparison 05-01) PDV administered for the first time at birth did not significantly Neither the Egger’s nor the Begg’s graphs and their corresponding differ from PDV administered for the first time at one month of tests on hepatitis B occurrence provided evidence for asymmetry age regarding the number of newborn infants having hepatitis B (Egger’s test, P = 0.31; Begg’s test, P = 0.23). occurrence (RR 0.70, 95% CI 0.18 to 2.77, 1 trial). Multiple hepatitis B immunoglobulin versus single hepatitis One type of PDV versus another type of PDV (Comparison B immunoglobulin administration (Comparison 10-01) 06-01) Multiple hepatitis B immunoglobulin plus PDV versus single hep- One trial compared two different types of PDV and no significant atitis B immunoglobulin plus PDV did not significantly reduced difference was found in terms of hepatitis B occurrence (Xu 1995 the risk of hepatitis B occurrence (RR 0.87, 95% CI 0.30 to 2.47, AB). 2 trials) with no heterogeneity (I2 = 0%).

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 6 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd PDV plus hepatitis B immunoglobulin versus placebo or no (RR 1.96, 95% CI 1.39 to 2.78). The advantage of RV might be intervention (Comparison 11-01 to 11-06) due to the difference in chemical and physical characteristics of Compared with placebo/no intervention, PDV plus hepatitis B the antigens components of the vaccines (Heijtink 2002). RV is immunoglobulin significantly reduced hepatitis B occurrence (RR the vaccine used in high-income countries due to the fear of hu- 0.08, 95% CI 0.03 to 0.17, 3 trials). The sensitivity analyses con- man immuno-deficiency virus infection and other infections, in- firmed the robustness of the finding. Subgroup analyses did not cluding transmissible spongiform encephalopathies (MacGregor find a significant difference between high- and low-quality trials, 2004). Our finding seems to support the introduction of RVs in the mother’s HBeAg status, or time of hepatitis B immunoglob- clinical practice. ulin injection (tests of interaction, P = 0.13, 0.28, and 0.22, re- The recommended prevention regimen for immune prophylaxis spectively). varies among countries (David 1996; CDC 1999). Similarly in One trial reported the number of adverse events: 3 out of 71 infants our included trials, the reported doses and schedules varied sub- given vaccination versus 5 out of 34 in control group (Ip 1989 stantially (Table 02). In general, we were unable to demonstrate AD/Ip 1989 BD). The results showed no significant difference significant differences among different doses, different schedules, (0.29, 0.07 to 1.13) and different forms of PDV and RV on hepatitis B occurrence. Furthermore, our subgroup analyses did not show strong associa- tions between timing of injection (within 12, 24, or 48 hours) and DISCUSSION magnitude of effects. The number of newborn infants evaluated in these comparisons was small. Therefore, future trials ought to be Our systematic review demonstrates that hepatitis B vaccine, hep- much larger before equivalence or non-inferiority can be claimed. atitis B immunoglobulin, or the combination of vaccine plus hep- Our meta-analyses demonstrated that hepatitis B immunoglobu- atitis B immunoglobulin given to newborn infants of HBsAg-pos- lin alone or when added to hepatitis B vaccine significantly de- itive mothers prevent hepatitis B occurrence. Further, the combi- creased the risk of hepatitis B infection (RR 0.52, 95% CI 0.44 nation of vaccine plus hepatitis B immunoglobulin was superior to 0.63). A recent non-randomised study reported no benefit of to vaccine alone. These benefits were not significantly associated adding hepatitis B immunoglobulin to vaccine in HBeAg-negative with the methodological quality of the trials, the mother’s HBeAg mothers (Yang 2003). In our analysis, only one small trial out of 11 status, time of immunisation, or the number of infants dropping trials included newborn infants of HBeAg-negative mothers (Xu out. 1995 AB). Our subgroup analysis, not surprisingly, did not find Our review has several potential limitations. First, some analyses any statistically significant difference between newborn infants include few trials and a small number of newborn infants. Second, of HBeAg-negative and of HBeAg-positive mothers. Accordingly, most trials had low methodological quality. However, we did not more randomised trials on adding hepatitis B immunoglobulin find strong association between the methodological quality and to vaccine for newborn infants of HBeAg-negative mothers seem the trial results. This supports the robustness of our results, but warranted. It should be noticed that hepatitis B immunoglobulin, does not exclude the possibility of bias affecting our results (Schultz as PDV, has the potential of transmitting blood-borne infections 1995; Moher 1998; Kjaergard 2001; Als-Nielsen 2004). Third, (CDC 1991). although we did not find funnel plot asymmetries, we cannot ex- Few trials reported on adverse events. According to what has clude publication bias. Fourth, only few investigators responded been reported, hepatitis B vaccine and hepatitis B immunoglob- to our request for further information and often the information ulin seem safe. These results are in accordance with two recent was that the details were lost. Fifth, most trials only reported sur- Cochrane reviews on hepatitis B vaccination for dialysis patients rogate outcomes (HBsAg status or anti-HBs level) and not long- and health-care workers (Niu 1996; Chen 2005). Furthermore, term clinical outcomes. Of note is the fact that one trial with long- several cohort studies found that hepatitis B vaccination is well term follow-up found more patients with chronic hepatitis in the tolerated and severe adverse events are rare (ICH 1997; Niu 1999; PDV plus hepatitis B immunoglobulin group compared with the DuVernoy 2000; Kojouharova 2001; Lewis 2001; Bohlke 2003; PDV group (Ip 1989 AC). Such an increase of chronic hepatitis Deeks 2003). However, one cohort study found that vaccine in- could be due to contamination of hepatitis B immunoglobulin creased the risk of chronic arthritis and acute ear infections (Fisher with hepatitis C virus. 2001). We are unable to determine if this is a reliable finding due to Our results convincingly demonstrate that hepatitis B vaccination the methodological weakness of cohort studies (CDC 1999). On reduces hepatitis B infection in newborn infants of hepatitis B the other hand, randomised clinical trials may overlook adverse surface antigen-positive mothers. We found no significant differ- events due to relatively low numbers of participants and/or poor ence between RV and PDV on hepatitis B infections (RR 1.00, reporting of adverse events (Hayashi 1996; Ioannidis 2001; Etmi- 95% CI 0.70 to 1.42). However, a greater number of newborn nan 2004). Further trials ought to focus on these adverse events infants on PDV did not achieve anti-HBs level above 10 IU/L following ICH-GCP (ICH 1997).

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 7 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd The risk of perinatal transmission from HBeAg-negative moth- needed to treat to prevent a hepatitis B event is probably much ers is considered much lower than in HBeAg-positive mothers larger than in mothers who are both HBsAg and HBeAg positive. (Okada 1976). If infected, the newborn infants of HBeAg-neg- Implications for research ative mothers often clear an asymptomatic infection (Dusheiko 1998). Our findings are mainly based on immune prophylaxis for The potential adverse events related to hepatitis B prophylaxis newborn infants of mothers being HBsAg and HBeAg positive. should be studied further, especially the risk for ear infection and Evidence from randomised clinical trials is insufficient to either chronic arthritis. The new way of preventing hepatitis B prophy- support or refute immune prophylaxis for infants of hepatitis B laxis in newborn infants - the hepatitis B immunoglobulin ad- e antigen negative mothers. The applicability of our findings to ministration to the pregnant mother - need to be examined in mothers negative for HBeAg, which are of high proportions in eg, randomised clinical trials of high quality. The cost-effectiveness the States and northern Europe, is therefore limited (Funk 2002). of hepatitis B vaccination and hepatitis B immunoglobulin ought to be further evaluated based on results from randomised clini- Cost-effectiveness studies indicate that hepatitis B vaccination cal trials. Further trials need to examine the effects of hepatitis B for newborn infants of HBsAg-positive mothers are cost effec- vaccine and hepatitis B immunoglobulin in newborn infants of tive in countries with low (Bloom 1993; Tormans 1993; Da Villa HBsAg positive mothers who are HBsAg negative. Further trials 1999; Harris 2001), intermediate, and high prevalence of hep- need to examine the effects of hepatitis B vaccine and hepatitis B atitis B (Hall 1993; Liu 1995; Margolis 1995; Sriprakash 1997). immunoglobulin in preterm infants and low birth-weight infants We identified no cost-effectiveness studies assessing the effects of of HBsAg-positive mothers. Further trials need to examine if hep- adding hepatitis B immunoglobulin to vaccine. As hepatitis B im- atitis B vaccine plus multiple hepatitis B immunoglobulin doses munoglobulin seems able to reduce the risk of hepatitis B infec- is superior to hepatitis B vaccine plus a single dose of hepatitis B tion, the need to perform cost-effectiveness studies based on ran- immunoglobulin. domised trials seems justified. Two trials examined a new way to prevent vertical transmission of hepatitis B, which could not be included according to our in- NOTES clusion criteria (Lee 2004). The two trials randomised pregnant women positive for hepatitis B surface antigen to hepatitis B im- 1. A protocol for a systematic review on this topic was first pub- munoglobulin versus no intervention before delivery (Zhu 1997; lished in Issue 2, 1998 of The Cochrane Library and continued to Li 2003). In the group receiving immunoglobulin, fewer infants be published until Issue 1, 2004 with a title ’Vaccines for prevent- were positive for hepatitis B surface antigen at follow-up. The ing hepatitis B in high risk newborn infants’. The authors, Jeffer- methodological quality of the two trials was low. Furthermore, the son TO, Pratt M, Buttery J, and El-Shukri N, have abandoned mothers are at risk of developing immune complex disease due to the systematic review. This necessitated an update of the protocol hepatitis B immunoglobulin reacting with their own circulating and the conduct of the review be performed by a new team of hepatitis B surface antigens. More trials are therefore needed be- reviewers who now consists of Lee C, Gong Y, Brok J, Boxall EH, fore this intervention should be adopted. and Gluud C. 2. We modified the definition of hepatitis B occurence as shown in the present review. AUTHORS’ CONCLUSIONS 3. In our protocol we demanded that each trial had to assess sero- logical outcome in two and more consecutive blood specimens. We realized that this requirement was not detainable in the major- Implications for practice ity of the trials. We therefore decided to delete this requirement. HBsAg positive mothers who are HBeAg positive Evidence suggests that hepatitis B vaccine, hepatitis B immunoglobulin, and the combination of hepatitis B vaccine and POTENTIAL CONFLICT OF hepatitis B immunoglobulin reduce the risk of perinatal transmis- INTEREST sion of hepatitis B in newborn infants of HBsAg positive mothers who are also positive for HBeAg. However, the optimal treatment None known. regimen remains unclear. HBsAg positive mothers who are HBeAg negative ACKNOWLEDGEMENTS There is insufficient evidence to support or refute the use of hepatitis B vaccine, hepatitis B immunoglobulin, and the combination We thank TO Jefferson, M Pratt, J Buttery, and N El-Shukri who of hepatitis B vaccine and immunoglobulin in newborn infants participated in the formulation of the first Cochrane protocol on of HBsAg postive mother who are HBeAg negative. The number this topic. D Nikolova, The Cochrane Hepato-Biliary Group, is

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 8 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd thanked for translating a Russian trial and retrieving articles. We thank D Haughton, The Cochrane Neonatal Review Group, for retrieving articles. We thank Y Poovorawan and M Piazza who clariﬁed information on their trials. We thank A Dutta, MM Has- san, and SD Lee for providing assistance in our work to identify trial authors, and JU Olsen, GlaxoSmithKline, Denmark, for 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 Re- search, H:S Rigshospitalet DENMARK

REFERENCES

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Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 9 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd hepatitis B vaccine in infants born to mothers positive for HBsAg, in Ip HM, Wong VC, Lelie PN, Reesink HW,Schaasberg W,Yeung CY, Shanghai, China. International Journal of Epidemiology 1992;21(3): et al.Hepatitis B infection in infants after neonatal immunization. 564–73. Acta Paediatric Japanese 1989;31(6):654–8. Halliday 1992 DC {published data only} ∗Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE, Halliday ML, Kang LY, Rankin JG, Coates RA, Corey PN, Hu ZH, Yeung CY, et al.Prevention of the HBsAg carrier state in newborn in- et al.An efficacy trial of a mammalian cell-derived recombinant DNA fants of mothers who are chronic carriers of HBsAg and HBeAg by ad- hepatitis B vaccine in infants born to mothers positive for HBsAg, in ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin. Shanghai, China. International Journal of Epidemiology 1992;21(3): Double-blind randomised placebo-controlled study. Lancet 1984;1 564–73. (8383):921–6. Hieu 2002 {published data only} Ip 1989 CD {published data only} Hieu NT, Kim KH, Janowicz Z, Timmermans I. Comparative ef- Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW.Prevention of ficacy, safety and immunogenicity of Hepavax-Gene and Engerix- hepatitis B virus carrier state in infants according to maternal serum B, recombinant hepatitis B vaccines, in infants born to HBsAg and levels of HBV DNA. Lancet 1989;1(8635):406–10. HBeAg positive mothers in Vietnam: an assessment at 2 years. Vac- cine 2002;20(13-14):1803–8. Ip HM, Wong VC, Lelie PN, Reesink HW,Schaasberg W,Yeung CY, et al.Hepatitis B infection in infants after neonatal immunization. Ip 1989 AB {published data only} Acta Paediatric Japanese 1989;31(6):654–8. ∗Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention ∗ of hepatitis B virus carrier state in infants according to maternal serum Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE, levels of HBV DNA. Lancet 1989;1(8635):406–10. Yeung CY, et al.Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by ad- Ip HM, Wong VC, Lelie PN, Reesink HW,Schaasberg W,Yeung CY, ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin. et al.Hepatitis B infection in infants after neonatal immunization. Double-blind randomised placebo-controlled study. Lancet 1984;1 Acta Paediatric Japanese 1989;31(6):654–8. (8383):921–6. Ip 1989 AC {published data only} Kang 1995 {published data only} ∗ Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW. Prevention ∗Kang P, Shen XM, Yu HM. [Study on the efficacy of genetically of hepatitis B virus carrier state in infants according to maternal serum engineered vaccines against hepatitis B for interruption of perinatal levels of HBV DNA. Lancet 1989;1(8635):406–10. transmission]. Zhonghua Hu Li Za Zhi 1995;30(7):390–2. Ip HM, Wong VC, Lelie PN, Reesink HW,Schaasberg W,Yeung CY, Khukhlovich 1996 {published data only} et al.Hepatitis B infection in infants after neonatal immunization. Khukhlovich PA, Shakhgil’dian IV, Narkevich MI, Anan’ev VA, Acta Paediatric Japanese 1989;31(6):654–8. Kuzin SN, Sergeeva NA, et al.[The vaccinal prophylaxis of hepatitis B among children born to mothers with persistent HBs-antigene- Ip 1989 AD {published data only} mia]. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 1996; Ip HM, Lelie PN, Wong VC, Kuhns MC, Reesink HW.Prevention of 2:55–9. hepatitis B virus carrier state in infants according to maternal serum Kuru 1995 AB {published data only} levels of HBV DNA. Lancet 1989;1(8635):406–10. Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated Ip HM, Wong VC, Lelie PN, Reesink HW,Schaasberg W,Yeung CY, infants born to HBsAg-positive mothers with different hepatitis B et al.Hepatitis B infection in infants after neonatal immunization. vaccines and doses. The Turkish Journal of Pediatrics 1995;37(2):93– Acta Paediatric Japanese 1989;31(6):654–8. 102. ∗ Kuru 1995 AC {published data only} Wong VC, Ip HM, Reesink HW, Lelie PN, Reerink-Brongers EE, Kuru U, Turan O, Kuru N, Saglam Z, Alver A. Results of vaccinated Yeung CY, et al.Prevention of the HBsAg carrier state in newborn in- infants born to HBsAg-positive mothers with different hepatitis B fants of mothers who are chronic carriers of HBsAg and HBeAg by ad- vaccines and doses. The Turkish Journal of Pediatrics 1995;37(2):93– ministration of hepatitis-B vaccine and hepatitis-B immunoglobulin. 102. Double-blind randomised placebo-controlled study. Lancet 1984;1 (8383):921–6. Kuru 1995 BC {published data only} Kuru U, Turan O, Kuru N, Saglam Z, Alver A. 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Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 10 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd born to mothers with hepatitis B e antigen. The Journal of Pediatrics versus vaccine alone in the interruption of the perinatal transmission 1995;126(5 Pt 1):716–21. of HBV carrier state]. Zhonghua Liu Xing Bing Xue Za Zhi 1987;8 (6):325–8. ∗Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up study of combined vaccination with plasma-derived and recombinant Liu 1987 CB {published data only} hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9. Liu LH. [Comparative study of the efficacy of hepatitis B virus (HBV) vaccine combined with hepatitis B immunoglobulin(HBIG) Lee 1995 CA {published data only} versus vaccine alone in the interruption of the perinatal transmission Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, Sung JL, et al.The of HBV carrier state]. Zhonghua Liu Xing Bing Xue Za Zhi 1987;8 protective efficacy of recombinant hepatitis B vaccine in newborn (6):325–8. infants of hepatitis B e antigen-positive-hepatitis B surface antigen carrier mothers. The Pediatric infectious Disease Journal 1991;10(4): Lo 1985 AB {published data only} 299–303. Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et al.Prevention of hepatitis B virus infection in children born toHBsAg Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re- positive/HBeAg positive mothers. Preliminary results of active and combinant hepatitis B vaccine and risk of natural infection in infants passive-active immunization. Developmental Biology Standard 1983; born to mothers with hepatitis B e antigen. The Journal of Pediatrics 54:399–404. 1995;126(5 Pt 1):716–21. ∗ ∗ Lo KJ, Tsai YT, Lee SD, Yeh CL, Wang JY, Chiang BN, et Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up al.Combined passive and active immunization for interruption of study of combined vaccination with plasma-derived and recombinant perinatal transmission of hepatitis B virus in Taiwan. Hepatogastroen- hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9. terology 1985;32(2):65–8. Lee 1995 CB {published data only} Lo 1985 CA {published data only} Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, Sung JL, et al.The Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et protective efficacy of recombinant hepatitis B vaccine in newborn al.Prevention of hepatitis B virus infection in children born toHBsAg infants of hepatitis B e antigen-positive-hepatitis B surface antigen positive/HBeAg positive mothers. Preliminary results of active and carrier mothers. 1991;10(4): The Pediatric infectious Disease Journal passive-active immunization. Developmental Biology Standard 1983; 299–303. 54:399–404. Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re- ∗ Lo KJ, Tsai YT, Lee SD, Yeh CL, Wang JY, Chiang BN, et combinant hepatitis B vaccine and risk of natural infection in infants al.Combined passive and active immunization for interruption of born to mothers with hepatitis B e antigen. The Journal of Pediatrics perinatal transmission of hepatitis B virus in Taiwan. Hepatogastroen- 1995;126(5 Pt 1):716–21. terology 1985;32(2):65–8. ∗ Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up Lo 1985 CB {published data only} study of combined vaccination with plasma-derived and recombinant Goudeau A, Lo KJ, Coursaget P, Tong MJ, Yeh CL, Tsai YT, et hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9. al.Prevention of hepatitis B virus infection in children born toHBsAg Lee 1995 DE {published data only} positive/HBeAg positive mothers. Preliminary results of active and Lee CY, Huang LM, Chang MH, Hsu CY, Wu SJ, Sung JL, et al.The passive-active immunization. Developmental Biology Standard 1983; protective efficacy of recombinant hepatitis B vaccine in newborn 54:399–404. infants of hepatitis B e antigen-positive-hepatitis B surface antigen ∗Lo KJ, Tsai YT, Lee SD, Yeh CL, Wang JY, Chiang BN, et carrier mothers. The Pediatric infectious Disease Journal 1991;10(4): al.Combined passive and active immunization for interruption of 299–303. perinatal transmission of hepatitis B virus in Taiwan. Hepatogastroen- Lee PI, Lee CY, Huang LM, Chang MH. Long-term efficacy of re- terology 1985;32(2):65–8. combinant hepatitis B vaccine and risk of natural infection in infants Lolekha 2002 {published data only} born to mothers with hepatitis B e antigen. The Journal of Pediatrics Lolekha S, Warachit B, Hirunyachote A, Bowonkiratikachorn P,West 1995;126(5 Pt 1):716–21. DJ, Poerschke G. Protective efficacy of hepatitis B vaccine without ∗Lee PI, Lee CY, Huang LM, Chen JM, Chang MH. A follow-up HBIG in infants of HBeAg-positive carrier mothers in Thailand. study of combined vaccination with plasma-derived and recombinant Vaccine 2002;20(31-32):3739–43. hepatitis B vaccines in infants. Vaccine 1995;13(17):1685–9. Oon 1986 AB {published data only} Liu 1987 AB {published data only} Oon CJ, Tan KL, Goh KT, Wong-Yong L, Viegas O, McCarthy T, Liu LH. [Comparative study of the efficacy of hepatitis B virus et al.Evaluation of a low dose of hepatitis B vaccine given within a (HBV) vaccine combined with hepatitis B immunoglobulin(HBIG) childhood immunisation programme in Singapore. The Journal of versus vaccine alone in the interruption of the perinatal transmission Infection 1986;13(3):255–67. of HBV carrier state]. Zhonghua Liu Xing Bing Xue Za Zhi 1987;8 Oon 1986 CD {published data only} (6):325–8. Oon CJ, Tan KL, Goh KT, Wong-Yong L, Viegas O, McCarthy T, Liu 1987 CA {published data only} et al.Evaluation of a low dose of hepatitis B vaccine given within a Liu LH. [Comparative study of the efficacy of hepatitis B virus childhood immunisation programme in Singapore. The Journal of (HBV) vaccine combined with hepatitis B immunoglobulin(HBIG) Infection 1986;13(3):255–67.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 11 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Piazza 1985 {published data only} Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et Piazza M, Picciotto L, Villari R, Guadagnino V, Orlando R, Isabella al.Prevention of hepatitis B virus carriage of infants using HBV vac- L, et al.Hepatitis B immunisation with a reduced number of doses cine in Shanghai. Preliminary report of a randomized double-blind in newborn babies and children. Lancet 1985;1(8435):949–51. placebo-controlled trial. Chinese Medical Journal 1985;98(9):623–6. Pongpipat 1986 {published data only} Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, Pongpipat D, Suvatte V, Assateerawatts A. Efficacy of hepatitis-B et al.Prevention of perinatal acquisition of hepatitis B virus car- immunoglobulin and hepatitis-B vaccine in prevention of the HBsAg riage using vaccine: preliminary report of a randomized, double- carrier state in newborn infants of mothers who are chronic carriers blind placebo-controlled and comparative trial. Pediatrics 1985;76 of HBsAg and HBeAg. Asian Pacific Journal of Allergy Immunology (5):713–8. 1986;4(1):33–6. Xu 1995 AD {published data only} Pongpipat 1988 {published data only} ∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman Pongpipat D, Suvatte V,Assateerawatts A. Hepatitis B immunization PJ, et al.Long-term efficacy of active postexposure immunization of in high risk neonates born from HBsAg and HBeAg positive mothers: infants for prevention of hepatitis B virus infection. United States- comparison of standard and low dose regimens. Asian Pacific Journal People’s Republic of China Study Group on Hepatitis B. The Journal of Allergy Immunology 1988;6(2):107–10. of Infectious Diseases 1995;171(1):54–60. Pongpipat 1989 {published data only} Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et Pongpipat D, Suvatte V,Assateerawatts A. Hepatitis B immunization al.Prevention of hepatitis B virus carriage of infants using HBV vac- in high risk neonates born from HBsAg positive mothers: comparison cine in Shanghai. Preliminary report of a randomized double-blind between plasma derived and recombinant DNA vaccine. Asian Pacific placebo-controlled trial. Chinese Medical Journal 1985;98(9):623–6. Journal of Allergy Immunology 1989;7(1):37–40. Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, Poovorawan 1997 {published data only} et al.Prevention of perinatal acquisition of hepatitis B virus car- ∗ Poovorawan Y, Sanpavat S, Chumdermpadetsuk S, Safary A. Long- riage using vaccine: preliminary report of a randomized, double- term hepatitis B vaccine in infants born to hepatitis B e antigen blind placebo-controlled and comparative trial. Pediatrics 1985;76 positive mothers. Archives of Disease in Childhood. Fetal and Neonatal (5):713–8. Edition 1997;77(1):F47–F51. Xu 1995 BD {published data only} ∗ Poovorawan Y, Sanpavat S, Pongpunglert W, Chumdermpadetsuk S, Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman Sentrakul P, Vandepapeliere P, et al.Long term efficacy of hepatitis PJ, et al.Long-term efficacy of active postexposure immunization of B vaccine in infants born to hepatitis B e antigen-positive mothers. infants for prevention of hepatitis B virus infection. United States- The Pediatric Infectious Disease Journal 1992;11(10):816–21. People’s Republic of China Study Group on Hepatitis B. The Journal of Infectious Diseases 1995;171(1):54–60. Sehgal 1992 {published data only} Sehgal A, Gupta I, Sehgal R, Ganguly NK. Hepatitis B vaccine alone Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et or in combination with anti-HBs immunoglobulin in the perinatal al.Prevention of hepatitis B virus carriage of infants using HBV vac- prophylaxis of babies born to HBsAg carrier mothers. Acta Virologica cine in Shanghai. Preliminary report of a randomized double-blind 1992;36(4):359–66. placebo-controlled trial. Chinese Medical Journal 1985;98(9):623–6.

∗Sehgal A, Sehgal R, Gupta I, Bhakoo ON, Ganguly NK. Use of Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, hepatitis B vaccine alone or in combination with hepatitis B im- et al.Prevention of perinatal acquisition of hepatitis B virus car- munoglobulin for immunoprophylaxis of perinatal hepatitis B infec- riage using vaccine: preliminary report of a randomized, double- tion. Journal of Tropical Pediatrics 1992;38(5):247–51. blind placebo-controlled and comparative trial. Pediatrics 1985;76 (5):713–8. Theppisai 1987 {published data only} Theppisai U, Thanuntaseth C, Chiewsilp P,Siripoonya P.A compar- Xu 1995 CB {published data only} ∗ ison between the efficacy of passive-active and active immunization Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman for prevention of perinatal transmission of hepatitis B virus. Journal PJ, et al.Long-term efficacy of active postexposure immunization of of Medical Association, Thailand 1987;70(8):459–62. infants for prevention of hepatitis B virus infection. United States- People’s Republic of China Study Group on Hepatitis B. The Journal Theppisai 1990 {published data only} of Infectious Diseases 1995;171(1):54–60. Theppisai U, Thanuntaseth C, Chiewsilp P,Siripoonya P.Prevention of hepatitis B infection in infants born to hepatitis B carrier moth- Xu ZY, Francis DP, Liu CB, Purcell RH, Duan SC, Chen RJ, et ers: low dosage vaccination. International Journal of Gynaecology and al.Prevention of hepatitis B virus carriage of infants using HBV vac- Obstetrics 1990;32(4):353–7. cine in Shanghai. Preliminary report of a randomized double-blind placebo-controlled trial. Chinese Medical Journal 1985;98(9):623–6. Xu 1995 AB {published data only} ∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, PJ, et al.Long-term efficacy of active postexposure immunization of et al.Prevention of perinatal acquisition of hepatitis B virus car- infants for prevention of hepatitis B virus infection. United States- riage using vaccine: preliminary report of a randomized, double- People’s Republic of China Study Group on Hepatitis B. The Journal blind placebo-controlled and comparative trial. Pediatrics 1985;76 of Infectious Diseases 1995;171(1):54–60. (5):713–8.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 12 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Xu 1995 CD {published data only} Esteban 1986 ∗Xu ZY, Duan SC, Margolis HS, Purcell RH, Ou-Yang PY, Coleman Esteban JI, Genesca J, Esteban R, Hernandez JM, Seijo G, Buti M, PJ, et al.Long-term efficacy of active postexposure immunization of et al.Immunoprophylaxis of perinatal transmission of the hepatitis B infants for prevention of hepatitis B virus infection. United States- virus: efficacy of hepatitis B immune globulin and hepatitis B vaccine People’s Republic of China Study Group on Hepatitis B. The Journal in a low-prevalence area. Journal of Medical Virology 1986;18(4):381– of Infectious Diseases 1995;171(1):54–60. 91. Goh 1992 Xu ZY, Francis DP,Liu CB, Purcell RH, Duan SC, et al.Prevention of Goh KT, Tan KL, Kong KH, Oon CJ, Chan SH. Comparison of the hepatitis B virus carriage of infants using HBV vaccine in Shanghai. immune response of four different dosages of a yeast-recombinant Preliminary report of a randomized double-blind placebo-controlled hepatitis B vaccine in Singapore children: a four-year follow-up study. trial. Chinese Medical Journal 1985;98(9):623–6. Bulletin of the World Health Organization 1992;70(2):233–9. Xu ZY, Liu CB, Francis DP, Purcell RH, Gun ZL, Duan SC, Kang 1986 et al.Prevention of perinatal acquisition of hepatitis B virus car- Kang Y. Efficacy of domestic hepatitis B viral vaccines in preventing riage using vaccine: preliminary report of a randomized, double- transmission of eantigen frommothers to newborn infants. Zhonghua blind placebo-controlled and comparative trial. Pediatrics 1985;76 Liu Xing Bing Xue Za Zhi 1986;7(2):81–3. (5):713–8. Lai 1986 Yeoh 1986 {published data only} Lai CL, Yeoh EK, Chang WK, Lo VW, Ng LN. Use of the hepatitis Yeoh EK, Chang WK, Ip P,Chan KH, Chan E, Fung C. Efficacy and B recombinant DNA yeast vaccine (H-B-VAX II) in children: two safety of recombinant hepatitis B vaccine in infants born to HBsAg- doses vs. three doses of 5 micrograms regime; an interim report. The positive mothers. The Journal of Infection 1986;13 Suppl A:15–8. Journal of Infection 1986;13 Suppl A:19–25. Zhu 1987 {published data only} Lai 1993 Zhu Q-Y, Radvan GH. A randomized controlled trial of hepatitis Lai CL, Wong BC, Yeoh EK, Lim WL, Chang WK, Lin HJ. Five- B vaccine in high risk newborn infants in China. Australian & New year follow-up of a prospective randomized trial of hepatitis B recom- Zealand Journal of Medicine 1987;17:498. binant DNA yeast vaccine vs. plasma-derived vaccine in children: immunogenicity and anamnestic responses. Hepatology 1993;18(4): Zhu 1994 {published data only} 763–7. Zhu QR, Gu XH, Duan SC, Xu HF. Long-term immunogenicity Laille 1988 and efficacy of recombinant yeast derived hepatitis B vaccine for in- Laille M, Brethes B, Moreau JP, Pillot J. [Trial of hepatitis B pro- terruption of mother-infant transmission of hepatitis B virus. Chinese phylaxis in children born to mothers carrying HBs antigen in New Medical Journal 1994;107(12):915–8. Caledonia]. Bulletin de la Societe de Pathologie Exotique et de ses Filiales References to studies excluded from this review 1988;81(4):673–8. Lin 1987 Chung 1988 Lin KH, Twu SJ, Chen DS, Su S, Lee CJ. Efficacy of the national Chung WK. Persistence and boosting response of antibody to HBsAg hepatitis B vaccination program in the Republic of China: prelim- induced by vaccine treatment. Tropical Gastroenterology 1988;9(1): inary observations from Taoyuan area. Taiwan Yi Xue Hui Za Zhi 26–30. 1987;86(8):869–72. Chung 1988 B Linder 2000 Chung WK, Choi KY, Shim KS, Chung JW, Sun HS, Chung KW, Linder N, Handsher R, German B, Sirota L, Bachman M, Zinger et al.Safety, immunogenicity, and efficacy of a new heat-inactivated S, et al.Controlled trial of immune response of preterm infants to hepatitis B vaccine in the newborn. Viral Hepatitis and Liver Disease recombinant hepatitis B and inactivated poliovirus vaccines adminis- 1988:1014–6. tered simultaneously shortly after birth. Archives of Disease in Child- Coursaget 1984 hood. Fetal and neonatal edition 2000;83(1):F24–F27. Coursaget P, Deciron F, Tortey E, Barin F, Chiron JP, Yvonnet B, et Milne 1989 al.Immune response to hepatitis B vaccine in infants and newborns: Milne A, Heydon JL, Hindle RC, Pearce NE. Prevalence of hepatitis B control trial in an endemic area (Senegal). International Agency for in children in a high risk New Zealand community, and control using Research on Cancer 1984;63:319–35. recombinant DNA vaccine. New Zealand Medical Journal 1989;102 Da 1995 (866):182–4. Da Villa G, Picciottoc L, Elia S, Peluso F, Montanaro F, Maisto T. Mittal 1994 Hepatitis B vaccination: universal vaccination of newborn babies and Mittal SK, Rao S, Kumari S, Aggarwal V, Prakash C, Thirupuram S. children at 12 years of age versus high risk groups. A comparison in Simultaneous administration of hepatitis B vaccine with other E.P.I. the field. Vaccine 1995;13(13):1240–3. vaccines. Indian Journal of Pediatrics 1994;61(2):183–8. Delage 1993 Moulia-Pelat 1994 Delage G, Remy-Prince S, Montplaisir S. Combined active-passive Moulia-Pelat JP,Spiegel A, Martin PM, Cardines R, Boutin JP,Roux immunization against the hepatitis B virus: five-year follow-up of JF, et al.A 5-year immunization field trial against hepatitis B using a children born to hepatitis B surface antigen-positive mothers. The Chinese hamster ovary cell recombinant vaccine in French Polynesian Pediatric Infectious Disease Journal 1993;12(2):126–30. newborns: results at 3 years. Vaccine 1994;12(6):499–502.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 13 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Nair 1984 with use of a preS2-containing vaccine in Bali, Indonesia. Vaccine Nair PV, Weissman JY, Tong MJ, Thursby MW, Paul RH, Henne- Research 1996;5(4):203–12. man CE. Efficacy of hepatitis B immune globulin in prevention of Suwignyo 1994 perinatal transmission of the hepatitis B virus. Gastroenterology 1984; Suwignyo S, Surya IGP, Mulyanto, Montessori, Domoto K, Tsuda 87(2):293–8. F, et al.The use of a PreS2-containing recombinant vaccine for the Okoth 1994 prevention of maternal transmission of hepatitis B virus in Indonesian Okoth FA, Kobayashi M, Takayanagi N, Kapttich DC, Kaiguri PM, neonates. Viral Hepatitis and Liver Disease 1994:536–9. Tukei PM. Efficacy of hepatitis B vaccine in a rural community in Theppisai 1988 Muranga, Kenya. East African Medical Journal 1994;71(4):250–2. Theppisai U, Thanuntaseh C, Chiewsilp P, Siripoonya P. Two-year Perrin 1986 study of passive-active immunization for prevention of hepatitis B Perrin J, Coursaget P,Ntareme F, Chiron JP.Hepatitis B immuniza- infection in newborns. Journal of the Medical Association of Thailand tion of newborns according to a two dose protocol. Vaccine 1986;4 1988;71(8):413–6. (4):241–4. Theppisai 1989 Pongpipat 1984 Theppisai U, Thanuntaseth C, Chiewsilp P,Siripoonya P.Long-term Pongpipat D, Suvatte V, Assateerawatts A. Vaccination against hep- immunoprophylaxis of hepatitis B surface antigen carrier in infants atitis B virus infection in neonates. Helvetica Paediatrica Acta 1984; born to hepatitis B surface antigen positive mothers using plasma 39(3):231–6. derived vaccine. Asia Oceania Journal of Obstetrics and Gynaecology Poovorawan 1989 1989;15(2):111–5. Poovorawan Y, Sanpavat S, Pongpunlert W, Chumdermpadetsuk S, Wheeley 1991 Sentrakul P, Safary A. Protective efficacy of a recombinant DNA Wheeley SM, Jackson PT, Boxall EH, Tarlow MJ, Gatrad AR, An- hepatitis B vaccine in neonates of HBe antigen-positive mothers. The derson J, et al.Prevention of perinatal transmission of hepatitis B Journal of the American Medical Association 1989;261(22):3278–81. virus (HBV): a comparison of two prophylactic schedules. Journal of Poovorawan 1990 Medical Virology 1991;35(3):212–5. Poovorawan Y, Sanpavat S, Pongpunlert W, Chumdermpadetsuk S, Young 2003 Sentrakul P, Chitinand S, et al.Comparison of a recombinant DNA Young BW, Lee SS, Lim WL, Yeoh EK. The long-term efficacy of hepatitis B vaccine alone or in combination with hepatitis B immune plasma-derived hepatitis B vaccine in babies born to carrier mothers. globulin for the prevention of perinatal acquisition of hepatitis B Journal of Viral Hepatitis 2003;10(1):23–30. carriage. Vaccine 1990;8 Suppl:S56-S59; discussion S60-S62. Yuen 1999 Shikata 1984 Yuen MF,Lim WL, Cheng CC, Lam SK, Lai CL. Twelve-year follow- Shikata T, Yano M, Shiraki K, Oda T. Efficacy trial of HBIG and up of a prospective randomized trial of hepatitis B recombinant DNA hepatitis B vaccine for the prevention of perinatal HBV transmission. yeast vaccine versus plasma-derived vaccine without booster doses in Viral Hepatitis and Liver Disease 1984:596–7. children. Hepatology 1999;29(3):924–7. Stevens 1987 Zanetti 1986 Stevens CE, Taylor PE, Tong MJ, Toy PT, Vyas GN, Nair PV, et Zanetti AR, Dentico P, Del Vecchio Blanco C, Sagnelli E, Villa E, al.Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B Ferroni P,et al.Multicenter trial on the efficacy of HBIG and vaccine immune globulin in prevention of perinatal hepatitis B virus trans- in preventing perinatal hepatitis B. Final report. Journal of Medical mission. The Journal of the American Medical Association 1987;257 Virology 1986;18(4):327–34. (19):2612–6. Zhu 2003 Stevens 1988 Zhu Q, Yu G, Yu H, Lu Q, Gu X, Dong Z, et al.A randomized Stevens CE, Taylor PE, Tong MJ, Toy PT, Vyas GN, Zang EA, et control trial on interruption of HBV transmission in uterus. Chinese al.Prevention of perinatal hepatitis B virus infection with hepatitis B Medical Journal 2003;116(5):685–7. immune globulin and hepatitis B vaccine. Viral Hepatitis and Liver Disease 1988:982–8. Additional references Stevens 1990 Aggarwal 2004 Stevens CE, Taylor PE, Tong MJ, Toy PT. Hepatitis B immune glob- Aggarwal R, Ranjan P.Preventing and treating hepatitis B infection. ulin and yeast-recombinant hepatitis B vaccine in prevention of peri- BMJ (Clinical Research Ed.) 2004;329(7474):1080–6. natal HBV infection in the USA. Viral Hepatits and Hepatocellular Akhter 1992 Carcinoma 1990:377–84. Akhter S, Talukder MQ, Bhuiyan N, Chowdhury TA, Islam MN, Stevens 1992 Begum S. Hepatitis B virus infection in pregnant mothers and its Stevens CE, Toy PT, Taylor PE, Lee T, Yip HY. 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Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 15 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Hayashi 1996 Moher 1998 Hayashi K, Walker AM. Japanese and American reports of random- Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al.Does ized trials: Differences in the reporting of adverse effects. Controlled quality of reports of randomised trials affect estimates of intervention Clinical Trials 1996;17(2):99–110. efficacy reported in meta-analyses. Lancet 1998;352(9128):609–13. Heijtink 2002 [MEDLINE: 9746022]. Heijtink RA, Kruining J, van Bergen P, de Rave S, van Hattum J, Nayak 1987 Schutten M, et al.Characterization of a human monoclonal antibody Nayak NC, Panda SK, Zuckerman AJ, Bhan MK, Guha DK. Dy- obtained after immunization with plasma vaccine and a booster with namics and impact of perinatal transmission of hepatitis B virus in recombinant-DNA hepatitis B vaccine. 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Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 16 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 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 HBsAg Anti-HBs Anti-HBc Notes Follow-up time: 14, 18 or 30 months. Adverse events: there were no serious reactions to the vaccine, and the adverse effects observed were mild and transient. Local swelling and erythema were observed in 3.3% of neonates. Allocation concealment B – Unclear

Study Beasley 1983a AB Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: unclear - described as double blind, but method of blinding not described. Follow-up: adequate - number and reasons reported. Participants Country: Taiwan. Publication language: English. Inclusion criteria: HBsAg- and HBeAg-positive mothers. Infant birth weight over 2500 gm with Apgar scores > 8 at 1 minute. Exclusion criteria:

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 17 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) HBeAg negative mother.

Participants: (1) Group A (control group) received no prophylaxis against HBV.23 were infants born in the same hospital and 61 were those randomised blind to receive placebo in another HBIG prophylaxis trial. Birth weight: (3239+-407) gram Older siblings (mean number): 0.5+-0.6 Cord blood positive (%): 29.5% Age 1st treatment (minutes): 36.0+-76.8 Age 2nd treatment (minutes): 98.4+-9.0 Age 3rd treatment (minutes): 190.1+-8.8 Mother’s mean age: 24.8+-3.1 HBsAg titer: 12.1+-1.7 Drop-out: 12

(2) Group B Birth weight: (3209+-308) gram Older siblings (mean number): 0.7+-0.6 Cord blood positive (%): 23.9% Age 1st treatment (minutes): 20.5+-20.4 Age 2nd treatment (minutes): 97.1+-7.9 Age 3rd treatment (minutes): 186.8+-10.3 Mother’s mean age: 26.3+-3.7 HBsAg titer: 11.9+-1.8 Drop-out: 9

(3) Group C Birth weight: (3232+-372) gram Older siblings (mean number): 0.6+-0.7 Cord blood positive (%): 22.8% Age 1st treatment (minutes): 35.8+-135.1 Age 2nd treatment (minutes): 98.0+-8.0 Age 3rd treatment (minutes): 189.0+-9.5 Mother’s mean age: 25.5+-3.3 HBsAg titer: 12.0+-1.9 Drop-out: 6 Interventions Group A: HBIG 1.0 mL (180 mIU, Abbott) at birth and saline at 3 and 6 months.

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

Group C: given HBIG 0.5 mL (90 mIU, Abbott) diluted in 0.5 mL of immune serum globulin at birth, 3 and 6 months.

The mean administration time of HBIG was within 36 minutes of birth: 95% were treated within an hour; all were treated within 30 hours. Outcomes Hepatitis events at 15 months follow-up. HBsAg, Anti-HBs, Anti-HBc, and HBeAg. Notes Follow-up time: 15 months.

Adverse events: One infant died, but the death appeared unrelated to HBIG. 12 dropouts in Group A, including 10 refuse and 2 lost; 9 in Group B, including 7 refuse and 2 lost; 6 dropouts in Group C, all because of refusal. Allocation concealment B – Unclear

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 18 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 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).

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 19 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Group A: HBIG 0.5 mL (145 IU, Abbott) at birth, a second dose at 3 months of age, at which time vaccination (20 microgram, Merck Sharp and Dohme) is initiated (88.6+-14.5 days). Followed by boosters a month and 6 month later. Group B: HBIG 0.5 mL at birth only and vaccination was initiated when they were 4 to 7 days old (6.3+- 1.5). Followed by boosters a month and 6 month later. Group C: HBIG 0.5 mL only and vaccination was initiated when they were approximately 1 month old (30.2+-4.3 days). Followed by boosters a month and 6 month later. Outcomes Hepatitis events at maximum HBsAg, anti-HBs. Notes Follow-up time: 9 months. Adverse events: The data in control group (84 infants) were obtained from another trial (Beasley, 1983) Allocation concealment B – Unclear

Study Farmer 1987 Methods Generation of allocation sequence: adequate - random number list. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - not speciﬁed in the each groups. Participants Country: New Zealand. Publication language: English. Inclusion criteria: Both HBsAg and HBeAg positive mothers. infant birth weight over 2500 gm with Apgar scores > 8 at 1 minute. Exclusion criteria: not reported. Participants: (1) Group A (3) Group B Interventions Group A: 0.25 mL (5 microgram) Hepavax (PDV, Merck Sharp and Dohme) I.M. at birth, 6 weeks and 6 months. Group B: 0.25 mL (5 microgram) Hepavax (PDV, Merck Sharp and Dohme) I.M. plus HBIG 0.25 mL (25 IU/kg) at birth then Hepavax + HBIG 0.25 mL (25 IU/kg) at 6 weeks. Finally, another Hepavax vaccine in 6 months. Outcomes Hepatitis events at maximum follow-up. HBsAg. HBeAg and anti-HBs. Notes Follow-up time: 12 months. Adverse events: not reported. Four infants were lost to follow-up. Allocation concealment B – Unclear

Study Garcia 1992 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: unclear - described as double blind but the method of blinding was not described.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 20 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Follow-up: inadequate - not described. Participants Country: Cuba. Publication language: Spanish. Inclusion criteria: HBsAg positive mothers. Interventions Group A (Cuban): RV 10 microgram at birth, 1 and 2 months. Group B (SK): RV 10 microgram at birth, 1, and 2 months. Outcomes Anti-HBs, HBsAg, Anti-HBc. Notes Follow up time: 6 months. Adverse events: not reported. Allocation concealment B – Unclear

Study Grosheide 1993 Methods Generation of allocation sequence: unclear - described as randomised, but the method not described. Allocation concealment: adequate - sealed envelops. Blinding: not performed. Follow-up: adequate - number and reasons for dropouts described. Participants Country: Netherlands Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Exclusion criteria: Participants: Group A: Mother median age: 23 (19;33) Country of birth, No. (%) The Netherlands +other: 3 (8.6) Mediterranean: 15 (42.9) Surinam: 5 (14.3) Asia: 12 (34.3) Group B: Mother median age: 24 (17;38) Country of birth, No. (%) The Netherlands +other: 2 (5.4) Mediterranean: 16 (43.2) Surinam: 7 (18.9) Asia: 12 (32.4) Eight infants (schedule A, three infants; schedule B, ﬁve infants) were excluded from further analysis. Interventions Group A: HBIG (0.5 mL/kg body weight) given within 2 hours of birth and PDV 10 microgram 2 days after birth, 1, 2, and 11 months. Group B: HBIG (0.5 mL/kg body weight) and PDV 10 microgram at 3, 4, 5 and 11 months (with diphtheria, pertussis, tetanus, poliomyelitis concomitantly. HBIG (0.5 mL/kg body weight) was given at the age of 3 months. Outcomes Number of HBsAg positive children in each group. Anti-HBs level. Notes Follow-up time: 12 months.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 21 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Adverse events: no side-effect were observed after neither passive or active immunisation (data from Mazel et al, 1984, a duplication publication). The data in this trial were not usable because the PDV vaccination schedule were different. Allocation concealment A – Adequate

Study Halliday 1992 AB Methods Generation of allocation sequence: adequate - random code. Allocation concealment: adequate - by independent unit. Blinding: adequate - injection was administered by a doctor who was not part of the research team. No one on the research team, or in the laboratory that performed the HBV marker tests, knew which vaccine was administered or whether the infant received HBIG. Follow-up: adequate - number and reasons described in each groups. Participants Country: China. Publication language: English. Inclusion criteria: HBsAg positive mothers. infant weight equal to or greater than 2500 gm and a 5-minute Apgar score equal to or greater than 7 or infant weights less than 2500 gm but greater than 1600 gm and a 5-minute Apgar score of at least 9. Exclusion criteria: not reported. Participants: (1) Group A (2) Group B (3) Group C (4) Group D Interventions Group A: Betagen (20 microgram, RV) at birth, and 1 and 6 months. Group B: Lanzhou (20 microgram, PDV) at birth, and 1 and 6 months. Group C: HBIG (260 IU) at birth and RV (10 microgram) at birth, and 1 and 6 months. Group D: HBIG (260 IU) at birth and RV (20 microgram) at birth, and 1 and 6 months. Outcomes Percentage of infants with HBsAg at maxim (12 months) follow-up. Percentage of infants with HBsAg, by mother’s HBsAg/HBeAg status. Geometric mean titre of anti-HBs in each group. Percentage of infants in each group with anti-HBsAg level higher than 10 mIU/mL. Notes Follow-up time: 12 months. Reasons not to entering the trial: living too far to travel for follow-up visits too many blood tests did not want the baby to be hurt did not think vaccination was necessary would be going away. Allocation concealment A – Adequate

Study Halliday 1992 CA Methods This trial is the same as Halliday 1992 BA, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 22 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Participants Interventions Outcomes Notes Allocation concealment A – Adequate

Study Halliday 1992 DC Methods This trial is the same as Halliday 1992 BA, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment A – Adequate

Study Hieu 2002 Methods Generation of allocation sequence: adequate - sequence generated by a computer program. Allocation concealment: adequate - sealed envelopes. Blinding: not performed. Follow-up: inadequate - not described. Participants Country: Vietnam. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. birth weight more than 2500 gm. Apgar score at least 8 at 1 minute. gestational age >= 37 completed weeks. In good general health as determined by birth history and physical examination. Exclusion criteria: Fever or significant malnutrition. confirmed HIV positive individuals. Evidence of significant haematological, cardiovascular or neoplastic disease. Participants: (1) Hepavax-Gene Group (n = 53) Mother’s mean age: 26.8 (2) Engerix-B Group (n = 51) Mother’s mean age: 27.9 Interventions Hepavax-Gene Group : HBIG 100 microgram+ Hepavax 10 microgram I.M. at birth, then Hepavax at 30 days and 180 days of age. Engerix-B Group: HBIG 100 microgram+ Engerix-B 10 microgram I.M. at birth, then Engerix-B at 30 days and 180 days of age. Outcomes Number of infants with HBsAg during the follow-up period. Anti-HBs Anti-HBs titer GMT of Anti-HBs Number of anti-HBc positive infants.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 23 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Notes Follow-up times: 30-60-180-210-360 days and 2 years. Adverse events: The majority of AEs were mild fever of less than 38 C degree. One infant had mild hyperexcitability (excessive crying). Allocation concealment A – Adequate

Study Ip 1989 AB Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: unclear - described as double blind, but method of blinding not described. Follow-up: inadequate - not described in each group. Participants Country: HongKong, China. Publication language: English. Inclusion criteria: HBeAg positive mothers. Participants: (1) Group A: (2) Group B: (3) Group C: (4) Group D: (control) Interventions Group A: received four 3 microgram of PDV at birth and at the age of 1, 2, and 6 months, respectively. Also, received HBIG 200 IU at birth, and 100 IU at monthly intervals during the ﬁrst 6 months after birth. Group B: received four 3 microgram of PDV at birth and at the age of 1, 2, and 6 months. Also, received HBIG 200 IU at birth. Group C: received four 3 microgram of PDV at birth and at the age of 1, 2, and 6 months. Group D: control group (not randomised). Outcomes HBsAg HBeAg, HBV DNA Notes Follow-up time: 36 months. Adverse events: not reported. The code was broken in Oct, 1983. After that no new babies entered the placebo group and eligible babies were only randomly allocated to one of the ﬁrst three intervention groups. Part of the infants of the Ip 1989 trial originated from the Wong 1984 trial. Allocation concealment B – Unclear

Study Ip 1989 AC Methods This trial is the same as Ip 1989 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 24 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Study Ip 1989 AD Methods Generation of allocation sequence: unclear - not described. Allocation concealment: adequate. Blinding: adequate. Follow-up: inadequate - reasons for dropouts described only, number was not reported. Participants Country: China. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Exclusion criteria: Infants birthweight less than 2500 gm, gestational age less than 37 weeks, Apgar score less than 7, or in whom there were gross congenital abnormalities. Participants: Group A (n = 36): Mothers: age (yr): 26.0+-4.3 number of pregnancies: 1.7+-1.1 parity: 0.6+-0.1 duration of labour (minutes): 371+-268 mode of delivery: normal: 64% forceps: 8% lower section caesarean section: 8% induction of labour: 28% Infants: males: 47% birthweight (gm): 3112+-307 maturity (weeks): 40+-1 breastfed: 18% Group B (n = 35): Mothers: age (yr): 24.20+-3.6 number of pregnancies: 1.4+-0.8 parity: 0.5+-1.0 duration of labour (minutes): 452+-252 mode of delivery: normal: 51% forceps: 23% lower section caesarean section: 26% induction of labour: 21% Infants: males: 60% birthweight (gm): 3204+-341 maturity(weeks): 40+-1 breastfed: 18% Group C (n = 35): Mothers: age (yr): 25.6+-4.1

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 25 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) number of pregnancies: 1.5+-1.0 parity: 0.5+-0.8 duration of labour (minutes): 396+-243 mode of delivery: normal: 60% forceps: 23% lower section caesarean section: 17% induction of labour: 20%

Infants: males: 57% birthweight (gm): 3107+-393 maturity(weeks): 40+-2 breastfed: 21%

Group D (n = 34): Mothers: age (yr): 24.6+-3.8 number of pregnancies: 1.4+-0.6 parity: 0.3+-0.6 duration of labour (minutes): 430+-231 mode of delivery: normal: 56% forceps: 12% lower section caesarean section: 32% induction of labour: 24%

Infants: males: 47% birthweight (gm): 3231+-362 maturity(weeks): 40+-2 breastfed: 21%. Interventions Group A: HBIG 200 IU and PDV 3 microgram were given at birth. Then HBIG 100 IU was given at 1, 2, 3, 4, 5, and 6 months. PDV 3 microgram were given at 1, 2, and 6 months.

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

Group C: PDV 3 microgram was given at birth, 1, 2 and 6 months. Placebo B was given at birth, 1, 2, 3, 4, 5 and 6 months.

Group D: placebo B was given at birth, 1, 2, 3, 4, 5, and 6 months. Placebo A was given at birth, 1, 2, and 6 months. Outcomes HBsAg HBeAg Anti-HBs Anti-HBe IgM-anti-HBc

Notes Follow-up time: 12 months.

Adverse events:

No serious side-effects from the injections were noticed. Six mothers observed a small swelling at the site of injection for 1 day; 6 babies had low-grade fever for 1 day; and 2 babies had low-grade fever for 1 day. Deﬁnition of persistent HBsAg antigenemia: all babies having been HBsAg-positive for over 6 months. The Wong 1984 trial constituted part of the infants in the Ip 1989 trial.

Allocation concealment A – Adequate

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 26 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Study Ip 1989 BC Methods This trial is the same as Ip 1989 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Ip 1989 BD Methods This trial is the same as Ip 1989 AD, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment A – Adequate

Study Ip 1989 CD Methods This trial is the same as Ip 1989 AD, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment A – Adequate

Study Kang 1995 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - not described. Participants Country: China. Publication language: Chinese. Inclusion criteria: HBsAg+ HBeAg positive mothers. Participants: (1) Group A: (2) Group B: (3) Group C: Interventions Group A: received 20 microgram of RV at birth and at the age of 1 and 6 months, respectively. Group B: received 20 microgram of genetic engineering vaccine at birth and at the age of 1 and 6 months. Group C: received 10 microgram of genetic engineering vaccine and HBIG 200 IU at birth and 10 microgram doses of genetic engineering vaccine at the age of 1 and 6 months. Outcomes HBsAg, Anti-HBs

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 27 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Anti-HBc Notes Follow-up time: 7 months 1% soap solution was applied to avoid contamination by mothers’ faeces. No adverse events was reported. Data was comparable for Group A and Group B. Allocation concealment B – Unclear

Study Khukhlovich 1996 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: unclear - described as double blind, but method of blinding not described. Follow-up: inadequate - not described. Participants Country: Uzbekistan and Moldova (former Soviet Union). Publication language: Russian. Inclusion criteria: HBsAg positive carrier mothers. The children were healthy without any contraindications. Interventions Treatment Group: Engerix B 1 mL was given at birth, 1, 2, and 14 months. Control Group: no vaccines. Outcomes Anti-HBs, HBsAg. Notes Follow-up time:2 years. Adverse events: skin reactions, weak pain, little swollen of the injection site (transient reactions, disappeared within 1-3 days). Rare adverse events: without good sleep, over excited, dyspepsia, subfebrile temperature. After the vaccination, no other adverse event was observed. Allocation concealment B – Unclear

Study Kuru 1995 AB Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: unclear. Participants Country: Turkey. Publication language: English. Inclusion criteria: HBsAg positive mothers. Participants: (1) Group A (Hevac B 0.5 mL) (2) Group B (Hevac B 1 mL) (3) Group C (Engerix B). Interventions Group A (Hevac B 0.5 mL): received 2.5 microgram of vaccine and HBIG 200 IU at birth and vaccine at the age of 1, 2, and 12 months, respectively. Group B (Hevac B 1 mL): received 5 microgram of vaccine and HBIG 200 IU at birth and vaccine at the age of 1, 2, and 12 months respectively. Group C (Engerix B 0.5 mL): received 10 microgram of vaccine and HBIG 200 IU at birth and vaccine at the age of 1, 2, and 12 months, respectively. Outcomes HBsAg,

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 28 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Anti-HBs (geometric mean titer, GMT), HBeAg, Anti-HBe. Notes Follow-up time:13 months without the primary outcome deﬁned in the protocol, which is Hepatitis B events at maximum follow-up. Adverse events: no side effects in the infants after the vaccination. Allocation concealment B – Unclear

Study Kuru 1995 AC Methods This trial is the same as Kuru 1995 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Kuru 1995 BC Methods This trial is the same as Kuru 1995 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Lee 1995 AB Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: Not performed. Follow-up: inadequate - number of dropouts reported, but reasons not described. Participants Country: Taiwan. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive/negative mothers. Interventions Group A (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ Engerix-B 10 microgram (1)+ Engerix-B 10 microgram (2)+ Engerix-B 10 microgram (12) Group B (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ PDV 5 microgram (1)+ PDV 5 microgram (2)+ PDV 5 microgram (12) Group C (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ H-B-VAX II 5 microgram (1)+ H- B-VAX II 5 microgram (2)+ H-B-VAX II 5 microgram (12) Group D (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ PDV 5 microgram (1)+ H-B-VAX II 5 microgram (2)+ H-B-VAX II 5 microgram (12) Group E (HBeAg+ mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ PDV 5 microgram (1)+ Engerix- B 10 microgram (2)+ Engerix 10 microgram (12) Group F (HBeAg- mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ Engerix-B 10 microgram (2)+ Engerix-B 10 microgram (6)

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 29 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Group G (HBeAg- mother): HBIG 145 IU (0)+ PDV 5 microgram (0)+ H-B-VAX II 5 microgram(2)+ H- B-VAX II 5 microgram(6) Outcomes HBsAg, HBeAg, Anti-HBs by radioimmunoassay. Notes Follow-up time: 6, 14, and 30 months (high risk infants). Adverse events: there was no signiﬁcant adverse reaction in any of the children during the study period. Allocation concealment B – Unclear

Study Lee 1995 CA Methods This trial is the same as Lee 1995 A1C, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Lee 1995 CB Methods This trial is the same as Lee 1995 A1C, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Lee 1995 DE Methods This trial is the same as Lee 1995 A1C, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Liu 1987 AB Methods Generation of allocation sequence: unclear - not described. Allocation concealment: adequate - sealed envelopes. Blinding: adequate - with placebo. Follow-up: inadequate - not described. Participants Country: China. Publication language: Chinese. Inclusion criteria: HBsAg+ HBeAg positive mothers or HBsAg titre >= 1:512. Interventions Group A: received 20 microgram of vaccine at birth and at the age of 1, 2, and 6 months, respectively.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 30 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Group B: placebo (normal saline) at birth and at the age of 1, 2, and 6 months, respectively. Group C: received 20 microgram of vaccine and HBIG 1: 1600,000 to 1: 3200,000 (RIA) at birth and vaccine at the age of 1, 2, and 6 months respectively. Outcomes Overall number of HBsAg newborns in each tests. Anti-HBs, Anti-HBc (RIA) Notes Follow-up time: 6-9-12 months. The numbers of HBsAg newborns were the sum of number of HBsAg positive newborns detected in 6, 9 and 12 months, not only in 12 months follow-up. Adverse events: no systemic reaction and serious local events. Some infants had local swollen and red, but all disappeared in 1 to 2 days. Allocation concealment A – Adequate

Study Liu 1987 CA Methods This trial is the same as Liu 1987 AC, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment A – Adequate

Study Liu 1987 CB Methods This trial is the same as Liu 1987 AC, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment A – Adequate

Study Lo 1985 AB Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: unclear. Participants Country: Taiwan. Publication language: English. Inclusion criteria: HBsAg+ HBeAg positive mothers. Mother age: 20 to 36 years, mean 27 years old. Interventions Group A: received HBIG 50 IU at birth, then Hevac-B 5 microgram at 2 weeks, 6 weeks, and 10 weeks. Group B: received Hevac-B 5 microgram at 2 weeks, 6 weeks, and 10 weeks. Group C: received Hevac-B 5 microgram at 2 weeks, 6 weeks, and 10 weeks. Plus HBIG 50 IU at birth and one month of age.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 31 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Group D: control group (refused vaccination). Outcomes The status of HBsAg and HBeAg in infants Number of infants with HBsAg positive in 6 weeks, 10 weeks and 6 months of age. The incidence of persistent HBsAg carrier state. A summary of adverse events of HBV vaccination. Notes Follow-up time: 6 weeks- 10 weeks- 6 months (all with number of infants HBsAg (+)). Adverse events: Fever: 2.8% Diarrhoea: 0.5% Swelling erythema: 6.6% Restlessness: 22.2% Two infants in Group 3 had an ALT rise. One was considered to be related to the use of traditional herbal drug. The other could not be accounted for. Both children returned to normal ALT within the follow-up period. Allocation concealment B – Unclear

Study Lo 1985 CA Methods This trial is the same as Lo 1985 BA, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Lo 1985 CB Methods This trial is the same as Lo 1985 BA, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Lolekha 2002 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - not described. Participants Country: Thailand. Publication language: English. Inclusion criteria: HBsAg- and HBeAg-positive mothers. Infant birth weight >= 2000 gram, Apgar score >= 7 at 5 minutes Participants: (1) Group A

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 32 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Male (%): 52 Female (%): 48 Birth weight (kg) Range: 2.15-4.26 Mean: 3.1 Median: 3.05 (2) Group B Male (%): 51 Female (%): 49 Birth weight (kg) Range: 2.34-4.25 Mean: 3.04 Median: 3.02 Interventions Group A: received 5 microgram of vaccine at birth (0 to 3 days) and at the age of 1 and 6 months, respectively. Group B: received 5 microgram of vaccine at birth (0 to 3 days) and at the age of 1, 2, and 12 months, respectively. Outcomes HBsAg HBeAg Anti-HBc Anti-HBs Notes Follow-up time: 13 months. Adverse events: None of the vaccines had a serious adverse experience and none withdrew from the study because of a vaccine related adverse experience. Allocation concealment B – Unclear

Study Oon 1986 AB Methods Generation of allocation sequence: adequate - by lottery or the use of coded numbers. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - not described. Participants Country: Singapore Publication language: English. Inclusion criteria: HBsAg positive and negative mothers. Participants: Group A: HBsAg (-) mothers (n = 28) Group B: HBeAg (-)/HBsAg (+) mothers (n = 188) Group C: HBeAg (+)/HBsAg (+) mothers (n = 99) Group D: HBsAg (-) mothers (n = 39) Group E: HBeAg (-)/HBsAg (+) mothers (n = 205) Group F: HBeAg (+)/HBsAg (+) mothers (n = 103) Interventions Group A: 10 microgram PDV at birth, 1 and 2 months. Group B: 5 microgram PDV at birth, 1 and 2 months. Group C: HBIG 100 IU and 10 microgram PDV at birth and 10 microgram PDV at 1 and 2 months. Group D: HBIG 0.5 mL (100 IU) and 5 microgram PDV at birth and 5 microgram PDV at 1 and 2 months. Group E: 5 microgram PDV at birth, 1 and 2 months.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 33 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Group F: 10 microgram PDV at birth, 1 and 2 months. Outcomes HBsAg HBeAg Anti-HBs Notes Follow-up time: 12 months. Adverse effects: none was observed during the surveillance period. Allocation concealment B – Unclear

Study Oon 1986 CD Methods This trial is the same as Oon 1986 EB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Piazza 1985 Methods Generation of allocation sequence: adequate - random number. Allocation concealment: adequate - sealed envelopes. Blinding: unclear. Follow-up: adequate - reasons and numbers described. Participants Country: Italy. Publication language: English. Inclusion criteria: HBsAg-positive mothers. Mothers with HBsAg, anti-HBs, anti-HBc negative were also included in this study with different comparison groups. Participants: (partly included, some children were not infants) Group A: 2 withdrawn by their parents. Group B: 1 withdrawn by their parents. Group C: 5 withdrawn by their parents. Group D: 5 withdrawn by their parents. Interventions Group A: HBIG 50 IU at birth, PDV 5 microgram within 5 days after birth and at 2 months. Group B: HBIG 50 IU at birth, PDV 5 microgram within 5 days after birth and at 1 and 2 months. Group C: PDV 5 microgram within 5 days after birth and at 2 months. Group D: PDV 5 microgram within 5 days after birth and at 1 and 2 months. Outcomes HBsAg Anti-HBc Notes Follow-up time: 6 months. Adverse events: 2 children reported a sore arm after the 2nd dose of vaccine, and in both the complaint resolved a few hours later. There were no other adverse reactions. Allocation concealment A – Adequate

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 34 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Study Pongpipat 1986 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - reasons not described. Participants Country: Thailand. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Interventions Group A: HBIG (Gamma-protect) 200 IU (at birth) + Havac B 5 microgram (birth-1-2 months). Group B: HBIG (Hepatect) 100 IU (0)+ HB vax (PDV) 10 microgram (birth-1-6 months). Outcomes HBsAg Anti-HBc Notes Follow-up time: 12 months. Adverse events: neither local nor systemic reactions were observed after immunisation. Allocation concealment B – Unclear

Study Pongpipat 1988 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - number reported only. Participants Country: Thailand. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Participants: Group A: Group B: Interventions Group A (HBIG+ Hevac B): received 5 microgram of vaccine and HBIG 100 IU at birth and vaccine at the age of 1, 2, and 12 months, respectively. Group B (HBIG+ Hevac B): received 2 microgram of vaccine and HBIG 100 IU at birth and vaccine at the age of 1, 2, and 12 months respectively. Outcomes GMT (anti-HBs) seroconversion rate HBsAg Anti-PreS2 Anti-HBc Notes Follow-up time: 4, 6, 12, and 13 months. Adverse events: neither local nor systemic reactions were observed after immunization with HBIG and hepatitis B vaccine. Allocation concealment B – Unclear

Study Pongpipat 1989 Methods Generation of allocation sequence: unclear - not described.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 35 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - number for dropouts described only. Participants Country: Thailand. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Participants: Group A: Group B: Interventions Group A (HBIG+ HBVax): received 10 microgram of PDV and HBIG 100 IU (0.5mL) at birth and vaccine at the age of 1, 2, and 12 months, respectively. Group B (HBIG+ HBVax II): received 5 microgram of RV and HBIG 100 IU (0.5mL) at birth and vaccine at the age of 1, 2, and 12 months respectively. Outcomes GMT (anti-HBs) seroconversion rate (deﬁnition: higher than 5 mIU/mL after vaccination) HBsAg. Notes Follow-up time: 12 months. Adverse events: neither local nor systemic reactions were observed after immunization with HBIG and both kinds of hepatitis B vaccine. Allocation concealment B – Unclear

Study Poovorawan 1997 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - reasons for dropouts described only, number was not reported. Participants Country: Thailand. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Weight of 2 kg or more at birth and with a 5 minute Apgar score of 7 or higher. Interventions Open design without randomisation Group A: were vaccinated with Engerix-B (RV) 10 microgram at birth and subsequently at 1, 2, and 12 months of age. Group B: were vaccinated with Engerix-B (RV) 10 microgram and HBIG 100 IU at birth and Engerix-B (RV) 10 microgram and Engerix-B 10 microgram subsequently at 1, 2, and 12 months of age. Randomised groups: Group C: were vaccinated with Engerix-B (RV) 10 microgram at birth and subsequently at 1 and 6 months of age. Group D: were vaccinated with Engerix-B (RV) 10 microgram and HBIG 100 IU at birth and Engerix-B 10 microgram subsequently at 1 and 6 months of age. A booster was administered at 60 months for Group C and Group D. Outcomes HBsAg GMT (Anti-HBs) Anti-HBc

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 36 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Notes Follow-up time: 60 months. Adverse events: not reported. Only the data in Group C and D were used for analysis. Allocation concealment B – Unclear

Study Sehgal 1992 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate. Participants Country: India. Publication language: English. Inclusion criteria: HBsAg positive mothers. Interventions Group A: 10 microgram PDV within 24 hours of birth, 4 and 8 weeks. Group B: HBIG and 10 microgram PDV within 24 hours of birth, and PDV given at 4 and 8 weeks. Group C (control group): not vaccinated. Outcomes HBsAg HBeAg Anti-HBe Anti-HBs Notes Follow-up time: 3 and 6 months. Adverse events: not reported. Allocation concealment B – Unclear

Study Theppisai 1987 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: adequate - no dropouts. Participants Country: Thailand. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Interventions Group A: 10 microgram PDV given at 21 to 72 minutes of birth and the age of 1 and 6 months. Group B: HBIG 200 IU and 10 microgram PDV given at 21-72 minutes (average 67 minutes) of birth and 10 microgram PDV given the age of 1 and 6 months. Outcomes HBsAg HBeAg Anti-HBs Anti-HBe Notes Follow-up time: 3 and 6 months. Adverse events: not reported Allocation concealment B – Unclear

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 37 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Study Theppisai 1990 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - number reported, but the reasons for dropouts not described. Participants Country: Thailand. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive mothers. Historical control group. Interventions Group A: HBIG 200 IU administered within 3 hours of birth, and 5 microgram PDV given at the age of 2 days, 1, 2, and 12 months. Group B: HBIG 200 IU administered within 3 hours of birth, and 2 microgram PDV given at the age of 2 days, 1, 2, and 12 months. Control group (historical control): no vaccination. Outcomes HBsAg Anti-HBs GMT seroconversion rate. Notes Follow-up time: 4, 6, 12 and 13 months Adverse events: not reported. Allocation concealment B – Unclear

Study Xu 1995 AB Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: unclear - described as double blind, but method of blinding not described. Follow-up: inadequate - number for dropouts described only, reasons was not reported. Participants Country: China. Publication language: English. Inclusion criteria: HBsAg and HBeAg positive/negative mothers. Exclusion criteria Infants birthweight less than 2500 gm, gestational age less than 37 weeks, Apgar score less than 7, or whom there were gross congenital abnormalities. Interventions Group A: NIAID vaccine (PDV produced by the U.S.) vaccine 16 microgram at birth, 1 and 6 months. Group B: BIVS vaccine (PDV produced by China) vaccine 20 microgram at birth, 1, and 6 months. Group C: randomisation into Group C was not begun until later in the trial): HBIG 250 IU at birth and BIVS vaccine 20 microgram at birth, 1, and 6 months. Group D (placebo): vaccine diluent plus adjuvant at birth, 1, and 6 months. Outcomes HBsAg Anti-HBs Anti-HBc Notes Follow-up time: 60 months, but due to the poor reporting, data on 6th month were extracted. Adverse events: not reported HBsAg event was deﬁned as HBsAg positive at any time >= 1 month of age.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 38 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Chronic HBsAg was deﬁned as HBsAg positive for >= 6 months. Allocation concealment B – Unclear

Study Xu 1995 AD Methods This trial is the same as Xu 1995 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Xu 1995 BD Methods This trial is the same as Xu 1995 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Xu 1995 CB Methods This trial is the same as Xu 1995 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Xu 1995 CD Methods This trial is the same as Xu 1995 AB, but has been entered with its own identiﬁer due to technical limits of RevMan in order to make data comparison. Participants Interventions Outcomes Notes Allocation concealment B – Unclear

Study Yeoh 1986 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate. Participants Country: China. Publication language: English.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 39 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of included studies (Continued ) Inclusion criteria: HBsAg-positive mothers. Infants birthweight over 2000 gm. Apgar score >= 7 at 5 minutes. Interventions HBsAg(+)/ HBeAg(+) mothers (150 infants): Group A: HBIG 0.5 mL at birth and PDV 10 microgram were administered at birth, 1, and 6 months. Group B: HBIG 0.5 mL at birth and RV 5 microgram were administered at birth, 1, and 6 months. HBsAg(+)/ HBeAg(-) mothers (150 infants). Group C: HBIG 0.5 mL at birth and PDV 10 microgram were administered at birth, 1, and 6 months. Group D: HBIG 0.5 mL at birth and RV 5 microgram were administered at birth, 1, and 6 months. Outcomes HBsAg HBeAg Anti-HBs Anti-HBc Anti-HBe Notes This trial was published as an abstract. We were not able to extract any relevant data from this abstract. Follow-up time: 6 and 9 months. Adverse events were few and minor, and no serious side-effects were attributable to either vaccine. Allocation concealment B – Unclear

Study Zhu 1987 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: unclear - described as double blind, but method of blinding not described. Follow-up: inadequate. Participants Country: China Publication language: English. Inclusion criteria: HBsAg positive mothers. Interventions Treatment group: 16 microgram vaccine (PDV or RV ?) was given at birth, 1, and 6 months. Control group (n = 57): buffer of HBV at the same interval. Outcomes Transaminase abnormalities and hepatitis markers. Notes This trial was published as an abstract. We were not able to extract relevant data from this abstract. Follow-up time: 24 months. Adverse events: not reported. Allocation concealment B – Unclear

Study Zhu 1994 Methods Generation of allocation sequence: unclear - not described. Allocation concealment: unclear - not described. Blinding: not performed. Follow-up: inadequate - number for dropouts described only, reasons was not reported. Participants Country: China. Publication language: English.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 40 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Inclusion criteria: HBsAg and HBeAg positive mothers. Participants: Group 1 (RV): Birth weight: (mean+-SD): 3290+- 312 Apgar score: 9.3 No of male infants (%): 28 (52%) No of caesarean births (%): 9 (17%) Group 2 (PDV): Birth weight: (mean+-SD): 3301+- 347 Apgar score: 9.1 No of male infants (%): 26 (50%) No of caesarean births (%): 7 (14%) Interventions Group A: RV 20 microgram was administered at birth, 1 and 6 months. Group B: PDV 20 microgram was administered at birth, 1, and 6 months. Outcomes HBsAg Anti-HBs Notes Follow-up time: 6, 12, 24, 36, 48 and 60 months. Adverse events: These recipients of RV have no side effects and the vaccine is safe. Regarding Table 2 and 3. We considered ” negative” patients as having no anti-HBs despite it is unclear in the report. Allocation concealment B – Unclear

Characteristics of excluded studies

Study Reason for exclusion Chung 1988 Non-randomised clinical study. Chung 1988 B Not newborns of HBsAg-positive mothers. Coursaget 1984 Non-randomised clinical study. Da 1995 Non-randomised clinical study. Delage 1993 Non-randomised clinical study. Esteban 1986 Non-randomised clinical study. Goh 1992 The study population were not newborns but 1-12 year-old children. Kang 1986 Non-randomised clinical study. Lai 1986 The study population were not newborns but 3 months to 11 year-old children and the mothers were negative for all hepatitis B viral markers. Lai 1993 The study population were not newborns but 3 months to 11 year-old children. Laille 1988 Non-randomised clinical study. Lin 1987 Non-randomised clinical study. Linder 2000 The study population were not high-risk newborns. Milne 1989 The study population were healthy newborns, not high-risk newborns of HBsAg-positive mothers. Mittal 1994 Non-randomised clinical study. Moulia-Pelat 1994 The study population were healthy newborns, not high-risk newborns of HBsAg-positive mothers.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 41 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Characteristics of excluded studies (Continued ) Nair 1984 Non-randomised clinical study. Okoth 1994 The study population was not newborns of HBsAg-positive mothers. Perrin 1986 The study population in this study was not newborns of HBsAg-positive mothers. Pongpipat 1984 Non-randomised clinical study. Poovorawan 1989 Non-randomised clinical study. Poovorawan 1990 Non-randomised clinical study. Shikata 1984 Non-randomised clinical study. Stevens 1987 Non-randomised clinical study. Stevens 1988 Non-randomised clinical study. Stevens 1990 Non-randomised clinical study. Stevens 1992 Non-randomised clinical study. Surya 1996 Non-randomised clinical study. Suwignyo 1994 Non-randomised clinical study. Theppisai 1988 Non-randomised clinical study. Theppisai 1989 Non-randomised clinical study. Wheeley 1991 Non-randomised clinical study. Young 2003 Non-randomised clinical study. Yuen 1999 The study population was not newborns of HBsAg-positive mothers. Zanetti 1986 Non-randomised clinical study. Zhu 2003 The study population was not exclusively newborns of HBsAg-positive mothers.

ADDITIONAL TABLES

Table 01. Search strategies

Database Period Search strategy The Cochrane Hepato-Biliary Group Controlled Until February 2004 vaccin* AND ’hepatitis B’ AND (newborn* OR Trials Register infant* OR child* OR baby OR babies) AND ’high risk’ The Cochrane Neonatal Group Controlled 20 February 2004 A request for search on the Neonatal Group Trials Register Controlled Trials Register was made (20 Feb, 2004) The Cochrane Vaccines Field Controlled Trials Not obtained A request for search on the Vaccine Field Register Controlled Trials Register was made (20 Feb, 2004). But no reply were obtained. The Cochrane Central Register of Controlled Until February 2004 vaccin* AND ’hepatitis B’ AND (newborn* OR Trials (CENTRAL/CCTR) in The Cochrane infant* OR child* OR baby OR babies) AND Library ’high risk’ PubMed Until February 2004 #1 explode “Vaccination”/ all subheadings #2 explode “Hepatitis-B-Vaccines”/ all subheadings

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 42 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Table 01. Search strategies (Continued )

Database Period Search strategy

#3 explode “Vaccines”/ all subheadings #4 vaccin* #5 PDV #6 YDV #7 #1 or #2 or #3 or #4 or #5 or #6 #8 explode “Hepatitis-B”/ all subheadings #9 hepatitis B #10 #8 or #9 #11 explode “Infant-Newborn”/ all subheadings #12 newborn* or infant* or child* or baby or babies #13 #11 or #12 #14 #13 and high risk #15 #7 and #10 and #14 #16 random* or blind* or placebo* or meta- analysis #17 #15 and #16 #18 (DTP-HB or Hib-HB or Comvax or Pediarix)

MEDLINE January 1966 to February 2004 #1 explode “Vaccination”/ all subheadings #2 explode “Hepatitis-B-Vaccines”/ all subheadings #3 explode “Vaccines”/ all subheadings #4 vaccin* #5 PDV #6 YDV #7 #1 or #2 or #3 or #4 or #5 or #6 #8 explode “Hepatitis-B”/ all subheadings #9 hepatitis B #10 #8 or #9 #11 explode “Infant-Newborn”/ all subheadings #12 newborn* or infant* or child* or baby or babies #13 #11 or #12 #14 #13 and high risk #15 #7 and #10 and #14 #16 random* or blind* or placebo* or meta- analysis #17 #15 and #16 #18 (DTP-HB or Hib-HB or Comvax or Pediarix) EMBASE January 1980 to February 2004 #1 explode “vaccination”/ all subheadings #2 explode “hepatitis-B-vaccine”/ all subheadings #3 explode “hepatitis-vaccine”/ all subheadings #4 explode “vaccine”/ all subheadings #5 vaccin* #6 PDV

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 43 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Table 01. Search strategies (Continued )

Database Period Search strategy

#7 YDV #8 #1 or #2 or #3 or #4 or #5 or #6 or #7 #9 explode “hepatitis-B”/ all subheadings #10 hepatitis B #11 #9 or #10 #12 explode “infant”/ all subheadings #13 explode “newborn”/ all subheadings #14 explode “newborn-hepatitis”/ all subheadings #15 explode “baby”/ all subheadings #16 #12 or #13 or #14 or #15 #17 newborn* or infant* or child* or baby or babies #18 #16 or #17 #19 #18 and high risk #20 #8 and #11 and #19 #21 random* or blind* or placebo* or meta- analysis #22 #20 and #21 #23 (DTP-HB or Hib-HB or Comvax or Pediarix)

Table 02. Intervention by group

Trial Intervention group Control group

Assateerawatt 1993 A*: HBIG 100 IU at birth and RV 20 B: RV 20 microgram at birth and at 1, 2, microgram at birth and at 1, 2, and 12 and 12 months. months. Beasley 1983a A: HBIG 1.0 ml (180 IU) at birth and B: saline at birth and 3 and 6 months. 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. Beasley 1983b A: HBIG 0.5 ml (145 IU) at birth and B: HBIG 0.5 ml (145 IU) and PDV PDV 20 microgram at 4-7 days. Followed 20 microgram at 1 month. Followed by by boosters 1 and 6 months later. boosters 1 and 6 months later. Farmer 1987 A: PDV 0.25 ml (5 microgram) + HBIG B: PDV 0.25 ml (5 microgram) at birth 0.25 ml (25 IU/kg) at birth then PDV + and at 6 weeks and 6 months. HBIG 0.25 ml (25 IU/kg) at 6 weeks and PDV at 6 months. Garcia 1992 A: 10 microgram RV-1 at birth and at 1 B: 10 microgram RV-2 at birth and at 1 and 2 months. and 2 months. Grosheide 1993 A: HBIG 0.5 ml/kg body weight at birth B: HBIG 0.5 ml/kg body weight and PDV and PDV 10 microgram at 2 days and at 10 microgram at 3, 4, 5, and 11 months 1, 2, and 11 months. (with diphtheria, pertussis, tetanus,

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 44 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Table 02. Intervention by group (Continued )

Trial Intervention group Control group

poliomyelitis concomitantly). HBIG 0.5 ml/kg body weight at 3 months.

Halliday 1992 A: RV 20 microgram at birth and at 1 and B: PDV 20 microgram at birth and at 1 6 months. C: HBIG 260 IU at birth and and 6 months. D: HBIG 260 IU at birth RV 20 microgram at birth and at 1 and 6 and RV 10 microgram at birth and at 1 months. and 6 months. Hieu 2002 A: HBIG 100 microgram + 10 microgram B: HBIG 100 microgram + 10 microgram RV-1 at birth and Hepavax at 30 and 180 RV-2 at birth and Engerix-B at 30 and days. 180 days. Ip 1989 A: PDV 3 microgram at birth and at 1, B: PDV 3 microgram at birth and at 1, 2, 2, and 6 months. Also, HBIG 200 IU and 6 months + HBIG 200 IU at birth. at birth, and HBIG 100 IU at monthly D: placebo. intervals during the ﬁrst 6 months after birth. C: PDV 3 microgram at birth and at 1, 2, and 6 months. Kang 1995 A: 20 microgram RV-1 at birth and at 1 B: 20 microgram RV-2 at birth and at 1 and 6 months. and 6 months. Khukhlovich 1996 A: RV 1 ml at birth and at 1, 2, and 14 B: No vaccines. months. Kuru 1995 A: PDV 0.5 ml (2.5 microgram) and B: PDV 1 ml (5 microgram) and HBIG HBIG 200 IU at birth and PDV at 1, 200 IU at birth and PDV at 1, 2, and 12 2, and 12 months. C: RV 0.5 ml (10 months. microgram) and HBIG 200 IU at birth and RV at 1, 2, and 12 months. Lee 1995 * A: HBIG 145 IU at birth + PDV 5 B: HBIG 145 IU at birth + PDV 5 microgram at birth + 10 microgram RV-1 microgram at birth + PDV 5 microgram at at 1, 2, and 12 months. 1, 2, and 12 months. C: HBIG 145 IU at birth + PDV 5 D: HBIG 145 IU at birth + PDV 5 microgram at birth + 5 microgram RV-2 microgram at birth and 1 month + 5 at 1, 2, and 12 months. microgram RV-2 at 2 and 12 months. E: HBIG 145 IU at birth + PDV 5 F: HBIG 145 IU at birth + PDV 5 microgram at birth and 1 month + 10 microgram at birth and RV-1 at 2 and 6 microgram RV-1 at 2 and 12 months. months. G: HBIG 145 IU at birth + PDV 5 microgram at birth and RV-2 at 2 and 6 months. Liu 1987 A: PDV 20 microgram at birth and at 1, 2, B: placebo (normal saline) at birth and at and 6 months. C: PDV 20 microgram at 1, 2, and 6 months. birth and at 1, 2, and 6 months and HBIG at birth. Lo 1985 A: HBIG 50 IU at birth, then PDV 5 B: PDV 5 microgram at 2, 6, and 10 microgram at 2, 6, and 10 weeks. C: PDV weeks. 5 microgram at 2, 6, and 10 weeks + HBIG 50 IU at birth and 1 month.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 45 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Table 02. Intervention by group (Continued )

Trial Intervention group Control group Lolekha 2002 A: RV 5 microgram at birth and at 1 and 6 B: RV 5 microgram at birth and at 1, 2, months. and 12 months. Oon 1986 A: PDV 10 microgram at birth and at B: PDV 5 microgram at birth and at 1 and 1 and 2 months. C: HBIG 100 IU and 2 months. D: HBIG 100 IU and PDV 5 PDV 10 microgram at birth and PDV 10 microgram at birth and PDV 5 microgram microgram at 1 and 2 months. at 1 and 2 months. Piazza 1985 A: PDV 5 microgram and HBIG 50 IU at B:PDV 5 microgram and HBIG 50 IU at birth and PDV at 1 and 2 months. birth and PDV at 2 months. Pongpipat 1986 A: 200 IU HBIG-1 at birth + 5 microgram B: 100 IU HBIG-2 at birth + 10 PDV1 at birth and at 1 and 6 months. microgram PDV2 at birth and at 1 and 6 months. Pongpipat 1988 A: PDV 5 microgram and HBIG 100 IU B:PDV 2 microgram and HBIG 100 IU at at birth + PDV at 1, 2, and 12 months. birth + PDV at 1, 2, and 12 months. Pongpipat 1989 A: RV 5 microgram and HBIG 100 IU at B: PDV 10 microgram and HBIG 100 IU birth and RV at 1, 2, and 12 months. at birth and PDV at 1, 2, and 12 months. Poovorawan 1997 A: RV 10 microgram and HBIG 100 IU B: RV 10 microgram at birth and at 1 and at birth and RV 10 microgram at 1 and 6 6 months. A booster was administered at months. A booster was administered at 60 60 months. months. Sehgal 1992 A: HBIG 0.5 ml and PDV 10 microgram B: PDV 10 microgram at birth and at 4 at birth, and PDV at 4 and 8 weeks. and 8 weeks. Theppisai 1987 A: HBIG 200 IU and PDV 10 microgram B: PDV 10 microgram at birth and at 1 at birth and PDV 10 microgram at 1 and and 6 months. 6 months. Theppisai 1990 A: HBIG 200 IU at birth and PDV 5 B: HBIG 200 IU at birth and PDV 2 microgram at the age of 2 days, 1, 2, and microgram at the age of 2 days, 1, 2, and 12 months. 12 months. Xu 1995 A: 16 microgram PDV-1 at birth and at 1 B: 20 microgram PDV-2 at birth and at and 6 months. C: HBIG 250 IU at birth 1 and 6 months. D: vaccine diluent plus and 20 microgram PDV2 at birth and at 1 adjuvant at birth and at 1 and 6 months. and 6 months. Yeoh 1986 A: HBsAg(+)/ HBeAg(+) mothers (150 B: HBsAg(+)/ HBeAg(+) mothers (150 infants): HBIG 0.5 ml at birth and PDV infants): HBIG 0.5 ml at birth and RV 5 10 microgram at birth and at 1 and 6 microgram at birth and at 1 and 6 months. months. C: HBsAg(+)/ HBeAg(-) mothers D: HBsAg(+)/ HBeAg(-) mothers (150 (150 infants). HBIG 0.5 ml at birth and infants). HBIG 0.5 ml at birth and RV 5 PDV 10 microgram at birth and at 1 and microgram at birth and at 1 and 6 months. 6 months. Zhu 1987 A: 16 microgram vaccine given at birth, 1 B: buffer of HBV given at birth, 1 and 6 and 6 months. months Zhu 1994 A: RV 20 microgram at birth and at 1 and B: PDV 20 microgram at birth and at 1 6 months. and 6 months.

* HBeAg-positive mothers in A to E

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 46 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 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

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events according to 5 403 Relative Risk (Fixed) 95% CI 0.28 [0.20, 0.40] type of vaccine 02 Hepatitis B events according to 5 403 Relative Risk (Fixed) 95% CI 0.28 [0.20, 0.40] methodological quality 03 Hepatitis B events - Sensitivity Relative Risk (Fixed) 95% CI Subtotals only analyses 04 Hepatitis B events according to 7 403 Relative Risk (Fixed) 95% CI 0.29 [0.20, 0.41] the mother’s HBeAg status 05 Hepatitis B events according 5 403 Relative Risk (Fixed) 95% CI 0.28 [0.20, 0.40] to ﬁrst time of vaccine administration

Comparison 02. RV versus PDV

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 5 382 Relative Risk (Fixed) 95% CI 1.00 [0.70, 1.42] 02 Hepatitis B events according to 5 382 Relative Risk (Fixed) 95% CI 1.00 [0.70, 1.42] methodological quality 03 Hepatitis B events - sensitivity Relative Risk (Fixed) 95% CI Subtotals only analyses 04 Hepatitis B events according to 5 382 Relative Risk (Fixed) 95% CI 1.00 [0.70, 1.42] the mother’s HBeAg status 05 Anti-HBs less than 10 IU/L 4 256 Relative Risk (Fixed) 95% CI 0.51 [0.36, 0.72]

Comparison 03. High-dose versus low-dose vaccine

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 5 582 Relative Risk (Fixed) 95% CI 0.91 [0.57, 1.46] 02 Hepatitis B events according to 5 582 Relative Risk (Fixed) 95% CI 0.91 [0.57, 1.46] methodological quality 03 Hepatitis B events - sensitivity Relative Risk (Fixed) 95% CI Subtotals only analyses 04 Hepatitis B events according to 5 582 Relative Risk (Fixed) 95% CI 0.91 [0.57, 1.46] the mother’s HBeAg status

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 47 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 05 Anti-HBs less than 10 IU/L 2 166 Relative Risk (Fixed) 95% CI 1.02 [0.82, 1.27]

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

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 1 74 Relative Risk (Fixed) 95% CI 0.50 [0.05, 5.28] 02 Anti-HBs less than 10 IU/L 1 74 Relative Risk (Fixed) 95% CI 0.05 [0.00, 0.78]

Comparison 05. PDV at birth versus PDV at one month

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 1 108 Relative Risk (Fixed) 95% CI 0.70 [0.18, 2.77]

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

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 1 120 Relative Risk (Fixed) 95% CI 0.50 [0.22, 1.15]

Comparison 07. Four RV vaccinations versus three RV vaccinations

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 1 97 Relative Risk (Fixed) 95% CI 1.49 [0.51, 4.37] 02 Anti-HBs level less than 10 1 97 Relative Risk (Fixed) 95% CI 0.53 [0.10, 2.77] IU/L

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

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events Relative Risk (Fixed) 95% CI Subtotals only 02 Anti-HBs less than 10 IU/L Relative Risk (Fixed) 95% CI Subtotals only

Comparison 09. HBIG versus placebo or no intervention

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 14 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63] 02 Hepatitis B events according to 14 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63] methodological quality of the trials 03 Hepatitis B events - sensitivity Relative Risk (Fixed) 95% CI Subtotals only analyses 04 Hepatitis B events according to 15 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63] the mother’s HBeAg status 05 Hepatitis B events according to 14 1086 Relative Risk (Fixed) 95% CI 0.52 [0.44, 0.63] time of HBIG administration 06 Hepatitis B events according to 9 711 Relative Risk (Fixed) 95% CI 0.53 [0.39, 0.74] standard and rapid schedule of vaccines

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 48 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 07 Anti-HBs less than 10 IU/L 4 348 Relative Risk (Fixed) 95% CI 1.55 [0.89, 2.73] 08 Anti-HBs level Weighted Mean Difference (Fixed) 95% CI Subtotals only 09 Adverse events 1 136 Relative Risk (Fixed) 95% CI 3.47 [0.14, 83.67]

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

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 2 198 Relative Risk (Fixed) 95% CI 0.87 [0.30, 2.47]

Comparison 11. PDV plus HBIG versus placebo or no intervention

No. of No. of Outcome title studies participants Statistical method Effect size 01 Hepatitis B events 4 246 Relative Risk (Fixed) 95% CI 0.08 [0.03, 0.17] 02 Hepatitis B events according to 4 246 Relative Risk (Fixed) 95% CI 0.08 [0.03, 0.17] methodological quality of the trials 03 Hepatitis B events - sensitivity Relative Risk (Fixed) 95% CI Subtotals only analyses 04 Hepatitis B events according to 5 246 Relative Risk (Fixed) 95% CI 0.08 [0.04, 0.18] mother’s HBeAg status 05 Hepatitis B events according to 4 246 Relative Risk (Fixed) 95% CI 0.08 [0.03, 0.17] time of HBIG administration 06 Adverse events 2 105 Relative Risk (Fixed) 95% CI 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.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 49 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Issue protocol ﬁrst published 2004/2

Review ﬁrst published 2006/2

Date of most recent amendment 22 February 2006

Date of most recent 22 February 2006 SUBSTANTIVE amendment

What’s New Information not supplied by author

Date new studies sought but Information not supplied by author none found

Date new studies found but not Information not supplied by author yet included/excluded

Date new studies found and 01 February 2004 included/excluded

Date authors’ conclusions Information not supplied by author 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

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 50 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd 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 Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 01 Vaccine versus placebo or no intervention Outcome: 01 Hepatitis B events according to type of vaccine

Study Vaccine Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 PDV versus placebo or no intervention Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

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

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

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ] Subtotal (95% CI) 182 120 86.0 0.31 [ 0.21, 0.45 ] Total events: 31 (Vaccine), 68 (Control) Test for heterogeneity chi-square=6.00 df=3 p=0.11 I² =50.0% Test for overall effect z=6.03 p<0.00001

02 RV versus no intervention Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ] Subtotal (95% CI) 70 31 14.0 0.10 [ 0.02, 0.43 ] Total events: 2 (Vaccine), 9 (Control) Test for heterogeneity: not applicable Test for overall effect z=3.09 p=0.002 Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ] Total events: 33 (Vaccine), 77 (Control) Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2% Test for overall effect z=6.83 p<0.00001

0.01 0.1 1 10 100 Vaccine better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 51 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 01.02. Comparison 01 Vaccine versus placebo or no intervention, Outcome 02 Hepatitis B events according to methodological quality Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 01 Vaccine versus placebo or no intervention Outcome: 02 Hepatitis B events according to methodological quality Study Vaccine Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 High-quality trials Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

Liu 1987 AB 3/27 21/26 24.0 0.14 [ 0.05, 0.41 ] Subtotal (95% CI) 62 60 50.1 0.22 [ 0.12, 0.40 ] Total events: 10 (Vaccine), 44 (Control) Test for heterogeneity chi-square=1.40 df=1 p=0.24 I² =28.7% Test for overall effect z=5.03 p<0.00001

02 Low-quality trials Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ]

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

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ] Subtotal (95% CI) 190 91 49.9 0.34 [ 0.22, 0.54 ] Total events: 23 (Vaccine), 33 (Control) Test for heterogeneity chi-square=5.61 df=2 p=0.06 I² =64.3% Test for overall effect z=4.56 p<0.00001 Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ] Total events: 33 (Vaccine), 77 (Control) Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2% Test for overall effect z=6.83 p<0.00001

0.01 0.1 1 10 100 Vaccine better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 52 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 01.03. Comparison 01 Vaccine versus placebo or no intervention, Outcome 03 Hepatitis B events - Sensitivity analyses Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 01 Vaccine versus placebo or no intervention Outcome: 03 Hepatitis B events - Sensitivity analyses Study Vaccine Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 Available patients’ course analysis Ip 1989 CD 7/35 23/34 28.2 0.30 [ 0.15, 0.60 ]

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

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

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

Xu 1995 BD 10/56 10/28 16.1 0.50 [ 0.24, 1.06 ] Subtotal (95% CI) 243 146 100.0 0.23 [ 0.15, 0.35 ] Total events: 24 (Vaccine), 72 (Control) Test for heterogeneity chi-square=7.74 df=4 p=0.10 I² =48.3% Test for overall effect z=6.94 p<0.00001

02 Assuming poor outcome Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

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

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

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

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ] Subtotal (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ] Total events: 33 (Vaccine), 77 (Control) Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2% Test for overall effect z=6.83 p<0.00001

03 Assuming good outcome Ip 1989 CD 7/35 23/34 28.3 0.30 [ 0.15, 0.60 ]

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

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

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

Xu 1995 BD 10/60 10/30 16.2 0.50 [ 0.23, 1.07 ] Subtotal (95% CI) 252 151 100.0 0.23 [ 0.15, 0.35 ] Total events: 24 (Vaccine), 72 (Control) Test for heterogeneity chi-square=7.57 df=4 p=0.11 I² =47.2% Test for overall effect z=6.91 p<0.00001

0.01 0.1 1 10 100 Vaccine better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 53 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study Vaccine Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI 04 Extreme case favouring vaccine Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

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

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

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

Xu 1995 BD 10/60 12/30 17.9 0.42 [ 0.20, 0.85 ] Subtotal (95% CI) 252 151 100.0 0.21 [ 0.14, 0.32 ] Total events: 24 (Vaccine), 77 (Control) Test for heterogeneity chi-square=7.53 df=4 p=0.11 I² =46.8% Test for overall effect z=7.39 p<0.00001

05 Extreme case favouring control Ip 1989 CD 7/35 23/34 28.3 0.30 [ 0.15, 0.60 ]

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

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

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

Xu 1995 BD 14/60 10/30 16.2 0.70 [ 0.35, 1.39 ] Subtotal (95% CI) 252 151 100.0 0.30 [ 0.21, 0.44 ] Total events: 33 (Vaccine), 72 (Control) Test for heterogeneity chi-square=10.35 df=4 p=0.03 I² =61.4% Test for overall effect z=6.26 p<0.00001

0.01 0.1 1 10 100 Vaccine better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 54 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 01.04. Comparison 01 Vaccine versus placebo or no intervention, Outcome 04 Hepatitis B events according to the mother’s HBeAg status Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 01 Vaccine versus placebo or no intervention Outcome: 04 Hepatitis B events according to the mother’s HBeAg status Study Vaccine Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

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

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

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

Xu 1995 BD 9/29 11/16 16.0 0.45 [ 0.24, 0.85 ] Subtotal (95% CI) 121 91 81.4 0.27 [ 0.18, 0.40 ] Total events: 24 (Vaccine), 65 (Control) Test for heterogeneity chi-square=4.08 df=3 p=0.25 I² =26.4% Test for overall effect z=6.43 p<0.00001

02 HBeAg unknown Khukhlovich 1996 2/70 9/31 14.1 0.10 [ 0.02, 0.43 ] Subtotal (95% CI) 70 31 14.1 0.10 [ 0.02, 0.43 ] Total events: 2 (Vaccine), 9 (Control) Test for heterogeneity: not applicable Test for overall effect z=3.09 p=0.002

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

Xu 1995 BD 5/31 2/15 3.0 1.21 [ 0.26, 5.53 ] Subtotal (95% CI) 61 29 4.6 1.12 [ 0.31, 3.97 ] Total events: 7 (Vaccine), 3 (Control) Test for heterogeneity chi-square=0.03 df=1 p=0.85 I² =0.0% Test for overall effect z=0.17 p=0.9 Total (95% CI) 252 151 100.0 0.29 [ 0.20, 0.41 ] Total events: 33 (Vaccine), 77 (Control) Test for heterogeneity chi-square=10.33 df=6 p=0.11 I² =41.9% Test for overall effect z=6.88 p<0.00001

0.01 0.1 1 10 100 Vaccine better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 55 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 01.05. Comparison 01 Vaccine versus placebo or no intervention, Outcome 05 Hepatitis B events according to ﬁrst time of vaccine administration Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 01 Vaccine versus placebo or no intervention Outcome: 05 Hepatitis B events according to ﬁrst time of vaccine administration

Study Vaccine Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 Vaccine administered within 12 hours of birth Ip 1989 CD 7/35 23/34 26.2 0.30 [ 0.15, 0.60 ]

Khukhlovich 1996 2/70 9/31 14.0 0.10 [ 0.02, 0.43 ] Subtotal (95% CI) 105 65 40.1 0.23 [ 0.12, 0.42 ] Total events: 9 (Vaccine), 32 (Control) Test for heterogeneity chi-square=1.78 df=1 p=0.18 I² =43.9% Test for overall effect z=4.67 p<0.00001

02 Vaccine administered within 24 hours of birth Xu 1995 AD 7/60 12/30 17.9 0.29 [ 0.13, 0.66 ]

Xu 1995 BD 14/60 12/30 17.9 0.58 [ 0.31, 1.10 ] Subtotal (95% CI) 120 60 35.9 0.44 [ 0.27, 0.72 ] Total events: 21 (Vaccine), 24 (Control) Test for heterogeneity chi-square=1.72 df=1 p=0.19 I² =42.0% Test for overall effect z=3.26 p=0.001

03 Vaccine administered within 48 hours of birth Liu 1987 AB 3/27 21/26 24.0 0.14 [ 0.05, 0.41 ] Subtotal (95% CI) 27 26 24.0 0.14 [ 0.05, 0.41 ] Total events: 3 (Vaccine), 21 (Control) Test for heterogeneity: not applicable Test for overall effect z=3.59 p=0.0003 Total (95% CI) 252 151 100.0 0.28 [ 0.20, 0.40 ] Total events: 33 (Vaccine), 77 (Control) Test for heterogeneity chi-square=8.74 df=4 p=0.07 I² =54.2% Test for overall effect z=6.83 p<0.00001

0.01 0.1 1 10 100 Vaccine better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 56 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 02.01. Comparison 02 RV versus PDV, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 02 RV versus PDV Outcome: 01 Hepatitis B events

Study RV PDV RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

01 RV versus PDV Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ]

Zhu 1994 17/54 21/52 45.9 0.78 [ 0.47, 1.30 ] Subtotal (95% CI) 109 107 84.5 0.75 [ 0.51, 1.12 ] Total events: 30 (RV), 39 (PDV) Test for heterogeneity chi-square=0.04 df=1 p=0.85 I² =0.0% Test for overall effect z=1.41 p=0.2

02 RV plus HBIG versus PDV plus HBIG Lee 1995 AB 15/51 2/14 6.7 2.06 [ 0.53, 7.96 ]

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

Pongpipat 1989 3/20 1/20 2.1 3.00 [ 0.34, 26.45 ] Subtotal (95% CI) 118 48 15.5 2.33 [ 0.97, 5.56 ] Total events: 34 (RV), 5 (PDV) Test for heterogeneity chi-square=0.09 df=2 p=0.96 I² =0.0% Test for overall effect z=1.90 p=0.06 Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ] Total events: 64 (RV), 44 (PDV) Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4% Test for overall effect z=0.02 p=1

0.01 0.1 1 10 100 RV better PDV better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 57 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 02.02. Comparison 02 RV versus PDV, Outcome 02 Hepatitis B events according to methodological quality Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 02 RV versus PDV Outcome: 02 Hepatitis B events according to methodological quality Study RV PDV RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

01 High-quality trials Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ] Subtotal (95% CI) 55 55 38.6 0.72 [ 0.39, 1.33 ] Total events: 13 (RV), 18 (PDV) Test for heterogeneity: not applicable Test for overall effect z=1.05 p=0.3

02 Low-quality trials Lee 1995 AB 15/51 2/14 6.7 2.06 [ 0.53, 7.96 ]

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

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

Zhu 1994 17/54 21/52 45.9 0.78 [ 0.47, 1.30 ] Subtotal (95% CI) 172 100 61.4 1.17 [ 0.75, 1.82 ] Total events: 51 (RV), 26 (PDV) Test for heterogeneity chi-square=4.87 df=3 p=0.18 I² =38.4% Test for overall effect z=0.70 p=0.5 Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ] Total events: 64 (RV), 44 (PDV) Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4% Test for overall effect z=0.02 p=1

0.01 0.1 1 10 100 RV better PDV better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 58 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 02.03. Comparison 02 RV versus PDV, Outcome 03 Hepatitis B events - sensitivity analyses Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 02 RV versus PDV Outcome: 03 Hepatitis B events - sensitivity analyses Study RV PDV RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

01 Available patients’ course analysis Halliday 1992 AB 4/46 12/49 42.0 0.36 [ 0.12, 1.02 ]

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

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

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

Zhu 1994 6/43 9/40 33.7 0.62 [ 0.24, 1.59 ] Subtotal (95% CI) 180 137 100.0 0.53 [ 0.30, 0.95 ] Total events: 17 (RV), 26 (PDV) Test for heterogeneity chi-square=2.20 df=4 p=0.70 I² =0.0% Test for overall effect z=2.13 p=0.03

02 Assuming poor outcome Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ]

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

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

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

Zhu 1994 17/54 21/52 45.9 0.78 [ 0.47, 1.30 ] Subtotal (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ] Total events: 64 (RV), 44 (PDV) Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4% Test for overall effect z=0.02 p=1

03 Assuming good outcome Halliday 1992 AB 4/55 12/55 42.3 0.33 [ 0.11, 0.97 ]

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

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

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

Zhu 1994 6/54 9/52 32.3 0.64 [ 0.25, 1.68 ] Subtotal (95% CI) 227 155 100.0 0.50 [ 0.28, 0.89 ] Total events: 17 (RV), 26 (PDV) Test for heterogeneity chi-square=2.60 df=4 p=0.63 I² =0.0% Test for overall effect z=2.34 p=0.02

0.01 0.1 1 10 100 RV better PDV better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 59 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study RV PDV RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI 04 Extreme case favouring RV Halliday 1992 AB 4/55 18/55 38.6 0.22 [ 0.08, 0.61 ]

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

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

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

Zhu 1994 6/54 21/52 45.9 0.28 [ 0.12, 0.63 ] Subtotal (95% CI) 227 155 100.0 0.30 [ 0.18, 0.52 ] Total events: 17 (RV), 44 (PDV) Test for heterogeneity chi-square=3.17 df=4 p=0.53 I² =0.0% Test for overall effect z=4.33 p=0.00001

05 Extreme case favouring PDV Halliday 1992 AB 13/55 12/55 42.3 1.08 [ 0.54, 2.16 ]

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

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

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

Zhu 1994 17/54 9/52 32.3 1.82 [ 0.89, 3.71 ] Subtotal (95% CI) 227 155 100.0 1.64 [ 1.07, 2.52 ] Total events: 64 (RV), 26 (PDV) Test for heterogeneity chi-square=2.17 df=4 p=0.70 I² =0.0% Test for overall effect z=2.25 p=0.02

0.01 0.1 1 10 100 RV better PDV better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 60 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 02.04. Comparison 02 RV versus PDV, Outcome 04 Hepatitis B events according to the mother’s HBeAg status Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 02 RV versus PDV Outcome: 04 Hepatitis B events according to the mother’s HBeAg status Study RV PDV RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

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

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

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

02 HBeAg unknown Halliday 1992 AB 13/55 18/55 38.6 0.72 [ 0.39, 1.33 ] Subtotal (95% CI) 55 55 38.6 0.72 [ 0.39, 1.33 ] Total events: 13 (RV), 18 (PDV) Test for heterogeneity: not applicable Test for overall effect z=1.05 p=0.3

03 HBeAg negative Subtotal (95% CI) 0 0 0.0 Not estimable Total events: 0 (RV), 0 (PDV) Test for heterogeneity: not applicable Test for overall effect: not applicable Total (95% CI) 227 155 100.0 1.00 [ 0.70, 1.42 ] Total events: 64 (RV), 44 (PDV) Test for heterogeneity chi-square=5.67 df=4 p=0.23 I² =29.4% Test for overall effect z=0.02 p=1

0.01 0.1 1 10 100 RV better PDV better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 61 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 02.05. Comparison 02 RV versus PDV, Outcome 05 Anti-HBs less than 10 IU/L Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 02 RV versus PDV Outcome: 05 Anti-HBs less than 10 IU/L

Study RV PDV RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

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

Kuru 1995 AC 0/5 0/25 0.0 Notestimable

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

Zhu 1994 19/43 33/40 68.2 0.54 [ 0.37, 0.77 ] Total (95% CI) 100 156 100.0 0.51 [ 0.36, 0.72 ] Total events: 25 (RV), 50 (PDV) Test for heterogeneity chi-square=1.17 df=2 p=0.56 I² =0.0% Test for overall effect z=3.81 p=0.0001

0.01 0.1 1 10 100 RV better PDV better

Analysis 03.01. Comparison 03 High-dose versus low-dose vaccine, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 03 High-dose versus low-dose vaccine Outcome: 01 Hepatitis B events Study Highdose Lowdose RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 High-dose PDV versus low-dose PDV Oon 1986 AB 0/141 0/102 0.0 Notestimable Subtotal (95% CI) 141 102 0.0 Not estimable Total events: 0 (High dose), 0 (Low dose) Test for heterogeneity: not applicable Test for overall effect: not applicable

02 High-dose PDV plus HBIG versus low-dose PDV plus HBIG Oon 1986 CD 10/70 10/59 36.4 0.84 [ 0.38, 1.89 ]

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

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ] Subtotal (95% CI) 120 109 69.9 0.97 [ 0.55, 1.68 ] Total events: 21 (High dose), 20 (Low dose) Test for heterogeneity chi-square=2.91 df=2 p=0.23 I² =31.3% Test for overall effect z=0.12 p=0.9

0.01 0.1 1 10 100 High dose better Low dose better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 62 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study Highdose Lowdose RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI 03 High-dose RV plus HBIG versus low-dose RV plus HBIG Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ] Subtotal (95% CI) 55 55 30.1 0.78 [ 0.31, 1.94 ] Total events: 7 (High dose), 9 (Low dose) Test for heterogeneity: not applicable Test for overall effect z=0.54 p=0.6 Total (95% CI) 316 266 100.0 0.91 [ 0.57, 1.46 ] Total events: 28 (High dose), 29 (Low dose) Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8% Test for overall effect z=0.39 p=0.7

0.01 0.1 1 10 100 High dose better Low dose better

Analysis 03.02. Comparison 03 High-dose versus low-dose vaccine, Outcome 02 Hepatitis B events according to methodological quality Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 03 High-dose versus low-dose vaccine Outcome: 02 Hepatitis B events according to methodological quality Study High-dosevaccine Low-dosevaccine RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

01 High-quality trials Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ] Subtotal (95% CI) 55 55 30.1 0.78 [ 0.31, 1.94 ] Total events: 7 (High-dose vaccine), 9 (Low-dose vaccine) Test for heterogeneity: not applicable Test for overall effect z=0.54 p=0.6

02 Low-quality trials Oon 1986 AB 0/141 0/102 0.0 Notestimable

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

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

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ] Subtotal (95% CI) 261 211 69.9 0.97 [ 0.55, 1.68 ] Total events: 21 (High-dose vaccine), 20 (Low-dose vaccine) Test for heterogeneity chi-square=2.91 df=2 p=0.23 I² =31.3% Test for overall effect z=0.12 p=0.9 Total (95% CI) 316 266 100.0 0.91 [ 0.57, 1.46 ]

0.01 0.1 1 10 100 High dose better Low dose better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 63 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study High-dosevaccine Low-dosevaccine RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI Total events: 28 (High-dose vaccine), 29 (Low-dose vaccine) Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8% Test for overall effect z=0.39 p=0.7

0.01 0.1 1 10 100 High dose better Low dose better

Analysis 03.03. Comparison 03 High-dose versus low-dose vaccine, Outcome 03 Hepatitis B events - sensitivity analyses Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 03 High-dose versus low-dose vaccine Outcome: 03 Hepatitis B events - sensitivity analyses Study High-dosevaccine Low-dosevaccine RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

01 Available patients’ course analysis Halliday 1992 DC 2/50 3/49 18.0 0.65 [ 0.11, 3.74 ]

Oon 1986 AB 0/141 0/102 0.0 Notestimable

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

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

Theppisai 1990 2/24 2/28 11.0 1.17 [ 0.18, 7.67 ] Subtotal (95% CI) 303 253 100.0 0.84 [ 0.44, 1.63 ] Total events: 15 (High-dose vaccine), 16 (Low-dose vaccine) Test for heterogeneity chi-square=0.20 df=3 p=0.98 I² =0.0% Test for overall effect z=0.51 p=0.6

02 Assuming poor oucome Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ]

Oon 1986 AB 0/141 0/102 0.0 Notestimable

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

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

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ] Subtotal (95% CI) 316 266 100.0 0.91 [ 0.57, 1.46 ] Total events: 28 (High-dose vaccine), 29 (Low-dose vaccine) Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8% Test for overall effect z=0.39 p=0.7

03 Assuming good outcome

0.01 0.1 1 10 100 High dose better Low dose better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 64 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study High-dosevaccine Low-dosevaccine RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI Halliday 1992 DC 2/55 3/55 17.8 0.67 [ 0.12, 3.84 ]

Oon 1986 AB 0/141 0/102 0.0 Notestimable

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

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

Theppisai 1990 2/30 2/30 11.9 1.00 [ 0.15, 6.64 ] Subtotal (95% CI) 316 266 100.0 0.84 [ 0.43, 1.63 ] Total events: 15 (High-dose vaccine), 16 (Low-dose vaccine) Test for heterogeneity chi-square=0.12 df=3 p=0.99 I² =0.0% Test for overall effect z=0.52 p=0.6

04 Extreme case favouring high-dose vaccine Halliday 1992 DC 2/55 9/55 32.3 0.22 [ 0.05, 0.98 ]

Oon 1986 AB 0/141 0/102 0.0 Notestimable

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

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

Theppisai 1990 8/30 2/30 7.2 4.00 [ 0.92, 17.30 ] Subtotal (95% CI) 316 266 100.0 0.72 [ 0.42, 1.24 ] Total events: 21 (High-dose vaccine), 27 (Low-dose vaccine) Test for heterogeneity chi-square=9.82 df=3 p=0.02 I² =69.5% Test for overall effect z=1.18 p=0.2

05 Extreme case favouring low-dose vaccine Halliday 1992 DC 7/55 3/55 15.9 2.33 [ 0.64, 8.56 ]

Oon 1986 AB 0/141 0/102 0.0 Notestimable

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

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

Theppisai 1990 8/30 4/30 21.2 2.00 [ 0.67, 5.94 ] Subtotal (95% CI) 316 266 100.0 1.44 [ 0.84, 2.48 ] Total events: 28 (High-dose vaccine), 18 (Low-dose vaccine) Test for heterogeneity chi-square=3.02 df=3 p=0.39 I² =0.5% Test for overall effect z=1.31 p=0.2

0.01 0.1 1 10 100 High dose better Low dose better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 65 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 03.04. Comparison 03 High-dose versus low-dose vaccine, Outcome 04 Hepatitis B events according to the mother’s HBeAg status Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 03 High-dose versus low-dose vaccine Outcome: 04 Hepatitis B events according to the mother’s HBeAg status

Study High-dosevaccine Low-dosevaccine RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

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

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

Theppisai 1990 8/30 4/30 13.4 2.00 [ 0.67, 5.94 ] Subtotal (95% CI) 120 109 69.9 0.97 [ 0.55, 1.68 ] Total events: 21 (High-dose vaccine), 20 (Low-dose vaccine) Test for heterogeneity chi-square=2.91 df=2 p=0.23 I² =31.3% Test for overall effect z=0.12 p=0.9

02 HBeAg unknown Halliday 1992 DC 7/55 9/55 30.1 0.78 [ 0.31, 1.94 ] Subtotal (95% CI) 55 55 30.1 0.78 [ 0.31, 1.94 ] Total events: 7 (High-dose vaccine), 9 (Low-dose vaccine) Test for heterogeneity: not applicable Test for overall effect z=0.54 p=0.6

03 HBeAg negative Oon 1986 AB 0/102 0/141 0.0 Notestimable Subtotal (95% CI) 102 141 0.0 Not estimable Total events: 0 (High-dose vaccine), 0 (Low-dose vaccine) Test for heterogeneity: not applicable Test for overall effect: not applicable Total (95% CI) 277 305 100.0 0.91 [ 0.57, 1.46 ] Total events: 28 (High-dose vaccine), 29 (Low-dose vaccine) Test for heterogeneity chi-square=3.06 df=3 p=0.38 I² =1.8% Test for overall effect z=0.39 p=0.7

0.01 0.1 1 10 100 High dose better Low dose better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 66 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 03.05. Comparison 03 High-dose versus low-dose vaccine, Outcome 05 Anti-HBs less than 10 IU/L Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 03 High-dose versus low-dose vaccine Outcome: 05 Anti-HBs less than 10 IU/L

Study High-dosevaccine Low-dosevaccine RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

01 High dose PDV versus low dose PDV Kuru 1995 AB 1/42 0/25 1.6 1.81 [ 0.08, 42.90 ] Subtotal (95% CI) 42 25 1.6 1.81 [ 0.08, 42.90 ] Total events: 1 (High-dose vaccine), 0 (Low-dose vaccine) Test for heterogeneity: not applicable Test for overall effect z=0.37 p=0.7

02 High dose RV versus low dose RV Halliday 1992 DC 39/50 38/49 98.4 1.01 [ 0.81, 1.24 ] Subtotal (95% CI) 50 49 98.4 1.01 [ 0.81, 1.24 ] Total events: 39 (High-dose vaccine), 38 (Low-dose vaccine) Test for heterogeneity: not applicable Test for overall effect z=0.05 p=1 Total (95% CI) 92 74 100.0 1.02 [ 0.82, 1.27 ] Total events: 40 (High-dose vaccine), 38 (Low-dose vaccine) Test for heterogeneity chi-square=0.14 df=1 p=0.71 I² =0.0% Test for overall effect z=0.17 p=0.9

0.001 0.01 0.1 1 10 100 1000 High dose better Low dose better

Analysis 04.01. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG Outcome: 01 Hepatitis B events

Study Threedoses Twodoses RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

Piazza 1985 1/37 2/37 100.0 0.50 [ 0.05, 5.28 ] Total (95% CI) 37 37 100.0 0.50 [ 0.05, 5.28 ] Total events: 1 (Three doses), 2 (Two doses) Test for heterogeneity: not applicable Test for overall effect z=0.58 p=0.6

0.01 0.1 1 10 100 Three doses better Two doses better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 67 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 04.02. Comparison 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG, Outcome 02 Anti-HBs less than 10 IU/L Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 04 Three-dose PDV plus HBIG versus two-dose PDV plus HBIG Outcome: 02 Anti-HBs less than 10 IU/L

Study Threedoses Twodoses RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

Piazza 1985 0/37 10/37 100.0 0.05 [ 0.00, 0.78 ] Total (95% CI) 37 37 100.0 0.05 [ 0.00, 0.78 ] Total events: 0 (Three doses), 10 (Two doses) Test for heterogeneity: not applicable Test for overall effect z=2.13 p=0.03

0.001 0.01 0.1 1 10 100 1000 Three doses better Two doses better

Analysis 05.01. Comparison 05 PDV at birth versus PDV at one month, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 05 PDV at birth versus PDV at one month Outcome: 01 Hepatitis B events

Study Atbirth Atonemonth RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

Beasley 1983b 3/50 5/58 100.0 0.70 [ 0.18, 2.77 ] Total (95% CI) 50 58 100.0 0.70 [ 0.18, 2.77 ] Total events: 3 (At birth), 5 (At one month) Test for heterogeneity: not applicable Test for overall effect z=0.51 p=0.6

0.01 0.1 1 10 100 At birth better One month better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 68 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 06.01. Comparison 06 One type of PDV versus another type of PDV, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 06 One type of PDV versus another type of PDV Outcome: 01 Hepatitis B events

Study NIAID BIVS RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 NIAID versus BIVS Xu 1995 AB 7/60 14/60 100.0 0.50 [ 0.22, 1.15 ] Total (95% CI) 60 60 100.0 0.50 [ 0.22, 1.15 ] Total events: 7 (NIAID), 14 (BIVS) Test for heterogeneity: not applicable Test for overall effect z=1.63 p=0.1

0.01 0.1 1 10 100 NIAID better BIVS better

Analysis 07.01. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 07 Four RV vaccinations versus three RV vaccinations Outcome: 01 Hepatitis B events

Study 0-1-2-12 schedule 0-1-6 schedule Relative Risk (Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

Lolekha 2002 7/47 5/50 100.0 1.49 [ 0.51, 4.37 ] Total (95% CI) 47 50 100.0 1.49 [ 0.51, 4.37 ] Total events: 7 (0-1-2-12 schedule), 5 (0-1-6 schedule) Test for heterogeneity: not applicable Test for overall effect z=0.73 p=0.5

0.01 0.1 1 10 100 0-1-2-12 better 0-1-6 better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 69 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 07.02. Comparison 07 Four RV vaccinations versus three RV vaccinations, Outcome 02 Anti-HBs level less than 10 IU/L Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 07 Four RV vaccinations versus three RV vaccinations Outcome: 02 Anti-HBs level less than 10 IU/L

Study 0-1-2-12 schedule 0-1-6 schedule Relative Risk (Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

Lolekha 2002 2/47 4/50 100.0 0.53 [ 0.10, 2.77 ] Total (95% CI) 47 50 100.0 0.53 [ 0.10, 2.77 ] Total events: 2 (0-1-2-12 schedule), 4 (0-1-6 schedule) Test for heterogeneity: not applicable Test for overall effect z=0.75 p=0.5

0.01 0.1 1 10 100 0-1-2-12 better 0-1-6 better

Analysis 08.01. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule, Outcome 01 Hepatitis B events

Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 08 One type of RV versus another type of RV with the same vaccination schedule Outcome: 01 Hepatitis B events

Study RV1 RV2 RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

01 Hepavax-Gene plus HBIG versus Engerix-B plus HBIG Hieu 2002 1/53 2/52 100.0 0.49 [ 0.05, 5.25 ] Subtotal (95% CI) 53 52 100.0 0.49 [ 0.05, 5.25 ] Total events: 1 (RV1), 2 (RV2) Test for heterogeneity: not applicable Test for overall effect z=0.59 p=0.6

02 HB VAX II plus HBIG versus Engerix-B plus HBIG Lee 1995 CA 3/34 2/38 31.8 1.68 [ 0.30, 9.44 ]

Lee 1995 DE 3/36 4/35 68.2 0.73 [ 0.18, 3.03 ] Subtotal (95% CI) 70 73 100.0 1.03 [ 0.35, 3.02 ] Total events: 6 (RV1), 6 (RV2) Test for heterogeneity chi-square=0.53 df=1 p=0.47 I² =0.0% Test for overall effect z=0.05 p=1

03 RV1 (Beijing, China) versus RV2 (Institute of Preventive Medicine, China ) Kang 1995 9/57 5/41 100.0 1.29 [ 0.47, 3.58 ] Subtotal (95% CI) 57 41 100.0 1.29 [ 0.47, 3.58 ] Total events: 9 (RV1), 5 (RV2) Test for heterogeneity: not applicable Test for overall effect z=0.50 p=0.6

0.01 0.1 1 10 100 RV1 better RV2 better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 70 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 08.02. Comparison 08 One type of RV versus another type of RV with the same vaccination schedule, Outcome 02 Anti-HBs less than 10 IU/L Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 08 One type of RV versus another type of RV with the same vaccination schedule Outcome: 02 Anti-HBs less than 10 IU/L

Study RV Engerix-B RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 Hepavax-Gene versus Engerix-B Hieu 2002 4/53 5/52 100.0 0.78 [ 0.22, 2.76 ] Subtotal (95% CI) 53 52 100.0 0.78 [ 0.22, 2.76 ] Total events: 4 (RV), 5 (Engerix-B) Test for heterogeneity: not applicable Test for overall effect z=0.38 p=0.7

02 Cuban versus Engerix-B Garcia 1992 0/54 1/24 100.0 0.15 [ 0.01, 3.59 ] Subtotal (95% CI) 54 24 100.0 0.15 [ 0.01, 3.59 ] Total events: 0 (RV), 1 (Engerix-B) Test for heterogeneity: not applicable Test for overall effect z=1.17 p=0.2

0.001 0.01 0.1 1 10 100 1000 RV better Engerix-B better

Analysis 09.01. Comparison 09 HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 01 Hepatitis B events Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 HBIG versus placebo or no intervention Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ] Subtotal (95% CI) 139 73 46.9 0.50 [ 0.41, 0.60 ] Total events: 66 (HBIG), 68 (Control) Test for heterogeneity chi-square=7.81 df=1 p=0.005 I² =87.2% Test for overall effect z=7.17 p<0.00001

02 HBIG plus PDV versus PDV Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 71 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ] Subtotal (95% CI) 328 249 29.0 0.49 [ 0.32, 0.74 ] Total events: 33 (HBIG), 51 (Control) Test for heterogeneity chi-square=5.97 df=8 p=0.65 I² =0.0% Test for overall effect z=3.38 p=0.0007

03 HBIG plus RV versus RV Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ] Subtotal (95% CI) 148 149 24.1 0.61 [ 0.41, 0.92 ] Total events: 28 (HBIG), 46 (Control) Test for heterogeneity chi-square=0.35 df=2 p=0.84 I² =0.0% Test for overall effect z=2.35 p=0.02 Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ] Total events: 127 (HBIG), 165 (Control) Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3% Test for overall effect z=7.03 p<0.00001

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 72 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 09.02. Comparison 09 HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events according to methodological quality of the trials Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 02 Hepatitis B events according to methodological quality of the trials

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 High-quality trials Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ] Subtotal (95% CI) 82 82 8.7 0.45 [ 0.20, 1.01 ] Total events: 7 (HBIG), 16 (Control) Test for heterogeneity chi-square=0.76 df=1 p=0.38 I² =0.0% Test for overall effect z=1.93 p=0.05

02 Low-quality trials Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ] Subtotal (95% CI) 533 389 91.3 0.53 [ 0.44, 0.64 ] Total events: 120 (HBIG), 149 (Control) Test for heterogeneity chi-square=12.89 df=11 p=0.30 I² =14.7% Test for overall effect z=6.79 p<0.00001 Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ] Total events: 127 (HBIG), 165 (Control) Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3% Test for overall effect z=7.03 p<0.00001

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 73 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 09.03. Comparison 09 HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events - sensitivity analyses Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 03 Hepatitis B events - sensitivity analyses Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 Available patients’ course analysis Assateerawatt 1993 1/25 3/22 2.5 0.29 [ 0.03, 2.62 ]

Beasley 1983a AB 36/67 28/30 29.9 0.58 [ 0.45, 0.73 ]

Beasley 1983a CB 15/57 28/31 28.1 0.29 [ 0.19, 0.46 ]

Farmer 1987 3/21 4/18 3.3 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 2/50 4/46 3.2 0.46 [ 0.09, 2.39 ]

Ip 1989 AC 5/60 7/32 7.1 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 8.3 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 2.7 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 4.1 0.53 [ 0.15, 1.88 ]

Poovorawan 1997 0/48 3/45 2.8 0.13 [ 0.01, 2.53 ]

Sehgal 1992 3/24 1/21 0.8 2.63 [ 0.29, 23.36 ]

Theppisai 1987 0/25 2/18 2.2 0.15 [ 0.01, 2.87 ]

Xu 1995 CB 1/27 10/56 5.0 0.21 [ 0.03, 1.54 ] Subtotal (95% CI) 531 397 100.0 0.44 [ 0.35, 0.55 ] Total events: 79 (HBIG), 105 (Control) Test for heterogeneity chi-square=13.95 df=12 p=0.30 I² =14.0% Test for overall effect z=7.11 p<0.00001

02 Assuming poor outcome Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 74 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ] Subtotal (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ] Total events: 127 (HBIG), 165 (Control) Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3% Test for overall effect z=7.03 p<0.00001

03 Assuming good outcome Assateerawatt 1993 1/30 3/30 2.2 0.33 [ 0.04, 3.03 ]

Beasley 1983a AB 36/76 28/36 28.4 0.61 [ 0.45, 0.82 ]

Beasley 1983a CB 15/63 28/37 26.4 0.31 [ 0.20, 0.51 ]

Farmer 1987 3/21 4/18 3.2 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 2/55 4/55 3.0 0.50 [ 0.10, 2.62 ]

Ip 1989 AC 5/60 7/32 6.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 8.0 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 2.6 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 3.9 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 5.0 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 0/63 3/64 2.6 0.15 [ 0.01, 2.75 ]

Sehgal 1992 3/27 1/24 0.8 2.67 [ 0.30, 23.96 ]

Theppisai 1987 0/27 2/18 2.2 0.14 [ 0.01, 2.67 ]

Xu 1995 CB 1/28 10/60 4.8 0.21 [ 0.03, 1.59 ] Subtotal (95% CI) 615 471 100.0 0.44 [ 0.35, 0.56 ] Total events: 81 (HBIG), 110 (Control) Test for heterogeneity chi-square=13.12 df=13 p=0.44 I² =0.9% Test for overall effect z=6.76 p<0.00001

04 Extreme case favouring HBIG Assateerawatt 1993 1/30 11/30 5.8 0.09 [ 0.01, 0.66 ]

Beasley 1983a AB 36/76 34/36 24.5 0.50 [ 0.39, 0.64 ]

Beasley 1983a CB 15/63 34/37 22.7 0.26 [ 0.16, 0.41 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 2/55 13/55 6.9 0.15 [ 0.04, 0.65 ]

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 75 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.7 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.9 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 0/63 22/64 11.9 0.02 [ 0.00, 0.36 ]

Sehgal 1992 3/27 4/24 2.2 0.67 [ 0.17, 2.68 ]

Theppisai 1987 0/27 2/18 1.6 0.14 [ 0.01, 2.67 ]

Xu 1995 CB 2/28 10/60 3.4 0.43 [ 0.10, 1.83 ] Subtotal (95% CI) 615 471 100.0 0.32 [ 0.26, 0.40 ] Total events: 82 (HBIG), 161 (Control) Test for heterogeneity chi-square=24.65 df=13 p=0.03 I² =47.3% Test for overall effect z=9.85 p<0.00001

05 Extreme case favouring control Assateerawatt 1993 6/30 3/30 2.2 2.00 [ 0.55, 7.27 ]

Beasley 1983a AB 45/76 28/36 28.1 0.76 [ 0.59, 0.98 ]

Beasley 1983a CB 21/63 28/37 26.1 0.44 [ 0.30, 0.65 ]

Farmer 1987 3/21 4/18 3.2 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 7/55 4/55 3.0 1.75 [ 0.54, 5.64 ]

Ip 1989 AC 5/60 7/32 6.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 7.9 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 2.6 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 3.9 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 4.9 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 3/64 2.2 5.08 [ 1.55, 16.69 ]

Sehgal 1992 6/27 1/24 0.8 5.33 [ 0.69, 41.20 ]

Theppisai 1987 2/27 2/18 1.8 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 1/28 14/60 6.6 0.15 [ 0.02, 1.11 ] Subtotal (95% CI) 615 471 100.0 0.73 [ 0.59, 0.89 ] Total events: 126 (HBIG), 114 (Control) Test for heterogeneity chi-square=33.05 df=13 p=0.002 I² =60.7% Test for overall effect z=3.12 p=0.002

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 76 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 09.04. Comparison 09 HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events according to the mother’s HBeAg status Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 04 Hepatitis B events according to the mother’s HBeAg status Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 HBeAg positive Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Beasley 1983a AB 45/76 34/36 24.2 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.5 0.36 [ 0.25, 0.52 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ]

Lo 1985 AB 4/36 4/19 2.7 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/17 9/29 3.5 0.38 [ 0.09, 1.55 ] Subtotal (95% CI) 522 361 89.4 0.51 [ 0.42, 0.61 ] Total events: 114 (HBIG), 143 (Control) Test for heterogeneity chi-square=11.50 df=11 p=0.40 I² =4.4% Test for overall effect z=7.18 p<0.00001

02 HBeAg unknown Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ] Subtotal (95% CI) 82 79 9.0 0.73 [ 0.38, 1.42 ] Total events: 13 (HBIG), 17 (Control) Test for heterogeneity chi-square=1.58 df=1 p=0.21 I² =36.6% Test for overall effect z=0.92 p=0.4

03 HBeAg negative Xu 1995 CB 0/11 5/31 1.6 0.24 [ 0.01, 4.06 ] Subtotal (95% CI) 11 31 1.6 0.24 [ 0.01, 4.06 ] Total events: 0 (HBIG), 5 (Control) Test for heterogeneity: not applicable Test for overall effect z=0.99 p=0.3

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 77 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ] Total events: 127 (HBIG), 165 (Control) Test for heterogeneity chi-square=13.79 df=14 p=0.47 I² =0.0% Test for overall effect z=7.04 p<0.00001

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better

Analysis 09.05. Comparison 09 HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events according to time of HBIG administration Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 05 Hepatitis B events according to time of HBIG administration Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 HBIG administered within 12 hours of birth Beasley 1983a AB 45/76 34/36 24.3 0.63 [ 0.51, 0.77 ]

Beasley 1983a CB 21/63 34/37 22.6 0.36 [ 0.25, 0.52 ]

Halliday 1992 CA 7/55 13/55 6.8 0.54 [ 0.23, 1.25 ]

Ip 1989 AC 5/60 7/32 4.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 5.6 0.56 [ 0.24, 1.32 ]

Lo 1985 AB 4/36 4/19 2.8 0.53 [ 0.15, 1.88 ]

Lo 1985 CB 2/38 5/19 3.5 0.20 [ 0.04, 0.94 ]

Poovorawan 1997 15/63 22/64 11.5 0.69 [ 0.40, 1.21 ]

Theppisai 1987 2/27 2/18 1.3 0.67 [ 0.10, 4.31 ] Subtotal (95% CI) 482 312 83.2 0.52 [ 0.43, 0.62 ] Total events: 110 (HBIG), 129 (Control) Test for heterogeneity chi-square=10.07 df=8 p=0.26 I² =20.6% Test for overall effect z=6.92 p<0.00001

02 HBIG administered within 24 hours of birth Assateerawatt 1993 6/30 11/30 5.8 0.55 [ 0.23, 1.28 ]

Farmer 1987 3/21 4/18 2.3 0.64 [ 0.17, 2.50 ]

Sehgal 1992 6/27 4/24 2.2 1.33 [ 0.43, 4.17 ]

Xu 1995 CB 2/28 14/60 4.7 0.31 [ 0.07, 1.26 ]

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 78 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI Subtotal (95% CI) 106 132 15.0 0.60 [ 0.35, 1.05 ] Total events: 17 (HBIG), 33 (Control) Test for heterogeneity chi-square=2.81 df=3 p=0.42 I² =0.0% Test for overall effect z=1.79 p=0.07

03 HBIG administered within 48 hours of birth Liu 1987 CA 0/27 3/27 1.8 0.14 [ 0.01, 2.64 ] Subtotal (95% CI) 27 27 1.8 0.14 [ 0.01, 2.64 ] Total events: 0 (HBIG), 3 (Control) Test for heterogeneity: not applicable Test for overall effect z=1.31 p=0.2 Total (95% CI) 615 471 100.0 0.52 [ 0.44, 0.63 ] Total events: 127 (HBIG), 165 (Control) Test for heterogeneity chi-square=13.88 df=13 p=0.38 I² =6.3% Test for overall effect z=7.03 p<0.00001

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better

Analysis 09.06. Comparison 09 HBIG versus placebo or no intervention, Outcome 06 Hepatitis B events according to standard and rapid schedule of vaccines Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 06 Hepatitis B events according to standard and rapid schedule of vaccines Study HBIG+vaccine Vaccine RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 Standard schedule (0-1-6 months) Farmer 1987 3/21 4/18 5.1 0.64 [ 0.17, 2.50 ]

Halliday 1992 CA 7/55 13/55 15.3 0.54 [ 0.23, 1.25 ]

Theppisai 1987 2/27 2/18 2.8 0.67 [ 0.10, 4.31 ]

Xu 1995 CB 2/28 14/60 10.5 0.31 [ 0.07, 1.26 ] Subtotal (95% CI) 131 151 33.8 0.49 [ 0.27, 0.90 ] Total events: 14 (HBIG+vaccine), 33 (Vaccine) Test for heterogeneity chi-square=0.73 df=3 p=0.87 I² =0.0% Test for overall effect z=2.29 p=0.02

02 Rapid schedule (0-1-2-6 or 0-1-2-12 months) Assateerawatt 1993 6/30 11/30 13.0 0.55 [ 0.23, 1.28 ]

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 79 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study HBIG+vaccine Vaccine RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI Ip 1989 AC 5/60 7/32 10.8 0.38 [ 0.13, 1.10 ]

Ip 1989 BC 9/64 8/32 12.6 0.56 [ 0.24, 1.32 ]

Liu 1987 CA 0/27 3/27 4.1 0.14 [ 0.01, 2.64 ]

Poovorawan 1997 15/63 22/64 25.8 0.69 [ 0.40, 1.21 ] Subtotal (95% CI) 244 185 66.2 0.55 [ 0.38, 0.81 ] Total events: 35 (HBIG+vaccine), 51 (Vaccine) Test for heterogeneity chi-square=1.93 df=4 p=0.75 I² =0.0% Test for overall effect z=3.07 p=0.002 Total (95% CI) 375 336 100.0 0.53 [ 0.39, 0.74 ] Total events: 49 (HBIG+vaccine), 84 (Vaccine) Test for heterogeneity chi-square=2.75 df=8 p=0.95 I² =0.0% Test for overall effect z=3.83 p=0.0001

0.001 0.01 0.1 1 10 100 1000 HBIG better Control better

Analysis 09.07. Comparison 09 HBIG versus placebo or no intervention, Outcome 07 Anti-HBs less than 10 IU/L Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 07 Anti-HBs less than 10 IU/L Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

01 HBIG plus PDV versus PDV Sehgal 1992 6/27 4/24 24.6 1.33 [ 0.43, 4.17 ] Subtotal (95% CI) 27 24 24.6 1.33 [ 0.43, 4.17 ] Total events: 6 (HBIG), 4 (Control) Test for heterogeneity: not applicable Test for overall effect z=0.49 p=0.6

02 HBIG plus RV versus RV Assateerawatt 1993 1/30 1/30 5.8 1.00 [ 0.07, 15.26 ]

Halliday 1992 CA 11/55 6/55 34.9 1.83 [ 0.73, 4.61 ]

Poovorawan 1997 9/63 6/64 34.6 1.52 [ 0.58, 4.03 ] Subtotal (95% CI) 148 149 75.4 1.63 [ 0.85, 3.11 ] Total events: 21 (HBIG), 13 (Control) Test for heterogeneity chi-square=0.20 df=2 p=0.90 I² =0.0%

0.01 0.1 1 10 100 HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 80 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI Test for overall effect z=1.47 p=0.1 Total (95% CI) 175 173 100.0 1.55 [ 0.89, 2.73 ] Total events: 27 (HBIG), 17 (Control) Test for heterogeneity chi-square=0.30 df=3 p=0.96 I² =0.0% Test for overall effect z=1.54 p=0.1

0.01 0.1 1 10 100 HBIG better Control better

Analysis 09.08. Comparison 09 HBIG versus placebo or no intervention, Outcome 08 Anti-HBs level Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 08 Anti-HBs level

Study HBIG Control WeightedMeanDifference(Fixed) Weight Weighted Mean Difference (Fixed) N Mean(SD) N Mean(SD) 95% CI (%) 95% CI

Poovorawan 1997 45 3.64 (1.44) 48 3.74 (1.43) 100.0 -0.10 [ -0.68, 0.48 ] Subtotal (95% CI) 45 48 100.0 -0.10 [ -0.68, 0.48 ] Test for heterogeneity: not applicable Test for overall effect z=0.34 p=0.7

-10 -5 0 5 10 HBIG better Control better

Analysis 09.09. Comparison 09 HBIG versus placebo or no intervention, Outcome 09 Adverse events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 09 HBIG versus placebo or no intervention Outcome: 09 Adverse events

Study HBIG Control RelativeRisk(Fixed) Weight RelativeRisk (Fixed) n/N n/N 95% CI (%) 95% CI

Beasley 1983a CB 1/63 0/73 100.0 3.47 [ 0.14, 83.67 ] Total (95% CI) 63 73 100.0 3.47 [ 0.14, 83.67 ] Total events: 1 (HBIG), 0 (Control) Test for heterogeneity: not applicable Test for overall effect z=0.77 p=0.4

0.01 0.1 1 10 100 HBIG better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 81 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 10.01. Comparison 10 Multiple HBIG plus PDV versus single HBIG plus PDV, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 10 Multiple HBIG plus PDV versus single HBIG plus PDV Outcome: 01 Hepatitis B events

Study MultipleHBIG SingleHBIG RelativeRisk(Fixed) Weight RelativeRisk(Fixed) n/N n/N 95% CI (%) 95% CI

Ip 1989 AB 4/60 3/64 41.4 1.42 [ 0.33, 6.09 ]

Lo 1985 CA 2/38 4/36 58.6 0.47 [ 0.09, 2.43 ] Total (95% CI) 98 100 100.0 0.87 [ 0.30, 2.47 ] Total events: 6 (Multiple HBIG), 7 (Single HBIG) Test for heterogeneity chi-square=0.97 df=1 p=0.32 I² =0.0% Test for overall effect z=0.27 p=0.8

0.1 0.2 0.5 1 2 5 10 Mutliple HBIG better Single HBIG better

Analysis 11.01. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 01 Hepatitis B events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 11 PDV plus HBIG versus placebo or no intervention Outcome: 01 Hepatitis B events

Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ] Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ] Total events: 5 (PDV + HBIG), 68 (Control) Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0% Test for overall effect z=6.17 p<0.00001

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 82 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 11.02. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 02 Hepatitis B events according to methodological quality of the trials Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 11 PDV plus HBIG versus placebo or no intervention Outcome: 02 Hepatitis B events according to methodological quality of the trials

Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 High-quality trials Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ] Subtotal (95% CI) 98 60 77.6 0.05 [ 0.02, 0.14 ] Total events: 3 (PDV + HBIG), 44 (Control) Test for heterogeneity chi-square=1.13 df=2 p=0.57 I² =0.0% Test for overall effect z=5.44 p<0.00001

02 Low-quality trials Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ] Subtotal (95% CI) 28 60 22.4 0.18 [ 0.05, 0.70 ] Total events: 2 (PDV + HBIG), 24 (Control) Test for heterogeneity: not applicable Test for overall effect z=2.46 p=0.01 Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ] Total events: 5 (PDV + HBIG), 68 (Control) Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0% Test for overall effect z=6.17 p<0.00001

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG better Control better

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 83 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd Analysis 11.03. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 03 Hepatitis B events - sensitivity analyses Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 11 PDV plus HBIG versus placebo or no intervention Outcome: 03 Hepatitis B events - sensitivity analyses Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 Available patients’ course analysis Ip 1989 AD 1/36 12/17 24.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 22.6 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 33.4 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 1/27 19/55 19.1 0.11 [ 0.02, 0.76 ] Subtotal (95% CI) 125 115 100.0 0.06 [ 0.02, 0.15 ] Total events: 4 (PDV + HBIG), 63 (Control) Test for heterogeneity chi-square=1.34 df=3 p=0.72 I² =0.0% Test for overall effect z=5.89 p<0.00001

02 Assuming poor outcome Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ] Subtotal (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ] Total events: 5 (PDV + HBIG), 68 (Control) Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0% Test for overall effect z=6.17 p<0.00001

03 Assuming good outcome Ip 1989 AD 1/36 12/17 25.0 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 22.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 33.6 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 1/28 19/60 18.6 0.11 [ 0.02, 0.80 ] Subtotal (95% CI) 126 120 100.0 0.06 [ 0.02, 0.15 ] Total events: 4 (PDV + HBIG), 63 (Control) Test for heterogeneity chi-square=1.39 df=3 p=0.71 I² =0.0% Test for overall effect z=5.87 p<0.00001

04 Extreme case favouring PDV plus HBIG Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ]

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 84 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 1/28 24/60 22.4 0.09 [ 0.01, 0.63 ] Subtotal (95% CI) 126 120 100.0 0.06 [ 0.02, 0.15 ] Total events: 4 (PDV + HBIG), 68 (Control) Test for heterogeneity chi-square=1.19 df=3 p=0.76 I² =0.0% Test for overall effect z=5.91 p<0.00001

05 Extreme case favouring control Ip 1989 AD 1/36 12/17 25.0 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 22.7 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 33.6 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/28 19/60 18.6 0.23 [ 0.06, 0.90 ] Subtotal (95% CI) 126 120 100.0 0.08 [ 0.04, 0.18 ] Total events: 5 (PDV + HBIG), 63 (Control) Test for heterogeneity chi-square=3.51 df=3 p=0.32 I² =14.4% Test for overall effect z=6.11 p<0.00001

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG better Control better

Analysis 11.04. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 04 Hepatitis B events according to mother’s HBeAg status Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 11 PDV plus HBIG versus placebo or no intervention Outcome: 04 Hepatitis B events according to mother’s HBeAg status Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 HBeAg positive Ip 1989 AD 1/36 12/17 23.3 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.2 0.09 [ 0.02, 0.35 ]

Liu 1987 CB 0/27 21/26 31.3 0.02 [ 0.00, 0.35 ]

Xu 1995 CD 2/17 21/31 21.3 0.17 [ 0.05, 0.65 ] Subtotal (95% CI) 115 91 97.1 0.07 [ 0.03, 0.17 ] Total events: 5 (PDV + HBIG), 65 (Control) Test for heterogeneity chi-square=2.78 df=3 p=0.43 I² =0.0% Test for overall effect z=6.26 p<0.00001

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG better Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 85 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI 02 HBeAg unknown Subtotal (95% CI) 0 0 0.0 Not estimable Total events: 0 (PDV + HBIG), 0 (Control) Test for heterogeneity: not applicable Test for overall effect: not applicable

03 HBeAg negative Xu 1995 CD 0/11 3/29 2.9 0.36 [ 0.02, 6.40 ] Subtotal (95% CI) 11 29 2.9 0.36 [ 0.02, 6.40 ] Total events: 0 (PDV + HBIG), 3 (Control) Test for heterogeneity: not applicable Test for overall effect z=0.70 p=0.5 Total (95% CI) 126 120 100.0 0.08 [ 0.04, 0.18 ] Total events: 5 (PDV + HBIG), 68 (Control) Test for heterogeneity chi-square=3.63 df=4 p=0.46 I² =0.0% Test for overall effect z=6.36 p<0.00001

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG better Control better

Analysis 11.05. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 05 Hepatitis B events according to time of HBIG administration Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 11 PDV plus HBIG versus placebo or no intervention Outcome: 05 Hepatitis B events according to time of HBIG administration Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

01 HBIG administered within 12 hours of birth Ip 1989 AD 1/36 12/17 23.9 0.04 [ 0.01, 0.28 ]

Ip 1989 BD 2/35 11/17 21.7 0.09 [ 0.02, 0.35 ] Subtotal (95% CI) 71 34 45.6 0.06 [ 0.02, 0.19 ] Total events: 3 (PDV + HBIG), 23 (Control) Test for heterogeneity chi-square=0.45 df=1 p=0.50 I² =0.0% Test for overall effect z=4.80 p<0.00001

02 HBIG administered within 24 hours of birth Xu 1995 CD 2/28 24/60 22.4 0.18 [ 0.05, 0.70 ] Subtotal (95% CI) 28 60 22.4 0.18 [ 0.05, 0.70 ] Total events: 2 (PDV + HBIG), 24 (Control)

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG Control better (Continued ... )

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers (Review) 86 Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd (... Continued)

Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI Test for heterogeneity: not applicable Test for overall effect z=2.46 p=0.01

03 HBIG administered within 48 hours of birth Liu 1987 CB 0/27 21/26 32.1 0.02 [ 0.00, 0.35 ] Subtotal (95% CI) 27 26 32.1 0.02 [ 0.00, 0.35 ] Total events: 0 (PDV + HBIG), 21 (Control) Test for heterogeneity: not applicable Test for overall effect z=2.70 p=0.007 Total (95% CI) 126 120 100.0 0.08 [ 0.03, 0.17 ] Total events: 5 (PDV + HBIG), 68 (Control) Test for heterogeneity chi-square=2.73 df=3 p=0.43 I² =0.0% Test for overall effect z=6.17 p<0.00001

0.001 0.01 0.1 1 10 100 1000 PDV + HBIG Control better

Analysis 11.06. Comparison 11 PDV plus HBIG versus placebo or no intervention, Outcome 06 Adverse events Review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers Comparison: 11 PDV plus HBIG versus placebo or no intervention Outcome: 06 Adverse events

Study PDV+HBIG Control RelativeRisk(Fixed) Weight Relative Risk (Fixed) n/N n/N 95% CI (%) 95% CI

Ip 1989 AD 1/36 2/17 40.2 0.24 [ 0.02, 2.43 ]

Ip 1989 BD 2/35 3/17 59.8 0.32 [ 0.06, 1.76 ] Total (95% CI) 71 34 100.0 0.29 [ 0.07, 1.13 ] Total events: 3 (PDV+HBIG), 5 (Control) Test for heterogeneity chi-square=0.05 df=1 p=0.83 I² =0.0% Test for overall effect z=1.78 p=0.07

0.01 0.1 1 10 100 PDV+HBIG better Control better