Effect of hepatitis B immunisation in newborn infants of by ihd16607

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                     Effect of hepatitis B immunisation in newborn
                     infants of mothers positive for hepatitis B
                     surface antigen: systematic review and
                     meta-analysis
                     Chuanfang Lee, Yan Gong, Jesper Brok, Elizabeth H Boxall and Christian
                     Gluud

                     BMJ 2006;332;328-336; originally published online 27 Jan 2006;
                     doi:10.1136/bmj.38719.435833.7C


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                     Cite this article as: BMJ, doi:10.1136/bmj.38719.435833.7C (published 27 January 2006)

Research


Effect of hepatitis B immunisation in newborn infants of mothers
positive for hepatitis B surface antigen: systematic review and
meta-analysis
Chuanfang Lee, Yan Gong, Jesper Brok, Elizabeth H Boxall, Christian Gluud



Abstract                                                               gen, 70% to 90% of her children become chronically infected.3 4
                                                                       If a mother is positive for the surface antigen but negative for the
Objective To evaluate the effects of hepatitis B vaccine and           e antigen, the risk of transmission is significantly lower.5–9
immunoglobulin in newborn infants of mothers positive for                   Two types of vaccines for hepatitis B have been licensed. One
hepatitis B surface antigen.                                           is derived from plasma (plasma derived vaccine) and the other is
Design Systematic review and meta-analysis of randomised               derived from yeast or mammalian cells (recombinant vaccine).10
clinical trials.                                                       Repeated injections over months are required to mount an
Data sources Electronic databases and hand searches.                   effective antibody response with vaccination. Hepatitis B immu-
Review methods Randomised clinical trials were assessed for            noglobulin has high levels of antibody to hepatitis B surface anti-
methodological quality. Meta-analysis was undertaken on three          gen. The immunoglobulin is immediately effective and seems
outcomes: the relative risks of hepatitis B occurrence, antibody       protective for several months, after which it wanes.11 12 In the
levels to hepatitis B surface antigen, and adverse events.             present systematic review, we assessed the beneficial and harmful
Results 29 randomised clinical trials were identified, five of         effects of hepatitis B vaccines and hepatitis B immunoglobulin in
which were considered high quality. Only three trials reported         newborn infants of mothers positive for hepatitis B surface anti-
inclusion of mothers negative for hepatitis B e antigen.               gen.
Compared with placebo or no intervention, vaccination
reduced the occurrence of hepatitis B (relative risk 0.28, 95%
confidence interval 0.20 to 0.40; four trials). No significant         Methods
difference in hepatitis B occurrence was found between
                                                                       We applied the Cochrane Collaboration methodology13
recombinant vaccine and plasma derived vaccine (1.00, 0.71 to
                                                                       described in our predefined and peer reviewed protocol for this
1.42; four trials) and between high dose versus low dose vaccine
                                                                       review.14We included all trials that randomised newborn infants
(plasma derived vaccine 0.97, 0.55 to 1.68, three trials;
                                                                       of mothers positive for hepatitis B surface antigen to hepatitis B
recombinant vaccine 0.78, 0.31 to 1.94, one trial). Compared
                                                                       vaccination and hepatitis B immunoglobulin within the first
with placebo or no intervention, hepatitis B immunoglobulin or
                                                                       month of life. We identified randomised trials from the registers
the combination of plasma derived vaccine and hepatitis B
                                                                       of the Cochrane Neonatal Group, the Cochrane Hepato-Biliary
immunoglobulin reduced hepatitis B occurrence
                                                                       Group, the Cochrane central register of controlled trials,
(immunoglobulin 0.50, 0.41 to 0.60, one trial; vaccine and
                                                                       Medline, PubMed, and Embase. The last search was carried out
immunoglobulin 0.08, 0.03 to 0.17, three trials). Compared with
                                                                       in February 2004. We scanned references lists and contacted
vaccine alone, vaccine plus hepatitis B immunoglobulin
                                                                       manufacturers of hepatitis B vaccine to ask for unpublished ran-
reduced hepatitis B occurrence (0.54, 0.41 to 0.73; 10 trials).
                                                                       domised trials. We wrote to the authors of trials when data were
Hepatitis B vaccine and hepatitis B immunoglobulin seem safe,
                                                                       not provided in the report. Our primary outcome measure was
but few trials reported adverse events.
                                                                       the occurrence of hepatitis B, defined as a blood specimen posi-
Conclusion Hepatitis B vaccine, hepatitis B immunoglobulin,
                                                                       tive for hepatitis B surface antigen, hepatitis B e antigen, or anti-
and vaccine plus immunoglobulin prevent hepatitis B
                                                                       body to hepatitis B core antigen.15 The secondary outcome
occurrence in newborn infants of mothers positive for hepatitis
                                                                       measures were antibody levels to hepatitis B surface antigen
B surface antigen.
                                                                        < 10 IU/l (considered insufficient to prevent hepatitis B virus
                                                                       infection16 17) and adverse events.
                                                                            We assessed the methodological quality of trials on the basis
Introduction                                                           of their published reports, and information from the authors. We
Hepatitis B is a global communicable disease, associated with an       post hoc classified trials as high quality if they had at least two of
estimated 350 million chronically infected patients.1 Mother to        the following components: adequate generation of allocation
child transmission occurs often, either in utero or through expo-      sequence, adequate allocation concealment, or adequate
sure to blood or blood contaminated fluids at or around birth.         blinding. We did this because only one trial had high quality for
Such perinatal transmission is believed to account for 35% to          all the components. We carried out meta-analyses using a fixed
50% of hepatitis B carriers.2 The risk of perinatal transmission is    effect model and a random effects model in RevMan analyses
associated with the hepatitis B e antigen status of the mother. If a   4.2. If the results of both analyses concurred, we reported the
mother is positive for both hepatitis B surface antigen and e anti-    results of the fixed effect model only.


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Research

    We presented binary outcomes as relative risks with 95%                        Hepatitis B vaccine versus placebo or no intervention
confidence intervals. Data were analysed by the intention to treat                 Compared with placebo or no intervention, hepatitis B vaccina-
principle, including all randomised participants. Heterogeneity                    tion significantly decreased the risk of hepatitis B occurrence
was explored by 2 test, with significance set at a P value < 0.10.                 (relative risk 0.28, 95% confidence interval 0.20 to 0.40; four tri-
The extent of heterogeneity was measured by I2.18 We carried out                   als) (fig 2). Heterogeneity was considerable (P = 0.07, I2 = 54.2%).
metaregression analysis using Stata if more than 10 trials were                    The results of sensitivity analyses for drop outs were consistent,
included on hepatitis B occurrence. Metaregression examined                        indicating the robustness of the finding. Analyses of plasma
the intervention effect in relation to methodological quality of                   derived vaccine and recombinant vaccine individually showed
trials, dosage of hepatitis B immunoglobulin and vaccine, and                      that both vaccines significantly decreased the risk of hepatitis B
time of injection.13 We carried out subgroup analyses according                    occurrence.
to methodological quality, hepatitis B e antigen status of the                          Subgroup analyses between high quality and low quality tri-
mother, and time of injection. We used the test for interaction to                 als, the mother’s hepatitis B e antigen status, or time of vaccina-
estimate the difference between two subgroups.19 For hepatitis B                   tion were not significantly different (tests for interaction,
occurrence we included infants with incomplete or missing data                     P = 0.25, P = 0.07, and P = 0.11, respectively).
in sensitivity analyses by imputing them into the following                             Retrospective subgroup analyses according to vaccine sched-
scenarios (the last four being intention to treat analyses): case                  ules (0, 1, and 6 months v 0, 1, 2, and 6 or 12 months) showed no
analysis available, poor outcome assumed, good outcome                             significant difference (test for interaction, P = 0.75). No data on
assumed, extreme case favours experimental intervention, and                       adverse events were reported.
extreme case favours control group.20 We used funnel plot and
Stata to detect publication bias and other biases according to the                 Recombinant vaccine versus plasma derived vaccine
methods of Begg and Egger.21 22                                                    Recombinant vaccine and plasma derived vaccine showed no
                                                                                   significant difference in hepatitis B occurrence (1.00, 0.70 to
                                                                                   1.42; four trials) (fig 3). Heterogeneity was moderate (I2 = 29.4%).
Results                                                                            Sensitivity analyses for drop outs confirmed the finding of no
Overall, 226 references were identified, 187 of which were                         significant difference between the two vaccines. Subgroup analy-
excluded. The remaining 39 references,7 23–60 referring to 29 ran-                 ses for methodological quality or mother’s hepatitis B e antigen
domised clinical trials, were included. Three of the trials did not                status showed no significant difference (tests for interaction, both
provide relevant data on our outcome measures (fig 1).29 58 60                     P = 0.21).
    The immunisation schedules varied substantially. A number                          Significantly fewer infants receiving recombinant vaccine
of trials had several intervention groups. Table 1 lists the relevant              compared with plasma derived vaccine had antibody levels to
comparisons of the included trials. Eighteen trials included                       hepatitis B surface antigen < 10 IU/l (0.51, 0.36 to 0.72; three
mothers positive for hepatitis B e antigen, three included moth-                   trials).
ers positive and negative for hepatitis B e antigen, and eight did
not report on the mother’s hepatitis B e antigen status. Ten trials                High dose versus low dose vaccine
reported exclusion of low birthweight infants (the limits for                      High dose vaccine and low dose vaccine showed no significant
exclusion varied from 1600 g to 3000 g). The remaining 19 trials                   difference in hepatitis B occurrence (plasma derived vaccine
did not report any exclusion criteria for birth weight. The                        0.97, 0.55 to 1.68, three trials; recombinant vaccine 0.78, 0.31 to
average duration of follow-up was 19 months (range 6 to 60                         1.94, one trial). Owing to too few trials, it was inappropriate to
months).                                                                           carry out sensitivity and subgroup analyses. No significant differ-
                                                                                   ence was found between high dose vaccine versus low dose vac-
Methodological quality of included trials                                          cine on antibody levels to hepatitis B surface antigen < 10 IU/l
Generation of the allocation sequence was adequately described                     (1.02, 0.82 to 1.27; two trials).
in six trials.23 26 30 31 43 44 Treatment allocation was adequately con-
cealed in six trials.29–32 40 44 Adequate methods of double blinding               Schedules and types of recombinant vaccine and plasma
were reported in three trials.30 32 40 Five trials were classified by us           derived vaccine
as of high quality (table 2).30–32 40 44 The numbers and reasons for               No significant differences were found in hepatitis B occurrences
drop outs and withdrawals were adequately described in six                         among different vaccination schedules, different recombinant
trials.7 24 29 30 44 52                                                            vaccines, and different plasma derived vaccines (data not shown).


                                                 References identified from searches (n=226)

                                                                    Clearly irrelevant references excluded (n=150)

                                              References collected for further assessment (n=76)

                                                                        Did not fulfil inclusion criteria (n=37)

                                              References referring to 29 randomised trials (n=39)

                                                                  Relevant data not given in randomised trial (n=3)

                                                      Randomised trials analysed (n=26)


Fig 1   Flow diagram of trial selection


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                                                                                                                                                                                 Research


Table 1 Interventions in experimental and control groups of included                               Trial                        Experimental group                         Control group
randomised clinical trials assessing effects of hepatitis B vaccines and                           Liu 198740       A: Plasma derived vaccine 20 g at birth      B: Placebo (normal saline) at
                                                                                                                    and at 1, 2, and 6 months. C: Plasma         birth and at 1, 2, and 6 months
immunoglobulin for newborn infants of hepatitis B surface antigen positive                                          derived vaccine 20 g at birth and at 1,
mothers                                                                                                             2, and 6 months and hepatitis B
                                                                                                                    immunoglobulin at birth
Trial                         Experimental group                         Control group
                                                                                                   Lo 198528 41     A: Hepatitis B immunoglobulin 50 IU at       B: Plasma derived vaccine 5 g
                   A*: Hepatitis B immunoglobulin 100 IU at     B: Recombinant vaccine 20 g
Assateerawatt                                                                                                       birth and plasma derived vaccine 5 g at      at 2, 6, and 10 weeks
                   birth and recombinant vaccine 20 g at        at birth and at 1, 2, and 12
  199323                                                                                                            2, 6, and 10 weeks. C: Plasma derived
                   birth and at 1, 2, and 12 months             months
                                                                                                                    vaccine 5 g at 2, 6, and 10 weeks and
Beasley 19837      A: Hepatitis B immunoglobulin 1.0 ml         B: Saline at birth and 3 and 6                      hepatitis B immunoglobulin 50 IU at birth
  24               (180 IU) at birth and saline at 3 and 6      months                                              and at 1 month
                   months. C: Hepatitis B immunoglobulin
                                                                                                   Lolekha 200242   A: Recombinant vaccine 5 g at birth and      B: Recombinant vaccine 5 g at
                   0.5 ml (90 IU) diluted in 0.5 ml of
                                                                                                                    at 1 and 6 months                            birth and at 1, 2, and 12
                   immune serum globulin at birth and at 3
                                                                                                                                                                 months
                   and 6 months
                                                                                                   Oon 198643       A: Plasma derived vaccine 10 g at birth      B: Plasma derived vaccine 5 g
Beasley 198325     A: Hepatitis B immunoglobulin 0.5 ml     B: Hepatitis B immunoglobulin
                                                                                                                    and at 1 and 2 months. C: Hepatitis B        at birth and at 1 and 2 months.
                   (145 IU) at birth and plasma derived     0.5 ml (145 IU) and plasma
                                                                                                                    immunoglobulin 100 IU and plasma             D: Hepatitis B immunoglobulin
                   vaccine 20 g at 4 to 7 days. Followed by derived vaccine 20 g at 1
                                                                                                                    derived vaccine 10 g at birth and plasma     100 IU and plasma derived
                   boosters 1 and 6 months later            month. Followed by boosters 1
                                                                                                                    derived vaccine 10 g at 1 and 2 months       vaccine 5 g at birth and
                                                            and 6 months later
                                                                                                                                                                 plasma derived vaccine 5 g at
Farmer 198726      A: Plasma derived vaccine 0.25 ml (5         B: Plasma derived vaccine 0.25                                                                   1 and 2 months
                    g)+hepatitis B immunoglobulin 0.25 ml       ml (5 g) at birth and at 6
                                                                                                   Piazza 198544    A: Plasma derived vaccine 5 g and            B: Plasma derived vaccine 5 g
                   (25 IU/kg) at birth then plasma derived      weeks and 6 months
                                                                                                                    hepatitis B immunoglobulin 50 IU at birth    and hepatitis B immunoglobulin
                   vaccine+hepatitis B immunoglobulin 0.25
                                                                                                                    and plasma derived vaccine at 1 and 2        50 IU at birth and plasma
                   ml (25 IU/kg) at 6 weeks and plasma
                                                                                                                    months                                       derived vaccine at 2 months
                   derived vaccine at 6 months
                                                                                                   Pongpipat        A: 200 IU hepatitis B immunoglobulin-1       B: 100 IU hepatitis B
Garcia 199227      A: 10 g recombinant vaccine-1 at birth       B: 10 g recombinant vaccine-2
                                                                                                     198645         at birth and 5 g plasma derived              immunoglobulin-2 at birth and
                   and at 1 and 2 months                        at birth and at 1 and 2 months
                                                                                                                    vaccine-1 at birth and at 1 and 6 months     10 g plasma derived vaccine-2
Grosheide          A: Hepatitis B immunoglobulin 0.5 ml/kg      B: Hepatitis B immunoglobulin                                                                    at birth and at 1 and 6 months
  199329           body weight at birth and plasma derived      0.5 ml/kg body weight and
                                                                                                   Pongpipat        A: Plasma derived vaccine 5 g and            B: Plasma derived vaccine 2 g
                   vaccine 10 g at 2 days and at 1, 2, and      plasma derived vaccine 10 g
                                                                                                     198846         hepatitis B immunoglobulin 100 IU at         and hepatitis B immunoglobulin
                   11 months                                    at 3, 4, 5, and 11 months (with
                                                                                                                    birth and plasma derived vaccine at 1, 2,    100 IU at birth and plasma
                                                                diphtheria, pertussis, tetanus,
                                                                                                                    and 12 months                                derived vaccine at 1, 2, and 12
                                                                poliomyelitis concomitantly).
                                                                                                                                                                 months
                                                                Hepatitis B immunoglobulin 0.5
                                                                ml/kg body weight at 3 months      Pongpipat        A: Recombinant vaccine 5 g and               B: Plasma derived vaccine 10
                                                                                                     198947         hepatitis B immunoglobulin 100 IU at          g and hepatitis B
Halliday 199230    A: Recombinant vaccine 20 g at birth     B: Plasma derived vaccine 20
                                                                                                                    birth and recombinant vaccine at 1, 2,       immunoglobulin 100 IU at birth
                   and at 1 and 6 months. C: Hepatitis B     g at birth and at 1 and 6
                                                                                                                    and 12 months                                and plasma derived vaccine at
                   immunoglobulin 260 IU at birth and       months. D: Hepatitis B
                                                                                                                                                                 1, 2, and 12 months
                   recombinant vaccine 20 g at birth and at immunoglobulin 260 IU at birth
                   1 and 6 months                           and recombinant vaccine 10 g           Poovorawan       A: Recombinant vaccine 10 g and              B: Recombinant vaccine 10 g
                                                            at birth and at 1 and 6 months           199748 49      hepatitis B immunoglobulin 100 IU at         at birth and at 1 and 6 months.
                                                                                                                    birth and recombinant vaccine 10 g at 1      A booster was given at 60
Hieu 200231        A: Hepatitis B immunoglobulin 100 g          B: Hepatitis B immunoglobulin
                                                                                                                    and 6 months. A booster was given at 60      months
                   and 10 g recombinant vaccine-1 at birth      100 g and 10 g recombinant
                                                                                                                    months
                   and Hepavax at 30 and 180 days               vaccine-2 at birth and Engerix-B
                                                                at 30 and 180 days                 Sehgal 199250    A: Hepatitis B immunoglobulin 0.5 ml and B: Plasma derived vaccine 10
        32 33 54                                                                                     51             plasma derived vaccine 10 g at birth and g at birth and at 4 and 8
Ip 1989            A: Plasma derived vaccine 3 g at birth       B: Plasma derived vaccine 3 g
                                                                                                                    plasma derived vaccine at 4 and 8 weeks weeks
                   and at 1, 2, and 6 months. Also, hepatitis   at birth and at 1, 2, and 6
                   B immunoglobulin 200 IU at birth and         months+hepatitis B                 Theppisai        A: Hepatitis B immunoglobulin 200 IU     B: Plasma derived vaccine 10
                   hepatitis B immunoglobulin 100 IU at         immunoglobulin 200 IU at birth.      198752         and plasma derived vaccine 10 g at birth g at birth and at 1 and 6
                   monthly intervals during 6 months after      D: Placebo                                          and plasma derived vaccine 10 g at 1     months
                   birth. C: Plasma derived vaccine 3 g at                                                          and 6 months
                   birth and at 1, 2, and 6 months                                                 Theppisai        A: Hepatitis B immunoglobulin 200 IU at      B: Hepatitis B immunoglobulin
Kang 199534        A: 20 g recombinant vaccine-1 at birth       B: 20 g recombinant vaccine-2        199053         birth and plasma derived vaccine 5 g at      200 IU at birth and plasma
                   and at 1 and 6 months                        at birth and at 1 and 6 months                      2 days and 1, 2, and 12 months               derived vaccine 2 g at 2 days
                                                                                                                                                                 and 1, 2, and 12 months
Khukhlovich        A: Recombinant vaccine 1 ml at birth and     B: No vaccines
  199635           at 1, 2, and 14 months                                                          Xu 199555-57     A: 16 g plasma derived vaccine-1 at          B: 20 g plasma derived
            36                                                                                                      birth and at 1 and 6 months. C: Hepatitis    vaccine-2 at birth and at 1 and
Kuru 1995          A: Plasma derived vaccine 0.5 ml (2.5        B: Plasma derived vaccine 1 ml
                                                                                                                    B immunoglobulin 250 IU at birth and 20      6 months. D: Vaccine diluent
                    g) and hepatitis B immunoglobulin 200       (5 g) and hepatitis B
                                                                                                                     g plasma derived vaccine-2 at birth and     plus adjuvant at birth and at 1
                   IU at birth and plasma derived vaccine at    immunoglobulin 200 IU at birth
                                                                                                                    at 1 and 6 months                            and 6 months
                   1, 2, and 12 months. C: Recombinant          and plasma derived vaccine at
                   vaccine 0.5 ml (10 g), hepatitis B           1, 2, and 12 months                Yeoh 198658      A: Mothers positive for hepatitis B          B: Mothers positive for hepatitis
                   immunoglobulin 200 IU at birth and                                                               surface antigen and positive for hepatitis   B surface antigen and positive
                   recombinant vaccine at 1, 2, and 12                                                              B e antigen (150 infants): Hepatitis B       for hepatitis B e antigen (150
                   months                                                                                           immunoglobulin 0.5 ml at birth and           infants): Hepatitis B
                                                                                                                    plasma derived vaccine 10 g at birth and     immunoglobulin 0.5 ml at birth
Lee 199537-39      A: Hepatitis B immunoglobulin 145 IU         B: Hepatitis B immunoglobulin
                                                                                                                    at 1 and 6 months. C: Mothers positive       and recombinant vaccine 5 g
                   and plasma derived vaccine 5 g at birth      145 IU and plasma derived
                                                                                                                    for hepatitis B surface antigen and          at birth and at 1 and 6 months.
                   and 10 g recombinant vaccine-1 at 1, 2,      vaccine 5 g at birth and
                                                                                                                    negative for hepatitis B e antigen mothers   D: Mothers positive for hepatitis
                   and 12 months. C: Hepatitis B                plasma derived vaccine 5 g at
                                                                                                                    (150 infants). Hepatitis B immunoglobulin    B surface antigen and negative
                   immunoglobulin 145 IU and plasma             1, 2, and 12 months. D:
                                                                                                                    0.5 ml at birth and plasma derived           for hepatitis B e antigen (150
                   derived vaccine 5 g at birth and 5 g         Hepatitis B immunoglobulin 145
                                                                                                                    vaccine 10 g at birth and at 1 and 6         infants). Hepatitis B
                   recombinant vaccine-2 at 1, 2, and 12        IU and plasma derived vaccine
                                                                                                                    months                                       immunoglobulin 0.5 ml at birth
                   months. E: Hepatitis B immunoglobulin        5 g at birth and plasma
                                                                                                                                                                 and recombinant vaccine 5 g
                   145 IU at birth and plasma derived           derived vaccine 5 g at 1, 2,
                                                                                                                                                                 at birth and at 1 and 6 months
                   vaccine 5 g at birth and 1 month and 5       and 12 months. F: Hepatitis B
                    g recombinant vaccine-2 at 2 and 12         immunoglobulin 145 IU at birth     Zhu 198760       A: 16 g vaccine given at birth, 1 and 6      B: Buffer of vaccine given at
                   months                                       and plasma derived vaccine 5                        months                                       birth, 1 and 6 months
                                                                                                               59
                                                                 g at birth and at 1 month and     Zhu 1994         A: Recombinant vaccine 20 g at birth         B: Plasma derived vaccine 20
                                                                10 g recombinant vaccine-1 at                       and at 1 and 6 months                         g at birth and at 1 and 6
                                                                2 and 12 months                                                                                  months
                                                                                                   *A-F depicts the different intervention arms used to identify comparisons in trials with more
                                                                                                   than two interventions shown in figures 2-5.



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Research

                                                                                                     Hepatitis B immunoglobulin versus placebo or no
Table 2 Reported methodological quality of included randomised clinical
                                                                                                     intervention
trials assessing effects of hepatitis B vaccines and immunoglobulin for
newborn infants of mothers positive for hepatitis B surface antigen                                  Overall, hepatitis B immunoglobulin significantly decreased the
                                                                                                     risk of hepatitis B occurrence in infants (0.52, 0.44 to 0.63; 11 tri-
                             Generation of
                              allocation         Allocation                     Methodological       als) (fig 4). Compared with placebo or no intervention, hepatitis
Trial                          sequence         concealment      Blinding          quality           B immunoglobulin alone significantly reduced hepatitis B
Assateerawatt              Adequate            Unclear        Not done         Low                   occurrence (0.50, 0.41 to 0.60; one trial). Compared with
  199323
                                                                                                     vaccination, vaccination plus hepatitis B immunoglobulin signifi-
Beasley 19837 24           Unclear             Unclear        Unclear          Low
Beasley 198325             Unclear             Unclear        Unclear          Low
                                                                                                     cantly reduced hepatitis B occurrence (0.54, 0.41 to 0.73; 10 tri-
Farmer 198726              Adequate            Unclear        Not done         Low                   als). The sensitivity analyses for drop outs were consistent,
Garcia 199227              Unclear             Unclear        Unclear          Low                   indicating the robustness of the findings. In the metaregression
Grosheide 199329           Unclear             Adequate       Not done         Low                   analyses, none of the trial characteristics (methodological quality,
Halliday 199230            Adequate            Adequate       Adequate         High*                 dosage of hepatitis B immunoglobulin, or time of hepatitis B
Hieu 200231                Adequate            Adequate       Not done         High*                 immunoglobulin injection) was significantly associated with the
Ip 198932 33 54            Unclear             Adequate       Adequate         High*
                                                                                                     effect of hepatitis B immunoglobulin (P = 0.92, P = 0.67, and
Kang 199534                Unclear             Unclear        Not done         Low
                                                                                                     P = 0.79, respectively). Subgroup analyses did not show a signifi-
Khukhlovich 199635         Unclear             Unclear        Unclear          Low
                                                                                                     cant difference between high quality and low quality trials, the
Kuru 199536                Unclear             Unclear        Not reported     Low
Lee 199537-39              Unclear             Unclear        Not done         Low
                                                                                                     mother’s hepatitis B e antigen status, or time of hepatitis B
Liu 198740                 Unclear             Adequate       Adequate         High*                 immunoglobulin injection (tests for interaction, P = 0.70, 0.62,
Lo 198528 41               Unclear             Unclear        Not done         Low                   and 0.63, respectively).
Lolekha 200242             Unclear             Unclear        Not done         Low                        Hepatitis B immunoglobulin did not significantly reduce the
Oon 198643                 Adequate            Unclear        Not done         Low                   number of infants with antibody levels to hepatitis B surface
Piazza 198544              Adequate            Adequate       Unclear          High*                 antigen < 10 IU/l (1.55, 0.89 to 2.73; four trials).
Pongpipat 198645           Unclear             Unclear        Not done         Low
                                                                                                          Few trials reported adverse events. If reported, the authors
Pongpipat 198846           Unclear             Unclear        Not done         Low
                                                                                                     did not specify in which intervention group they occurred. A
Pongpipat 198947           Unclear             Unclear        Not done         Low
Poovorawan 199748          Unclear             Unclear        Not done         Low
                                                                                                     meta-analysis on adverse events could not, therefore, be carried
  49                                                                                                 out. In one trial,24 one infant who received hepatitis B
Sehgal 199250 51           Unclear             Unclear        Not done         Low                   immunoglobulin died. The death seemed to be unrelated to the
Theppisai 198752           Unclear             Unclear        Not done         Low                   immunoglobulin.
Theppisai 199053           Unclear             Unclear        Not done         Low                        Neither funnel plot on hepatitis B occurrence showed asym-
Xu 199555-57               Unclear             Unclear        Unclear          Low
                                                                                                     metry (Egger test, P = 0.31; Begg test, P = 0.23).
Yeoh 198658                Unclear             Unclear        Not done         Low
Zhu 198760                 Unclear             Unclear        Unclear          Low
Zhu 199459                 Unclear             Unclear        Not done         Low
                                                                                                     Multiple versus single injection of hepatitis B
                                                                                                     immunoglobulin
* Trials having low risk of bias.
                                                                                                     Multiple hepatitis B immunoglobulin plus plasma derived
                                                                                                     vaccine versus single hepatitis B immunoglobulin injection plus
                                                                                                     plasma derived vaccine did not significantly reduce the risk of
                                                                                                     hepatitis B occurrence (0.87, 0.30 to 2.47; two trials, I2 = 0%).


                                                                         No of participants with outcome/
                                                                             No of participants at risk

                  Trial                                                      Vaccine       Placebo or no                    Relative risk (fixed)                   Relative risk (fixed)
                                                                                            intervention                         (95% CI)                                (95% CI)
                  Plasma derived vaccine versus placebo or no intervention
                  Ip 1989 CD*                                                 7/35               23/34                                                              0.30 (0.15 to 0.60)
                  Liu 1987 AB*                                                3/27               21/26                                                              0.14 (0.05 to 0.41)
                  Xu 1995 AD*                                                 7/60               12/30                                                              0.29 (0.13 to 0.66)
                  Xu 1995 DD*                                                 14/60              12/30                                                              0.58 (0.31 to 1.10)
                  Subtotal (95% CI)                                          31/182              68/120                                                             0.31 (0.21 to 0.45)
                  Test for heterogeneity: χ2=6.00, df=3, P=0.11, I 2=50.0%
                  Test for overall effect: z=6.03, P<0.0001


                  Recombinant vaccine versus no intervention
                  Khukhlovich 1996                                            2/70                9/31                                                              0.10 (0.02 to 0.43)
                  Subtotal (95% CI)                                           2/70                9/31                                                              0.10 (0.02 to 0.43)
                  Test for overall effect: z=3.09, P=0.002


                  Total (95% CI)                                             33/252              77/151                                                             0.28 (0.20 to 0.40)
                  Test for heterogeneity: χ2=8.74, df=4, P=0.07, I 2=54.2%
                                                                                                          0.01        0.1            1              10       100
                  Test for overall effect: z=6.83, P<0.0001
                                                                                                          Vaccine better                           Placebo or no
                                                                                                                                              intervention better

Fig 2     Effect of hepatitis B vaccine on occurrence of hepatitis B in newborn infants. *Experimental and control groups (see table 1 for definitions)


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                                                                                                                                                                              Research

Vaccination plus hepatitis B immunoglobulin versus placebo                                   levels to hepatitis B surface antigen) and not long term clinical
or no intervention                                                                           outcomes. One trial with long term follow-up did find more
Compared with placebo or no intervention, plasma derived vac-                                patients with chronic hepatitis in the plasma derived vaccine plus
cine plus hepatitis B immunoglobulin significantly reduced                                   hepatitis B immunoglobulin group compared with the plasma
hepatitis B occurrence (0.08, 0.03 to 0.17; three trials) (fig 5). The                       derived vaccine group.32
sensitivity analyses confirmed the robustness of the finding. Sub-                               Our results show that hepatitis B vaccination prevents the
group analyses did not find a significant difference between high                            occurrence of hepatitis B in the newborn infants of mothers
quality and low quality trials, the mother’s hepatitis B e antigen                           positive for hepatitis B surface antigen. We found no significant
status, or time of hepatitis B immunoglobulin injection (tests for                           difference between recombinant vaccine and plasma derived
interaction, P = 0.13, P = 0.28, and P = 0.22, respectively).                                vaccine on hepatitis B infections (relative risk 1.00, 95% CI 0.70
    One trial reported the number of adverse events: three out of                            to 1.42). However, more infants who received recombinant
71 infants given vaccination compared with five out of 34 in the                             vaccine achieved antibody levels to hepatitis surface antigen
control group.32 The results showed no significant difference                                 > 10 IU/l (1.96, 1.39 to 2.78). The advantage of recombinant
(0.29, 0.07 to 1.13; one trial).                                                             vaccine might be due to the difference in chemical and physical
                                                                                             characteristics of the antigen components of the vaccines.64
                                                                                             Recombinant vaccine is used in high income countries owing to
Discussion                                                                                   the fear of acquiring human immunodeficiency virus and other
Our systematic reviews shows that hepatitis B vaccine, hepatitis B                           infections, including transmissible spongiform encephalopa-
immunoglobulin, or the combination of vaccine plus immu-                                     thies.65 Our finding seems to support the introduction of recom-
noglobulin given to the newborn infants of mothers positive for                              binant vaccines in clinical practice.
hepatitis B surface antigen prevents the occurrence of hepatitis                                 The recommended schedules for immune prophylaxis
B. Furthermore, the combination of vaccine plus immunoglobu-                                 against hepatitis B varies among countries.66 67 In general we
lin was superior to vaccine alone. These benefits were not signifi-                          were unable to show significant differences among different
cantly associated with the methodological quality of the trials, the                         doses, different schedules, and different forms of plasma derived
mother’s hepatitis B e antigen status, time of injection, or number                          vaccine and recombinant vaccine on hepatitis B occurrence. Fur-
of infants dropping out of the study.                                                        thermore, our subgroup analyses did not show a strong associa-
    Our review has several potential limitations. Firstly, some                              tion between timing of injection (within 12, 24, or 48 hours) and
analyses include few trials and a small number of newborn                                    magnitude of effects. The number of infants evaluated in these
infants. Secondly, most trials were of low methodological quality.                           comparisons was small. Therefore larger trials are needed before
We did not, however, find a strong association between                                       equivalence or non-inferiority can be claimed.
methodological quality and results. This supports the robustness                                 Our meta-analyses found that hepatitis B immunoglobulin
of our results, but does not exclude the possibility of bias.61–63                           alone or when added to hepatitis B vaccine decreased the risk of
Thirdly, although we did not find asymmetries in funnel plots, we                            hepatitis B infection (0.52, 0.44 to 0.63). A recent non-
cannot exclude publication bias. Fourthly, only a few investiga-                             randomised study reported no benefit of adding hepatitis B
tors responded to our request for further information and often                              immunoglobulin to vaccine in mothers negative for hepatitis B e
that the details were lost. Fifthly, most trials reported only surro-                        antigen.68 In our analysis, only one small trial out of 11 trials
gate outcomes (hepatitis B surface antigen status or antibody                                included infants of such mothers.55 Our subgroup analysis did


                                                                   No of participants with outcome/
                                                                       No of participants at risk

           Trial                                                   Recombinant     Plasma derived                  Relative risk (fixed)                     Relative risk (fixed)
                                                                     vaccine           vaccine                          (95% CI)                                  (95% CI)
           Recombinant vaccine versus plasma derived vaccine
           Halliday 1992 AB*                                           13/55            18/55                                                                0.72 (0.39 to 1.33)
           Zhu 1994                                                    17/54            21/52                                                                0.78 (0.47 to 1.30)
           Subtotal (95% CI)                                          30/109            39/107                                                               0.75 (0.51 to 1.12)
           Test for heterogeneity: χ2=0.04, df=1, P=0.85, I 2=0%
           Test for overall effect: z=1.41, P=0.16


           Recombinant vaccine plus HBIG versus plasma derived vaccine plus HBIG
           Lee 1995 AD*                                                15/51             2/14                                                                2.06 (0.53 to 7.96)
           Lee 1995 CD*                                                16/47             2/14                                                                2.38 (0.62 to 9.13)
           Pongpipat 1989                                              3/20              1/20                                                                3.00 (0.34 to 26.45)
           Subtotal (95% CI)                                          34/118             5/48                                                                2.33 (0.97 to 5.56)
           Test for heterogeneity: χ2=0.09, df=2, P=0.96, I 2=0%
           Test for overall effect: z=1.90, P=0.06


           Total (95% CI)                                             64/227            44/155                                                               1.00 (0.70 to 1.42)
           Test for heterogeneity: χ2=5.67, df=4, P=0.23, I 2=29.4%
                                                                                                 0.01        0.1            1              10         100
           Test for overall effect: z=0.02, P=0.99
                                                                                                 Recombinant                               Plasma derived
                                                                                                 vaccine better                             vaccine better

Fig 3 Effect of recombinant vaccine compared with plasma derived vaccine on occurrence of hepatitis B in newborn infants. HBIG=hepatitis B immunoglobulin.
*Experimental and control groups (see table 1 for definitions)


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Research

not find any statistically significant difference between infants of                              Few trials reported sufficiently on adverse events. According
mothers negative or positive for hepatitis B e antigen. More ran-                             to what was reported, hepatitis B vaccine and hepatitis B immu-
domised trials seem warranted on the addition of hepatitis B                                  noglobulin seem safe. These results are in accordance with two
immunoglobulin to vaccine for infants of mothers negative for                                 Cochrane reviews on hepatitis B vaccination of healthcare work-
hepatitis B e antigen. It should be noted that hepatitis B immu-                              ers and dialysis patients.70 71 Furthermore, cohort studies found
noglobulin, as with plasma derived vaccine, has the potential for                             that hepatitis B vaccination is well tolerated and that severe
transmission of bloodborne infections.69                                                      adverse events are rare.72–79 One cohort study did find, however,



                                                                    No of participants with outcome/
                                                                        No of participants at risk

            Trial                                                       HBIG            Control                   Relative risk (fixed)                    Relative risk (fixed)
                                                                                                                       (95% CI)                                 (95% CI)
            HBIG versus placebo or no intervention
            Beasley 1983 AB*                                            45/76            34/36                                                             0.63 (0.51 to 0.77)
            Beasley 1983 CB*                                            21/63            34/37                                                             0.36 (0.25 to 0.52)
            Subtotal (95% CI)                                           66/139           68/73                                                             0.50 (0.41 to 0.60)
            Test for heterogeneity: χ2=7.81, df=1, P=0.005, I 2=87.2%
            Test for overall effect: z=7.17, P<0.0001


            HBIG plus plasma derived vaccine versus plasma derived vaccine
            Farmer 1987                                                  3/21             4/18                                                             0.64 (0.17 to 2.50)
            Ip 1989 AC*                                                  5/60             7/32                                                             0.38 (0.13 to 1.10)
            Ip 1989 BC*                                                  9/64             8/32                                                             0.56 (0.24 to 1.32)
            Liu 1987 CA*                                                 0/27             3/27                                                             0.14 (0.01 to 2.64)
            Lo 1985 AB*                                                  4/36             4/19                                                             0.53 (0.15 to 1.88)
            Lo 1985 CB*                                                  2/38             5/19                                                             0.20 (0.04 to 0.94)
            Sehgal 1992                                                  6/27             4/24                                                             1.33 (0.43 to 4.17)
            Theppisai 1987                                               2/27             2/18                                                             0.67 (0.10 to 4.31)
            Xu 1995 CB*                                                  2/28            14/60                                                             0.31 (0.07 to 1.26)
            Subtotal (95% CI)                                           33/328           51/249                                                            0.49 (0.32 to 0.74)
            Test for heterogeneity: χ2=5.97, df=8, P=0.65, I 2=0%
            Test for overall effect: z=3.38, P=0.0007


            HBIG plus recombinant vaccine versus recombinant vaccine
            Assateerawatt 1993                                           6/30            11/30                                                             0.55 (0.23 to 1.28)
            Halliday 1992 CA*                                            7/55            13/55                                                             0.54 (0.23 to 1.25)
            Poovorawan 1997                                             15/63            22/64                                                             0.69 (0.40 to 1.21)
            Subtotal (95% CI)                                           28/148           46/149                                                            0.61 (0.41 to 0.92)
            Test for heterogeneity: χ2=0.35, df=2, P=0.84, I 2=0%
            Test for overall effect: z=2.35, P=0.02


            Total (95% CI)                                             127/615          165/471                                                            0.52 (0.44 to 0.63)
            Test for heterogeneity: χ2=13.88, df=13, P=0.38, I 2=6.3%
                                                                                                  0.001   0.01    0.1      1       10      100     1000
            Test for overall effect: z=7.03, P<0.0001
                                                                                                  HBIG better                             Control better
Fig 4   Effect of hepatitis B immunoglobulin (HBIG) on occurrence of hepatitis B in newborn infants. *Experimental and control groups (see table 1 for definitions)


                                                                    No of participants with outcome/
                                                                        No of participants at risk

            Trial                                                   Plasma derived   Placebo or no                Relative risk (fixed)                    Relative risk (fixed)
                                                                    vaccine + HBIG    intervention                     (95% CI)                                 (95% CI)


            Ip 1989 AD*                                                  1/36            12/17                                                             0.04 (0.01 to 0.28)
            Ip 1989 BD*                                                  2/35            11/17                                                             0.09 (0.02 to 0.35)
            Liu 1987 CB*                                                 0/27            21/26                                                             0.02 (0.00 to 0.35)
            Xu 199 CD*                                                   2/28            24/60                                                             0.18 (0.05 to 0.70)
            Total (95% CI)                                              5/126            68/120                                                            0.08 (0.03 to 0.17)
            Test for heterogeneity: χ2=2.73, df=3, P=0.43, I 2=0%
                                                                                                  0.001   0.01    0.1      1       10      100     1000
            Test for overall effect: z=6.17, P=0.0001
                                                                                                  Plasma derived vaccine                  Placebo or no
                                                                                                  + HBIG better                      intervention better

Fig 5 Effect of plasma derived vaccine and hepatitis B immunoglobulin (HBIG) on occurrence of hepatitis B in newborn infants. *Experimental and control groups
(see table 1 for definitions)


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                                                                                                                                                   Research

                                                                       We thank TO Jefferson, M Pratt, J Buttery, and N El-Shukri who participated
     What is already known on this topic                               in the formulation of the first Cochrane protocol on this topic; D Nikolova,
                                                                       the Cochrane Hepato-Biliary Group, for translating a Russian trial and
     Mother to child transmission accounts for up to 50% of            retrieving articles; D Haughton, the Cochrane Neonatal Review Group, for
     hepatitis B carriers                                              retrieving articles; Y Poovorawan and M Piazza who clarified information
                                                                       on their trials; A Dutta, MM Hassan, and SD Lee for providing assistance in
     Repeated vaccination over months is required to mount an          our work to identify trial authors, and JU Olsen, GlaxoSmithKline,
     effective antibody response                                       Denmark, for providing information on randomised clinical trials. This sys-
                                                                       tematic review was carried out using the recommendations of the Cochrane
                                                                       Collaboration and the Cochrane Hepato-Biliary Group. This review will be
     Immunoglobulin is immediately effective and seems                 published as a Cochrane review in the Cochrane Library. Cochrane reviews
     protective for several months, after which it wanes               are regularly updated as new evidence emerges and in response to
                                                                       comments and criticisms. The Cochrane Library should be consulted for
     What this study adds                                              the most recent version of the review.
     Vaccine decreased the risk of hepatitis B infection among         Contributors: CL developed the search strategy, identified trials, extracted
                                                                       data, carried out the statistical analyses, and drafted parts of the review. YG
     infants of mothers positive for hepatitis B surface antigen       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
     Immunoglobulin alone or added to vaccine decreased the            methodological quality of the included trials, validated data from six
     risk of hepatitis B infection among infants of mothers            randomly selected trials, drafted parts of the review, and revised the review.
     positive for hepatitis B surface antigen                          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
     Evidence on immunisation for infants of mothers positive
                                                                       of the review, and revised the review.
     for hepatitis B surface antigen but negative for hepatitis B e
                                                                       Funding: Tri-Service General Hospital, Taiwan; Copenhagen Trial Unit,
     antigen is weak                                                   Copenhagen University Hospital, Denmark; SC Van Foundation, Denmark;
                                                                       and Public Health Laboratory Service, United Kingdom.
                                                                       Competing interests: None declared.
                                                                       Ethical approval: Not required.
that hepatitis B vaccine increased the risk of chronic arthritis and
acute ear infections.80 We are unable to determine if the reliabil-
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