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Vaccination of Infants of Hepatitis B Mothers
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Immunising newborn infants of mothers with hepatitis B prevents infection being transmitted from mother to child, finds a study published online by the British Medical Journal (BMJ).
There are around 350 million hepatitis B carriers worldwide. The virus is transmitted by contact with blood or body fluids of an infected person. Mother to child transmission around the time of birth is common and accounts for up to half of all carriers.
Researchers analysed randomised trials to assess the beneficial and harmful effects of hepatitis B vaccines (active production of antibodies) and hepatitis B immunoglobulin (passive transfer of antibodies) in newborn infants of mothers positive for hepatitis B surface antigen.
They found that hepatitis B vaccine, hepatitis B immunoglobulin, or the combination of vaccine plus immunoglobulin given to the newborn infants of mothers positive for hepatitis B surface antigen prevents the occurrence of hepatitis B. Furthermore, the combination of vaccine plus immunoglobulin was superior to vaccine alone.
There was no difference between the two types of vaccine currently available.
"Although this study confirms that vaccines and immunoglobulin are effective, more research is needed to identify the optimal dose and treatment schedule of hepatitis B immunization," conclude the authors.
BMJ (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 1, Yan Gong 2*, Jesper Brok 2, Elizabeth H Boxall 3, Christian Gluud 2
1 Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Copenhagen University Hospital; Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan
2 Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, H:S Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
3 Health Protection Agency, Public Health Laboratory, Heart of England NHS Trust, Birmingham
Objective To evaluate the effects of hepatitis B vaccine and immunoglobulin in newborn infants of mothers positive for hepatitis B surface antigen.
Design Systematic review and meta-analysis of randomised clinical trials.
Data sources Electronic databases and hand searches.
Review methods Randomised clinical trials were assessed for methodological quality. Meta-analysis was undertaken on three outcomes: the relative risks of hepatitis B occurrence, antibody levels to hepatitis B surface antigen, and adverse events.
Results 29 randomised clinical trials were identified, five of which were considered high quality. Only three trials reported inclusion of mothers negative for hepatitis B e antigen. 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 difference in hepatitis B occurrence was found between recombinant vaccine and plasma derived vaccine (1.00, 0.71 to 1.42; four trials) and between high dose versus low dose vaccine (plasma derived vaccine 0.97, 0.55 to 1.68, three trials; recombinant vaccine 0.78, 0.31 to 1.94, one trial). Compared with placebo or no intervention, hepatitis B immunoglobulin or the combination of plasma derived vaccine and hepatitis B immunoglobulin reduced hepatitis B occurrence (immunoglobulin 0.50, 0.41 to 0.60, one trial; vaccine and immunoglobulin 0.08, 0.03 to 0.17, three trials). Compared with vaccine alone, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (0.54, 0.41 to 0.73; 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported adverse events.
Conclusion Hepatitis B vaccine, hepatitis B immunoglobulin, and vaccine plus immunoglobulin prevent hepatitis B occurrence in newborn infants of mothers positive for hepatitis B surface antigen.
Introduction
Hepatitis B is a global communicable disease, associated with an estimated 350 million chronically infected patients.1 Mother to child transmission occurs often, either in utero or through exposure to blood or blood contaminated fluids at or around birth. Such perinatal transmission is believed to account for 35% to 50% of hepatitis B carriers.2 The risk of perinatal transmission is
associated with the hepatitis B e antigen status of the mother. If a mother is positive for both hepatitis B surface antigen and e antigen, 70% to 90% of her children become chronically infected.3 4
If a mother is positive for the surface antigen but negative for the e antigen, the risk of transmission is significantly lower.5-9 Two types of vaccines for hepatitis B have been licensed. One is derived from plasma (plasma derived vaccine) and the other is derived from yeast or mammalian cells (recombinant vaccine).10
Repeated injections over months are required to mount an effective antibody response with vaccination. Hepatitis B immunoglobulin has high levels of antibody to hepatitis B surface antigen. The immunoglobulin is immediately effective and seems protective for several months, after which it wanes.11 12 In the present systematic review, we assessed the beneficial and harmful effects of hepatitis B vaccines and hepatitis B immunoglobulin in newborn infants of mothers positive for hepatitis B surface antigen.
Discussion
Our systematic reviews shows that hepatitis B vaccine, hepatitis B immunoglobulin, or the combination of vaccine plus immunoglobulin given to the newborn infants of mothers positive for hepatitis B surface antigen prevents the occurrence of hepatitis B. Furthermore, the combination of vaccine plus immunoglobulin was superior to vaccine alone. These benefits were not significantly associated with the methodological quality of the trials, the
mother's hepatitis B e antigen status, time of injection, or number of infants dropping out of the study.
Our review has several potential limitations. Firstly, some analyses include few trials and a small number of newborn infants. Secondly, most trials were of low methodological quality. We did not, however, find a strong association between
methodological quality and results. This supports the robustness of our results, but does not exclude the possibility of bias.61-63 Thirdly, although we did not find asymmetries in funnel plots, we cannot exclude publication bias. Fourthly, only a few investigators responded to our request for further information and often that the details were lost. Fifthly, most trials reported only surrogate
outcomes (hepatitis B surface antigen status or antibody levels to hepatitis B surface antigen) and not long term clinical outcomes. One trial with long term follow-up did find more patients with chronic hepatitis in the plasma derived vaccine plus hepatitis B immunoglobulin group compared with the plasma
derived vaccine group.32
Our results show that hepatitis B vaccination prevents the occurrence of hepatitis B in the newborn infants of mothers positive for hepatitis B surface antigen. We found no significant difference between recombinant vaccine and plasma derived
vaccine on hepatitis B infections (relative risk 1.00, 95% CI 0.70 to 1.42). However, more infants who received recombinant vaccine achieved antibody levels to hepatitis surface antigen > 10 IU/l (1.96, 1.39 to 2.78). The advantage of recombinant 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 the fear of acquiring human immunodeficiency virus and other infections, including transmissible spongiform encephalopathies.65 Our finding seems to support the introduction of recombinant vaccines in clinical practice.
The recommended schedules for immune prophylaxis against hepatitis B varies among countries.66 67 In general we were unable to show significant differences among different doses, different schedules, and different forms of plasma derived
vaccine and recombinant vaccine on hepatitis B occurrence. Furthermore,
our subgroup analyses did not show a strong association between timing of injection (within 12, 24, or 48 hours) and magnitude of effects. The number of infants evaluated in these comparisons was small. Therefore larger trials are needed before equivalence or non-inferiority can be claimed.
Our meta-analyses found that hepatitis B immunoglobulin alone or when added to hepatitis B vaccine decreased the risk of hepatitis B infection (0.52, 0.44 to 0.63). A recent nonrandomized study reported no benefit of adding hepatitis B
immunoglobulin to vaccine in mothers negative for hepatitis B e antigen.68 In our analysis, only one small trial out of 11 trials included infants of such mothers.55
Our subgroup analysis did not find any statistically significant difference between infants of mothers negative or positive for hepatitis B e antigen. More randomised
trials seem warranted on the addition of hepatitis B immunoglobulin to vaccine for infants of mothers negative for hepatitis B e antigen. It should be noted that hepatitis B immunoglobulin, as with plasma derived vaccine, has the potential for
transmission of bloodborne infections.69 Few trials reported sufficiently on adverse events. According to what was reported, hepatitis B vaccine and hepatitis B immunoglobulin seem safe. These results are in accordance with two
Cochrane reviews on hepatitis B vaccination of healthcare workers and dialysis patients.70 71 Furthermore, cohort studies found that hepatitis B vaccination is well tolerated and that severe adverse events are rare.72-79 One cohort study did find, however, that hepatitis B vaccine increased the risk of chronic arthritis and acute ear infections.80 We are unable to determine if the reliability
of this finding owing to the methodological weaknesses of cohort studies.66
Randomised clinical trials may overlook adverse events because of the relatively low numbers of participants or poor reporting of adverse events.81-83 Further trials ought to focus on adverse events after the International Conference on
Harmonisation's guidelines for clinical trials.79
In general, the risk of perinatal transmission from mothers negative for hepatitis B e antigen is considered much lower than that from mothers who are positive for the antigen.5-9 Further, the infants of hepatitis B e antigen negative mothers often clear an asymptomatic infection.15 Our findings are mainly based on
immune prophylaxis for infants of mothers positive for hepatitis B surface antigen and hepatitis B e antigen. Evidence from randomized clinical trials is insufficient to either support or refute immune prophylaxis for infants of mothers negative for hepatitis B e antigen. The applicability of our findings to mothers negative for hepatitis B e antigen, which are of high proportions in, for example, the United States and northern Europe, is therefore limited.84 Cost effectiveness studies indicate that hepatitis B vaccination for infants of mothers positive for hepatitis B surface antigen are cost effective in countries with low,85-88 intermediate,
and high prevalence.89-92We identified no cost effectiveness studies assessing the effects of adding hepatitis B immunoglobulin to vaccine. As hepatitis B immunoglobulin may reduce the risk of hepatitis B infection, the need to carry out cost effectiveness studies based on randomised trials seems justified.
Two trials that discussed a new way to potentially prevent vertical transmission of hepatitis B did not fulfil our inclusion criteria.14 The two trials randomised pregnant women positive for hepatitis B surface antigen to hepatitis B immunoglobulin versus no intervention before delivery.93 94 In the group receiving immunoglobulin, fewer infants were positive for hepatitis B surface
antigen at follow-up. The methodological quality of those trials was low. Furthermore, the mothers are at risk of developing immune complex disease due to hepatitis B immunoglobulin reacting with their own circulating hepatitis B surface antigens. More trials are therefore needed before this intervention should
be adopted.
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