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RESEARCH: Chuanfang Lee, Yan Gong, Jesper Brok, Elizabeth H Boxall, and Christian Gluud Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis BMJ 2006; 332: 328-336 [Abstract] [Full text]

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Effect of Hepatitis B Vaccine and Immunoglobulin

Sundhar Rajhan Shunmugam Kanagasabapathy, Katy Elders, Samuel Ghebrehewet   (24 February 2006)

Authors’ reply

Yan Gong, Jesper Brok, Elizabeth H. Boxall, Chuanfang Lee, and Christian Gluud   (23 March 2006)

Effect of Hepatitis B Vaccine and Immunoglobulin 24 February 2006
Sundhar Rajhan Shunmugam Kanagasabapathy, Foundation Year 2 Health Protection Agency,Countess of Chester Health Park,Chester CH2 1UL, Katy Elders, Samuel Ghebrehewet Send response to journal: Re: Effect of Hepatitis B Vaccine and Immunoglobulin	EDITOR- We read with interest the systematic review and meta-analysis on the effect of Hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen(1). We recognise the difficulty in conducting the first meta-analysis on this subject using some small sample size trials and many with low methodological quality. As one might expect from the Cochrane Collaboration Group, the authors have undertaken an extensive search for published and unpublished trials on this subject. The risk of perinatal transmission if the mother is positive for HbsAg and HbeAg is higher compared to when the mother is positive for HbsAg only(2). Therefore, even if there is no intervention at birth (vaccine/HBIG), one would expect a significantly lower number of infected infants from mothers who are positive for HbsAg only. Although it might have led to exclusion of some of the good quality trials, we felt that trials that did not report HbeAg status of mothers should have been excluded from the meta-analysis. We also know that low birth weight babies are less likely to mount an adequate immune response to Hepatitis B vaccine(3), and yet 10 of the trials studied had excluded low birth weight babies. Excluding low birth weight babies from studies may well inflate the beneficial effect of immunisation. Furthermore, the follow up period of some of the trials that were included in the meta-analysis was very short at only 6 months which makes it difficult to conclude infection is absent, given the long incubation period. The trials were very disparate. Trials differed in vaccination schedules, age of child at vaccination, dose of HBIG and vaccine types which affected the outcome, for example, one trial(4) used Hepatitis B vaccine (plasma derived) and HBIG at birth and at 6 weeks, when 2nd dose of HBIG is not usual and not recommended in the UK. The statement “evidence on immunisation for infants of mothers positive for hepatitis B surface antigen but negative for hepatitis B e antigen is weak” (“What this study adds” section(1)) is not supported by the meta-analysis. Although the authors admit that the applicability of their findings to mothers negative for HbeAg is limited, in our view, the inclusion of the above statement with the meta-analysis results may lead to less use of this very effective and safe vaccine. This may also have more impact in countries where universal hepatitis B immunization (1991 WHO recommendation) is not adopted. It is reassuring to see that the new revised UK policy to prevent hepatitis B in newborn babies is comprehensive, i.e., Hepatitis B vaccine and HBIG are recommended when the mother of the newborn is HbsAg +ve and HbeAg +ve, or when HbsAg +ve, HbeAg –ve and anti-Hbe –ve, or when HbeAg status is unknown, and in acute hepatitis B during pregnancy; if the mother is HbsAg +ve and anti-Hbe +ve then only Hepatitis B vaccine is advised(5). It is evident from this meta-analysis that some newborns were not protected even when they had HBIG and vaccine, and we agree with the authors suggestion that more good quality trials are needed to investigate the possible factors such as timing of infection i.e., intrauterine or perinatal, optimal schedule of intervention, circumstances at delivery, method of delivery etc. Sundhar Rajhan Shunmugam Kanagasabapathy F2 in Public Health drsundarr@yahoo.com Katy Elders Specialist Registrar in Public Health KElders@nwhpa.nhs.uk Samuel Ghebrehewet Consultant in Communicable Disease Control sghebrehewet@nwhpa.nhs.uk Cheshire & Merseyside Health Protection Team, Health Protection Agency, Chester Microbiology Laboratory, Countess of Chester Health Park, Liverpool Road, Chester CH2 1UL References: 1. Chuanfang Lee, Yan Gong, Jesper Brok, Elizabeth H Boxall, Christian Gludd. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatits B surface antigen: systematic review and meta-analysis. BMJ 2006;328-332. 2. Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977;105:94 -8 3. Losonsky GA, Wassermann SS, Stephens I et al. Hepatitis B vaccination of premature infants: a reassessment of current recommendations for delayed immunization. Paediatrics 1999:103 (2):E14 4. Farmer K, Gunn T, Woodfield DG. A combination of Hepatitis B vaccine and immunoglobulin does not protect all infants born to hepatitis B e antigen positive mothers. NZ med J 1987;100:412-4. 5. Immunisation against Infectious Disease (revised) Nov 2005 Department of Health,Welsh Office, Scottish Office Department of Health, DHSS (Northern Ireland). http://www.dh.gov.uk/assetRoot/04/12/32/33/04123233.pdf Competing interests: None declared
Authors’ reply 23 March 2006
Yan Gong, research assistant Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, H:S Rigshospitalet, 2100, Denmark, Jesper Brok, Elizabeth H. Boxall, Chuanfang Lee, and Christian Gluud Send response to journal: Re: Authors’ reply	EDITOR – We thank for the response by Kanagasabapathy et al., ‘Effect of Hepatitis B Vaccine and Immunoglobulin’ published on 24 February 2006 on our Cochrane Hepato-Biliary Group systematic review (1). We agree with Kanagasabapathy et al. that the risk of perinatal transmission of hepatitis B is lower, if mothers are positive for hepatitis B surface antigen but negative for hepatitis B e antigen compared to mothers positive for both. However, we think, this observation is not an argument for excluding those trials assessing interventions in mother with unknown hepatitis B e antigen status from our meta-analysis. We included trials according to our protocol, i.e., mothers being positive for hepatitis B surface antigen irrespective of hepatitis B e antigen status (2). This protocol, specifying the inclusion criteria of the trials, is peer-reviewed and published in The Cochrane Library (2). Furthermore, we did several subgroup analyses according to mother’s hepatitis B e antigen status (positive compared to negative compared to unknown) to support the statement ‘evidence on immunisation for infants of mothers positive for hepatitis B surface antigen but negative for hepatitis B e antigen is weak.’ Because of space limits, we were not able to present these analyses in the BMJ but it will be available in The Cochrane Library 2006, Issue 2 (3). For example, for mothers being positive for hepatitis surface antigen and e antigen, hepatitis B events are significantly lower in infants receiving hepatitis B immunoglobulin than in infants getting placebo or no intervention (relative risk 0.51, 95% confidence interval 0.42 to 0.61, 9 trials). While for mothers with unknown and negative hepatitis B e antigen, the prevention effect of hepatitis B immunoglobulin was not different compared with placebo or no intervention (relative risk 0.73, 95% confidence interval 0.38 to 1.42, 2 trials; relative risk 0.24, 95% confidence interval 0.01 to 4.06, 1 trial). We emphasise that our review identified a lack of randomised clinical trials on mothers negative for hepatitis B e antigen (1). This is not as same as saying that we should not immunise infants born to those mothers. Whether to immunise those infants is an individual or national decision, based on our review and other studies. We agree that the effects of hepatitis B vaccine and immunoglobulin on low birth weight infants should be further evaluated in randomised trials. We specifically wrote this in our review (1). In addition, the effects of vaccine and immunoglobulin on clinical outcomes during longer follow-up should also be further evaluated. We are interested to see new evidence supporting the use of hepatitis B vaccine and immunoglobulin in acute hepatitis B during pregnancy. If new evidence fulfils our inclusion criteria, we will be happy to include it when updating our review in the future. References: (1). Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis. BMJ 2006;332:328- 336, doi:10.1136/bmj.38719.435833.7C (2). Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B prophylaxis for newborns of hepatitis B surface antigen-positive mothers [protocol for a Cochrane review]. The Cochrane Database of Systematic Reviews 2004, Issue 2: CD004790. (3). Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. The Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.:CD004790.pub2. DOI: 10.1002/14651858.CD004790.pub2 Competing interests: None declared