Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysisBMJ 2006; 332 doi: https://doi.org/10.1136/bmj.38719.435833.7C (Published 09 February 2006) Cite this as: BMJ 2006;332:328
All rapid responses
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
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.
(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-
(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: No competing interests
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
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
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
Katy Elders Specialist Registrar in Public Health
Samuel Ghebrehewet Consultant in Communicable Disease Control
Cheshire & Merseyside Health Protection Team,
Health Protection Agency,
Chester Microbiology Laboratory,
Countess of Chester Health Park,
Chester CH2 1UL
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
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).
Competing interests: No competing interests