Preventive strategies for group B streptococcal and other bacterial infections in early infancy: cost effectiveness and value of information analyses

Dear Sir

We were interested to read the article by Colbourn and colleagues
about the cost-effectiveness of screening for GBS infection in pregnancy
to prevent neonatal sepsis. The authors conclusions suggest that current
practice in the UK is not cost-effective. However, as with all complex
models it is important to review the evidence that was used in the
construction of the model and some of the assumptions made before deciding
whether the results of this study are valid.

We have identified a substantial number of assumptions which may
impact on the robustness of the models findings. Those that are most
serious include:

All the “cost-effective” strategies include offering intrapartum
antibiotics to all women presenting in preterm labour. The Cochrane review
of antibiotics to prevent preterm birth for those women who currently
present in preterm labour with intact membranes includes a number of
randomised controlled trials using a variety of different antibiotic
regimens (1). None of these are specifically about preventing mother to
child transmission of GBS, but when the trials are combined in meta-
analysis there is no evidence of benefit and a suggestion of an increased
risk of neonatal mortality (Peto Odds Ratio 1.50, 95%CI 1.00 to 2.25). The
Cochrane review authors therefore recommend that antibiotics are not used
routinely for this group of women. Although none of these trials used
benzyl penicillin, there are concerns that widespread use of antibiotics
in this group of women may be detrimental to the fetus. The decision-
analytic model did not include this important information.

In addition, all the “cost-effective” strategies include giving
antibiotic prophylaxis to all women undergoing elective caesarean section
at term. The evidence base for including this group came from a national
UK surveillance study where there was a single case of early-onset
neonatal GBS sepsis in a woman who had an elective caesarean section (2).
On detailed investigation of this report, the woman was found to have
ruptured membranes prior to her planned caesarean section and was
therefore misclassified as an elective caesarean section with intact
membranes at term. As a result the number of women requiring antibiotics
in all of the cost-effective screening strategies can be decreased by
approximately 8-10%.

In their model, the authors did not accept the findings of the
Cochrane review of randomised controlled trials of intrapartum antibiotics
for the prevention of mother to child transmission of GBS (3) and
constructed a new meta-analysis, using Bayesian methods, and using
different selection criteria to include a slightly different population of
trials. The Cochrane review suggests that antibiotics are 80% to 90%
effective at preventing infant colonisation and infant sepsis. The meta-
analysis in the decision-analytic model suggests the effectiveness is over
97%. The authors have not considered the in-vitro evidence that
intrapartum antibiotics are more likely to result in culture-negative
sepsis (4). The presence of antibiotic in the infant’s bloodstream will
prevent the culture of the organism, even though the baby may have
clinical manifestations of infection. Culture negative sepsis makes up
approximately 40% of all cases of neonatal sepsis. As all the existing
randomised controlled trials have used positive cultures to assess
efficacy, they will all tend to overestimate the efficacy of antibiotics
in preventing neonatal sepsis. If a more ‘realistic’ estimate of the
effectiveness of this treatment was included all the strategies would
become more costly and less effective.

Of interest is that if the apparently “cost-effective” strategies in
this model do not include treating all women in preterm labour and do not
include treating all women undergoing planned elective caesarean section,
they resemble current UK practice (5).

Finally, the proposed trial referred to by the authors was developed
over 2 years by a group of 26 experts in the clinical management and
epidemiology of perinatal GBS infection as well as clinical trialists,
microbiologists and health economists (www.npeu.ox.ac.uk/gbstrial). After
very careful review of the detailed modelling work undertaken by Colburn
and colleagues, the trial protocol development group concluded that the
serious flaws in the model, some of which are referred to above, meant
that the findings were unreliable and that evidence of relative cost-
effectiveness could not be used in designing subsequent research. The
proposed trial, therefore, aims to compare current clinical practice with
the screening strategy used in the USA and many other countries where
observational data suggest this strategy is cost-effective.

(1) King J, Flenady V. Prophylactic antibiotics for inhibiting
preterm labour with intact membranes. Cochrane Database of Systematic
Reviews 2002, Issue 4. Art. No.: CD000246. DOI: 10.1002/14651858.CD000246.

(2) Heath PT, Balfour G, Weisnor AM, Efstratiou A, Lamagni TL, Tighe
H, O’Connell LAF, Cafferkey M, Verlander NQ, Nicoll A, McCartney C on
behalf of PHLS GBS Working Group. Group B streptococcal disease in UK and
Irish Infants younger than 90 days. Lancet 2004, 363; 292-294.

(3) Smaill F. Intrapartum antibiotics for Group B Streptococcal
colonisation. In.Cochrane Library Issue 1. Oxford Update software 1996.

(4) Hsu K, Pelton S, Shapiro D. Detection of group B streptococcal
bacteremia in simulated intrapartum antimicrobial prophylaxis. Diagn
Microbiol Infec Dis 2003;45:23-27.

(5) RCOG 2003. Prevention of early onset neonatal group B
streptococcal disease. Guideline Number 36, Available:
http/www.rcog.org.uk.

Competing interests:
None declared