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The effect of fluconazole prophylaxis in very low birthweight infants is overestimated by before-after studies
  1. W McGuire1,
  2. L Clerihew2
  1. 1Centre for Reviews and Dissemination, Hull York Medical School, York, UK
  2. 2Ninewells Hospital and Medical School, University of Dundee, UK
  1. Correspondence to Professor William McGuire, Centre for Reviews and Dissemination, HYMS, University of York, York YO10 5DD, UK; william.mcguire{at}


Background The validity and applicability of before-after studies compared to randomised controlled trials (RCTs) of fluconazole prophylaxis for very low birthweight (VLBW) infants is uncertain.

Objectives The aim was to examine whether the study design (before-after studies compared to RCTs) affected the estimate of effect size yielded in meta-analyses and to explore possible causes for any differences detected.

Methods A systematic review and meta-analysis of before-after studies, which assessed the effect of fluconazole prophylaxis on the incidence of invasive fungal infection in VLBW infants, was undertaken. Data were compared with estimates generated from meta-analyses of RCTs. Funnel plots were examined for evidence of publication bias.

Results Meta-analysis of 11 before-after studies found a reduced risk of invasive fungal infection following introduction of fluconazole prophylaxis: RR 0.19 (95% CI 0.13 to 0.27). This estimate is significantly lower than the estimate generated from meta-analysis of RCTs: RR 0.48 (95% CI 0.31 to 0.73). Inspection of a funnel plot of before-after studies revealed that smaller studies with large effects sizes contributed an excess of data points.

Conclusions Publication bias may be an important cause of effect size estimate inflation of before-after studies. Data from before-after studies of antifungal prophylaxis for VLBW infants should be interpreted and applied cautiously. Evidence to guide policy and practice for should instead be derived from well-designed RCTs.

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  • Competing interests In 2002, the authors received a grant from Pfizer Ltd, a manufacturer of fluconazole, to support a UK national surveillance study of invasive fungal infection in VLBW infants.

  • Provenance and peer review Not commissioned; not externally peer reviewed.

  • Detail has been removed from this case description or these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.