Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants

Abstract

Background: Invasive fungal infection is an increasingly common cause of mortality and morbidity in very low birth weight infants. As the diagnosis is often difficult, and treatment is often delayed, there is a need to assess whether antifungal prophylaxis is beneficial.

Objectives: To assess whether prophylactic intravenous antifungal therapy reduces mortality and adverse neurodevelopmental outcomes in very low birth weight infants.

Search strategy: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2003), MEDLINE (1966 - October 2003), EMBASE (1980 - October 2003), conference proceedings, and previous reviews.

Selection criteria: Randomised controlled trials that compared the effect of prophylactic intravenous antifungal therapy versus placebo, or no drug, or another antifungal agent, in very low birth weight infants.

Data collection and analysis: We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using relative risk and risk difference. The pre-specified outcomes were death prior to hospital discharge, longer term neurodevelopment, incidence of invasive fungal infection, emergence of antifungal resistance, and adverse drug reactions.

Main results: We identified three eligible trials enrolling a total of 214 infants. Each of the trials compared the effect of prophylactic intravenous fluconazole versus placebo. Two of the trials reported death prior to hospital discharge as an outcome. 29 of the 203 infants recruited to these studies died. Meta-analysis revealed a statistically significantly reduced risk of death prior to hospital discharge for the infants who received fluconazole prophylaxis: typical relative risk: 0.44 (95% confidence interval 0.21, 0.91); typical risk difference: -0.11 (95% confidence interval -0.21, -0.02); number needed to treat: 9 (95% confidence interval 5, 50). None of the trials reported data on longer term outcomes.

Reviewer's conclusions: We have found some evidence that prophylactic intravenous fluconazole reduces mortality prior to hospital discharge in very low birth weight infants. The meta-analysis suggests that there will be one fewer death in every nine infants treated with this intervention, but the 95% confidence interval around this estimate of effect is wide. The longer term neurodevelopmental consequences for infants exposed to this intervention remain to be determined. It will be important to identify any subgroups of very low birth weight infants that receive the most benefit from this intervention. There is also a need for further data on the effect of the intervention on the emergence of organisms with stable antifungal resistance.