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

Invasive fungal infection is an important cause of mortality and morbidity in very low birth weight infants. Early diagnosis is difficult, and treatment is often delayed. The available data are insufficient to conclude that topical/oral prophylaxis (usually nystatin and/or miconazole) prevents invasive fungal infection or mortality in very low birth weight infants. Systemic antifungal agents (usually azoles) are increasingly used as prophylaxis against invasive fungal infection.

To assess the effect of prophylactic systemic antifungal therapy on mortality and morbidity in very low birth weight infants.

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - May 2007), EMBASE (1980 - May 2007), conference proceedings, and previous reviews.

Randomised controlled trials that compared the effect of prophylactic systemic antifungal therapy versus placebo, or no drug, or another antifungal agent or dose regimen, in very low birth weight infants.

Data were extracted 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, risk difference, and weighted mean difference. The pre-specified outcomes were death prior to hospital discharge, long-term neurodevelopment, incidence of invasive fungal infection, emergence of antifungal resistance, and adverse drug reactions.

Seven eligible trials enrolling a total of 638 participating infants were identified. Meta-analysis of data from four trials that compared prophylactic fluconazole versus placebo revealed a statistically significant reduction in the risk of invasive fungal infection in the infants who received prophylaxis [typical relative risk: 0.23 (95% confidence interval 0.11, 0.46); typical risk difference: -0.11 (95% confidence interval -0.16, -0.06); number needed to treat: 9 (95% confidence interval 6, 17)]. There was no statistically significant difference in the risk of death prior to hospital discharge [typical relative risk: 0.61 (95% confidence interval 0.37, 1.03); typical risk difference: -0.05 (95% confidence interval -0.11, -0.00)]. Only one trial reported long term neurodevelopmental outcomes. There were no statistically significant differences in the incidence of developmental delay, or motor or sensory neurological impairment in children assessed at a median age of 16 months. One small trial that compared systemic versus oral/topical prophylaxis did not detect a statistically significant effect on invasive fungal infection or mortality. Two trials compared different dosing regimens of prophylactic intravenous fluconazole. These did not detect any significant differences in infection rates or mortality.

Prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very low birth weight infants. This finding should be interpreted cautiously. The incidence of invasive fungal infection was very high in the control groups of some of the included trials. Furthermore, the trials may have been affected by ascertainment bias since use of prophylactic fluconazole may reduce the sensitivity of microbiological culture for detecting fungi in blood, urine, or cerebrospinal fluid. Meta-analysis does not demonstrate a statistically significant effect on overall mortality rates, but the 95% confidence interval around this estimate of effect is wide. There are currently only limited data on the long-term neurodevelopmental consequences for infants exposed to this intervention. In addition, there is a need for further data on the effect of the intervention on the emergence of organisms with antifungal resistance.