Background. Preterm infants with very low birth weight are at increased risk of invasive fungal infections. Preventive strategies are needed to improve their clinical course and survival.

Objectives. To assess the efficacy and safety of antifungal agents as prophylaxis in controlling invasive fungal infection and mortality in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants in neonatal intensive care units.

Methods. We searched MEDLINE (PubMed), Cochrane databases, Google Scholar, Trip database, Herdin, and ClinicalTrials.gov without language restriction and publications from January 1988 to May 2021. We included randomized controlled trials or controlled clinical trials that compared the effect of prophylactic oral or systemic antifungal agents versus placebo in preterm infants < 37 weeks age of gestation and with birth weight lower than 1500 grams. We conducted a meta-analysis using RevMan 5.4.1 and certainty of evidence rating using GRADEpro software.

Results. A total of 14 studies (including 3,001 preterm infants with VLBW) were included. We found that prophylactic use of nystatin significantly reduced the incidence of invasive fungal infections (IFI) (pooled RR 0.16; 95% CI 0.11, 0.23; 4 RCTs, N = 1295; P < 0.00001; moderate certainty evidence) in preterm infants compared to placebo but had no significant effect on the mortality (RR 0.87; 95% CI 0.62, 1.23; 4 RCTs, N = 1295; P = 0.43; low certainty evidence). Similarly, fluconazole decreased the incidence of IFI (RR 0.38; 95% CI 0.28, 0.53; P = 0.02) and showed statistically significant reduction in mortality (RR 0.78; 95% CI 0.61, 0.99; RCTs, N = 1484; P = 0.04; high certainty evidence). The comparison of the two antifungals showed a trend favoring fluconazole, however the difference was not statistically significant in decreasing IFI (RR 1.60; 95% CI 0.68, 3.77; P = 0.28) and mortality (RR 1.62; 95% CI 0.76, 3.45; P = 0.21).

Conclusion. Administration of antifungal prophylaxis proves to be beneficial and can probably decrease invasive fungal infection and mortality. The evidence showed that Fluconazole is superior as antifungal prophylaxis compared to placebo while there is no significant difference between fluconazole and nystatin in decreasing fungal infection and mortality among preterm neonates.