Probiotics for prevention of necrotizing enterocolitis in preterm infants

Background Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics ( live microbial supplements) may play a role in reducing NEC and associated morbidity. Objectives To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and/or sepsis in preterm infants. Search strategy The standard search strategy for the Cochrane Neonatal Review Group was performed by two review authors. Searches were made of MEDLINE ( 1966 to December 2006), EMBASE ( 1980 to December 2006), Cochrane Library Controlled Trials Register ( CENTRAL, The Cochrane Library Issue 3, 2006), and abstracts of annual meetings of the Society for Pediatric Research (1995 - 2006). The authors of published articles were contacted. Selection criteria Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age and/or << 2500 g birth weight were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. Data collection and analysis Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials. Retrieved articles were assessed for eligibility and data abstracted independently by two review authors. Where data were incomplete, the primary investigator were contacted for further information and clarification. Where appropriate, data of individual trials were combined using meta-analytic techniques to provide a pooled estimate of effect assuming a fixed effect model. Main results Nine eligible trials randomizing 1425 infants were included. Included trials were highly variable with regard to enrollment criteria (i.e. birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight infants ( ELBW) could not be extrapolated. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC ( stage II or more) [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 ( 95% CI 0.25, 0.75]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 ( 95% CI 0.73, 1.19)] or days on total parenteral nutrition (TPN) [WMD - 1.9 ( 95% CI -4.6, 0.77)]. The included trials reported no systemic infection with the probiotics supplemental organism. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. Authors' conclusions Enteral supplementation of probiotics reduced the risk of severe NEC and mortality in preterm infants. This analysis supports a change in practice in premature infants > 1000 g at birth. Data regarding outcome of ELBW infants could not be extracted from the available studies; therefore, a reliable estimate of the safety and efficacy of administration of probiotic supplements cannot be made in this high risk group. A large randomized controlled trial is required to investigate the potential benefits and safety profile of probiotics supplementation in ELBW infants.