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Necrotizing enterocolitis (NEC) is the most commonly acquired neonatal intraabdominal emergency and causes significant morbidity and mortality. A proposed strategy for the prevention of NEC is the administration of oral probiotics. Probiotics have been shown to reduce NEC in experimental rat models and have been used in clinical trials. The authors aimed to review the existing data on the use of oral probiotics for the prevention of NEC in preterm infants (age <33 weeks) and those with very low birth weight (VLBW).Systematic review of randomized controlled trials (RCTs) and quasi-RCTs was performed to find outcome measures of incidence, severity, need for surgery, and mortality in NEC. Electronic searches were performed on Medline and CINAHL databases using key word and subject headings with combinations of the terms “infant, preterm”; “infant, VLBW”; “enterocolitis, necrotizing”; and “probiotics.” In addition, citation searches were performed for all potential studies.Six potential RCTs were identified for inclusion, but there were no systematic or Cochrane database reviews identified. One study was discounted because of the use of historical controls, so 5 studies were selected for analysis. Cumulatively, 640 infants were treated with probiotics and 627 were used as control subjects. All of the studies showed a trend toward less NEC in the treatment group. The heterogeneity of probiotic formulations and the timing and methods of interventions in the identified studies made synthesis and comparison of data inappropriate.The data appear to lend support to the use of oral probiotics for the prevention of NEC in preterm infants and those with VLBW. However, the data are insufficient to comment on their short- and long-term safety. Type of probiotics used, as well as the timing and dosage, are still to be optimized. Further understanding of the pathogenesis of NEC and the mechanisms by which probiotics prevent it may lead to evidence-based treatment strategies.