Efficacy and Safety of Probiotic Supplementation in Preventing Necrotizing Enterocolitis in Preterm Infants: A Systematic Review and Meta-analysis

Background: Necrotizing enterocolitis (NEC) is a serious gastrointestinal condition that affects preterm infants and is still linked to high levels of illness and death. Despite advances in neonatal care, effective prevention methods remain limited. Probiotic supplementation has garnered attention as a promising intervention, but uncertainty persists regarding which strains are most effective. This systematic review and meta-analysis aimed to evaluate the safety and effectiveness of probiotics in preventing NEC and to identify the regimens that offer the greatest protective benefits. Material and Methods: A thorough search of PubMed, EMBASE, the Cochrane Library, and Web of Science was conducted to find randomized controlled trials assessing probiotics for NEC prevention. Primary outcomes included NEC incidence (≥ Stage II), all-cause mortality, and late-onset sepsis. Random-effects models calculated risk ratios with 95% confidence intervals. Subgroup analyses were performed based on probiotic strains, feeding type, birth weight, and baseline NEC risk. The GRADE method was used to assess the quality of evidence. Results: Fifty-one trials involving 10,664 infants and 29 probiotic regimens were included. Probiotics significantly lowered NEC incidence, mortality, and late-onset sepsis. The most effective regimens combined Bovine lactoferrin with Lactobacillus rhamnosus GG and Lactobacillus acidophilus LB. Multi-strain probiotics outperformed single-strain formulations. Benefits were observed in both human milk-fed and formula-fed infants, and no cases of probiotic-associated sepsis were reported. Conclusion: Probiotic supplementation is a safe and effective strategy for reducing NEC, mortality, and sepsis in preterm infants. Multi-strain regimens, especially those containing Lactobacillus rhamnosus GG or Bovine lactoferrin, show the highest efficacy and could be considered for standard use in neonatal care settings.