Probiotics for Preventing Necrotizing Enterocolitis: A Meta-Analysis with Trial Sequential Analysis

What is Known and Objective. The role of probiotics, especially the different genera of probiotics, in managing necrotizing enterocolitis (NEC) is controversial. Thus, we performed a meta-analysis with trial sequential analysis (TSA) to determine the efficacy and safety of probiotics for preventing NEC. Methods. Medline, Embase, CENTRAL, WorldCat, TROVE, DART-Europe, and CBM were searched from inception to May 2022. Two investigators independently screened the literature, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using RevMan 5.4, and TSA was conducted using TSA 0.9 beta. Results and Discussion. Fifty-five studies involving 12897 newborns were eligible. The use of probiotics for preventing NEC reduced the incidence of NEC (RR 0.48, 95% CI 0.41 to 0.57, and P  < 0.05) and sepsis (RR 0.77, 95% CI 0.64 to 0.94, and P  < 0.05), the risk of mortality (RR 0.69, 95% CI 0.58 to 0.84, and P  < 0.05), and shortened the average days of hospitalization (MD −3.12, 95% CI −4.98 to −1.26, and P  < 0.05). However, subgroup analysis revealed that different genera of probiotics gave rise to different outcomes. In addition, TSA indicated that the cumulative z-curve crossed the traditional and trial sequential monitoring boundaries for benefit, providing firm evidence that multiple strains and Lactobacillus species of probiotics decreased the incidence of NEC. However, the current evidence was inconclusive for Bifidobacterium and Saccharomyces species. What is New and Conclusions. Probiotics are effective in preventing NEC and sepsis and could provide added benefits, including decreasing mortality and the number of days of hospitalization. However, considering the heterogeneity of probiotics regimens and the risk of selective reporting of RCTs, more high-quality clinical trials targeting different genera of probiotics with suitable doses and timing to prophylactic use of probiotics are needed to avoid overestimating the role of probiotics in preterm infants.