Supplementary Material for: The “Golden Age” of Probiotics: A Systematic Review and Meta-Analysis of Randomized and Observational Studies in Preterm Infants

<p><b><i>Background:</i></b> Over the last few years, probiotics have been one of the most studied interventions in neonatal medicine. <b><i>Objectives:</i></b> The aim of this work was to analyse all studies (randomized controlled trials, RCTs, and observational studies) assessing the use of probiotics in very low birth weight (VLBW) preterm infants. <b><i>Search Methods:</i></b> A systematic literature search was conducted using PubMed, Embase, Cochrane Library, and Web of Science. The data from RCTs and observational studies were pooled and analysed separately. <b><i>Selection Criteria:</i></b> RCTs and observational studies that enrolled VLBW infants with enteral administration of probiotics were considered. Extracted study data included probiotic characteristics and at least 1 clinical outcome (necrotizing enterocolitis [NEC], late-onset sepsis or all-cause mortality). <b><i>Data Collection and Analysis:</i></b> Forty-four studies were eligible for our review: 30 RCTs and 14 observational studies. Severe NEC rates (stage II or more) and all-cause mortality were reduced among the probiotic groups in both the RCTs (RR 0.57, 95% CI 0.47-0.70, and RR 0.77, 95% CI 0.65-0.92, respectively) and the observational studies (RR 0.51, 95% CI 0.37-0.70, and RR 0.71, 95% CI 0.62-0.81, respectively). Furthermore, there was a 12% reduction in the risk of sepsis in RCTs and a 19% reduction in observational studies. The meta-analysis of observational studies showed a reduction in the risk of NEC in extremely low birth weight infants. However, this was not statistically significant. <b><i>Conclusions:</i></b> This meta-analysis of RCT and observational studies found that the use of probiotics was beneficial for the prevention of severe NEC, late-onset sepsis, and all-cause mortality in VLBW infants.</p>