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

Background: Over the last few years, probiotics have been one of the most studied interventions in neonatal medicine. Objectives: 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. Search Methods: 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. Selection Criteria: 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). Data Collection and Analysis: 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. Conclusions: 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.研究背景：近数年来，益生菌一直是新生儿医学领域研究最为深入的干预手段之一。 研究目的：本研究旨在系统分析所有评估益生菌用于极低出生体重（very low birth weight, VLBW）早产儿的相关研究，包括随机对照试验（randomized controlled trial, RCT）与观察性研究。 检索方法：本研究通过PubMed、Embase、Cochrane图书馆及Web of Science开展系统性文献检索。将随机对照试验与观察性研究的数据分别进行合并与分析。 纳入标准：纳入经肠内给予益生菌的极低出生体重婴儿相关的随机对照试验与观察性研究。提取的研究数据包括益生菌特性及至少1项临床结局指标，如坏死性小肠结肠炎（necrotizing enterocolitis, NEC）、晚发性脓毒症或全因死亡率。 数据收集与分析：本综述最终纳入44项符合标准的研究，其中30项为随机对照试验，14项为观察性研究。在益生菌干预组中，随机对照试验与观察性研究的重度坏死性小肠结肠炎（Ⅱ期及以上）发生率与全因死亡率均显著降低：随机对照试验组的相对风险（RR）分别为0.57（95%置信区间[confidence interval, CI]：0.47~0.70）与0.77（95%CI：0.65~0.92）；观察性研究组的RR分别为0.51（95%CI：0.37~0.70）与0.71（95%CI：0.62~0.81）。此外，随机对照试验组脓毒症风险降低12%，观察性研究组降低19%。对观察性研究的荟萃分析显示，极极低出生体重婴儿的坏死性小肠结肠炎风险有所降低，但该结果未达到统计学显著性。 研究结论：本项针对随机对照试验与观察性研究的荟萃分析表明，益生菌干预可有效预防极低出生体重婴儿发生重度坏死性小肠结肠炎、晚发性脓毒症及全因死亡。