Probiotics, Prebiotics, and Synbiotics for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis of Randomized Trials

Abstract

Background: Bacteriotherapy and modulation of intestinal microbiome by administering probiotics, prebiotics, or both have long been suggested to prevent morbidity and mortality in premature infants. Our objective was to assess the comparative effectiveness of different prophylactic strategies in a network meta-analysis (NMA) of randomized trials. Methods: We searched MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane Central, BIOSIS Previews, and Google Scholar from inception up until December 1, 2018· All-cause mortality, severe necrotizing enterocolitis (NEC - Bell stage II or more), and culture proven sepsis were our a priori primary outcomes. We used a frequentist approach for NMA and assessed the certainty of evidence using the GRADE approach. Findings: We included 79 trials involving 17,655 preterm infants. Multiple-strain probiotics alone proved the only intervention with moderate- or high-quality evidence of reduced all-cause mortality relative to placebo (OR = 0·67; 95% CI: 0·52, 0·87; high certainty; absolute risk reduction = 1·5%). Compared to placebo, multiple-strain probiotics (OR = 0·35; 95% CI: 0·26, 0·47; moderate certainty; absolute risk reduction = 4·1%), and single-strain probiotics alone (OR = 0·63; 95% CI: 0·46, 0·86; moderate certainty; absolute risk reduction = 2·3%) or in combination with lactoferrin (OR = 0·04; 95% CI: 0·01, 0·62; moderate certainty; absolute risk reduction = 6·2%) were among the interventions with moderate- or high-quality evidence that significantly reduced severe NEC. Among the intervention with moderate- or high-quality evidence relative to placebo, single-strain probiotics combined with lactoferrin (OR = 0·27; 95% CI: 0·10, 0·72; moderate certainty; absolute risk reduction = 11·00%) or alone (OR = 0·80; 95% CI: 0·65, 0·99; moderate certainty; absolute risk reduction = 2·6%) and lactoferrin alone (OR = 0·44; 95% CI: 0·27, 0·74; moderate certainty; absolute risk reduction = 5·1%) demonstrated statistically significant reduction in culture proven late-onset sepsis. Interpretation: Moderate-to-high certainty evidence demonstrates the superiority of single and multi-strain probiotics over alternative preventive treatments. Synbiotics (multiple-strain probiotics in combination with prebiotics) provide the largest reduction in morbidity and mortality in preterm infants but this is supported by only low-to-very low certainty evidence; thus, prioritizing synbiotics in future trials may provide important insights. Funding: Mitacs in partnership with Nestle Canada. Declaration of Interest: PMS is the recipient of research support provided by Lallemand Human Nutrition Inc. (Montreal, Quebec, Canada) through a Mitacs Accelerates Internship awarded to Shaiya Robinson, PhD. PMS has received honoraria for CME activities from Nestle Nutrition, Abbott Nutrition, and Mead Johnson Nutrition.