Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants

Sahar Sharif, Nicholas Meader, Sam J Oddie, Maria Ximena Rojas-Reyes, William McGuire, Sahar Sharif, Nicholas Meader, Sam J Oddie, Maria Ximena Rojas-Reyes, William McGuire

Abstract

Background: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity. OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and mortality and morbidity in very preterm or very low birth weight infants.

Search methods: We searched Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 2) in the Cochrane Library; MEDLINE Ovid (1946 to 17 Feb 2020), Embase Ovid (1974 to 17 Feb 2020), Maternity & Infant Care Database Ovid (1971 to 17 Feb 2020), the Cumulative Index to Nursing and Allied Health Literature (1982 to 18 Feb 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs.

Selection criteria: We included RCTs and quasi-RCTs comparing probiotic supplementation with placebo or no probiotics in very preterm or very low birth weight infants.

Data collection and analysis: We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on NEC, all-cause mortality, late-onset infection, and severe neurodevelopmental impairment.

Main results: We included 56 trials in which 10,812 infants participated. Most trials were small (median sample size 149). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were the main potential sources of bias in about half of the trials. Trials varied by the formulation of the probiotics. The most commonly used preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., and Streptococcus spp. alone or in combinations. Meta-analysis showed that probiotics may reduce the risk of NEC: RR 0.54, 95% CI 0.45 to 0.65 (54 trials, 10,604 infants; I² = 17%); RD -0.03, 95% CI -0.04 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 25 to 50. Evidence was assessed as low certainty because of the limitations in trials design, and the presence of funnel plot asymmetry consistent with publication bias. Sensitivity meta-analysis of trials at low risk of bias showed a reduced risk of NEC: RR 0.70, 95% CI 0.55 to 0.89 (16 trials, 4597 infants; I² = 25%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100. Meta-analyses showed that probiotics probably reduce mortality (RR 0.76, 95% CI 0.65 to 0.89; (51 trials, 10,170 infants; I² = 0%); RD -0.02, 95% CI -0.02 to -0.01; NNTB 50, 95% CI 50 to 100), and late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; (47 trials, 9762 infants; I² = 19%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100). Evidence was assessed as moderate certainty for both these outcomes because of the limitations in trials design. Sensitivity meta-analyses of 16 trials (4597 infants) at low risk of bias did not show an effect on mortality or infection. Meta-analysis showed that probiotics may have little or no effect on severe neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26 (five trials, 1518 infants; I² = 0%). The certainty on this evidence is low because of limitations in trials design and serious imprecision of effect estimate. Few data (from seven of the trials) were available for extremely preterm or extremely low birth weight infants. Meta-analyses did not show effects on NEC, death, or infection (low-certainty evidence).

Authors' conclusions: Given the low to moderate level of certainty about the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants, and particularly for extremely preterm or extremely low birth weight infants, further, large, high-quality trials are needed to provide evidence of sufficient quality and applicability to inform policy and practice.

Trial registration: ClinicalTrials.gov NCT01315821 NCT00977912 NCT01181791 NCT01375309 NCT02552706.