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

Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) 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 in very preterm or VLBW infants.

To determine the effect of supplemental probiotics on the risk of NEC and associated mortality and morbidity in very preterm or very low birth weight infants.

We searched CENTRAL, MEDLINE, Embase, the Maternity and Infant Care database, and CINAHL from inception to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles.

We included randomised controlled trials (RCTs) and quasi-RCTs comparing probiotics with placebo or no probiotics in very preterm infants (born before 32 weeks' gestation) and VLBW infants (weighing less than 1500 g at birth).

Two review authors independently evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with associated 95% confidence intervals (CIs). The primary outcomes were NEC and all-cause mortality; secondary outcome measures were late-onset invasive infection (more than 48 hours after birth), duration of hospitalisation from birth, and neurodevelopmental impairment. We used the GRADE approach to assess the certainty of the evidence.

We included 60 trials with 11,156 infants. Most trials were small (median sample size 145 infants). The main potential sources of bias were unclear reporting of methods for concealing allocation and masking caregivers or investigators in about half of the trials. The formulation of the probiotics varied across trials. The most common preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., andStreptococcus spp., alone or in combination. Very preterm or very low birth weight infants Probiotics may reduce the risk of NEC (RR 0.54, 95% CI 0.46 to 0.65; I² = 17%; 57 trials, 10,918 infants; low certainty). The number needed to treat for an additional beneficial outcome (NNTB) was 33 (95% CI 25 to 50). Probiotics probably reduce mortality slightly (RR 0.77, 95% CI 0.66 to 0.90; I² = 0%; 54 trials, 10,484 infants; moderate certainty); the NNTB was 50 (95% CI 50 to 100). Probiotics probably have little or no effect on the risk of late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; I² = 22%; 49 trials, 9876 infants; moderate certainty). Probiotics may have little or no effect on neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26; I² = 0%; 5 trials, 1518 infants; low certainty). Extremely preterm or extremely low birth weight infants Few data were available for extremely preterm or extremely low birth weight (ELBW) infants. In this population, probiotics may have little or no effect on NEC (RR 0.92, 95% CI 0.69 to 1.22, I² = 0%; 10 trials, 1836 infants; low certainty), all-cause mortality (RR 0.92, 95% CI 0.72 to 1.18; I² = 0%; 7 trials, 1723 infants; low certainty), or late-onset invasive infection (RR 0.93, 95% CI 0.78 to 1.09; I² = 0%; 7 trials, 1533 infants; low certainty). No trials provided data for measures of neurodevelopmental impairment in extremely preterm or ELBW infants.

Given the low to moderate certainty of evidence for the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or VLBW infants, and particularly for extremely preterm or ELBW infants, there is a need for further large, high-quality trials to provide evidence of sufficient validity and applicability to inform policy and practice.