Prebiotics for preventing necrotising enterocolitis in preterm infants

Review question
Does giving very preterm or very low birth weight infants prebiotics prevent necrotising enterocolitis?

Very preterm (born more than eight weeks early) and very low birth weight (less than 1.5 kg) infants are at risk of developing necrotising enterocolitis, a severe condition where some lining of the infant's bowel becomes inflamed and dies. This condition is associated with death, serious infection, and long-term disability and developmental problems. One way to help prevent necrotising enterocolitis may be to add prebiotics (non-digestible sugar chains to support intestinal colonisation with healthy 'probiotic' bacteria) to milk feeds.

What did we do?

We searched for trials that looked examined the effect of prebiotics on the risk of necrotising enterocolitis in very preterm or very low birth weight infants. We compared and summarised the results of the trials and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?
We found seven trials involving 705 infant participants in total. Trials were mostly small, and most had design flaws that might bias their findings.

Key results
Combined analyses showed that giving very preterm or very low birth weight infants prebiotics may result in little or no difference in the risk of necrotising enterocolitis, death, or serious infection, but we have little confidence in the evidence. One trial assessed the effect on disability or developmental outcomes, but we have very little confidence in this evidence.

What are the limitations of the evidence?
We have little confidence in the evidence for effects on necrotising enterocolitis, death, and serious infection (and very little confidence for the effect on disability or developmental outcomes) because of concerns that the methods used in the included trials may have introduced biases that exaggerated the benefits of prebiotics supplementation, and because some effect estimates are imprecise.

How up to date is this evidence?

The evidence is up to date to July 2022.

Authors' conclusions: 

The available trial data provide low-certainty evidence about the effects of prebiotics on the risk of NEC, all-cause mortality before discharge, and invasive infection, and very low-certainty evidence about the effect on neurodevelopmental impairment for very preterm or VLBW infants. Our confidence in the effect estimates is limited; the true effects may be substantially different. Large, high-quality trials are needed to provide evidence of sufficient validity to inform policy and practice decisions.

Read the full abstract...

Dietary supplementation with prebiotic oligosaccharides to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or very low birth weight (VLBW) infants.


To assess the benefits and harms of enteral supplementation with prebiotics (versus placebo or no treatment) for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care database and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to July 2022. We searched clinical trials databases and conference proceedings, and examined the reference lists of retrieved articles.

Selection criteria: 

We included randomised controlled trials (RCTs) and quasi-RCTs comparing prebiotics with placebo or no prebiotics in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants. The primary outcomes were NEC and all-cause mortality, and the secondary outcomes were late-onset invasive infection, duration of hospitalisation since birth, and neurodevelopmental impairment.

Data collection and analysis: 

Two review authors separately evaluated risk of bias of the trials, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference (MD), with associated 95% confidence intervals (CIs). The primary outcomes of interest were NEC and all-cause mortality; our secondary outcome measures were late-onset (> 48 hours after birth) invasive infection, duration of hospitalisation, and neurodevelopmental impairment. We used the GRADE approach to assess the level of certainty of the evidence.

Main results: 

We included seven trials in which a total of 705 infants participated. All the trials were small (mean sample size 100). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were potential sources of bias in three of the trials. The studied prebiotics were fructo- and galacto-oligosaccharides, inulin, and lactulose, typically administered daily with enteral feeds during birth hospitalisation.

Meta-analyses of data from seven trials (686 infants) suggest that prebiotics may result in little or no difference in NEC (RR 0.97, 95% CI 0.60 to 1.56; RD none fewer per 1000, 95% CI 50 fewer to 40 more; low-certainty evidence), all-cause mortality (RR 0.43, 95% CI 0.20 to 0.92; 40 per 1000 fewer, 95% CI 70 fewer to none fewer; low-certainty evidence), or late-onset invasive infection (RR 0.79, 95% CI 0.60 to 1.06; 50 per 1000 fewer, 95% CI 100 fewer to 10 more; low-certainty evidence) prior to hospital discharge. The certainty of this evidence is low because of concerns about the risk of bias in some trials and the imprecision of the effect size estimates. The data available from one trial provided only very low-certainty evidence about the effect of prebiotics on measures of neurodevelopmental impairment (Bayley Scales of Infant Development (BSID) Mental Development Index score < 85: RR 0.84, 95% CI 0.25 to 2.90; very low-certainty evidence; BSID Psychomotor Development Index score < 85: RR 0.24, 95% 0.03 to 2.00; very low-certainty evidence; cerebral palsy: RR 0.35, 95% CI 0.01 to 8.35; very low-certainty evidence).