Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates

Despite advances in neonatal intensive care, the incidence of necrotizing eneterocolitis (NEC) among preterm infants has not changed significantly and definite NEC continues to be associated with significant mortality and long-term neurodevelopmental impairment (NDI). Probiotics may prevent NEC by promoting colonization of the gut with beneficial organisms, thus limiting colonization by pathogens, by improving gut maturity and functions, and modulating the immune system of the host. The results of a meta-analysis of randomized, controlled trials (RCTs) of probiotic supplementation in very low birth weight (VLBW) infants, published in 2007, indicated that the risk for all-cause mortality and NEC was reduced by 53% and 64%, respectively, in neonates who received probiotic supplementation compared with control group neonates. These results were subsequently confirmed by two more systematic reviews and have influenced clinical practice.
The first meta-analysis on the effects of probiotics was updated by the authors including the latest trials available. Randomized clinical trials of any enteral probiotic supplementation that started within first 10 days and continued for ≥7 days in preterm VLBW neonates and reported on stage 2 NEC or higher were eligible for inclusion.
In total, 11 trials (N=2176) were analyzed, including 4 (N=783) new studies. The risk for NEC (Relative risk [RR]: 0.35; 95% Confidence Interval [95% CI]: 0.23-0.55; P<0.00001) and death from all causes (RR: 0.42; 95% CI: 0.29-0.62; P%l 0.00001) were significantly lower in infants receiving probiotics. Risk for late-onset sepsis (LOS) did not differ significantly between groups. No significant adverse effects were reported.
Given that definite NEC is associated with higher risk for long-term NDI, it is important to assess the neurodevelopmental outcome of survivors. At present there is only one study reporting the lack of long-term NDI in neonates included in an RCT of oral probiotics for NEC. The authors suggest all investigators involved in all RCTs should monitor the enrolled neonates and report long-term neurodevelopmental outcomes.
Considering the robustness of the evidence provided and the very significant benefits in terms of reduced risk for all-cause mortality and definite NEC, the authors suggest that probiotics should now be offered as a routine therapy for preterm neonates and that additional placebo-controlled trials are not warranted anymore. The lack of reduction in the risk for LOS might be explained by the presence of multiple sources of pathogens, thus relating the benefits of probiotics to the type of microorganisms responsible for LOS.
It must be noted that the effect of a probiotic bacterium is strain-specific and cannot be extrapolated to other strains of the same species. Moreover, selection of a safe and suitable product with documented probiotic properties and close monitoring of the target population is necessary before offering this therapy as a routine in VLBW infants. Other important questions (e.g., product/ strain(s), dosage, duration, practicalities of administration) can be easily addressed by well-designed observational or head-to-head studies.

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