Safety and Efficacy of Probiotics for Preterm Infants

Drs Edwards and Soll drafted the commentary and reviewed it critically for important intellectual content. Both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.One would think we have sufficient evidence on which to draw our conclusions regarding the use of probiotics in preterm infants. There is a strong biological rationale to support the idea that very preterm infants benefit from modification of the intestinal microbiome,1 and clinical trials provide a tsunami of evidence that probiotic supplementation reduces the chances of poor outcomes. The most recent Cochrane Review publication of probiotic administration includes 60 trials enrolling 11 156 infants.2 In this analysis, probiotic administration reduced the risk of necrotizing enterocolitis (NEC) (relative risk [RR] 0.54; 95% CI, 0.46–0.65; 57 trials, 10 918 infants) and probably lead to a reduction in mortality (RR 0.77; 95% CI, 0.66–0.90; 54 trials, 10 484 infants; moderate certainty evidence). These data suggest that for every 100 infants treated with a probiotic agent, we would see 3 fewer cases of NEC and 2 fewer deaths. Little or no effect was seen on the risk of late-onset infection.In the United States, adoption of probiotics for preterm infants has been slow and variable. Agha et al3 studied changes in probiotic use in 807 US neonatal intensive care units (NICUs) participating in the Vermont Oxford Network (VON) between 2012 and 2019. Only 17% of NICUs had adopted routine use of probiotics by 2019. Higher rates of probiotic use (39%) were reported at Children’s Hospital Neonatal Consortium and Pediatrix Medical Group institutions.4 In this survey, centers reported using 14 different probiotic formulations.Why have most centers chosen not to introduce routine administration of probiotics to at-risk preterm infants? Many therapies with far less evidence are routinely in use. What are the barriers to implementation?Despite the promising results, there are concerns regarding how certain we can be in the results of the meta-analyses. Most trials were small (median sample size 145 infants), and the probiotic formulations used in the trials varied greatly. Many studies were unblinded. The trials provided little data to allow a precise estimate of the effects in extremely preterm or extremely low birth weight infants. The studies reporting on NEC have raised concerns of publication bias, suggested by the asymmetric funnel plot and research that demonstrate probiotic studies are less likely to be published than antibiotic trials in a similar population.5From a practical point of view, there are concerns regarding the safety of a live biologic agent. Currently, no live biologic product is approved for neonates by the US Food and Drug Administration.6 To gain approval, a live biologic product must be “safe, pure and potent” and manufactured in a way that these attributes can be guaranteed. Even if we can agree that the current trials have demonstrated “potency,” we still can question the safety and purity of available products. There are many reports in the literature of neonatal sepsis associated with probiotic supplementation.6 Infection with probiotic agents has occurred in both supplemented infants as well as neighboring infants not treated with probiotic supplementation.7 Additionally, when we administer 1 of the available probiotic products, it is not clear that we are giving what we expect. Lewis et al8 analyzed 16 different commercially available probiotic products to assess whether the product contained the bacterial species listed on the label and found significant variability in product composition with 1 product not containing any of the species listed. Given these concerns, it is not surprising that recommendations for routine use of probiotics are cautious and vary worldwide.9,10In this issue of Pediatrics, Alshaikh et al11 address some of these concerns. They evaluated the effectiveness and risks of probiotics among 32 667 infants aged less than 34 weeks’ gestation and less than 1000 g birth weight admitted to 33 Canadian Neonatal Network centers between January 1, 2016 and December 31, 2022. The majority of centers (N = 30) used a multistrain probiotic product, which has been suggested to be the most effective way to use probiotics.12 Among the eligible infants, 18 793 (57.5%) received probiotics. In the overall population as well as in the population restricted to infants of less than 1000 g birth weight, receipt of probiotics was associated with a decrease in mortality and in the combined outcome of NEC or mortality. Importantly, probiotic sepsis was rare, occurring in 27 (1.4 of 1000) infants aged less than 34 weeks’ gestation and 20 (4 of 1000) infants weighing less than 1000 g, and these instances were only reported in infants receiving probiotic supplementation.Data from other neonatal outcomes databases also suggest clinical improvement associated with probiotic treatment. In the Agha et al3 study of US VON centers comparing “nonadopting” centers with “adopting centers” (centers that treated over 20% of very low birth weight infants with probiotic supplementation) among 307 905 very low birth weight infants, probiotic supplementation reduced the risk of NEC but not sepsis or mortality. The reductions in NEC, sepsis, and mortality were smaller than would have been predicted by the totality of trial evidence but were consistent with a meta-analysis restricted to studies at low risk of bias.Does the current work bring us any closer to being comfortable with the decision to administer probiotic supplementation to preterm infants? The reported effectiveness of probiotic supplementation in infants less than 1000 g birth weight and the rare cases of probiotic sepsis give some comfort to those choosing to use available probiotic agents. However, the exact species of probiotic and the role of breastfeeding (and possible improvements in how we obtain and feed breast milk to critically ill preterm infants) require further research. Trials are underway or recently completed that may offer answers that will address the regulatory hurdles.13 The evidence that we have made little if any improvement in the rates of NEC over the past decade adds urgency to the efforts to find an effective product that will meet regulatory standards.14

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