A Cautionary Note on Instituting Probiotics Into Routine Clinical Care for Premature Infants

We read with great interest the recent articles published in Pediatrics relating to probiotic supplementation in preterm infants.1–3 In their updated meta-analysis, Deshpande et al1 concluded that there are significant benefits of probiotics in reducing all-cause mortality rates and necrotizing enterocolitis (NEC) that, coupled with the reduction in time to establish full enteral feeds, warrant their use as routine therapy in preterm neonates (subject to a suitable probiotic product being available). Moreover, they suggested that further placebo-controlled trials are unnecessary given the statistical significance, including tight confidence intervals, extremely low P values, and low number needed to treat to prevent a case of NEC.1 In their commentary on this study, Tarnow-Mordi et al2 argued passionately that changing practice to supplement premature infants with probiotics would result in thousands more survivors each year. They then questioned whether placebo-controlled trials should continue.Similar to Soll,3 we would suggest a more cautious approach because there are so many unknowns about probiotics. For example, we do not know yet which probiotic or probiotic combination is the best to use, and we do not know the quality of currently available products (Do they contain the numbers of organisms specified on the label? Do they contain extraneous organisms? Are the organisms specified viable?). It should be noted that there are no licensed probiotics to prescribe outside clinical trials. Yet to be determined is the appropriate dose and when to commence or discontinue probiotics. The potential for sepsis from probiotics is unknown, because in most diagnostic laboratories blood culture media would not support the fastidious anaerobic probiotic growth. In addition, the authors of the meta-analyses failed to provide reasons for the reduction in mortality.Although the reported findings are encouraging, we agree with our west-Australian colleagues that the selection of a safe and suitable product with documented probiotic properties and close monitoring is essential before probiotics can be provided as a routine therapy. Therefore, we believe that it is extremely important that well-designed randomized controlled trials be completed to address these outstanding issues. Indeed, on the basis of encouraging data from the earlier studies of Lin et al4 and Bin-Nun et al,5 we embarked on and are halfway through recruiting for the ProPrems Study, a multicenter probiotic study, to investigate the effect of probiotic supplementation on the incidence and severity of definite late-onset sepsis for very premature infants (<1500 g and <32 weeks' gestation) from soon after birth. There are multiple secondary outcome factors including NEC, death, and longer-term morbidity, including allergy. After 2 interim analyses, the data safety monitoring committee agreed that the ProPrems trial should continue. In addition, and novel to other trials, molecular biology tools are being used to ascertain colonization of the infants' intestines by the ingested probiotics and to ensure the integrity of each batch of probiotic used.We were warmed by the rational editorial by Soll,3 who concluded that the neonatal community needs to push for larger probiotic trials such as ProPrems. We continue to welcome Australasian centers to join the ProPrems study. Soll also stated that little is known about probiotics in extremely low birth weight infants or in infants receiving breast milk. Although ProPrems was not powered to address these issues, valuable information about these subgroups will be ascertained. Ultimately, we all want any changes in clinical practice to be well informed by the best evidence, which will translate to better neonatal outcomes.