CONTEXT: Late-onset sepsis (LOS) is a major cause of mortality and morbidity in preterm infants. Despite various preventive measures, its incidence continues to remain high, hence the urgent need for additional approaches. One such potential strategy is supplementation with probiotics. The updated Cochrane Review (2014) did not find benefits of probiotics in reducing the risk of LOS in preterm infants (19 studies, N = 5338). Currently there are >30 randomized controlled trials (RCTs) of probiotics in preterm infants that have reported on LOS. OBJECTIVES:To conduct a systematic review including all relevant RCTs.DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and E-abstracts from the Pediatric Academic Society meetings and other pediatric and neonatal conference proceedings were searched in June and August 2015.STUDY SELECTION: RCTs comparing probiotics versus placebo/no probiotic were included. DATA EXTRACTION:Relevant data were extracted independently by 3 reviewers. RESULTS:Pooled results from 37 RCTs (N = 9416) using fixed effects model meta analysis showed that probiotics significantly decreased the risk of LOS (675/4852 [13.9%] vs 744/4564 [16.3%]; relative risk, 0.86; 95% confidence interval, 0.78-0.94; P = .0007; I 2 = 35%; number needed to treat, 44). The results were significant even after excluding studies with high risk of bias. CONCLUSIONS: Probiotic supplementation reduces the risk of LOS in preterm infants.a Neonatal ICU, King Edward Memorial Hospital for Women, Perth, Western Australia; b Neonatal ICU, Princess Margaret Hospital for Children, Perth, Western Australia; c Centre for Neonatal Research and Education, School of Pediatrics and Child Health, University of Western Australia, Perth, Western Australia; d Neonatal ICU, Nepean Hospital, Kingswood, NSW, Australia; and e Sydney Medical School, Nepean, University of Sydney, Australia Dr Rao conceptualized and designed the study, performed an independent literature search, selected studies for inclusion, extracted and interpreted data, assessed risk of bias of included studies, handled the meta-analysis software, and wrote the fi rst and fi nal drafts of the manuscript; Dr Athalye-Jape performed an independent literature search, selected studies for inclusion, contacted authors for additional information where necessary, extracted and interpreted the data, checked the data entered by S.C.R. on the meta-analysis software, assessed the risk of bias of included studies, and helped with the fi rst and the fi nal draft of the manuscript; Dr Deshpande performed an independent literature search, selected studies for inclusion, verifi ed the extracted data, assessed risk of bias, interpreted data, and oversaw translation of manuscripts in the Chinese language; Dr Simmer supervised the project, interpreted the data, and supervised the fi rst and fi nal versions of the manuscript; Dr Patole supervised the project, acted as referee author in case of d...

Current evidence supports the use of probiotics in preterm neonates for prevention of necrotizing enterocolitis, mortality and late onset sepsis. Despite the strong evidence, the uptake of this intervention has not been universal due to concerns including probiotic sepsis, pro-inflammatory response and transmission of antibiotic resistance. Critically ill extremely preterm neonates with potentially compromised gut integrity are at higher risk of probiotic sepsis due to translocation. In most countries, probiotics are sold as food supplements with poor quality control. The traditional definition of probiotics as “live microorganisms” has been challenged as many experts have questioned the importance of viability in the context of the beneficial effects of probiotics. Paraprobiotics (ghost probiotics), are defined as non-viable microbial cells (intact or broken) or crude cell extracts (i.e., with complex chemical composition), which, when administered (orally or topically) in adequate amounts, confer a benefit on the human or animal consumer. Current evidence indicates that paraprobiotics could be safe alternatives to probiotics in preterm neonates. High-quality pre-clinical and clinical studies including adequately powered randomised controlled trials (RCTs) are warranted in preterm neonates to explore this new frontier.

Probiotics reduced the time to full enteral feeds in preterm neonates. Additional research is necessary to assess the optimal dose, duration, and probiotic strain or strains used specifically for facilitating enteral nutrition in this population.