NICU by the Numbers

Probiotic Exposure Varies Internationally

Issue 12 – October 2021


Exposing very low birth weight infants to probiotics may reduce severe necrotizing enterocolitis, late onset sepsis, and mortality1-3. Regulation of probiotics varies from country to country4. We examined exposure to probiotics among very low birth weight and very preterm infants in 2018 to 2020 by geographic region.


Of 178,297 infants who were born from 401 to 1500 grams or 22 to 29 weeks’ gestational age, survived to NICU admission, and were reported by 1,130 centers, 17.9% were exposed to probiotics in 2018 to 2020. The proportion of infants exposed to probiotics varied internationally; European countries had the highest rates and South American countries had the lowest rates (Figure).

From 2018 to 2020, exposure increased in European countries from 46.6% to 53.1% and in North American countries from 12.1% to 16.0% but decreased in Asian countries from 42.1% to 29.8%. Exposure rates in African, Middle Eastern, and South American countries did not change.



Roger Soll, MD

In NICUs, we expose infants to medications that are regulated by governments but used off-label, or not for the approved purpose. Some drugs may have little clinical evidence showing benefit (or harm) in our population, but we use our professional judgment and local guidance to guide our practice.

In the case of probiotics, evidence from over 50 randomized trials enrolling over 11,000 infants suggest reduced rates of necrotizing enterocolitis, late onset sepsis, and mortality1-3. However, probiotics are live cultures, and government regulation of probiotics differs greatly from country to country4, as does guidance from professional societies. For example, in the United States, probiotics do not undergo the Food and Drug Administration approval process for safety, efficacy, and manufacturing standards, and the American Academy of Pediatrics does not recommend universal administration of probiotics, particularly to those born less than 1 kg7. In Canada, probiotics are licensed health products5 and the Canadian Pediatric Society recommends probiotic use to prevent necrotizing enterocolitis in infants greater than 1 kg at birth6. The European Society for Paediatric Gastroenterology Hepatology and Nutrition recommends use of specific strains to reduce necrotizing enterocolitis rates8, but regulation varies by whether a country is part of the European Union, and even within EU membership.

How do we balance the evidence with this uncertainty about regulation? Perhaps we should treat probiotics as we treat off-label drug use. Neonatal care teams should form multidisciplinary teams including pharmacists, microbiologists, drug and therapeutics committees, Institutional Review Boards, and parents, and develop protocols based on local input, guidance from professional societies, and the latest evidence.


  1. Sharif S, Meader N, Oddie SJ, Rojas-Reyes MX, McGuire W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2020;(10): CD005496.
  2. Dermyshi E, Wang Y, Yan C, et al. The “golden age” of probiotics: a systematic review and meta-analysis of randomized and observational studies in preterm infants. Neonatology. 2017;112(1):9-23.
  3. Rao SC, Athalye-Jape GK, Deshpande GC, Simmer KN, Patole SK. Probiotic supplementation and late-onset sepsis in preterm infants: a meta-analysis. Pediatrics. 2016;137(3).
  4. de Simone C. The unregulated probiotic market. Clin Gastroenterol Hepatol. 2019 Apr;17(5):809-817.
  7. Poindexter B. Use of probiotics in preterm infants. Pediatrics. 2021;147(6): e2021051485.
  8. van den Akker CHP, van Goudoever JB, Shamir R, et al. Probiotics and preterm infants: a position paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr. 2020;70(5): 664–680.

Your Data in Action

This report is made possible by Vermont Oxford Network members who voluntarily contribute data in a global effort to improve the care of high-risk newborns. VON members can view center-specific data by logging on to Nightingale and benchmark against this NICU by the Numbers report.

Thank you to Leila Agha, PhD, and Douglas Staiger, PhD, both of Dartmouth University, who inspired this NICU By the Numbers.

Editor: Erika Edwards, PhD, MPH


Back to all NICU by the Numbers data briefs