Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Effects of prophylactic probiotics supplementation on infants born very preterm or very low birth weight



To evaluate the effects of guideline-driven prophylactic supplementation of a multi-strain neonatal intensive care unit-specific probiotic product on infants born very preterm (VP) or very low birth weight (VLBW).

Study design

A prospective cohort of 125 infants born in one year after implementation who received probiotics were compared to a retrospective cohort of eligible 126 VP or VLBW infants who did not receive probiotics. The primary outcome of interest was necrotizing enterocolitis (NEC).


The incidence of NEC decreased from 6.3 to 1.6%. After adjusting for multiple variables, there were no significant differences in primary or other outcomes of interest; odds ratio (95% confidence interval) NEC 0.27 (0.05–1.33), death 0.76 (0.26–2.21) and late-onset sepsis 0.54 (0.18–1.63). No adverse effects related to probiotics supplementation were observed.


Although nonsignificant, prophylactic probiotics supplementation in infants born VP or VLBW was associated with reduction of NEC.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Data availability

The de-identified dataset generated from the study is available on reasonable request and upon approval by the Institutional Review Board of Baylor Scott & White Health.


  1. Jacob J, Kamitsuka M, Clark RH, Kelleher AS, Spitzer AR. Etiologies of NICU deaths. Pediatrics. 2015;135:e59–65.

    Article  PubMed  Google Scholar 

  2. Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, DeMauro SB, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018. JAMA. 2022;327:248–63.

    Article  PubMed  Google Scholar 

  3. Claud EC, Walker WA. Hypothesis: inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis. FASEB J. 2001;15:1398–403.

    Article  CAS  PubMed  Google Scholar 

  4. Hunter CJ, Upperman JS, Ford HR, Camerini V. Understanding the susceptibility of the premature infant to necrotizing enterocolitis (NEC). Pediatr Res. 2008;63:117–23.

    Article  PubMed  Google Scholar 

  5. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J. 2009;3:944–54.

    Article  CAS  PubMed  Google Scholar 

  6. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11:506–14.

    Article  PubMed  Google Scholar 

  7. Halloran K, Underwood MA. Probiotic mechanisms of action. Early Hum Dev. 2019;135:58–65.

    Article  PubMed  Google Scholar 

  8. Patel RM, Underwood MA. Probiotics and necrotizing enterocolitis. Semin Pediatr Surg. 2018;27:39–46.

    Article  PubMed  Google Scholar 

  9. Xiong T, Maheshwari A, Neu J, Ei-Saie A, Pammi M. An Overview of Systematic Reviews of Randomized-Controlled Trials for Preventing Necrotizing Enterocolitis in Preterm Infants. Neonatology. 2020;117:46–56.

    Article  CAS  PubMed  Google Scholar 

  10. Sawh SC, Deshpande S, Jansen S, Reynaert CJ, Jones PM. Prevention of necrotizing enterocolitis with probiotics: a systematic review and meta-analysis. PeerJ. 2016;4:e2429.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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.

    PubMed  Google Scholar 

  12. Razak A, Patel RM, Gautham KS. Use of Probiotics to Prevent Necrotizing Enterocolitis: Evidence to Clinical Practice. JAMA Pediatr. 2021;175:773–4.

    Article  PubMed  Google Scholar 

  13. Viswanathan S, Lau C, Akbari H, Hoyen C, Walsh MC. Survey and evidence-based review of probiotics used in very low birth weight preterm infants within the United States. J Perinatol. 2016;36:1106–11.

    Article  CAS  PubMed  Google Scholar 

  14. Gray KD, Messina JA, Cortina C, Owens T, Fowler M, Foster M, et al. Probiotic Use and Safety in the Neonatal Intensive Care Unit: A Matched Cohort Study. J Pediatr. 2020;222:59–64.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Barbian ME, Buckle R, Denning PW, Patel RM. To start or not: Factors to consider when implementing routine probiotic use in the NICU. Early Hum Dev. 2019;135:66–71.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Patel AL, Engstrom JL, Meier PP, Kimura RE. Accuracy of methods for calculating postnatal growth velocity for extremely low birth weight infants. Pediatrics. 2005;116:1466–73.

    Article  PubMed  Google Scholar 

  17. Vermont Oxford Network. 2021 Manual of Operations, Part 2, Release 25.0. 2021.

  18. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116:1353–60.

    Article  PubMed  Google Scholar 

  19. Chiang MF, Quinn GE, Fielder AR, Ostmo SR, Paul Chan RV, Berrocal A, et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology. 2021;128:e51–68.

    Article  PubMed  Google Scholar 

  20. Papile L-A, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm. J Pediatr. 1978;92:529–34.

    Article  CAS  PubMed  Google Scholar 

  21. Deshmukh M, Patole S. Prophylactic Probiotic Supplementation for Preterm Neonates-A Systematic Review and Meta-Analysis of Nonrandomized Studies. Adv Nutr. 2021;12:1411–23.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Swanson JR, Hair A, Clark RH, Gordon PV. Spontaneous intestinal perforation (SIP) will soon become the most common form of surgical bowel disease in the extremely low birth weight (ELBW) infant. J Perinatol. 2022;42:423–9.

    Article  PubMed  Google Scholar 

  23. Neu J. Necrotizing Enterocolitis: The Future. Neonatology. 2020;117:240–4.

    Article  PubMed  Google Scholar 

  24. Patel RM, Ferguson J, McElroy SJ, Khashu M, Caplan MS. Defining necrotizing enterocolitis: current difficulties and future opportunities. Pediatr Res. 2020;88:10–5.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr. 2005;147:192–6.

    Article  PubMed  Google Scholar 

  26. Jacobs SE, Tobin JM, Opie GF, Donath S, Tabrizi SN, Pirotta M, et al. ProPrems Study Group. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics. 2013;132:1055–62.

    Article  PubMed  Google Scholar 

  27. Jacobs SE, Hickey L, Donath S, Opie GF, Anderson PJ, Garland SM, et al. ProPremsStudy Groups. Probiotics, prematurity and neurodevelopment: follow-up of a randomised trial. BMJ Paediatr Open. 2017;1:e000176.

    Article  PubMed  PubMed Central  Google Scholar 

  28. van den Akker CHP, van Goudoever JB, Shamir R, Domellöf M, Embleton ND, Hojsak I, 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;70:664–80.

    Article  PubMed  Google Scholar 

  29. Morgan RL, Preidis GA, Kashyap PC, Weizman AV, Sadeghirad B, McMaster Probiotic, Prebiotic, and Synbiotic Work Group. Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials. Gastroenterology. 2020;159:467–80.

    Article  CAS  PubMed  Google Scholar 

  30. van den Akker CHP, van Goudoever JB, Szajewska H, Embleton ND, Hojsak I, Reid D, et al. ESPGHAN Working Group for Probiotics, Prebiotics & Committee on Nutrition. Probiotics for Preterm Infants: A Strain-Specific Systematic Review and Network Meta-analysis. J Pediatr Gastroenterol Nutr. 2018;67:103–22.

    Article  PubMed  Google Scholar 

  31. Jungersen M, Wind A, Johansen E, Christensen JE, Stuer-Lauridsen B, Eskesen D. The Science behind the Probiotic Strain Bifidobacterium animalis subsp. lactis BB-12(®). Microorganisms. 2014;2:92–110.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Data on file. Abbott Nutrition. 2020.

  33. Poindexter B. COMMITTEE ON FETUS AND NEWBORN. Use of Probiotics in Preterm Infants. Pediatrics. 2021;147:e2021051485.

    Article  PubMed  Google Scholar 

  34. Marchand V. Using probiotics in the paediatric population. Paediatr Child Health. 2012;17:575–6.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Martin R, Nauta AJ, Ben Amor K, Knippels LM, Knol J, Garssen J. Early life: gut microbiota and immune development in infancy. Benef Microbes. 2010;1:367–82.

    Article  CAS  PubMed  Google Scholar 

  36. Torrazza RM, Neu J. The altered gut microbiome and necrotizing enterocolitis. Clin Perinatol. 2013;40:93–108.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hackam DJ, Sodhi CP. Toll-Like Receptor-Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis. Cell Mol Gastroenterol Hepatol. 2018;6:229–38.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gritz EC, Bhandari V. The human neonatal gut microbiome: a brief review. Front Pediatr. 2015;3:17.

    PubMed  PubMed Central  Google Scholar 

  39. Groer MW, Luciano AA, Dishaw LJ, Ashmeade TL, Miller E, Gilbert JA. Development of the preterm infant gut microbiome: a research priority. Microbiome. 2014;2:38.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hays S, Jacquot A, Gauthier H, Kempf C, Beissel A, Pidoux O, et al. Probiotics and growth in preterm infants: A randomized controlled trial, PREMAPRO study. Clin Nutr. 2016;35:802–11.

    Article  PubMed  Google Scholar 

  41. Million M, Angelakis E, Paul M, Armougom F, Leibovici L, Raoult D. Comparative meta-analysis of the effect of lactobacillus species on weight gain in humans and animals. Micro Pathog. 2012;53:100e8.

    Article  Google Scholar 

  42. Vallabhaneni S, Walker TA, Lockhart SR, Ng D, Chiller T, Melchreit R, et al. Centers for Disease Control and Prevention (CDC). Notes from the field: Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement—Connecticut, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:155–6.

    PubMed  PubMed Central  Google Scholar 

  43. Kulkarni T, Majarikar S, Deshmukh M, Ananthan A, Balasubramanian H, Keil A, et al. Probiotic sepsis in preterm neonates-a systematic review. Eur J Pediatr. 2022;181:2249–62.

    Article  PubMed  Google Scholar 

  44. Jena PK, Sheng L, Nagar N, Wu C, Barile D, Mills DA, et al. The effect of synbiotics Bifidobacterium infantis and milk oligosaccharides on shaping gut microbiota community structure and NASH treatment. Data Brief. 2018;19:1025–9.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chi C, Li C, Buys N, Wang W, Yin C, Sun J. Effects of Probiotics in Preterm Infants: A Network Meta-analysis. Pediatrics. 2021;147:e20200706.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations



AC contributed to conceptualization/design, methodology, data curation, formal analysis and drafted the paper. HH and RH contributed to the methodology, data curation, formal analysis and drafted the paper. AR and JR contributed to the methodology, data curation and reviewed the manuscript. SD contributed to the methodology, formal analysis and reviewed the paper. MS contributed to conceptualization/design, methodology and reviewed the paper.

Corresponding author

Correspondence to Arpitha Chiruvolu.

Ethics declarations

Competing interests

AC has received speaking honoraria from Abbott nutrition. The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chiruvolu, A., Hendrikson, H., Hanson, R. et al. Effects of prophylactic probiotics supplementation on infants born very preterm or very low birth weight. J Perinatol 43, 635–641 (2023).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links