Efficacy and Safety of Probiotic Supplementation in Preventing Necrotizing Enterocolitis in Preterm Infants: A Systematic Review and Meta-analysis
DOI:
https://doi.org/10.54361/LJMR.19.2.50Keywords:
Necrotizing Enterocolitis,, Probiotics, Preterm Infants, Meta-analysis, SepsisAbstract
Background: Necrotizing enterocolitis (NEC) is a serious gastrointestinal condition that affects preterm infants and is still linked to high levels of illness and death. Despite advances in neonatal care, effective prevention methods remain limited. Probiotic supplementation has garnered attention as a promising intervention, but uncertainty persists regarding which strains are most effective. This systematic review and meta-analysis aimed to evaluate the safety and effectiveness of probiotics in preventing NEC and to identify the regimens that offer the greatest protective benefits. Material and Methods: A thorough search of PubMed, EMBASE, the Cochrane Library, and Web of Science was conducted to find randomized controlled trials assessing probiotics for NEC prevention. Primary outcomes included NEC incidence (≥ Stage II), all-cause mortality, and late-onset sepsis. Random-effects models calculated risk ratios with 95% confidence intervals. Subgroup analyses were performed based on probiotic strains, feeding type, birth weight, and baseline NEC risk. The GRADE method was used to assess the quality of evidence. Results: Fifty-one trials involving 10,664 infants and 29 probiotic regimens were included. Probiotics significantly lowered NEC incidence, mortality, and late-onset sepsis. The most effective regimens combined Bovine lactoferrin with Lactobacillus rhamnosus GG and Lactobacillus acidophilus LB. Multi-strain probiotics outperformed single-strain formulations. Benefits were observed in both human milk-fed and formula-fed infants, and no cases of probiotic-associated sepsis were reported. Conclusion: Probiotic supplementation is a safe and effective strategy for reducing NEC, mortality, and sepsis in preterm infants. Multi-strain regimens, especially those containing Lactobacillus rhamnosus GG or Bovine lactoferrin, show the highest efficacy and could be considered for standard use in neonatal care settings.
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References
1. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011;364(3):255-264.
2. Stoll BJ, Hansen NI, Bell EF, et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015;314(10):1039-1051.
3. Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2007;92(3):F193-F198.
4. Nino DF, Sodhi CP, Hackam DJ. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol. 2016;13(10):590-600.
5. Neu J, Pammi M. Pathogenesis of NEC: impact of an altered intestinal microbiome. Semin Perinatol. 2017;41(1):29-35.
6. Warner BB, Deych E, Zhou Y, et al. Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study. Lancet. 2016;387(10031):1928-1936.
7. Gephart SM, McGrath JM, Effken JA, Halpern MD. Necrotizing enterocolitis risk: state of the science. Adv Neonatal Care. 2012;12(2):77-87.
8. Patel RM, Underwood MA. Probiotics and necrotizing enterocolitis. Semin Pediatr Surg. 2018;27(1):39-46.
9. Hill C, Guarner F, Reid G, 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(8):506-514.
10. Underwood MA, Sohn K. The microbiota of the extremely preterm infant. Clin Perinatol. 2017;44(2):407-427.
11. van den Akker CHP, van Goudoever JB, Szajewska H, et al. Probiotics for preterm infants: a strain-specific systematic review and network meta-analysis. J Pediatr Gastroenterol Nutr. 2018;67(1):103-122.
12. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2014;(4):CD005496.
13. 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.
14. 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.
15. Costeloe K, Hardy P, Juszczak E, Wilks M, Millar MR; Probiotics in Preterm Infants Study Collaborative Group. Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial. Lancet. 2016;387(10019):649-660.
16. Vallabhaneni S, Walker TA, Lockhart SR, et al. 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(6):155-156.
17. 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.
18. Morgan RL, Preidis GA, Kashyap PC, Weizman AV, Sadeghirad B. Probiotics reduce mortality and morbidity in preterm, low-birth-weight infants: a systematic review and network meta-analysis of randomized trials. Gastroenterology. 2020;159(2):467-480.
19. Chi C, Buys N, Li C, Sun J, Yin C. Effects of prebiotics on sepsis, necrotizing enterocolitis, mortality, feeding intolerance, time to full enteral feeding, length of hospital stay, and stool frequency in preterm infants: a meta-analysis. Eur J Clin Nutr. 2019;73(5):657-670.
20. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
21. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7.
22. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
23. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-926.
24. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
25. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634.
26. Deshpande G, Jape G, Rao S, Patole S. Benefits of probiotics in preterm neonates in low-income and medium-income countries: a systematic review of randomised controlled trials. BMJ Open. 2017;7(12):e017638.
27. Sun J, Marwah G, Westgarth M, Buys N, Ellwood D, Gray PH. Effects of probiotics on necrotizing enterocolitis, sepsis, intraventricular hemorrhage, mortality, length of hospital stay, and weight gain in very preterm infants: a meta-analysis. Adv Nutr. 2017;8(5):749-763.
28. Athalye-Jape G, Rao S, Patole S. Effects of probiotics on experimental necrotizing enterocolitis: a systematic review and meta-analysis. Pediatr Res. 2018;83(1-1):16-22.
29. Sherman MP, Adamkin DH, Niklas V, et al. Randomized controlled trial of talactoferrin oral solution in preterm infants. J Pediatr. 2016;175:68-73.e3.
30. Jacobs SE, Tobin JM, Opie GF, et al. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics. 2013;132(6):1055-1062.
31. Underwood MA, German JB, Lebrilla CB, Mills DA. Bifidobacterium longum subspecies infantis: champion colonizer of the infant gut. Pediatr Res. 2015;77(1-2):229-235.
32. Guthmann F, Kluthe C, Bührer C. Probiotics for prevention of necrotising enterocolitis: an updated meta-analysis. Klin Padiatr. 2010;222(5):284-290.
33. Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2019;7:CD002971.
34. Underwood MA, Gaerlan S, De Leoz ML, et al. Human milk oligosaccharides in premature infants: absorption, excretion, and influence on the intestinal microbiota. Pediatr Res. 2015;78(6):670-677.
35. Aceti A, Gori D, Barone G, et al. Probiotics for prevention of necrotizing enterocolitis in preterm infants: systematic review and meta-analysis. Ital J Pediatr. 2015;41:89.
36. Arboleya S, Binetti A, Salazar N, et al. Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiol Ecol. 2012;79(3):763-772.
37. Esaiassen E, Cavanagh P, Hjerde E, Simonsen GS, Støen R, Klingenberg C. Bifidobacterium longum subspecies infantis bacteremia in 3 extremely preterm infants receiving probiotics. Emerg Infect Dis. 2016;22(9):1664-1666.
38. Collado MC, Gueimonde M, Salminen S. Probiotics in adhesion of pathogens: mechanisms of action. In: Watson RR, Preedy VR, eds. Bioactive Foods in Promoting Health. Academic Press; 2010:353-370.
39. Patel RM, Myers LS, Kurundkar AR, et al. Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. Am J Pathol. 2012;180(2):626-635.
40. Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar N. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Physiol Gastrointest Liver Physiol. 2013;304(2):G132-G141.
41. Corr SC, Li Y, Riedel CU, O'Toole PW, Hill C, Gahan CG. Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proc Natl Acad Sci U S A. 2007;104(18):7617-7621.
42. Timmerman HM, Koning CJ, Mulder L, Rombouts FM, Beynen AC. Monostrain, multistrain and multispecies probiotics--A comparison of functionality and efficacy. Int J Food Microbiol. 2004;96(3):219-233.
43. Maldonado-Lobón JA, Gil-Campos M, Maldonado J, et al. Long-term safety of early consumption of Lactobacillus fermentum CECT5716: a 3-year follow-up of a randomized controlled trial. Pharmacol Res. 2015;95-96:12-19.
44. Ballard O, Morrow AL. Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am. 2013;60(1):49-74.
45. Manzoni P, Meyer M, Stolfi I, et al. Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial. Early Hum
46. Dev. 2014;90 Suppl 1:S60-S65.
47. Bertelli C, Pillonel T, Torregrossa A, et al. Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clin Infect Dis. 2015;60(6):924-927.
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Copyright (c) 2025 Amani EH Bidalla, Ahmed S Mkeal, Rasha J Abraheem, Shadin Jummah Abraheem, Mahmoud A. Aloriby, Mohamed K A Elkawafi, Hamza A Osman, Abdulmunaim A.M Elkarimi, sabah salah abd alaleam (Author)
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