Probiotic dose-response studies in preterm neonates – a systematic review
Creators: name: Jape, Gayatri
name: Rath, Chandra
name: Shripada Rao
name: Patole, Sanjay
Publisher: name: Open Science Framework
Year: 2023
Subjects: subject: Medicine and Health Sciences

description: Survival of very preterm infants has improved significantly in the last few decades following the advances in neonatal intensive care. This population of infants is at high risk of morbidities such as necrotizing enterocolitis (NEC)(1), late onset sepsis (LOS)(2), and feeding intolerance, which are associated with poor long-term growth and neurodevelopmental outcomes(3-9). Evidence from systematic reviews of over 60 randomised controlled trials (RCTs) and 30 non-RCTs shows that probiotics significantly reduce the risk of all-cause mortality, NEC≥ Stage II, LOS, and feed intolerance in preterm infants(10-12). However, inadequate evidence on important aspects of supplementation including optimal dose and strains continue to be a barrier against adopting probiotics in routine practice for preterm infants (13). Probiotics are defined as “live microorganisms which when administered in an adequate amount, confer benefits to the host”(14). This definition does not clarify what an adequate dose is or should be. Pragmatically, it has been defined as the dose shown to be beneficial in a large RCT(15). Deshpande et al recommended a daily dose of 3 x 109 colony forming units (cfu) per day in preterm very low birth weight (VLBW) infants born &lt;32 weeks, based on the median dose used in RCTs(15). Administering an adequate dose is important for optimal response to probiotics. Critical assessment of current evidence from probiotic dose-response studies in preterm neonates is hence important. The need for such an assessment is supported by the increasing adoption of probiotics for preterm infants and the call for well-designed, strain-specific probiotic dose-response studies in this cohort (16, 17). Given the significance of the underlying issues, we aim to conduct a systematic review to evaluate the current evidence from such studies in preterm infants to guide clinical practice and research in this field. 1. Cotten CM. Modifiable risk factors in necrotizing enterocolitis. Clinics in Perinatology. 2019;46(1):129-43. 2. Gowda H, Norton R, White A, Kandasamy Y. Late-onset neonatal sepsis—a 10-year review from North Queensland, Australia. The Pediatric infectious disease journal. 2017;36(9):883-8. 3. Chan SH, Johnson MJ, Leaf AA, Vollmer B. Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review. Acta Paediatrica. 2016;105(6):587-99. 4. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006;117(4):1253-61. 5. Lee ES, Kim EK, Shin SH, Choi YH, Jung YH, Kim SY, et al. Factors associated with neurodevelopment in preterm infants with systematic inflammation. BMC Pediatr. 2021;21(1):114. 6. Mondal A, Misra D, Al-Jabir A, Hubail D, Ward T, Patel B. Necrotizing enterocolitis in neonates: Has the brain taken a hit 10 years later? Journal of Pediatric Neurosciences. 2021;16(1):30. 7. Schlapbach LJ, Aebischer M, Adams M, Natalucci G, Bonhoeffer J, Latzin P, et al. Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants. Pediatrics. 2011;128(2):e348-e57. 8. Strunk T, Inder T, Wang X, Burgner D, Mallard C, Levy O. Infection-induced inflammation and cerebral injury in preterm infants. The Lancet infectious diseases. 2014;14(8):751-62. 9. Zozaya C, Shah J, Pierro A, Zani A, Synnes A, Lee S, et al. Neurodevelopmental and growth outcomes of extremely preterm infants with necrotizing enterocolitis or spontaneous intestinal perforation. Journal of Pediatric Surgery. 2021;56(2):309-16. 10. Deshmukh M, Patole S. Prophylactic probiotic supplementation for preterm neonates—a systematic review and meta-analysis of nonrandomized studies. Advances in Nutrition. 2021;12(4):1411-23. 11. Morgan RL, Preidis GA, Kashyap PC, Weizman AV, Sadeghirad B, Chang Y, et al. 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):467-80. 12. 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 of Systematic Reviews. 2020(10). 13. Razak A, Patel RM, Gautham KS. Use of probiotics to prevent necrotizing enterocolitis: evidence to clinical practice. JAMA pediatrics. 2021;175(8):773-4. 14. FAO/WHO. Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. Joint FAO/WHO Expert Consultation Cordoba, Argentina; 2001. p. 1-34. 15. Deshpande GC, Rao SC, Keil AD, Patole SK. Evidence-based guidelines for use of probiotics in preterm neonates. BMC medicine. 2011;9(1):1-13. 16. Depoorter L, Vandenplas Y. Probiotics in Pediatrics. A Review and Practical Guide. Nutrients. 2021;13(7). 17. Ouwehand A. A review of dose-responses of probiotics in human studies. Beneficial Microbes. 2017;8(2):143-51.