Effects of oropharyngeal colostrum and minimal enteral nutrition on respiratory morbidity and necrotizing enterocolitis in preterm infants: A systematic review of randomized trials
Abstract
Background & Aim: Necrotizing enterocolitis is one of the most severe gastrointestinal complications in premature infants, characterized by acute intestinal inflammation and progressive mucosal damage. This systematic review aimed to evaluate the effects of minimal enteral nutrition and oropharyngeal or buccal colostrum administration on respiratory morbidity and the incidence of necrotizing enterocolitis in preterm neonates.
Materials & Methods: A comprehensive search was conducted using PubMed, Web of Science, Scopus, ProQuest, and Google Scholar databases. From 10,460 identified records, twelve randomized controlled trials published between 2015 and 2024 met inclusion criteria and were incorporated into the qualitative synthesis. Data were extracted regarding early growth, feeding tolerance, immune biomarkers, and safety outcomes.
Results: Minimal enteral nutrition was associated with improved early growth and reduced feeding intolerance. Oropharyngeal or buccal exposure to colostrum increased mucosal immune biomarkers, including immunoglobulin A, immunoglobulin M, and lactoferrin, and promoted early colonization of beneficial intestinal microorganisms. Some trials reported reductions in late‑onset sepsis and retinopathy of prematurity. However, neither minimal enteral nutrition nor colostrum‑based interventions significantly reduced the incidence of necrotizing enterocolitis (p > 0.05). Both approaches showed favorable safety profiles without increased adverse effects or clinical instability.
Conclusion: Minimal enteral nutrition and oropharyngeal or buccal colostrum administration appear to be safe, feasible, and biologically plausible strategies for enhancing early nutrition and mucosal immunity in premature infants. Larger, multicenter, and standardized clinical trials are warranted to determine their definitive impact on necrotizing enterocolitis prevention.
1. Müller M, Paul T, Seeliger S. Necrotizing enterocolitis in premature infants and newborns. Journal of Neonatal-Perinatal Medicine. 2016;9(3):233-42.
2. Liu Y, Jiang LF, Zhang RP, Zhang WT. Clinical significance of FABP2 expression in newborns with necrotizing enterocolitis. World Journal of Pediatrics. 2016;12(2):159-65.
3. Naim N, Haldun S. Prevalence of adverse outcomes of pregnancy in Sivas, Turkey, and their associated factors: a population-based survey. Nursing Practice Today. 2018;5(2).
4. Kosloske A. Epidemiology of necrotizing enterocolitis. Acta Paediatrica. 1994;83:2-7.
5. Kessler U, Schulte F, Cholewa D, Nelle M, Schaefer SC, Klimek PM, et al. Outcome in neonates with necrotizing enterocolitis and patent ductus arteriosus. World Journal of Pediatrics. 2016;12(1):55-9.
6. Su Y, Xu RH, Guo LY, Chen XQ, Han WX, Ma JJ, et al. Risk factors for necrotizing enterocolitis in neonates: a meta-analysis. Frontiers in Pediatrics. 2023;10:1079894.
7. Stoll BJ. Epidemiology of necrotizing enterocolitis. Clinics in Perinatology. 1994;21(2):205-18.
8. Canvasser J, Patel RM, Pryor E, Green L, Hintz SR, Fagan M, et al. Long-term outcomes and life-impacts of necrotizing enterocolitis: a survey of survivors and parents. Seminars in Perinatology. 2023.
9. Shi B, Lyu CJ, Le ZK, Ji HS, Xiao Y, Zhang YY, et al. NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis. World Journal of Pediatrics. 2024;20(2):153-64.
10. Craighead AF, Caughey AB, Chaudhuri A, Yieh L, Hersh AR, Dukhovny D. Cost-effectiveness of probiotics for necrotizing enterocolitis prevention in very low birth weight infants. Journal of Perinatology. 2020;40(11):1652-61.
11. Odom TL, Eubanks J, Redpath N, Davenport E, Tumin D, Akpan US. Development of necrotizing enterocolitis after blood transfusion in very premature neonates. World Journal of Pediatrics. 2023;19(1):68-75.
12. de Lange IH, van Gorp C, Eeftinck Schattenkerk LD, van Gemert WG, Derikx JP, Wolfs TG. Enteral feeding interventions in the prevention of necrotizing enterocolitis: a systematic review of experimental and clinical studies. Nutrients. 2021;13(5):1726.
13. Thänert R, Keen EC, Dantas G, Warner BB, Tarr PI. Necrotizing enterocolitis and the microbiome: current status and future directions. The Journal of Infectious Diseases. 2021;223(Suppl 3):S257-S63.
14. Bozkurt O, Alyamac Dizdar E, Bidev D, Sari FN, Uras N, Oguz SS. Prolonged minimal enteral nutrition versus early feeding advancements in preterm infants with birth weight ≤1250 g: a prospective randomized trial. Journal of Maternal-Fetal & Neonatal Medicine. 2022;35(2):341-7.
15. Siggers J, Sangild PT, Jensen TK, Siggers RH, Skovgaard K, Støy ACF, et al. Transition from parenteral to enteral nutrition induces immediate diet-dependent gut histological and immunological responses in preterm neonates. American Journal of Physiology Gastrointestinal and Liver Physiology. 2011;301(3):G435-G45.
16. Thoene M, Anderson-Berry A. Early enteral feeding in preterm infants: a narrative review of the nutritional, metabolic, and developmental benefits. Nutrients. 2021;13(7):2289.
17. Shanahan KH, Yu X, Miller LG, Freedman SD, Martin CR. Early serum gut hormone concentrations associated with time to full enteral feedings in preterm infants. Journal of Pediatric Gastroenterology and Nutrition. 2018;67(1):97-102.
18. Mezu-Ndubuisi O, Maheshwari A. Minimal enteral feeding. Nutrition for the Preterm Neonate: A Clinical Perspective. 2013:27-46.
19. Sohn K, Kalanetra K, Mills D, Underwood M. Buccal administration of human colostrum: impact on the oral microbiota of premature infants. Journal of Perinatology. 2016;36(2):106-11.
20. Sadeghirad B, Morgan RL, Zeraatkar D, Zea AM, Couban R, Johnston BC, et al. Human and bovine colostrum for prevention of necrotizing enterocolitis: A meta-analysis. Pediatrics. 2018;142(2):e20180767.
21. Poonia A, Shiva. Bioactive compounds, nutritional profile, and health benefits of colostrum: a review. Food Production, Processing, and Nutrition. 2022;4(1):26.
22. Panchal H, Athalye-Jape G, Patole S. Oropharyngeal colostrum for preterm infants: a systematic review and meta-analysis. Advances in Nutrition. 2019;10(6):1152-62.
23. Noel G, In JG, Lemme-Dumit JM, DeVine LR, Cole RN, Guerrerio AL, et al. Human breast milk enhances intestinal mucosal barrier function and innate immunity in a healthy pediatric human enteroid model. Frontiers in Cell and Developmental Biology. 2021;9:685171.
24. Lee J, Kim HS, Jung YH, Choi KY, Shin SH, Kim EK, et al. Oropharyngeal colostrum administration in extremely premature infants: an RCT. Pediatrics. 2015;135(2):e357-e66.
25. Huo M, Liu C, Mei H, Zhang Y, Liu C, Song D, et al. Intervention effect of oropharyngeal administration of colostrum in preterm infants: a meta-analysis. Frontiers in Pediatrics. 2022;10:895375.
26. Karagianni P, Briana DD, Mitsiakos G, Elias A, Theodoridis T, Chatziioannidis E, et al. Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal Doppler results. American Journal of Perinatology. 2010;27(5):367-73.
27. Viswanathan S, Merheb R, Wen X, Collin M, Groh-Wargo S. Standardized slow enteral feeding protocol reduces necrotizing enterocolitis in micropremies. Journal of Neonatal-Perinatal Medicine. 2017;10(2):171-80.
28. Sharma D, Kaur A, Farahbakhsh N, Agarwal S. Role of oropharyngeal administration of colostrum in very low birth weight infants for reducing necrotizing enterocolitis: a randomized controlled trial. American Journal of Perinatology. 2020;37(7):716-21.
29. Negarandeh R, Beykmirza R. Quality assessment in systematic reviews: The importance of choosing the right tools. Nursing Practice Today. 2020;7(3):161-2.
30. Sarkis-Onofre R, Catalá-López F, Aromataris E, Lockwood C. How to properly use the PRISMA statement. Systematic Reviews. 2021;10:1-3.
31. Rodriguez NA, Vento M, Claud EC, Wang CE, Caplan MS. Oropharyngeal administration of mother’s colostrum, health outcomes of premature infants: study protocol for a randomized controlled trial. Trials. 2015;16:1-14.
32. Yan X, Pan X, Ding L, Dai Y, Chen J, Yang Y, et al. Bovine colostrum to supplement the first feeding of very preterm infants: the PreColos randomized controlled trial. Clinical Nutrition. 2023;42(8):1408-17.
33. Kelich F, Qalehsari MQ, Zabihi A, Jafarian Amiri SR, Danaee N. The effect of oropharyngeal mother’s milk on nutritional outcomes in preterm infants: A randomized controlled trial. BMC Pediatrics. 2024;24(1):155.
34. OuYang X, Yang CY, Xiu WL, Hu YH, Mei SS, Lin Q. Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤32 weeks: a pilot single-center randomized controlled trial. International Breastfeeding Journal. 2021;16(1):59.
35. Farag MM, Thabet MAEH, Ahmed IS, Hanafi NF, Elsawy WS, Mohamed ES. Do preterm infants’ retinas like bovine colostrum? A randomized controlled trial. Italian Journal of Pediatrics. 2024;50(1):218.
36. Juhl SM, Ye X, Zhou P, Li Y, Iyore EO, Zhang L, et al. Bovine colostrum for preterm infants in the first days of life: a randomized controlled pilot trial. Journal of Pediatric Gastroenterology and Nutrition. 2018;66(3):471-8.
37. Martín-Álvarez E, Díaz-Castro J, Peña-Caballero M, Serrano-López L, Moreno-Fernández J, Sánchez-Martínez B, et al. Oropharyngeal colostrum positively modulates the inflammatory response in preterm neonates. Nutrients. 2020;12(2):413.
38. Chen LL, Liu J, Mu XH, Zhang XY, Yang CZ, Xiong XY, et al. Oropharyngeal administration of mother’s own milk influences levels of salivary sIgA in preterm infants fed by gastric tube. Scientific Reports. 2022;12(1):2233.
39. Behrooj N, Aziznejadroshan P, Akbarian Rad Z, Nikbakht HA, Zabihi A. Investigating the effect of oropharyngeal colostrum in the prevention of late-onset sepsis in preterm infants: A randomized controlled trial. Scientific Reports. 2025;15(1):1-9.
40. Moreno-Fernandez J, Sánchez-Martínez B, Serrano-López L, Martín-Álvarez E, Díaz-Castro J, Peña-Caballero M, et al. Enhancement of immune response mediated by oropharyngeal colostrum administration in preterm neonates. Pediatric Allergy and Immunology. 2019;30(2):234-41.
41. da Cruz Martins C, de Santana Xavier Ramos M, Viana Cardoso Amaral M, Santos Passos Costa J, Souza Cerqueira E, de Oliveira Vieira T, et al. Colostrum oropharyngeal immunotherapy for very low birth weight preterm infants: protocol of an intervention study. BMC Pediatrics. 2020;20:1-11.
42. Bombell S, McGuire W. Early trophic feeding for very low birth weight infants. Cochrane Database of Systematic Reviews. 2009;(3).
43. Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews. 2021;(8).
44. Xavier Ramos MdS, Martins CdC, Souza ES, Vieira GO, Gomes-Filho IS, Figueiredo ACMG, et al. Oropharyngeal colostrum immunotherapy and nutrition in preterm newborns: meta-analysis. Revista de Saude Publica. 2021;55:59.
45. Rodriguez NA, Meier PP, Groer MW, Zeller JM, Engstrom JL, Fogg L. A pilot study to determine the safety and feasibility of oropharyngeal administration of own mother’s colostrum to extremely low-birth-weight infants. Advances in Neonatal Care. 2010;10(4):206-12.
46. Gephart SM, Weller M. Colostrum as oral immune therapy to promote neonatal health. Advances in Neonatal Care. 2014;14(1):44-51.
2. Liu Y, Jiang LF, Zhang RP, Zhang WT. Clinical significance of FABP2 expression in newborns with necrotizing enterocolitis. World Journal of Pediatrics. 2016;12(2):159-65.
3. Naim N, Haldun S. Prevalence of adverse outcomes of pregnancy in Sivas, Turkey, and their associated factors: a population-based survey. Nursing Practice Today. 2018;5(2).
4. Kosloske A. Epidemiology of necrotizing enterocolitis. Acta Paediatrica. 1994;83:2-7.
5. Kessler U, Schulte F, Cholewa D, Nelle M, Schaefer SC, Klimek PM, et al. Outcome in neonates with necrotizing enterocolitis and patent ductus arteriosus. World Journal of Pediatrics. 2016;12(1):55-9.
6. Su Y, Xu RH, Guo LY, Chen XQ, Han WX, Ma JJ, et al. Risk factors for necrotizing enterocolitis in neonates: a meta-analysis. Frontiers in Pediatrics. 2023;10:1079894.
7. Stoll BJ. Epidemiology of necrotizing enterocolitis. Clinics in Perinatology. 1994;21(2):205-18.
8. Canvasser J, Patel RM, Pryor E, Green L, Hintz SR, Fagan M, et al. Long-term outcomes and life-impacts of necrotizing enterocolitis: a survey of survivors and parents. Seminars in Perinatology. 2023.
9. Shi B, Lyu CJ, Le ZK, Ji HS, Xiao Y, Zhang YY, et al. NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis. World Journal of Pediatrics. 2024;20(2):153-64.
10. Craighead AF, Caughey AB, Chaudhuri A, Yieh L, Hersh AR, Dukhovny D. Cost-effectiveness of probiotics for necrotizing enterocolitis prevention in very low birth weight infants. Journal of Perinatology. 2020;40(11):1652-61.
11. Odom TL, Eubanks J, Redpath N, Davenport E, Tumin D, Akpan US. Development of necrotizing enterocolitis after blood transfusion in very premature neonates. World Journal of Pediatrics. 2023;19(1):68-75.
12. de Lange IH, van Gorp C, Eeftinck Schattenkerk LD, van Gemert WG, Derikx JP, Wolfs TG. Enteral feeding interventions in the prevention of necrotizing enterocolitis: a systematic review of experimental and clinical studies. Nutrients. 2021;13(5):1726.
13. Thänert R, Keen EC, Dantas G, Warner BB, Tarr PI. Necrotizing enterocolitis and the microbiome: current status and future directions. The Journal of Infectious Diseases. 2021;223(Suppl 3):S257-S63.
14. Bozkurt O, Alyamac Dizdar E, Bidev D, Sari FN, Uras N, Oguz SS. Prolonged minimal enteral nutrition versus early feeding advancements in preterm infants with birth weight ≤1250 g: a prospective randomized trial. Journal of Maternal-Fetal & Neonatal Medicine. 2022;35(2):341-7.
15. Siggers J, Sangild PT, Jensen TK, Siggers RH, Skovgaard K, Støy ACF, et al. Transition from parenteral to enteral nutrition induces immediate diet-dependent gut histological and immunological responses in preterm neonates. American Journal of Physiology Gastrointestinal and Liver Physiology. 2011;301(3):G435-G45.
16. Thoene M, Anderson-Berry A. Early enteral feeding in preterm infants: a narrative review of the nutritional, metabolic, and developmental benefits. Nutrients. 2021;13(7):2289.
17. Shanahan KH, Yu X, Miller LG, Freedman SD, Martin CR. Early serum gut hormone concentrations associated with time to full enteral feedings in preterm infants. Journal of Pediatric Gastroenterology and Nutrition. 2018;67(1):97-102.
18. Mezu-Ndubuisi O, Maheshwari A. Minimal enteral feeding. Nutrition for the Preterm Neonate: A Clinical Perspective. 2013:27-46.
19. Sohn K, Kalanetra K, Mills D, Underwood M. Buccal administration of human colostrum: impact on the oral microbiota of premature infants. Journal of Perinatology. 2016;36(2):106-11.
20. Sadeghirad B, Morgan RL, Zeraatkar D, Zea AM, Couban R, Johnston BC, et al. Human and bovine colostrum for prevention of necrotizing enterocolitis: A meta-analysis. Pediatrics. 2018;142(2):e20180767.
21. Poonia A, Shiva. Bioactive compounds, nutritional profile, and health benefits of colostrum: a review. Food Production, Processing, and Nutrition. 2022;4(1):26.
22. Panchal H, Athalye-Jape G, Patole S. Oropharyngeal colostrum for preterm infants: a systematic review and meta-analysis. Advances in Nutrition. 2019;10(6):1152-62.
23. Noel G, In JG, Lemme-Dumit JM, DeVine LR, Cole RN, Guerrerio AL, et al. Human breast milk enhances intestinal mucosal barrier function and innate immunity in a healthy pediatric human enteroid model. Frontiers in Cell and Developmental Biology. 2021;9:685171.
24. Lee J, Kim HS, Jung YH, Choi KY, Shin SH, Kim EK, et al. Oropharyngeal colostrum administration in extremely premature infants: an RCT. Pediatrics. 2015;135(2):e357-e66.
25. Huo M, Liu C, Mei H, Zhang Y, Liu C, Song D, et al. Intervention effect of oropharyngeal administration of colostrum in preterm infants: a meta-analysis. Frontiers in Pediatrics. 2022;10:895375.
26. Karagianni P, Briana DD, Mitsiakos G, Elias A, Theodoridis T, Chatziioannidis E, et al. Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal Doppler results. American Journal of Perinatology. 2010;27(5):367-73.
27. Viswanathan S, Merheb R, Wen X, Collin M, Groh-Wargo S. Standardized slow enteral feeding protocol reduces necrotizing enterocolitis in micropremies. Journal of Neonatal-Perinatal Medicine. 2017;10(2):171-80.
28. Sharma D, Kaur A, Farahbakhsh N, Agarwal S. Role of oropharyngeal administration of colostrum in very low birth weight infants for reducing necrotizing enterocolitis: a randomized controlled trial. American Journal of Perinatology. 2020;37(7):716-21.
29. Negarandeh R, Beykmirza R. Quality assessment in systematic reviews: The importance of choosing the right tools. Nursing Practice Today. 2020;7(3):161-2.
30. Sarkis-Onofre R, Catalá-López F, Aromataris E, Lockwood C. How to properly use the PRISMA statement. Systematic Reviews. 2021;10:1-3.
31. Rodriguez NA, Vento M, Claud EC, Wang CE, Caplan MS. Oropharyngeal administration of mother’s colostrum, health outcomes of premature infants: study protocol for a randomized controlled trial. Trials. 2015;16:1-14.
32. Yan X, Pan X, Ding L, Dai Y, Chen J, Yang Y, et al. Bovine colostrum to supplement the first feeding of very preterm infants: the PreColos randomized controlled trial. Clinical Nutrition. 2023;42(8):1408-17.
33. Kelich F, Qalehsari MQ, Zabihi A, Jafarian Amiri SR, Danaee N. The effect of oropharyngeal mother’s milk on nutritional outcomes in preterm infants: A randomized controlled trial. BMC Pediatrics. 2024;24(1):155.
34. OuYang X, Yang CY, Xiu WL, Hu YH, Mei SS, Lin Q. Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤32 weeks: a pilot single-center randomized controlled trial. International Breastfeeding Journal. 2021;16(1):59.
35. Farag MM, Thabet MAEH, Ahmed IS, Hanafi NF, Elsawy WS, Mohamed ES. Do preterm infants’ retinas like bovine colostrum? A randomized controlled trial. Italian Journal of Pediatrics. 2024;50(1):218.
36. Juhl SM, Ye X, Zhou P, Li Y, Iyore EO, Zhang L, et al. Bovine colostrum for preterm infants in the first days of life: a randomized controlled pilot trial. Journal of Pediatric Gastroenterology and Nutrition. 2018;66(3):471-8.
37. Martín-Álvarez E, Díaz-Castro J, Peña-Caballero M, Serrano-López L, Moreno-Fernández J, Sánchez-Martínez B, et al. Oropharyngeal colostrum positively modulates the inflammatory response in preterm neonates. Nutrients. 2020;12(2):413.
38. Chen LL, Liu J, Mu XH, Zhang XY, Yang CZ, Xiong XY, et al. Oropharyngeal administration of mother’s own milk influences levels of salivary sIgA in preterm infants fed by gastric tube. Scientific Reports. 2022;12(1):2233.
39. Behrooj N, Aziznejadroshan P, Akbarian Rad Z, Nikbakht HA, Zabihi A. Investigating the effect of oropharyngeal colostrum in the prevention of late-onset sepsis in preterm infants: A randomized controlled trial. Scientific Reports. 2025;15(1):1-9.
40. Moreno-Fernandez J, Sánchez-Martínez B, Serrano-López L, Martín-Álvarez E, Díaz-Castro J, Peña-Caballero M, et al. Enhancement of immune response mediated by oropharyngeal colostrum administration in preterm neonates. Pediatric Allergy and Immunology. 2019;30(2):234-41.
41. da Cruz Martins C, de Santana Xavier Ramos M, Viana Cardoso Amaral M, Santos Passos Costa J, Souza Cerqueira E, de Oliveira Vieira T, et al. Colostrum oropharyngeal immunotherapy for very low birth weight preterm infants: protocol of an intervention study. BMC Pediatrics. 2020;20:1-11.
42. Bombell S, McGuire W. Early trophic feeding for very low birth weight infants. Cochrane Database of Systematic Reviews. 2009;(3).
43. Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews. 2021;(8).
44. Xavier Ramos MdS, Martins CdC, Souza ES, Vieira GO, Gomes-Filho IS, Figueiredo ACMG, et al. Oropharyngeal colostrum immunotherapy and nutrition in preterm newborns: meta-analysis. Revista de Saude Publica. 2021;55:59.
45. Rodriguez NA, Meier PP, Groer MW, Zeller JM, Engstrom JL, Fogg L. A pilot study to determine the safety and feasibility of oropharyngeal administration of own mother’s colostrum to extremely low-birth-weight infants. Advances in Neonatal Care. 2010;10(4):206-12.
46. Gephart SM, Weller M. Colostrum as oral immune therapy to promote neonatal health. Advances in Neonatal Care. 2014;14(1):44-51.
| Issue | Articles in Press | |
| Section | Review Article(s) | |
| Keywords | ||
| necrotizing enterocolitis colostrum premature birth early feeding enteral feeding neonatal nutrition | ||
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How to Cite
1.
Zarafrooz M, Begjani J. Effects of oropharyngeal colostrum and minimal enteral nutrition on respiratory morbidity and necrotizing enterocolitis in preterm infants: A systematic review of randomized trials. Nurs. pract. today. 2026;:X-X.
