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  • Clinical Research Article
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Early human milk feeding: Relationship to intestinal barrier maturation and postnatal growth

Pediatric Research volume 97, pages 2065–2073 (2025)Cite this article

Abstract

Objectives

Early exposure to mother’s own milk (MOM) promotes intestinal barrier maturation in preterm infants. We hypothesized (1) donor human milk (DHM) supplementation reduces intestinal permeability (IP) similar to exclusive MOM and (2) early HM exposure and low IP at 7–10 days postnatal age (PNA) are associated with improved growth outcomes.

Methods

IP was measured by the standard sugar absorption test (SAT) in infants <33 weeks gestation between 7–10 days PNA. Nutritional and anthropometric data were recorded. Postnatal growth failure (PNGF) was defined as a decrease in weight z-score >1 from birth to discharge to home.

Results

Of 158 preterm infants, the mean (SD) gestational age was 29.9(2.3) weeks and birthweight 1388(424) g. Diet prior to SAT was exclusive MOM [N = 55(35%)], DHM ± MOM [N = 52(33%)], or preterm formula±MOM [N = 51(32%)]. The mean Lactulose(La)/Rhamnose(Rh) ratio was lower in the exclusive MOM [0.06(0.07)] and DBM ± MOM [0.05(0.07)] groups compared to the preterm formula±MOM group [0.11(0.11)], p < 0.01). Cumulative intake >150 ml/kg MOM ± DHM, but not preterm formula within 7–10 days PNA was associated with early intestinal barrier maturation. Low IP was not associated with lower risk of PNGF at discharge.

Conclusions

Low IP is associated with cumulative intake of MOM alone or supplemented with DHM > 150 ml/kg within 7–10 days PNA.

Clinical trial registration

Clinicaltrials.gov NCT01756040; web link to study on registry:https://clinicaltrials.gov/study/NCT01756040.

Impact

  • Key message Early intestinal barrier maturation is associated with cumulative intake of exclusive MOM alone or supplemented with DHM > 150 ml/kg within 7–10 days after birth, but is not associated with lower risk of PNGF at time of discharge.

  • What it adds to existing literature? This observational study is the first study to demonstrate that supplemental DHM promotes intestinal barrier maturation similar to MOM alone.

  • What is the impact? The findings underscore the importance of early introduction of human milk feeds as MOM or MOM supplemented with DHM in sufficient volume to promote early intestinal barrier maturation.

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Fig. 1
Fig. 2: Cumulative dietary feeding volumes, IP and PNGF.
Fig. 3

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Data availability

Deidentified individual participant data (including data dictionaries) will be made available, in addition to the study protocol, the statistical analysis plan and the informed consent form. The data will be made available upon publication to researchers who provide a methodically sound proposal. Requests should be submitted to ssundararajan@som.umaryland.edu.

References

  1. Halpern, M. D. & Denning, P. W. The role of intestinal epithelial barrier function in the development of Nec. Tissue Barriers 3, e1000707 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Beach, R. C., Menzies, I. S., Clayden, G. S. & Scopes, J. W. Gastrointestinal permeability changes in the preterm neonate. Arch. Dis. Child 57, 141–145 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Corpeleijn, W. E., van Elburg, R. M., Kema, I. P. & van Goudoever, J. B. Assessment of intestinal permeability in (premature) neonates by sugar absorption tests. Methods Mol. Biol. 763, 95–104 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Stratiki, Z. et al. The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants. Early Hum. Dev. 83, 575–579 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. van Elburg, R. M., Fetter, W. P., Bunkers, C. M. & Heymans, H. S. Intestinal permeability in relation to birth weight and gestational and postnatal age. Arch. Dis. Child Fetal Neonatal Ed. 88, F52–F55 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Taylor, S. N., Basile, L. A., Ebeling, M. & Wagner, C. L. Intestinal permeability in preterm infants by feeding type: mother’s milk versus formula. Breastfeed. Med 4, 11–15 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Saleem, B. et al. Intestinal barrier maturation in very low birthweight infants: relationship to feeding and antibiotic exposure. J. Pediatr. 183, 31–36.e31 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ma, B. et al. Microbial biomarkers of intestinal barrier maturation in preterm infants. Front Microbiol 9, 2755 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ma, B. et al. Highly specialized carbohydrate metabolism capability in bifidobacterium strains associated with intestinal barrier maturation in early preterm infants. mBio 13, e0129922 (2022).

    Article  PubMed  Google Scholar 

  10. Lemme-Dumit, J. M. et al. Altered gut microbiome and fecal immune phenotype in early preterm infants with leaky gut. Front Immunol. 13, 815046 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shulman, R. J. et al. Early feeding, antenatal glucocorticoids, and human milk decrease intestinal permeability in preterm infants. Pediatr. Res 44, 519–523 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Sullivan, S. et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J. Pediatr. 156, 562–567.e561 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Hair, A. B. et al. Beyond necrotizing enterocolitis prevention: improving outcomes with an exclusive human milk-based diet. Breastfeed. Med 11, 70–74 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hair, A. B. et al. Neurodevelopmental outcomes of extremely preterm infants fed an exclusive human milk-based diet versus a mixed human milk + bovine milk-based diet: a multi-center study. J. Perinatol. 42, 1485–1488 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Section on, B. Breastfeeding and the use of human milk. Pediatrics 129, e827-e841 (2012).

  16. Stefanescu, B. M., Camacho, J., Stefanescu, A. R., DuPont, T. & Leung, R. Impact of a standardized nutrition bundle including donor human milk on hospital outcomes in very low birth-weight (VLBW) infants in a safety-net hospital. Adv. Neonatal Care 22, 503–512 (2022).

    Article  PubMed  Google Scholar 

  17. Ramirez, C. B. et al. Effects of Human Milk On Body Composition And Growth In Very Low Birthweight Infants. Pediatr. Res 93, 2028–2035 (2023).

    Article  CAS  PubMed  Google Scholar 

  18. Cartagena, D. et al. Differences in neonatal outcomes among premature infants exposed to mother’s own milk versus donor human milk. Adv. Neonatal Care 22, 539–549 (2022).

    Article  PubMed  Google Scholar 

  19. Sanchez-Rosado, M. et al. Growth after implementing a donor breast milk program in neonates <33 weeks gestational age or birthweight <1500 grams: retrospective cohort study. J. Perinatol. 43, 608–615 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Perrin, M. T. et al. The nutritional composition and energy content of donor human milk: a systematic review. Adv. Nutr. 11, 960–970 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Marx, C. et al. Human milk oligosaccharide composition differs between donor milk and mother’s own milk in the NICU. J. Hum. Lact 30, 54–61 (2014).

    Article  PubMed  Google Scholar 

  22. John, A. et al. Macronutrient variability in human milk from donors to a milk bank: implications for feeding preterm infants. PLoS One 14, e0210610 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Parra-Llorca, A. et al. Preterm gut microbiome depending on feeding type: significance of donor human milk. Front Microbiol 9, 1376 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Brownell, E. A. et al. Dose-response relationship between donor human milk, mother’s own milk, preterm formula, and neonatal growth outcomes. J. Pediatr. Gastroenterol. Nutr. 67, 90–96 (2018).

    Article  PubMed  Google Scholar 

  25. Colaizy, T. T. Effects of milk banking procedures on nutritional and bioactive components of donor human milk. Semin Perinatol. 45, 151382 (2021).

    Article  PubMed  Google Scholar 

  26. Chou, J. H., Roumiantsev, S. & Singh, R. Peditools electronic growth chart calculators: applications in clinical care, research, and quality improvement. J. Med Internet Res 22, e16204 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ofek Shlomai, N. et al. Neonatal morbidities and postnatal growth failure in very low birth weight, very preterm infants. Acta Paediatr. 111, 1536–1545 (2022).

    Article  PubMed  Google Scholar 

  28. Bagga, N. et al. Extrauterine growth restriction: need for an accurate definition. Newborn (Clarksville) 2, 198–202 (2023).

    Article  PubMed  Google Scholar 

  29. Peila, C. et al. Extrauterine growth restriction: definitions and predictability of outcomes in a cohort of very low birth weight infants or preterm neonates. Nutrients 12, 49–60 (2020).

    Article  Google Scholar 

  30. Patel, A. L., Engstrom, J. L., Meier, P. P. & Kimura, R. E. Accuracy of methods for calculating postnatal growth velocity for extremely low birth weight infants. Pediatrics 116, 1466–1473 (2005).

    Article  PubMed  Google Scholar 

  31. Patel, A. L., Engstrom, J. L., Meier, P. P., Jegier, B. J. & Kimura, R. E. Calculating postnatal growth velocity in very low birth weight (VLBW) premature infants. J. Perinatol. 29, 618–622 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fenton, T. R. et al. Accuracy of preterm infant weight gain velocity calculations vary depending on method used and infant age at time of measurement. Pediatr. Res 85, 650–654 (2019).

    Article  PubMed  Google Scholar 

  33. Berman, L. & Moss, R. L. Necrotizing enterocolitis: an update. Semin Fetal Neonatal Med 16, 145–150 (2011).

    Article  PubMed  Google Scholar 

  34. Fatemizadeh, R. et al. Incidence of spontaneous intestinal perforations exceeds necrotizing enterocolitis in extremely low birth weight infants fed an exclusive human milk-based diet: a single center experience. J. Pediatr. Surg. 56, 1051–1056 (2021).

    Article  PubMed  Google Scholar 

  35. Buckle, A. & Taylor, C. Cost and cost-effectiveness of donor human milk to prevent necrotizing enterocolitis: systematic review. Breastfeed. Med 12, 528–536 (2017).

    Article  PubMed  Google Scholar 

  36. Bajwa, R. U. et al. Infant nutrition (donor human milk vs. maternal milk) and long-term neurodevelopmental and growth outcomes in very low birth weight infants. J. Matern Fetal Neonatal Med 35, 10025–10029 (2022).

    Article  CAS  PubMed  Google Scholar 

  37. Noel, G. et al. Human breast milk enhances intestinal mucosal barrier function and innate immunity in a healthy pediatric human enteroid model. Front Cell Dev. Biol. 9, 685171 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Carneiro, L. et al. The sterilization of human milk by holder pasteurization or by high hydrostatic pressure processing leads to differential intestinal effects in mice. Nutrients 15, 4043 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rochow, N. et al. Physiological adjustment to postnatal growth trajectories in healthy preterm infants. Pediatr. Res 79, 870–879 (2016).

    Article  PubMed  Google Scholar 

  40. Fenton, T. R. et al. “Extrauterine growth restriction” and “postnatal growth failure” are misnomers for preterm infants. J. Perinatol. 40, 704–714 (2020).

    Article  PubMed  Google Scholar 

  41. El Rafei, R. et al. Postnatal growth restriction and neurodevelopment at 5 years of age: a European extremely preterm birth cohort study. Arch. Dis. Child Fetal Neonatal Ed. 108, 492–498 (2023).

    Article  PubMed  Google Scholar 

  42. Lunn, P. G., Northrop-Clewes, C. A. & Downes, R. M. Intestinal permeability, mucosal injury, and growth faltering in Gambian infants. Lancet 338, 907–910 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Campbell, R. K. et al. Environmental enteric dysfunction and systemic inflammation predict reduced weight but not length gain in rural Bangladeshi children. Br. J. Nutr. 119, 407–414 (2018).

    Article  CAS  PubMed  Google Scholar 

  44. Stevens, T. P. et al. Statewide initiative to reduce postnatal growth restriction among infants <31 weeks of gestation. J. Pediatr. 197, 82–89.e82 (2018).

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Jonathan Meddings, University of Calgary, Calgary, Alberta, Canada for the HPLC analysis of urine samples and Elise Janofsky for research assistance. This study was supported in part by The Gerber Foundation (award identifier 6361), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (R21DK123674), and a University of Maryland Institute for Clinical and Translational Research Accelerated Translational Incubator Pilot award.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Maryland School of Medicine, 22 S, Greene St, Baltimore, Maryland, 21201, USA

    Lisa Roskes, Alexandre E. Medina, Rose M. Viscardi & Sripriya Sundararajan

  2. Center for Translational Medicine, University of Maryland School of Pharmacy, S Greene St, Baltimore, Maryland, 21201, USA

    Athanasios Chamzas & Mathangi Gopalakrishnan

  3. Institute for Genome Sciences, Department of Microbiology and Immunology, University of Maryland School of Medicine, 22 S Greene St, Baltimore, Maryland, 21201, USA

    Bing Ma

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  1. Lisa Roskes
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Contributions

Drs. Sripriya Sundararajan, Rose M. Viscardi, and Bing Ma conceptualized and designed the study, obtained funding, designed the data collection instruments, coordinated and supervised data collection, participated in data analysis and interpretation, drafted the initial manuscript, and critically reviewed and revised the manuscript. Dr Lisa Roskes coordinated and supervised data collection, participated in data analysis and interpretation, contributed to drafting the initial manuscript and critically reviewed and revised the manuscript for important intellectual content. Dr Mathangi Gopalakrishnan, and Athanasios Chamzas, reviewed the collected data, carried out the statistical analyses, and critically reviewed and revised the manuscript. Dr. Alex Medina contributed to statistical analysis and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Sripriya Sundararajan.

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The authors declare no competing interest.

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Patient consent was obtained as per institutional guidelines prior to the enrollment of the study subjects.

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Roskes, L., Chamzas, A., Ma, B. et al. Early human milk feeding: Relationship to intestinal barrier maturation and postnatal growth. Pediatr Res 97, 2065–2073 (2025). https://doi.org/10.1038/s41390-024-03622-5

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