Bovine vs. Human Milk-Based Fortifier Study

Optimizing Mothers' Milk for Preterm Infants (OptiMoM) Program of Research: Study 2-Bovine vs. Human Milk-Based Fortifier Study

Most very low birth weight infants accumulate a nutrient deficit in hospital due to minimal nutrient reserves and elevated nutritional requirements which may contribute to poor outcome. Adding nutrients to human milk improves their nutritional status and growth, but it is unclear if adding bovine protein-based fortifiers as is the current standard of care has some unintended negative consequences to neonates. Infants will be randomized to have their feeds (mother's own milk or pasteurized donor breastmilk) nutrient enriched with a human milk-based fortifier or a bovine protein-based fortifier and will be followed in hospital to assess feeding tolerance, growth, gut inflammation, mother's milk and infant gut microbiome, and neonatal morbidity and mortality.

Percentage of infants with a significant feeding interruption as defined by days feedings held for ≥12 hours OR feeds reduced by >50% (ml/kg/d) not due to a clinical procedure or transitioning to the breast

84 days of age, hospital discharge or when able to consume two oral feeds a day without supplementation (e.g. tube feeding), whichever comes first

Daily weight measurements, weekly length measurements, weekly head circumference measurements, z-scores for anthropometric measures

84 days of age, hospital discharge or when able to consume two oral feeds a day without supplementation (e.g. tube feeding), whichever comes first

Percent and number of days of emesis, gastric aspirates >50% pre-feed volume, abdominal distension (>2 cm), percentage of infants where enteral feeding was terminated and parenteral nutrition had to be commenced, some assessment of the interruption of feeds, how long it takes to reach full enteral feeds (150 ml/kg/d)

84 days of age, hospital discharge or when able to consume two oral feeds a day without supplementation (e.g. tube feeding), whichever comes first

84 days of age, hospital discharge or when able to consume two oral feeds a day without supplementation (e.g. tube feeding), whichever comes first

Necrotizing enterocolitis, late onset sepsis, chronic lung disease, severe retinopathy of prematurity, death

84 days of age, hospital discharge or when able to consume two oral feeds a day without supplementation (e.g. tube feeding), whichever comes first

Inclusion Criteria: <1250g birth weight Parent(s) or guardian(s) agree to use donor breastmilk if own mother's milk supply is insufficient Exclusion Criteria: Infant receives formula or a nutrient fortifier prior to randomization >day 14 at the time of enrollment and enteral feeds have not commenced Infants with major congenital or chromosomal anomalies that could impact growth Enrollment in another research study affecting nutritional management during the feeding intervention Reasonable potential that the infant will be transferred to a neonatal intensive care unit where the study protocol will not be continued

Asbury MR, Shama S, Sa JY, Bando N, Butcher J, Comelli EM, Copeland JK, Forte V, Kiss A, Sherman PM, Stintzi A, Taibi A, Tomlinson C, Unger S, Wang PW, O'Connor DL; OptiMoM Feeding Group. Human milk nutrient fortifiers alter the developing gastrointestinal microbiota of very-low-birth-weight infants. Cell Host Microbe. 2022 Sep 14;30(9):1328-1339.e5. doi: 10.1016/j.chom.2022.07.011. Epub 2022 Aug 19.

Hopperton KE, Pitino MA, Walton K, Kiss A, Unger SL, O'Connor DL, Bazinet RP. Docosahexaenoic acid and arachidonic acid levels are correlated in human milk: Implications for new European infant formula regulations. Lipids. 2022 May;57(3):197-202. doi: 10.1002/lipd.12338. Epub 2022 Feb 15.

Hopperton KE, Pitino MA, Chouinard-Watkins R, Shama S, Sammut N, Bando N, Williams BA, Walton K, Kiss A, Unger SL, Bazinet RP, O'Connor DL. Determinants of fatty acid content and composition of human milk fed to infants born weighing <1250 g. Am J Clin Nutr. 2021 Oct 4;114(4):1523-1534. doi: 10.1093/ajcn/nqab222.

Hopperton KE, O'Connor DL, Bando N, Conway AM, Ng DVY, Kiss A, Jackson J, Ly L; OptiMoM Feeding Group; Unger SL. Nutrient Enrichment of Human Milk with Human and Bovine Milk-Based Fortifiers for Infants Born <1250 g: 18-Month Neurodevelopment Follow-Up of a Randomized Clinical Trial. Curr Dev Nutr. 2019 Nov 12;3(12):nzz129. doi: 10.1093/cdn/nzz129. eCollection 2019 Dec.

O'Connor DL, Kiss A, Tomlinson C, Bando N, Bayliss A, Campbell DM, Daneman A, Francis J, Kotsopoulos K, Shah PS, Vaz S, Williams B, Unger S; OptiMoM Feeding Group. Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants born weighing <1250 g: a randomized clinical trial. Am J Clin Nutr. 2018 Jul 1;108(1):108-116. doi: 10.1093/ajcn/nqy067. Erratum In: Am J Clin Nutr. 2019 Aug 1;110(2):529. Am J Clin Nutr. 2020 May 1;111(5):1112.