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. 2024 Feb 20;331(7):582-591.
doi: 10.1001/jama.2023.27693.

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial

Tarah T Colaizy  1 , Brenda B Poindexter  2 , Scott A McDonald  3 , Edward F Bell  1 , Waldemar A Carlo  4 , Susan J Carlson  1 , Sara B DeMauro  5 , Kathleen A Kennedy  6 , Leif D Nelin  7 , Pablo J Sánchez  7 , Betty R Vohr  8 , Karen J Johnson  1 , Dianne E Herron  9 , Abhik Das  10 , Margaret M Crawford  10 , Michele C Walsh  11 , Rosemary D Higgins  11   12 , Barbara J Stoll  2   6 ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; MILK Trial Investigators; Namisavayam Ambalavanan  4 , Myra H Wyckoff  13 , Carl T D'Angio  14 , George W Bugg  2 , Robin K Ohls  15   16 , Anne Marie Reynolds  17 , Gregory M Sokol  9 , Abbot R Laptook  8 , Steven L Olsen  18 , Jessica R White  19 , Sudarshan R Jadcherla  7 , Monika Bajaj  20 , Prabhu S Parimi  21 , Barbara Schmidt  5 , Matthew M Laughon  22 , John Barks  23 , Kimberley A Fisher  24 , Anna Maria Hibbs  25 , Myriam Peralta-Carcelen  4 , Noah Cook  26 , Roy J Heyne  13 , Brenna Cavanaugh  14 , Ira Adams-Chapman  2 , Janell Fuller  15 , Michelle E Hartley-McAndrew  17 , Heidi M Harmon  1 , Andrea F Duncan  27 , Abbey C Hines  9 , Howard W Kilbride  18 , Laurie A Richards  19 , Nathalie L Maitre  7 , Girija Natarajan  20 , Andrea N Trembath  22 , Martha D Carlson  23 , William F Malcolm  24 , Deanne E Wilson-Costello  25 ; MILK Trial Investigators; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
Collaborators, Affiliations

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial

Tarah T Colaizy et al. JAMA. .

Abstract

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula.

Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk.

Design, setting, and participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019.

Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge.

Main outcomes and measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death.

Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]).

Conclusions and relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula.

Trial registration: ClinicalTrials.gov Identifier: NCT01534481.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ambalavanan reported receiving personal fees from ResBiotic/AlveolusBio, Shire LLC/Oak Hill Bio, and Provepharm. Dr D’Angio reported receiving personal fees from Mead-Johnson/Reckitt. Dr Heyne reported serving on the board of directors for the Catholic Medical Association, the Catholic Medical Guild of Dallas, and the Low Birth Weight Development Center. Dr Maitre reported being the co-founder of Thrive Neuromedical and having equity in the company and having a patent pending for a movement sensor mat. Dr Malcolm reported receiving personal fees from Abbott Nutrition. No other disclosures were reported.

Figures

Figure.
Figure.. Recruitment, Randomization, and Patient Flow in the MILK Trial
aOne infant who was ineligible was randomized. bThere were missing data for 3 infants, 17 were fed an open-label diet but resumed the study diet, and 16 were switched permanently to an open-label diet. cTwo infants were too unstable to continue per the physician, 4 were withdrawn at parental request, 3 were withdrawn at physician request, and 1 was withdrawn for an unknown reason. dThere were missing data for 1 infant, 25 were fed an open-label diet but resumed the study diet, 8 were switched permanently to an open-label diet, and 1 received a diet that was prepared incorrectly. eOne infant was too unstable to continue per the physician, 8 were withdrawn at physician request, 7 were withdrawn at parental request, and 2 were withdrawn for unknown reasons.
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References

    1. Gilard V, Tebani A, Bekri S, Marret S. Intraventricular hemorrhage in very preterm infants: a comprehensive review. J Clin Med. 2020;9(8):2447. doi:10.3390/jcm9082447 - DOI - PMC - PubMed
    1. Cai S, Thompson DK, Anderson PJ, Yang JY. Short- and long-term neurodevelopmental outcomes of very preterm infants with neonatal sepsis: a systematic review and meta-analysis. Children (Basel). 2019;6(12):131. doi:10.3390/children6120131 - DOI - PMC - PubMed
    1. Blakely ML, Tyson JE, Lally KP, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Initial laparotomy versus peritoneal drainage in extremely low birthweight infants with surgical necrotizing enterocolitis or isolated intestinal perforation: a multicenter randomized clinical trial. Ann Surg. 2021;274(4):e370-e380. doi:10.1097/SLA.0000000000005099 - DOI - PMC - PubMed
    1. Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol. 2014;100(3):145-157. doi:10.1002/bdra.23235 - DOI - PMC - PubMed
    1. Cordova EG, Cherkerzian S, Bell K, et al. . Association of poor postnatal growth with neurodevelopmental impairment in infancy and childhood: comparing the fetus and the healthy preterm infant references. J Pediatr. 2020;225:37-43.e5. doi:10.1016/j.jpeds.2020.05.063 - DOI - PubMed

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