Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial

Abstract

Background: Human milk is recommended for very preterm infants, but its variable macronutrient content may contribute to undernutrition during a critical period in development. We hypothesize that individually targeted human milk fortification is more effective in meeting macronutrient requirements than the current standard of care.

Methods: We designed a single-center randomized, controlled trial enrolling 130 infants born < 31 completed weeks' gestation. Participants will receive fortified maternal and/or pasteurized donor milk but no formula. For participants in the intervention group, milk will be individually fortified with protein and fat modulars to achieve target levels based on daily point-of-care milk analysis with mid-infrared spectroscopy, in addition to standard fortification. The study diet will continue through 36 weeks' postmenstrual age (PMA). Clinical staff and parents will be masked to study group. Primary outcomes include: 1) body length and lean body mass by air displacement plethysmography at 36 weeks' PMA; 2) quantitative magnetic resonance imaging-based measures of brain size and microstructure at term equivalent age; and 3) Bayley-IV scales at 2 years' corrected age.

Discussion: We expect this trial to provide important data regarding the effectiveness of individually targeted human milk fortification in the neonatal intensive care unit (NICU).

Trial registration: NCT03977259 , registered 6 June, 2019.

Keywords: Growth; Human milk; Magnetic resonance imaging; Neonatal intensive care; Neurodevelopment; Nutrition; Randomized trial; Very preterm infant.

Fig. 1

Schematic of standard fortification and individually targeted fortification in the Nourish study. Standard fortification will be provided for all participants and comprises 1) multicomponent liquid human milk fortifier (Similac human milk fortifier hydrolyzed protein concentrated liquid, Abbott Laboratories), 5 mL added to 25 mL milk and 2) liquid protein fortifier (Abbott Laboratories) at 0.27 g/dL. Milk for infants in the intervention group will also be individually fortified with liquid protein (Abbott Laboratories) and/or medium chain triglyceride (MCT) oil (Dot Foods, Nestle USA) to ensure target levels in the ‘base’ milk of 1 g/dL for protein, 3.9 g/dL for fat, and 67.7 kcal/dL for energy. If maternal milk is in short supply, pasteurized donor milk expressed within 3 months of delivery will be used. The study diet will continue through 36 weeks’ postmenstrual age

Fig. 2

Nourish study timeline of enrollment, interventions, and assessment. The study diet will start the first weekday that the infant reaches a full volume, fortified enteral diet (≥140 mL/kg/day human milk). The study diet will end at 36 weeks’ postmenstrual age (PMA). Anthro is anthropometry (weight, length, head circumference). BC is body composition assessed with air displacement plethysmography. MRI will be obtained at 38–41 weeks’ PMA. Bayley Scales of Infant and Toddler Development, 4th edition will be used. Spatial working memory will be assessed with the “Spin the Pots” task, behavioral inhibition with the “Mommies and Babies” task, and executive function and behavioral difficulties with parent questionnaires (Behavioral Rating Inventory of Executive Function – Preschool Version; and Infant-Toddler Symptom Checklist—Long Version). Ages in the follow-up phase are corrected ages (age corrected for preterm birth)