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

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.

Associations of Growth and Body Composition with Brain Size in Preterm Infants.

OBJECTIVE: To assess the association of very preterm infants' brain size at term-equivalent age with physical growth from birth to term and body composition at term. STUDY DESIGN: We studied 62 infants born at <33 weeks of gestation. At birth and term, we measured weight and length and calculated body mass index. At term, infants underwent air displacement plethysmography to determine body composition (fat and fat-free mass) and magnetic resonance imaging to quantify brain size (bifrontal diameter, biparietal diameter, transverse cerebellar distance). We estimated associations of physical growth (Z-score change from birth to term) and body composition with brain size, adjusting for potential confounders using generalized estimating equations. RESULTS: The median gestational age was 29 weeks (range, 24.0-32.9 weeks). Positive gains in weight and body mass index Z-score were associated with increased brain size. Each additional 100 g of fat-free mass at term was associated with larger bifrontal diameter (0.6 mm; 95% CI, 0.2-1.0 mm), biparietal diameter (0.7 mm; 95% CI, 0.3-1.1 mm), and transverse cerebellar distance (0.3 mm; 95% CI, 0.003-0.5 mm). Associations between fat mass and brain metrics were not statistically significant. CONCLUSIONS: Weight and body mass index gain from birth to term, and lean mass-but not fat-at term, were associated with larger brain size. Factors that promote lean mass accrual among preterm infants may also promote brain growth.

Growth and Clinical Outcomes of Very Low-Birth-Weight Infants Receiving Acidified vs Nonacidified Liquid Human Milk Fortifiers.

BACKGROUND: Liquid human milk fortifiers are used commonly in neonatal intensive care. Use of an acidified HMF (A-HMF) is associated with transient metabolic acidosis, but whether growth outcomes differ between infants fed A-HMF vs nonacidified HMF (NA-HMF) remains unknown. METHODS: Retrospective cohort study of 255 infants born at <33 weeks' gestation and ≤1500 g who were receiving ≥75% fortified human milk on day of life 14, in a level III neonatal intensive care unit (NICU) from May 2015 to December 2018. Infants born before October 2017 (n = 165) received A-HMF, whereas infants born after October 2017 (n = 90) received NA-HMF. We used logistic regression to estimate odds of metabolic acidosis (serum bicarbonate <16 mEq/L in the first 21 days of life) in infants receiving A-HMF vs NA-HMF and linear mixed models to compare the mean size at discharge (weight, length, head z-scores) by HMF type. We adjusted models for confounders and accounted for the nonindependence of multiple births. RESULTS: Median gestational age was 28.7 weeks (range, 22.6-32.9) and birth weight 1.1 kg (range, 0.4-1.5). Infants receiving A-HMF had higher adjusted odds of metabolic acidosis than infants receiving NA-HMF (adjusted odds ratio, 2.7; 95% CI, 1.2-6.2). There were no differences between groups in size z-scores at discharge. CONCLUSIONS: In human-milkfed, very-low-birthweight infants, fortification with liquid A-HMF may contribute to metabolic acidosis in the first month of life, but this practice does not appear to impair growth through NICU discharge, compared with fortification with NA-HMF.

Macronutrient Intake from Human Milk, Infant Growth, and Body Composition at Term Equivalent Age: A Longitudinal Study of Hospitalized Very Preterm Infants.

The variable macronutrient content of human milk may contribute to growth deficits among preterm infants in the neonatal intensive care unit (NICU). In a longitudinal study of 37 infants < 32 weeks gestation, we aimed to (1) determine the between-infant variation in macronutrient intake from human milk and (2) examine associations of macronutrient intake with growth outcomes. We analyzed 1626 human milk samples (median, 43 samples/infant) with mid infrared spectroscopy. Outcomes at term equivalent age were weight, length, head circumference, fat mass, and fat-free mass. Median (range) intakes from human milk were: protein 1.37 (0.88, 2.43) g/kg/day; fat 4.20 (3.19, 5.82) g/kg/day; carbohydrate 8.94 (7.72, 9.85) g/kg/day; and energy 82.5 (68.7, 99.3) kcal/kg/day. In median regression models adjusted for birth size and gestational age, and other covariates, greater intakes of fat and energy were associated with higher weight (0.61 z-scores per g/kg/day fat, 95% CI 0.21, 1.01; 0.69 z-scores per 10 kcal/kg/day, 95% CI 0.28, 1.10), whereas greater protein intake was associated with greater body length (0.84 z-scores per g/kg/day protein, 95% CI 0.09, 1.58). Higher fat intake was also associated with higher fat mass and fat-free mass. Macronutrient intakes from human milk were highly variable and associated with growth outcomes despite routine fortification.