In preterm infants fed human milk, milk needs to be fortified to meet nutrient recommendations. Fortification can be 1) standard, 2) individualized (adjusted based on daily human milk nutrient analysis and milk volume), or 3) optimized (adjusted based on growth rate and serum analyses). The first specific aim will determine whether individualized and optimized nutrition during hospitalization results in improved growth in the neonatal intensive care unit (NICU) in extremely low gestational age (GA) neonates (ELGANs, \<29 weeks) and in small for GA (SGA, birth weight \<10th percentile for GA) preterm infants compared with optimized nutrition. The second specific aim will determine whether individualized and optimized nutrition in the NICU improves neurodevelopmental outcomes (acquisition of development milestones) and reduces the risk of disproportionate growth (i.e., excess fat) in the NICU and findings suggestive of metabolic syndrome in the first 3 years of life.
Hypotheses: 1. Primary hypothesis: In preterm infants (GA \<29 weeks or GA \<35 weeks and SGA) individualized and optimized nutrition will increase velocity of growth (weight gain velocity by 2 g x kg-1 x day-1 and length velocity by 0.2 cm per week) from birth to 36 weeks of postmenstrual age (GA plus postnatal age) or discharge (whichever comes first) in comparison with optimized nutrition. 2. Secondary hypotheses: Individualized and optimized nutrition will improve neurodevelopmental outcome and reduce the risk of disproportionate growth (excess fat) in the NICU and findings suggestive of metabolic syndrome in the first 3 years of life. Study design: Double-blinded randomized controlled trial (RCT): After consent, 150 neonates will be randomized to one of two groups. Study intervention: Patients will be randomized to either: 1. Control: optimized nutrition: Milk fortification will be based on current recommendations and optimized by adjustment of nutrients once a week based on blood levels of urea nitrogen and albumin and velocity of growth (weight and length). 2. Intervention: Individualized and optimized nutrition: Milk fortification will be optimized as in control neonates. In addition, nutrition will be individualized every day. Milk fortification will be adjusted based on daily measurements of macronutrients in human milk using near-infrared analysis. Randomization will be done by computer provided by a statistician using random block allocation and stratification by GA and size for age (AGA \[appropriate for GA\] 23-28 weeks, SGA 23-28 weeks and SGA 29-34 weeks). Twins and multiples will be randomized to the same arm of the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
120
Intake of macronutrients (protein, fat, and carbohydrate) will be individualized every day by adding one or more macronutrients to human milk based on daily measurements using near-infrared analysis. In patients receiving less milk than 140 ml x kg-1 x day-1 fortification of human milk will be adjusted to reach at least the average concentrations of protein, fat, and carbohydrate in donor's milk (Wojcik. J Am Diet Assoc. 2009 Jan;109:137-40) and 20 cal/oz as provided by the Mother's Milk Bank of North Texas. In those receiving at least 140 ml x kg-1 x day-1 of milk at 24 cal/oz fortification will be adjusted to meet recent guidelines from the the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition (ESPGHAN) (Agostoni et al. J Pediatr Gastroenterol Nutr. 2010 Jan;50:85-91).
Milk fortification will be based on current recommendations and optimized by adjustment of nutrients once a week based on blood levels of urea nitrogen (corrected for serum creatinine level) and albumin and velocity of growth (weight and length).
UT Southwestern Medical Center
Dallas, Texas, United States
Growth Velocity
Rate of weight gain \[g x kg-1 x day-1\] and length velocity \[cm x week-1\]
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Linear Growth Velocity
Increase in body length per week from birth to 36 weeks postmenstrual age or discharge
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Disproportionate Growth (Increased Fat Mass): BMI >90th Centile
Disproportionate growth (increased fat mass): BMI \> 90th centile for sex and age
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Blood Pressure
Systolic blood pressure (calm or sleeping)
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Hypertension or High Systolic Blood Pressure
Systolic blood pressure \>90th centile defined by the SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN
Time frame: at 33-48 months adjusted age
Neurodevelopment
Bayley Scale of Infant and Toddler Development, Third Edition (BSID-III): cognitive composite score Higher scores mean a better outcome. The composite scaled score has a mean of 100 and a SD of 15, a floor of 55 and a ceiling of 145. Bayley, N. (2006). Bayley Scales of Infant and Toddler Development- Third Edition. San Antonio, TX: Harcourt Assessment. DOI: 10.1177/0734282906297199
Time frame: 18-41 months adjusted age (postnatal age corrected for prematurity)
Neurodevelopment
Bayley Scale of Infant and Toddler Development, Third Edition (BSID-III): language composite score Higher scores mean a better outcome. The composite scaled score has a mean of 100 and a SD of 15, a floor of 47 and a ceiling of 153. Bayley, N. (2006). Bayley Scales of Infant and Toddler Development- Third Edition. San Antonio, TX: Harcourt Assessment. DOI: 10.1177/0734282906297199
Time frame: 18-41 months adjusted age (postnatal age corrected for prematurity) 18-41 months adjusted age (postnatal age corrected for prematurity) 18-41 months corrected age 18-41 months
Leptin
Serum levels of leptin (measure of adiposity)
Time frame: 33-48 months adjusted age
Renal Function
Serum level of cystatin C. This value increases if renal glomerular filtration decreases.
Time frame: 33-48 months adjusted age
Comparison of Weight With Expected Value for Age and Gender
Comparison of weight with expected value for age and gender: Z score for weight Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero with concomitant zero for length.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Comparison of Length With Expected Value for Age and Gender
Comparison of length with expected value for age and gender: Z score for length Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero with concomitant zero for weight.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Comparison of Head Size With Expected Value for Age and Gender
Comparison of head size with expected value for age and gender: Z score for fronto-occipital circumference Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Rate of Weight Gain
Rate of weight gain
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Rate of Linear Growth
Rate of linear growth
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Comparison of Rate of Head Growth With Expected Value for Age and Gender
Change in z score for fronto-occipital circumference from birth to endpoint Expected mean for age and gender is zero. Normal is -2 to +2.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Body Composition
Percent fat mass measured by Dexascan
Time frame: at 1 year of age and 3 years of age
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