Optimizing Individual Nutrition in Preterm Very Low Birth Weight Infants

Study Overview
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Brief Summary
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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.

Detailed Description
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Hypotheses: 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. 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: 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). 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.

Official Title
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Individualizing and Optimizing Nutrition to Prevent Metabolic Syndrome and To Improve Neurodevelopment in Preterm and Small for Gestational Age Infants

Conditions
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Infant, Premature, Diseases, Infant, Small for Gestational Age

Intervention / Treatment
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* Dietary Supplement: Individualized Nutrition
* Dietary Supplement: Optimized nutrition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants <29 weeks GA and SGA infants <35 weeks GA born at Parkland Health and Hospital System Maternal plan to breastfeed or to use milk from the donor milk bank From birth to 1 week of life Exclusion Criteria: Patients on comfort care only Patients with major congenital abnormalities Patients who are too unstable for the first 7 days to have an accurate length measurement

Ages Eligible for Study
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Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individualized and Optimized Nutrition<br>Individualized nutrition Optimized nutrition | Dietary Supplement: Individualized Nutrition<br>* 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).<br>* Other names: Targeted, customized;Dietary Supplement: Optimized nutrition<br>* 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).<br>* Other names: Adjustable;|
| Other: Optimized Nutrition<br>Optimized nutrition | Dietary Supplement: Optimized nutrition<br>* 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).<br>* Other names: Adjustable;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Growth Velocity | Rate of weight gain [g x kg-1 x day-1] and length velocity [cm x week-1] | 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 | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disproportionate Growth (Increased Fat Mass): BMI >90th Centile | Disproportionate growth (increased fat mass): BMI > 90th centile for sex and age | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | 
| Blood Pressure | Systolic blood pressure (calm or sleeping) | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | 
| Hypertension | Systolic blood pressure beyond limit defined by the SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN | at 1-3 years of 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 | 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 | 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 | 
| Assessment of Biomarkers of Adiposity | Serum levels of adipokines: leptin, adiponectin and resistin | at 1-3 years of age | 
| Assessment of Renal Glomerular Function | Assessment of renal glomerular function: Serum level of cystatin C | at 1-3 years of 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 | 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 | 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 | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | 
| Comparison of Rate of Weight Gain With Expected Value for Age and Gender | Comparison of rate of weight gain with expected value for age and gender: change in z score for weight from birth to time frame | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | 
| Comparison of Rate of Linear Growth With Expected Value for Age and Gender | Comparison of rate of linear growth with expected value for age and gender: Change in z score for length from birth to 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 time frame | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | 
| Body Composition | Percent fat mass measured by Dexascan | at 1 year of age and 3 years of age |