Donor Milk vs. Formula in Extremely Low Birth Weight (ELBW) Infants

Study Overview
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Brief Summary
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The Milk Trial seeks to determine the effect on neurodevelopmental outcomes at age 22-26 months of donor human milk as compared to preterm infant formula as the in-hospital diet for infants whose mothers choose not to provide breast milk or are able to provide only a minimal amount. Infants will be randomized to receive donor breast milk or formula during their hospital stay. Infant's will be followed until they reach 22-26 months of age.

Detailed Description
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There is strong evidence that maternal breast milk feedings in infancy confer multiple health benefits in the extremely preterm population (extremely low birth weight, ELBW, <1000 g). Studies suggest an IQ advantage of up to 8 points conferred by maternal milk feeding in this population. Rates of sepsis and necrotizing enterocolitis are also lower in human milk fed ELBW infants, and they experience shorter hospital stays and fewer re-hospitalizations in the first year of life. When mothers choose not to or are unable to provide milk, preterm formula is usually used. Recently, pasteurized donor human milk is available in some NICUs in the US as an alternative to preterm formula. Donor milk has not been well studied with regard to its safety and efficacy. It is unknown if donor human milk confers the same benefits as maternal milk with regard to neurodevelopmental and health outcomes. The proposed study will be the first US multicenter randomized trial of the health and developmental effects of donor milk as compared to preterm formula in ELBW infants receiving little or no maternal milk. Our long-term goal is to optimize neurodevelopmental and health outcomes for ELBW infants, maximizing their quality of life and societal functionality throughout their lives. If donor human milk has similar effects to maternal milk, the public health benefit of donor milk feedings in ELBW infants unable to receive maternal milk would be considerable.

Official Title
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Neurodevelopmental Effects of Donor Human Milk vs. Preterm Formula in Extremely Low Birth Weight (ELBW) Infants

Conditions
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Infant, Newborn, Infant, Small for Gestational Age, Infant, Extremely Low Birth Weight

Intervention / Treatment
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* Biological: Donor Milk
* Dietary Supplement: Preterm Formula


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age less than 29 weeks. Admitted to the NICU at less than or equal to 72 hours of life Survived at least 12 hours Exclusion Criteria: Chromosomal anomalies Cyanotic congenital heart disease Diagnosed intrauterine infection Other congenital disorders known to impair neurodevelopment NEC or IP prior to seeking consent Decision documented to limit intensive care therapies Congenital disorders that may affect feeding Feeding Group Eligibility: Sole Diet Group: Infants will be eligible for the sole diet feeding protocol if the mother declines to provide breast milk for the baby. Supplemental Diet (minimal maternal milk) Group: Infants whose mothers initially choose to provide breast milk and begin pumping will be re-screened for eligibility at least weekly until the infant is 21 days old. If the mother stops expressing milk at any point prior to the infant's 21st day of life, her infant will be eligible for randomization. In addition, those whose mothers are providing less than 20% of the infant's dietary needs (averaged over past 5 days) when the infant reaches 21 days of age will be eligible for randomization at this point. No infant will be randomized after reaching 21 days.

Ages Eligible for Study
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Maximum Age: 21 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Donor Milk<br>Donor milk provided by the Human Milk Banking Association of North America | Biological: Donor Milk<br>* Donor milk provided by the Human Milk Banking Association of North America<br>|
| Placebo Comparator: Preterm Formula<br>Preterm formula determined by center practice | Dietary Supplement: Preterm Formula<br>* Preterm Formula determined by center practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bayley Scales of Infant Development (BSID) Cognitive Composite Score | Mean cognitive composite score (standardized mean 100, SD 15, range 54-145). Subjects who died prior to follow-up assigned the score of 54. (lower scores indicating greater impairment) | At 22-26 months corrected age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Deaths Before Discharge | Infant died before discharge home. | From day of randomization to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 1 year following birth | 
| Late Onset Sepsis (LOS) | Number of infants diagnosed with LOS | From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth | 
| Necrotizing Enterocolitis (NEC) | Number of infants diagnosed with NEC | From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth | 
| Death or Necrotizing Enterocolitis (NEC) | A composite outcome that measures the occurrence of death or NEC | From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth | 
| Change in Weight-for-age Z-score During Study | Weight-for-age Z-scores were calculated at both baseline (study initiation) and study end (within one week of last study data collected) based on Fenton growth curves (2013). This outcome represents the change in weight-for-age Z-score during the course of the study (i.e., the Z-score at baseline was subtracted from the Z-score at study end). A value of 0 represents that the infant's weight-for-age Z-score is the same at the beginning and the end of the study. Positive values indicate the increase in the infant's weight-for-age Z-score during the study; negative values indicate the decrease in the infant's weight-for-age Z-score during the study. | During Study Intervention, the time between study randomization and discontinuation of study protocol. Infants exited from the study protocol 1-2 weeks prior to anticipated hospital discharge or 120 days, whichever is sooner | 
| Bayley Scales of Infant Development (BSID) Motor Composite Score | Mean motor composite score (standardized mean 100, range 44-155). Subjects who died prior to follow-up assigned the score of 44. (lower scores indicating greater impairment) | At 22-26 months corrected age | 
| Bayley Scales of Infant Development (BSID) Language Composite Score | Mean language composite score (standardized mean 100, range 46-155). Subjects who died prior to follow-up assigned the score of 46. (lower scores indicating greater impairment) | At 22-26 months corrected age | 
| Moderate to Severe Cerebral Palsy | Number of infants with moderate or severe grade of cerebral palsy | At 22-26 months corrected age | 
| Neurodevelopmental Impairment (NDI). | Number of infants with NDI. NDI is defined as any of the following: Gross Motor Function Classification System score greater than or equal to 2, Bayley III cognitive or motor score less than 85 (1 standard deviation), Vision Impairment or Hearing impairment | At 22-26 months corrected age | 
| Profound Impairment | Number of infants with profound impairment. | At 22-26 months corrected age | 
| Death or Neurodevelopmental Impairment (NDI) | A composite outcome that measures the occurrence of death through 22-26 months or NDI. | At 22-26 months corrected age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NICHD Neonatal Research Network, Extremely Low Birth Weight (ELBW), Prematurity, Neurodevelopmental Impairment, Donor Breast Milk, Preterm Formula