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

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

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.

Study Overview

• Status: Completed
• Conditions: Infant, Extremely Low Birth Weight; Infant, Small for Gestational Age; Infant, Newborn
• Intervention / Treatment: Biological: Donor Milk; Dietary supplement: Preterm Formula

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 483
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Research Institute at Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 weeks (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Donor Milk; Donor milk provided by the Human Milk Banking Association of North America	Biological: Donor Milk; Donor milk provided by the Human Milk Banking Association of North America
PLACEBO_COMPARATOR: Preterm Formula; Preterm formula determined by center practice	Dietary supplement: Preterm Formula; Preterm Formula determined by center practice.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Total Parental Nutrition (TPN) use	Number of days infants received TPN	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
Length of initial hospital stay (days) among survivors to discharge	Number of days infant stayed in the hospital during their initial hospital stay	From birth up to one year
Bronchopulmonary dysplasia (BPD) grade at 36 weeks postmenstrual age	BPD grade at 36 weeks postmenstrual age. BPD grades are defined as: 1) No support/room air; 2) Nasal cannula (NC) O2<=2L; 3) NC O2>2L or CPAP/NIPPV; 4) Invasive PPV	At 36 weeks postmenstrual age
Number of hospital admissions	Number of hospital readmissions between initial discharge and 2-year follow-up	At 22-26 months corrected age.
Death or Profound Impairment	A composite outcome that measures the occurrence of death or profound impairment. Profound Impairment is defined as defined as any of: Bayley Scales of Infant and Toddler Development-III (Bayley-III) cognitive composite score <70 (standardized mean 100, SD 15, range 54-145), motor composite score <70 (standardized mean 100, range 44-155) (lower scores indicating greater impairment), Gross Motor Function Classification System (GMFCS) level ≥ IV (on a scale from level I to V; I=normal and progressively higher levels indicate greater impairment), severe vision impairment in both eyes (consistent with refraction <20-200), or bilateral hearing impairment with or without amplification (by report).	At 22-26 months corrected age

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Study Director: Tarah Colaizy, MD, MPH, University of Iowa; Principal Investigator: Sara DeMauro, MD, University of Pennsylvania; Principal Investigator: Pablo J Sanchez, MD, Research Institute at Nationwide Children's Hospital

Publications and helpful links

Helpful Links

• NICHD Pregnancy & Perinatology Branch
• NICHD NRN Website

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2012
• Primary Completion (ACTUAL): November 30, 2021
• Study Completion (ACTUAL): November 30, 2021

Study Registration Dates

• First Submitted: February 13, 2012
• First Submitted That Met QC Criteria: February 13, 2012
• First Posted (ESTIMATE): February 16, 2012

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 1, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Prematurity; Neurodevelopmental Impairment; NICHD Neonatal Research Network; Extremely Low Birth Weight (ELBW); Donor Breast Milk; Preterm Formula
• Additional Relevant MeSH Terms: Body Weight; Birth Weight
• Other Study ID Numbers: NICHD-NRN-0047; U10HD036790 (U.S. NIH Grant/Contract); U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD040492 (U.S. NIH Grant/Contract); U10HD040689 (U.S. NIH Grant/Contract); U10HD053109 (U.S. NIH Grant/Contract); U10HD040461 (U.S. NIH Grant/Contract); U10HD068244 (U.S. NIH Grant/Contract); U10HD068263 (U.S. NIH Grant/Contract); U10HD068278 (U.S. NIH Grant/Contract); U10HD068284 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov)