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CompletedNCT01534481Updated Jul 16, 2026Results posted

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

A Phase 3 interventional study of Donor Milk and Preterm Formula in Infant, Newborn, Infant, Small for Gestational Age and Infant, Extremely Low Birth Weight, sponsored by NICHD Neonatal Research Network. Completed at 17 sites in United States. Open to participants aged Up to 21 Days. Per ClinicalTrials.gov, last updated 2026-07-16.

Sponsored by NICHD Neonatal Research Network · Phase 3, Interventional, and Prevention

Phase
Phase 3
Study type
Interventional
Enrollment
483
Allocation
Randomized
Ages
Up to 21 Days
Sex
All
01

Study summary

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.

Read the 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.

02

Conditions studied

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

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Keywords

  • NICHD Neonatal Research Network
  • Extremely Low Birth Weight (ELBW)
  • Prematurity
  • Neurodevelopmental Impairment
  • Donor Breast Milk
  • Preterm Formula
03

Who can participate

Ages eligible
Up to 21 Days
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
04

Study design

Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
483 participants (actual)

Study arms

  • Active comparator
    Donor Milk

    Donor milk provided by the Human Milk Banking Association of North America

    Biological: Donor Milk

  • Placebo comparator
    Preterm Formula

    Preterm formula determined by center practice

    Dietary Supplement: Preterm Formula

Interventions

  • BiologicalDonor Milk

    Donor milk provided by the Human Milk Banking Association of North America

  • Dietary supplementPreterm Formula

    Preterm Formula determined by center practice.

05

What researchers measure

Primary outcomes

  1. 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)

    Time frame: At 22-26 months corrected age

Secondary outcomes

  1. Total Deaths Before Discharge

    Infant died before discharge home.

    Time frame: 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

  2. Late Onset Sepsis (LOS)

    Number of infants diagnosed with LOS

    Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

  3. Necrotizing Enterocolitis (NEC)

    Number of infants diagnosed with NEC

    Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

  4. Death or Necrotizing Enterocolitis (NEC)

    A composite outcome that measures the occurrence of death or NEC

    Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth

  5. 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.

    Time frame: 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

  6. 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)

    Time frame: At 22-26 months corrected age

  7. 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)

    Time frame: At 22-26 months corrected age

  8. Moderate to Severe Cerebral Palsy

    Number of infants with moderate or severe grade of cerebral palsy

    Time frame: At 22-26 months corrected age

  9. 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

    Time frame: At 22-26 months corrected age

  10. Profound Impairment

    Number of infants with profound impairment.

    Time frame: At 22-26 months corrected age

  11. Death or Neurodevelopmental Impairment (NDI)

    A composite outcome that measures the occurrence of death through 22-26 months or NDI.

    Time frame: At 22-26 months corrected age

06

Results

Posted Feb 6, 2023

Participant flow

Participant flow — Overall Study
MilestoneDonor MilkFormula
Started239244
Complete data for bsid iii cognitive score at 22-26 months175192
Died after discharge57
Died before discharge2418
Survived to discharge215226
Completed204217
Not completed3527
Withdrew: Lost to follow-up2924
Withdrew: Incomplete follow-up or no study data63

Outcome measures

PrimaryBayley 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)

Time frame:
At 22-26 months corrected age
Reported as:
Mean · Score on a scale
Bayley Scales of Infant Development (BSID) Cognitive Composite Score
Score on a scaleDonor MilkFormula
Bayley Scales of Infant Development (BSID) Cognitive Composite Score80.7 ± 17.481.1 ± 16.7
SecondaryTotal Deaths Before Discharge

Infant died before discharge home.

Time frame:
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
Reported as:
Count of participants · Participants
Total Deaths Before Discharge
ParticipantsDonor MilkFormula
Death before discharge2418
Survival to discharge215226
SecondaryLate Onset Sepsis (LOS)

Number of infants diagnosed with LOS

Time frame:
From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Reported as:
Count of participants · Participants
Late Onset Sepsis (LOS)
ParticipantsDonor MilkFormula
Missing data10
Late-onset sepsis4737
No late-onset sepsis191207
SecondaryNecrotizing Enterocolitis (NEC)

Number of infants diagnosed with NEC

Time frame:
From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Reported as:
Count of participants · Participants
Necrotizing Enterocolitis (NEC)
ParticipantsDonor MilkFormula
Necrotizing enterocolitis1022
No necrotizing enterocolitis229222
SecondaryDeath or Necrotizing Enterocolitis (NEC)

A composite outcome that measures the occurrence of death or NEC

Time frame:
From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Reported as:
Count of participants · Participants
Death or Necrotizing Enterocolitis (NEC)
ParticipantsDonor MilkFormula
Death or NEC2733
Survival without NEC212211
SecondaryChange 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.

Time frame:
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
Reported as:
Mean · Change in Z-score (difference)
Change in Weight-for-age Z-score During Study
Change in Z-score (difference)Donor MilkFormula
Change in Weight-for-age Z-score During Study-0.4 ± 0.9-0.1 ± 0.9
SecondaryBayley 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)

Time frame:
At 22-26 months corrected age
Reported as:
Mean · Score on a scale
Bayley Scales of Infant Development (BSID) Motor Composite Score
Score on a scaleDonor MilkFormula
Bayley Scales of Infant Development (BSID) Motor Composite Score80.3 ± 21.680.1 ± 19.9
SecondaryBayley 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)

Time frame:
At 22-26 months corrected age
Reported as:
Mean · Score on a scale
Bayley Scales of Infant Development (BSID) Language Composite Score
Score on a scaleDonor MilkFormula
Bayley Scales of Infant Development (BSID) Language Composite Score76.7 ± 19.675.8 ± 18.6
SecondaryModerate to Severe Cerebral Palsy

Number of infants with moderate or severe grade of cerebral palsy

Time frame:
At 22-26 months corrected age
Reported as:
Count of participants · Participants
Moderate to Severe Cerebral Palsy
ParticipantsDonor MilkFormula
Missing data32
Moderate-severe cerebral palsy1420
No moderate-severe cerebral palsy171177
SecondaryNeurodevelopmental 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

Time frame:
At 22-26 months corrected age
Reported as:
Count of participants · Participants
Neurodevelopmental Impairment (NDI).
ParticipantsDonor MilkFormula
Missing data1110
Neurodevelopmental impairment8998
No neurodevelopmental impairment8891
SecondaryProfound Impairment

Number of infants with profound impairment.

Time frame:
At 22-26 months corrected age
Reported as:
Count of participants · Participants
Profound Impairment
ParticipantsDonor MilkFormula
Missing data45
No profound NDI154152
Profound NDI3042
SecondaryDeath or Neurodevelopmental Impairment (NDI)

A composite outcome that measures the occurrence of death through 22-26 months or NDI.

Time frame:
At 22-26 months corrected age
Reported as:
Count of participants · Participants
Death or Neurodevelopmental Impairment (NDI)
ParticipantsDonor MilkFormula
Missing data1110
Death or NDI118123
Survival without NDI8891

Adverse events

Collected over 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. For All-Cause Mortality, the time frame extends to follow-up (22-26 months) since deaths after discharge are included.. Non-serious events are listed at a 0.05% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Donor Milk29/239 (12.1%)48/239 (20.1%)19/239 (7.9%)
Formula25/244 (10.2%)47/244 (19.3%)17/244 (7%)
Most frequent serious events
Showing 10 of 50
Most frequent serious events
EventDonor MilkFormula
Necrotising enterocolitis neonatalGastrointestinal disorders13/23920/244
Sepsis neonatalInfections and infestations14/23914/244
Neonatal intestinal perforationGastrointestinal disorders4/2391/244
Neonatal respiratory distressRespiratory, thoracic and mediastinal disorders1/2394/244
Neonatal respiratory failureRespiratory, thoracic and mediastinal disorders1/2393/244
PneumoperitoneumGastrointestinal disorders2/2390/244
Cytomegalovirus infectionInfections and infestations2/2392/244
Neonatal hypoglycemiaMetabolism and nutrition disorders2/2390/244
Neonatal pneumoniaInfections and infestations0/2392/244
Urinary tract infection fungalInfections and infestations0/2392/244
Most frequent other events
Showing 10 of 26
Most frequent other events
EventDonor MilkFormula
Sepsis neonatalInfections and infestations13/2396/244
Necrotising enterocolitis neonatalGastrointestinal disorders2/2399/244
Cytomegalovirus infectionInfections and infestations1/2393/244
Patent ductus arteriosusCongenital, familial and genetic disorders2/2390/244
Retinopathy of prematurityEye disorders1/2390/244
Gastroesophageal reflux diseaseGastrointestinal disorders1/2390/244
Feeding intoleranceMetabolism and nutrition disorders1/2390/244
Metabolic acidosisMetabolism and nutrition disorders1/2390/244
Neonatal hypoglycemiaMetabolism and nutrition disorders1/2390/244
ApneaRespiratory, thoracic and mediastinal disorders1/2390/244

Baseline characteristics

Age, Continuous
Age, Continuous(weeks)DONORMILKFORMULATotal
Mean26 ± 1.826.1 ± 1.626 ± 1.7
Sex: Female, Male
Sex: Female, Male(Participants)DONORMILKFORMULATotal
Female133116249
Male106128234
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)DONORMILKFORMULATotal
Black126121247
Missing415
Other111425
White98108206
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)DONORMILKFORMULATotal
Hispanic or Latino373168
Missing112
Not Hispanic or Latino201212413
Weight of Infant at Birth
Weight of Infant at Birth(grams)DONORMILKFORMULATotal
Mean848.6 ± 232842.5 ± 219.8845.5 ± 225.8
Maternal Education
Maternal Education(Participants)DONORMILKFORMULATotal
College degree/more172340
High school degree8293175
Less than high school degree6457121
Missing191736
Partial college5754111
07

Study locations

17 sites
  • University of Alabama at Birmingham
    Birmingham, Alabama 35233, United States
  • Stanford University
    Palo Alto, California 94304, United States
  • Emory University
    Atlanta, Georgia 30303, United States
  • Indiana University
    Indianapolis, Indiana 46202, United States
  • University of Iowa
    Iowa City, Iowa 52242, United States
  • Wayne State University
    Detroit, Michigan 48201, United States
  • Children's Mercy Hospital
    Kansas City, Missouri 64108, United States
  • University of New Mexico
    Albuquerque, New Mexico 87131, United States
  • University of Rochester
    Rochester, New York 14642, United States
  • RTI International
    Durham, North Carolina 27705, United States
  • Duke University
    Durham, North Carolina 27710, United States
  • Case Western Reserve University, Rainbow Babies and Children's Hospital
    Cleveland, Ohio 44106, United States
  • Research Institute at Nationwide Children's Hospital
    Columbus, Ohio 43205, United States
  • University of Pennsylvania
    Philadelphia, Pennsylvania 19104, United States
  • Brown University, Women & Infants Hospital of Rhode Island
    Providence, Rhode Island 02905, United States
  • University of Texas Southwestern Medical Center at Dallas
    Dallas, Texas 75235, United States
  • University of Texas Health Science Center at Houston
    Houston, Texas 77030, United States
08

References and documents

Publications

  • Colaizy TT, Poindexter BB, McDonald SA, Bell EF, Carlo WA, Carlson SJ, DeMauro SB, Kennedy KA, Nelin LD, Sanchez PJ, Vohr BR, Johnson KJ, Herron DE, Das A, Crawford MM, Walsh MC, Higgins RD, Stoll BJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network; MILK Trial Investigators; Ambalavanan N, Wyckoff MH, D'Angio CT, Bugg GW, Ohls RK, Reynolds AM, Sokol GM, Laptook AR, Olsen SL, White JR, Jadcherla SR, Bajaj M, Parimi PS, Schmidt B, Laughon MM, Barks J, Fisher KA, Hibbs AM, Peralta-Carcelen M, Cook N, Heyne RJ, Cavanaugh B, Adams-Chapman I, Fuller J, Hartley-McAndrew ME, Harmon HM, Duncan AF, Hines AC, Kilbride HW, Richards LA, Maitre NL, Natarajan G, Trembath AN, Carlson MD, Malcolm WF, Wilson-Costello DE; MILK Trial Investigators; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial. JAMA. 2024 Feb 20;331(7):582-591. doi: 10.1001/jama.2023.27693. PubMed 38497706 ↗

Study documents

  • Protocol and statistical analysis plan · Jan 8, 2014
  • Informed consent form · Aug 20, 2012

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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)

09

Registry details

Key details

Study ID
NCT01534481
Lead sponsor
NICHD Neonatal Research Network
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Responsible party
Sponsor
First posted
Feb 16, 2012
Start date
Aug 2012
Primary completion
Nov 30, 2021
Completion
Nov 30, 2021
Results posted
Feb 6, 2023
Last update
Jul 16, 2026

Study contacts

Tarah Colaizy, MD, MPH
study director · University of Iowa
Michele C Walsh, MD
principal investigator · Case Western Reserve University, Rainbow Babies and Children's Hospital
Seetha Shankaran, MD
principal investigator · Wayne State University
Abbot R Laptook, MD
principal investigator · Brown University, Women & Infants Hospital of Rhode Island
C. Michael Cotten, MD
principal investigator · Duke University
David Carlton, MD
principal investigator · Emory University
Greg Sokol, MD
principal investigator · Indiana University
Abhik Das, PhD
principal investigator · RTI International
Krisa P Van Meurs, MD
principal investigator · Stanford University
Waldemar A Carlo, MD
principal investigator · University of Alabama at Birmingham
Kristi L Watterberg, MD
principal investigator · University of New Mexico
Myra Wyckoff, MD
principal investigator · University of Texas, Southwestern Medical Center at Dallas
Jon Tyson, MD, MPH
principal investigator · The University of Texas Health Science Center, Houston
Sara DeMauro, MD
principal investigator · University of Pennsylvania
Carl T D'Angio, MD
principal investigator · University of Rochester
Pablo J Sanchez, MD
principal investigator · Research Institute at Nationwide Children's Hospital
William Truog, MD
principal investigator · Children's Mercy Hospital Kansas City

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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