Infant, Newborn, Infant, Small for Gestational Age, Infant, Extremely Low Birth Weight
Conditions
Keywords
NICHD Neonatal Research Network, Extremely Low Birth Weight (ELBW), Prematurity, Neurodevelopmental Impairment, Donor Breast Milk, Preterm Formula
Brief 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.
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.
Interventions
BIOLOGICALDonor Milk
Donor milk provided by the Human Milk Banking Association of North America
DIETARY_SUPPLEMENTPreterm Formula
Preterm Formula determined by center practice.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD Neonatal Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Days
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bayley Scales of Infant Development (BSID) Cognitive Composite Score | At 22-26 months corrected age | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Deaths Before Discharge | 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 | Infant died before discharge home. |
| Late Onset Sepsis (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 | Number of infants diagnosed with LOS |
| Necrotizing Enterocolitis (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 | Number of infants diagnosed with NEC |
| Death or Neurodevelopmental Impairment (NDI) | At 22-26 months corrected age | A composite outcome that measures the occurrence of death through 22-26 months or NDI. |
| Death or Necrotizing Enterocolitis (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 | A composite outcome that measures the occurrence of death or NEC |
| Profound Impairment | At 22-26 months corrected age | Number of infants with profound impairment. |
| Bayley Scales of Infant Development (BSID) Motor Composite Score | At 22-26 months corrected age | 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) |
| Bayley Scales of Infant Development (BSID) Language Composite Score | At 22-26 months corrected age | 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) |
| Moderate to Severe Cerebral Palsy | At 22-26 months corrected age | Number of infants with moderate or severe grade of cerebral palsy |
| Neurodevelopmental Impairment (NDI). | At 22-26 months corrected age | 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 |
| Change in Weight-for-age Z-score During 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DONORMILK Pasteurized donor milk | 239 |
| FORMULA Preterm infant formula | 244 |
| Total | 483 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Incomplete Follow-up or No Study Data | 6 | 3 |
| Overall Study | Lost to Follow-up | 29 | 24 |
Baseline characteristics
| Characteristic | DONORMILK | Total | FORMULA |
|---|---|---|---|
| Age, Continuous | 26 weeks STANDARD_DEVIATION 1.8 | 26 weeks STANDARD_DEVIATION 1.7 | 26.1 weeks STANDARD_DEVIATION 1.6 |
| Maternal Education College degree/more | 17 Participants | 40 Participants | 23 Participants |
| Maternal Education High school degree | 82 Participants | 175 Participants | 93 Participants |
| Maternal Education Less than high school degree | 64 Participants | 121 Participants | 57 Participants |
| Maternal Education Missing | 19 Participants | 36 Participants | 17 Participants |
| Maternal Education Partial college | 57 Participants | 111 Participants | 54 Participants |
| Race/Ethnicity, Customized Black | 126 Participants | 247 Participants | 121 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 37 Participants | 68 Participants | 31 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 201 Participants | 413 Participants | 212 Participants |
| Race/Ethnicity, Customized Other | 11 Participants | 25 Participants | 14 Participants |
| Race/Ethnicity, Customized White | 98 Participants | 206 Participants | 108 Participants |
| Sex: Female, Male Female | 133 Participants | 249 Participants | 116 Participants |
| Sex: Female, Male Male | 106 Participants | 234 Participants | 128 Participants |
| Weight of Infant at Birth | 848.6 grams STANDARD_DEVIATION 232 | 845.5 grams STANDARD_DEVIATION 225.8 | 842.5 grams STANDARD_DEVIATION 219.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 29 / 239 | 25 / 244 |
| other Total, other adverse events | 19 / 239 | 17 / 244 |
| serious Total, serious adverse events | 48 / 239 | 47 / 244 |
Outcome results
Primary
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
Population: The analysis population includes all randomized infants who died or were followed at 22-26 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donor Milk | Bayley Scales of Infant Development (BSID) Cognitive Composite Score | 80.7 Score on a scale | Standard Deviation 17.4 |
| Formula | Bayley Scales of Infant Development (BSID) Cognitive Composite Score | 81.1 Score on a scale | Standard Deviation 16.7 |
Secondary
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
Population: The analysis population includes all randomized infants who died or were followed at 22-26 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donor Milk | Bayley Scales of Infant Development (BSID) Language Composite Score | 76.7 Score on a scale | Standard Deviation 19.6 |
| Formula | Bayley Scales of Infant Development (BSID) Language Composite Score | 75.8 Score on a scale | Standard Deviation 18.6 |
Secondary
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
Population: The analysis population includes all randomized infants who died or were followed at 22-26 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donor Milk | Bayley Scales of Infant Development (BSID) Motor Composite Score | 80.3 Score on a scale | Standard Deviation 21.6 |
| Formula | Bayley Scales of Infant Development (BSID) Motor Composite Score | 80.1 Score on a scale | Standard Deviation 19.9 |
Secondary
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
Population: The analysis population includes all randomized infants with non-missing data for weight at both the beginning and the end of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donor Milk | Change in Weight-for-age Z-score During Study | -0.4 Change in Z-score (difference) | Standard Deviation 0.9 |
| Formula | Change in Weight-for-age Z-score During Study | -0.1 Change in Z-score (difference) | Standard Deviation 0.9 |
Secondary
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
Population: The analysis population includes all randomized infants.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Death or Necrotizing Enterocolitis (NEC) | Death or NEC | 27 Participants |
| Donor Milk | Death or Necrotizing Enterocolitis (NEC) | Survival without NEC | 212 Participants |
| Formula | Death or Necrotizing Enterocolitis (NEC) | Death or NEC | 33 Participants |
| Formula | Death or Necrotizing Enterocolitis (NEC) | Survival without NEC | 211 Participants |
Secondary
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
Population: The analysis population includes all randomized infants who died or were followed (or adjudicated) at 22-26 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Death or Neurodevelopmental Impairment (NDI) | Missing data | 11 Participants |
| Donor Milk | Death or Neurodevelopmental Impairment (NDI) | Death or NDI | 118 Participants |
| Donor Milk | Death or Neurodevelopmental Impairment (NDI) | Survival without NDI | 88 Participants |
| Formula | Death or Neurodevelopmental Impairment (NDI) | Missing data | 10 Participants |
| Formula | Death or Neurodevelopmental Impairment (NDI) | Death or NDI | 123 Participants |
| Formula | Death or Neurodevelopmental Impairment (NDI) | Survival without NDI | 91 Participants |
Secondary
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
Population: The analysis population includes all randomized infants.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Late Onset Sepsis (LOS) | Missing data | 1 Participants |
| Donor Milk | Late Onset Sepsis (LOS) | Late-onset sepsis | 47 Participants |
| Donor Milk | Late Onset Sepsis (LOS) | No late-onset sepsis | 191 Participants |
| Formula | Late Onset Sepsis (LOS) | No late-onset sepsis | 207 Participants |
| Formula | Late Onset Sepsis (LOS) | Missing data | 0 Participants |
| Formula | Late Onset Sepsis (LOS) | Late-onset sepsis | 37 Participants |
Secondary
Moderate to Severe Cerebral Palsy
Number of infants with moderate or severe grade of cerebral palsy
Time frame: At 22-26 months corrected age
Population: The analysis population includes all randomized infants who were followed (or adjudicated) at 22-26 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Moderate to Severe Cerebral Palsy | Missing data | 3 Participants |
| Donor Milk | Moderate to Severe Cerebral Palsy | Moderate-severe cerebral palsy | 14 Participants |
| Donor Milk | Moderate to Severe Cerebral Palsy | No moderate-severe cerebral palsy | 171 Participants |
| Formula | Moderate to Severe Cerebral Palsy | Missing data | 2 Participants |
| Formula | Moderate to Severe Cerebral Palsy | Moderate-severe cerebral palsy | 20 Participants |
| Formula | Moderate to Severe Cerebral Palsy | No moderate-severe cerebral palsy | 177 Participants |
Secondary
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
Population: The analysis population includes all randomized infants.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Necrotizing Enterocolitis (NEC) | Necrotizing enterocolitis | 10 Participants |
| Donor Milk | Necrotizing Enterocolitis (NEC) | No necrotizing enterocolitis | 229 Participants |
| Formula | Necrotizing Enterocolitis (NEC) | Necrotizing enterocolitis | 22 Participants |
| Formula | Necrotizing Enterocolitis (NEC) | No necrotizing enterocolitis | 222 Participants |
Secondary
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
Population: The analysis population includes all randomized infants who were followed (or adjudicated) at 22-26 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Neurodevelopmental Impairment (NDI). | Missing data | 11 Participants |
| Donor Milk | Neurodevelopmental Impairment (NDI). | Neurodevelopmental impairment | 89 Participants |
| Donor Milk | Neurodevelopmental Impairment (NDI). | No neurodevelopmental impairment | 88 Participants |
| Formula | Neurodevelopmental Impairment (NDI). | Missing data | 10 Participants |
| Formula | Neurodevelopmental Impairment (NDI). | Neurodevelopmental impairment | 98 Participants |
| Formula | Neurodevelopmental Impairment (NDI). | No neurodevelopmental impairment | 91 Participants |
Secondary
Profound Impairment
Number of infants with profound impairment.
Time frame: At 22-26 months corrected age
Population: The analysis population includes all randomized infants who were followed (or adjudicated) at 22-26 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Profound Impairment | Missing data | 4 Participants |
| Donor Milk | Profound Impairment | No profound NDI | 154 Participants |
| Donor Milk | Profound Impairment | Profound NDI | 30 Participants |
| Formula | Profound Impairment | Missing data | 5 Participants |
| Formula | Profound Impairment | No profound NDI | 152 Participants |
| Formula | Profound Impairment | Profound NDI | 42 Participants |
Secondary
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
Population: The analysis population includes all randomized infants.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Donor Milk | Total Deaths Before Discharge | Death before discharge | 24 Participants |
| Donor Milk | Total Deaths Before Discharge | Survival to discharge | 215 Participants |
| Formula | Total Deaths Before Discharge | Death before discharge | 18 Participants |
| Formula | Total Deaths Before Discharge | Survival to discharge | 226 Participants |