Breast Milk Expression, Feeding Disorder Neonatal, Growth Failure, Microbial Colonization, Prematurity; Extreme
Conditions
Brief summary
The central hypothesis of this clinical trial is that, in extremely preterm infants, protein-enriched human milk diets compared to usual human milk diets during the first 2 weeks after birth increase fat-free mass (FFM)-for-age Z scores and promote maturation of the gut microbiome at term corrected age.
Detailed description
Masked randomized clinical trial in which extremely preterm infants fed human milk will be randomly assigned to receive either a protein-enriched diet (intervention group) or a usual diet (control group) within the first 96 hours after birth.
Interventions
PROCEDUREProtein-enriched human milk diet
1.2 g of human-based protein will be added to each 100 ml of human milk administered
PROCEDUREUsual human milk diet
Human-based protein will not be added to the human milk administered.
Sponsors
University of Alabama at Birmingham
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Caregivers and primary outcome evaluators will be masked. Nutrition room staff not involved in patient care will be responsible for determining participant allocation to one of the supplementation groups by opening sequentially numbered sealed envelopes, dispensing feeding syringes with the allocated human milk diet (protein-enriched or usual), and masking caregivers administering the assigned dietary intervention.
Eligibility
Sex/Gender
ALL
Age
1 Days to 4 Days
Healthy volunteers
No
Inclusion criteria
* Gestational age ≤ 28 weeks of gestation * Postnatal age \< 96 hours
Exclusion criteria
* Congenital malformations * Chromosomal anomalies * Terminal illness needing to limit or withhold support
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fat-free Mass(FFM)-For-age Z-score | 36 weeks or hospital discharge, up to 120 days following birth, whichever is longer | Estimated by air displacement plethysmography. FFM measurements were converted into Z-scores using updated, sex-specific reference curves of body composition in preterm infants (Norris et al, 2019). A Z-score of 0 represents the population mean. Z-score values closer to 0 represent a better outcome. No relevant thresholds have been defined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Growth Rate | Birth to 36 weeks postmenstrual age or hospital discharge (whichever occurred first) | Weight gain in g/kg/day |
| Number of Participants With Postnatal Growth Failure | 36 weeks or hospital discharge (whichever occurred first) | Diagnosis of growth failure (weight \< 10th percentile using the 2013 Fenton growth curves) |
| Number of Participants With Diagnosis of Necrotizing Enterocolitis | From birth up to 120 days following birth | Diagnosis of necrotizing enterocolitis stage 2 or 3 |
| Number of Participants With Diagnosis of Intestinal Perforation | From birth up to 120 days following birth | Diagnosis of intestinal perforation |
| Death | Birth to 120 days | Death prior to 121 days of life |
| Culture-proven Sepsis | Birth to 120 days | Diagnosis of sepsis with positive blood cultures |
| Number of Days Alive and Receiving Full Enteral Feeding | Birth to 28 days | Time to full enteral feeding days |
| Number of Episodes of Feeding Intolerance | Birth to 28 days | Interruption or cessation of enteral feeds for a period greater than 12 hours for abnormal abdominal examination |
| Duration of Hospital Stay in Days | Birth to 120 days or discharge, whichever occurs first | From day of admission to day of hospital discharge to home |
| Serum BUN | Birth to 28 days | Highest serum BUN value in the first 28 days after birth |
| Fat Mass(FM)-For-age Z-score | 36 weeks or hospital discharge, up to 120 days following birth, whichever is longer | Estimated by air displacement plethysmography. FM measurements were converted into Z-scores using updated, sex-specific reference curves of body composition in preterm infants (Norris et al, 2019). A Z-score of 0 represents the population mean. Z-score values closer to 0 represent a better outcome. No relevant thresholds have been defined. |
| Anthropometric Measurements | Birth to 36 weeks postmenstrual age or hospital discharge (whichever occurred first) | Weight, length, and head circumference measurements. Measurements were converted into Z-scores based on Fenton growth curves (2013). They were calculated at birth and at 36 weeks. This outcome represents the change in weight, length, and head circumference Z-score during the course of the study (i.e., the Z-score at birth was subtracted from the Z-score at 36 weeks). A value of 0 represents that the infant's Z-score is the same at the beginning and the end of the study. Positive values indicate the increase in the infant's Z-score during the study; negative values indicate the decrease in the infant's Z-score during the study. |
| Body Fat(BF)-For-age Z-score | 36 weeks or hospital discharge, up to 120 days following birth, whichever is longer | Body fat estimated by air displacement plethysmography. BF measurements were converted into Z-scores using updated, sex-specific reference curves of body composition in preterm infants (Norris et al, 2019). A Z-score of 0 represents the population mean. Z-score values closer to 0 represent a better outcome. No relevant thresholds have been defined. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAriel Salas, MD, MSPH
University of Alabama at Birmingham
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Protein-enriched Human Milk Diet Infants in this group will receive protein-enriched expressed human milk or donor human milk during the first 2 weeks after birth.
Protein-enriched human milk diet: 1.2 g of human-based protein will be added to each 100 ml of human milk administered | 75 |
| Usual Human Milk Diet Infants in this group will receive either expressed human milk or donor human milk during the first 2 weeks after birth.
Usual human milk diet: Human-based protein will not be added to the human milk administered. | 75 |
| Total | 150 |
Baseline characteristics
| Characteristic | Protein-enriched Human Milk Diet | Total | Usual Human Milk Diet |
|---|---|---|---|
| Age, Continuous | 26 weeks of gestation | 26 weeks of gestation | 26 weeks of gestation |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 12 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 70 Participants | 138 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 45 Participants | 83 Participants | 38 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 65 Participants | 36 Participants |
| Region of Enrollment United States | 75 Participants | 150 Participants | 75 Participants |
| Sex: Female, Male Female | 43 Participants | 72 Participants | 29 Participants |
| Sex: Female, Male Male | 32 Participants | 78 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 75 | 5 / 75 |
| other Total, other adverse events | 31 / 75 | 30 / 75 |
| serious Total, serious adverse events | 6 / 75 | 4 / 75 |
Outcome results
Primary
Fat-free Mass(FFM)-For-age Z-score
Estimated by air displacement plethysmography. FFM measurements were converted into Z-scores using updated, sex-specific reference curves of body composition in preterm infants (Norris et al, 2019). A Z-score of 0 represents the population mean. Z-score values closer to 0 represent a better outcome. No relevant thresholds have been defined.
Time frame: 36 weeks or hospital discharge, up to 120 days following birth, whichever is longer
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Protein-enriched Human Milk Diet | Fat-free Mass(FFM)-For-age Z-score | -1.7 Z-score | Standard Deviation 1.4 |
| Usual Human Milk Diet | Fat-free Mass(FFM)-For-age Z-score | -1.6 Z-score | Standard Deviation 1.5 |
Secondary
Anthropometric Measurements
Weight, length, and head circumference measurements. Measurements were converted into Z-scores based on Fenton growth curves (2013). They were calculated at birth and at 36 weeks. This outcome represents the change in weight, length, and head circumference Z-score during the course of the study (i.e., the Z-score at birth was subtracted from the Z-score at 36 weeks). A value of 0 represents that the infant's Z-score is the same at the beginning and the end of the study. Positive values indicate the increase in the infant's Z-score during the study; negative values indicate the decrease in the infant's Z-score during the study.
Time frame: Birth to 36 weeks postmenstrual age or hospital discharge (whichever occurred first)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Protein-enriched Human Milk Diet | Anthropometric Measurements | Weight | -1.0 Z-score | Standard Deviation 0.7 |
| Protein-enriched Human Milk Diet | Anthropometric Measurements | Length | -1.5 Z-score | Standard Deviation 1 |
| Protein-enriched Human Milk Diet | Anthropometric Measurements | Head circumference | -0.9 Z-score | Standard Deviation 0.8 |
| Usual Human Milk Diet | Anthropometric Measurements | Weight | -1.2 Z-score | Standard Deviation 0.8 |
| Usual Human Milk Diet | Anthropometric Measurements | Length | -1.9 Z-score | Standard Deviation 1.3 |
| Usual Human Milk Diet | Anthropometric Measurements | Head circumference | -1.3 Z-score | Standard Deviation 1.1 |
Secondary
Body Fat(BF)-For-age Z-score
Body fat estimated by air displacement plethysmography. BF measurements were converted into Z-scores using updated, sex-specific reference curves of body composition in preterm infants (Norris et al, 2019). A Z-score of 0 represents the population mean. Z-score values closer to 0 represent a better outcome. No relevant thresholds have been defined.
Time frame: 36 weeks or hospital discharge, up to 120 days following birth, whichever is longer
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Protein-enriched Human Milk Diet | Body Fat(BF)-For-age Z-score | 1.8 Z-score | Standard Deviation 1 |
| Usual Human Milk Diet | Body Fat(BF)-For-age Z-score | 1.9 Z-score | Standard Deviation 1.2 |
Secondary
Culture-proven Sepsis
Diagnosis of sepsis with positive blood cultures
Time frame: Birth to 120 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protein-enriched Human Milk Diet | Culture-proven Sepsis | 22 Participants |
| Usual Human Milk Diet | Culture-proven Sepsis | 16 Participants |
Secondary
Death
Death prior to 121 days of life
Time frame: Birth to 120 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protein-enriched Human Milk Diet | Death | 6 Participants |
| Usual Human Milk Diet | Death | 5 Participants |
Secondary
Duration of Hospital Stay in Days
From day of admission to day of hospital discharge to home
Time frame: Birth to 120 days or discharge, whichever occurs first
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Protein-enriched Human Milk Diet | Duration of Hospital Stay in Days | 107 days |
| Usual Human Milk Diet | Duration of Hospital Stay in Days | 107 days |
Secondary
Fat Mass(FM)-For-age Z-score
Estimated by air displacement plethysmography. FM measurements were converted into Z-scores using updated, sex-specific reference curves of body composition in preterm infants (Norris et al, 2019). A Z-score of 0 represents the population mean. Z-score values closer to 0 represent a better outcome. No relevant thresholds have been defined.
Time frame: 36 weeks or hospital discharge, up to 120 days following birth, whichever is longer
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Protein-enriched Human Milk Diet | Fat Mass(FM)-For-age Z-score | 1.0 Z-score | Standard Deviation 1.1 |
| Usual Human Milk Diet | Fat Mass(FM)-For-age Z-score | 1.3 Z-score | Standard Deviation 1.2 |
Secondary
Growth Rate
Weight gain in g/kg/day
Time frame: Birth to 36 weeks postmenstrual age or hospital discharge (whichever occurred first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Protein-enriched Human Milk Diet | Growth Rate | 14.7 g/kg/day | Standard Deviation 2.5 |
| Usual Human Milk Diet | Growth Rate | 13.9 g/kg/day | Standard Deviation 2.5 |
Secondary
Number of Days Alive and Receiving Full Enteral Feeding
Time to full enteral feeding days
Time frame: Birth to 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Protein-enriched Human Milk Diet | Number of Days Alive and Receiving Full Enteral Feeding | 18 days |
| Usual Human Milk Diet | Number of Days Alive and Receiving Full Enteral Feeding | 14 days |
Secondary
Number of Episodes of Feeding Intolerance
Interruption or cessation of enteral feeds for a period greater than 12 hours for abnormal abdominal examination
Time frame: Birth to 28 days
Population: Not collected
Secondary
Number of Participants With Diagnosis of Intestinal Perforation
Diagnosis of intestinal perforation
Time frame: From birth up to 120 days following birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protein-enriched Human Milk Diet | Number of Participants With Diagnosis of Intestinal Perforation | 5 Participants |
| Usual Human Milk Diet | Number of Participants With Diagnosis of Intestinal Perforation | 4 Participants |
Secondary
Number of Participants With Diagnosis of Necrotizing Enterocolitis
Diagnosis of necrotizing enterocolitis stage 2 or 3
Time frame: From birth up to 120 days following birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protein-enriched Human Milk Diet | Number of Participants With Diagnosis of Necrotizing Enterocolitis | 1 Participants |
| Usual Human Milk Diet | Number of Participants With Diagnosis of Necrotizing Enterocolitis | 3 Participants |
Secondary
Number of Participants With Postnatal Growth Failure
Diagnosis of growth failure (weight \< 10th percentile using the 2013 Fenton growth curves)
Time frame: 36 weeks or hospital discharge (whichever occurred first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Protein-enriched Human Milk Diet | Number of Participants With Postnatal Growth Failure | 31 Participants |
| Usual Human Milk Diet | Number of Participants With Postnatal Growth Failure | 30 Participants |
Secondary
Serum BUN
Highest serum BUN value in the first 28 days after birth
Time frame: Birth to 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Protein-enriched Human Milk Diet | Serum BUN | 33 mg/dL | Standard Deviation 24 |
| Usual Human Milk Diet | Serum BUN | 37 mg/dL | Standard Deviation 31 |
Other Pre-specified
Changes in Intestinal Microbiome
Determined by molecular analyses of fecal samples
Time frame: Birth to 36 weeks postmenstrual age
Other Pre-specified
Cognitive Outcomes
Determined by Bayley assessment
Time frame: 2 years of corrected age