Infant, Premature, Diseases, Infant, Small for Gestational Age
Conditions
Brief summary
In preterm infants fed human milk, milk needs to be fortified to meet nutrient recommendations. Fortification can be 1) standard, 2) individualized (adjusted based on daily human milk nutrient analysis and milk volume), or 3) optimized (adjusted based on growth rate and serum analyses). The first specific aim will determine whether individualized and optimized nutrition during hospitalization results in improved growth in the neonatal intensive care unit (NICU) in extremely low gestational age (GA) neonates (ELGANs, \<29 weeks) and in small for GA (SGA, birth weight \<10th percentile for GA) preterm infants compared with optimized nutrition. The second specific aim will determine whether individualized and optimized nutrition in the NICU improves neurodevelopmental outcomes (acquisition of development milestones) and reduces the risk of disproportionate growth (i.e., excess fat) in the NICU and findings suggestive of metabolic syndrome in the first 3 years of life.
Detailed description
Hypotheses: 1. Primary hypothesis: In preterm infants (GA \<29 weeks or GA \<35 weeks and SGA) individualized and optimized nutrition will increase velocity of growth (weight gain velocity by 2 g x kg-1 x day-1 and length velocity by 0.2 cm per week) from birth to 36 weeks of postmenstrual age (GA plus postnatal age) or discharge (whichever comes first) in comparison with optimized nutrition. 2. Secondary hypotheses: Individualized and optimized nutrition will improve neurodevelopmental outcome and reduce the risk of disproportionate growth (excess fat) in the NICU and findings suggestive of metabolic syndrome in the first 3 years of life. Study design: Double-blinded randomized controlled trial (RCT): After consent, 150 neonates will be randomized to one of two groups. Study intervention: Patients will be randomized to either: 1. Control: optimized nutrition: Milk fortification will be based on current recommendations and optimized by adjustment of nutrients once a week based on blood levels of urea nitrogen and albumin and velocity of growth (weight and length). 2. Intervention: Individualized and optimized nutrition: Milk fortification will be optimized as in control neonates. In addition, nutrition will be individualized every day. Milk fortification will be adjusted based on daily measurements of macronutrients in human milk using near-infrared analysis. Randomization will be done by computer provided by a statistician using random block allocation and stratification by GA and size for age (AGA \[appropriate for GA\] 23-28 weeks, SGA 23-28 weeks and SGA 29-34 weeks). Twins and multiples will be randomized to the same arm of the study.
Interventions
DIETARY_SUPPLEMENTIndividualized Nutrition
Intake of macronutrients (protein, fat, and carbohydrate) will be individualized every day by adding one or more macronutrients to human milk based on daily measurements using near-infrared analysis. In patients receiving less milk than 140 ml x kg-1 x day-1 fortification of human milk will be adjusted to reach at least the average concentrations of protein, fat, and carbohydrate in donor's milk (Wojcik. J Am Diet Assoc. 2009 Jan;109:137-40) and 20 cal/oz as provided by the Mother's Milk Bank of North Texas. In those receiving at least 140 ml x kg-1 x day-1 of milk at 24 cal/oz fortification will be adjusted to meet recent guidelines from the the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition (ESPGHAN) (Agostoni et al. J Pediatr Gastroenterol Nutr. 2010 Jan;50:85-91).
DIETARY_SUPPLEMENTOptimized nutrition
Milk fortification will be based on current recommendations and optimized by adjustment of nutrients once a week based on blood levels of urea nitrogen (corrected for serum creatinine level) and albumin and velocity of growth (weight and length).
Sponsors
Children's Medical Center Dallas
The Gerber Foundation
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Only the statistician and the formula technicians know the patients' allocation.
Eligibility
Sex/Gender
ALL
Age
No minimum to 7 Days
Healthy volunteers
No
Inclusion criteria
* Preterm infants \<29 weeks GA and SGA infants \<35 weeks GA born at Parkland Health and Hospital System * Maternal plan to breastfeed or to use milk from the donor milk bank * From birth to 1 week of life
Exclusion criteria
* Patients on comfort care only * Patients with major congenital abnormalities * Patients who are too unstable for the first 7 days to have an accurate length measurement
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Linear Growth Velocity | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Increase in body length per week from birth to 36 weeks postmenstrual age or discharge |
| Growth Velocity | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Rate of weight gain \[g x kg-1 x day-1\] and length velocity \[cm x week-1\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Composition | at 1 year of age and 3 years of age | Percent fat mass measured by Dexascan |
| Disproportionate Growth (Increased Fat Mass): BMI >90th Centile | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Disproportionate growth (increased fat mass): BMI \> 90th centile for sex and age |
| Blood Pressure | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Systolic blood pressure (calm or sleeping) |
| Hypertension or High Systolic Blood Pressure | at 33-48 months adjusted age | Systolic blood pressure \>90th centile defined by the SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN |
| Neurodevelopment | 18-41 months adjusted age (postnatal age corrected for prematurity) | Bayley Scale of Infant and Toddler Development, Third Edition (BSID-III): cognitive composite score Higher scores mean a better outcome. The composite scaled score has a mean of 100 and a SD of 15, a floor of 55 and a ceiling of 145. Bayley, N. (2006). Bayley Scales of Infant and Toddler Development- Third Edition. San Antonio, TX: Harcourt Assessment. DOI: 10.1177/0734282906297199 |
| Renal Function | 33-48 months adjusted age | Serum level of cystatin C. This value increases if renal glomerular filtration decreases. |
| Comparison of Weight With Expected Value for Age and Gender | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Comparison of weight with expected value for age and gender: Z score for weight Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero with concomitant zero for length. |
| Comparison of Length With Expected Value for Age and Gender | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Comparison of length with expected value for age and gender: Z score for length Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero with concomitant zero for weight. |
| Comparison of Head Size With Expected Value for Age and Gender | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Comparison of head size with expected value for age and gender: Z score for fronto-occipital circumference Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero. |
| Rate of Weight Gain | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Rate of weight gain |
| Rate of Linear Growth | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Rate of linear growth |
| Leptin | 33-48 months adjusted age | Serum levels of leptin (measure of adiposity) |
| Comparison of Rate of Head Growth With Expected Value for Age and Gender | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Change in z score for fronto-occipital circumference from birth to endpoint Expected mean for age and gender is zero. Normal is -2 to +2. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Percent of infants who died from birth to endpoint (36 weeks post menstrual age or discharge from the neonatal intensive care unit if earlier than 36 weeks) |
| Necrotizing Enterocolitis | 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first) | Percentage of infants who developed necrotizing enterocolitis stage II or greater (using the modified Bell stage classification) in the neonatal intensive care unit |
Countries
United States
Participant flow
Recruitment details
Preterm neonates born at Parkland Hospital between January 27, 2016 and September 10, 2018
Pre-assignment details
Neonates were excluded if they received comfort care only, had a major congenital abnormality, or were too unstable for the first 7 days to have an accurate length measurement using a length board or a caliper.
Participants by arm
| Arm | Count |
|---|---|
| Individualized and Optimized Nutrition Both individualized and optimized nutrition | 62 |
| Optimized Nutrition Optimized nutrition only | 58 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
Baseline characteristics
| Characteristic | Total | Individualized and Optimized Nutrition | Optimized Nutrition |
|---|---|---|---|
| Age, Continuous | 28 weeks STANDARD_DEVIATION 3 | 28 weeks STANDARD_DEVIATION 3 | 28 weeks STANDARD_DEVIATION 3 |
| Birth fronto-occipital circumference | 24.8 cm STANDARD_DEVIATION 2.4 | 24.7 cm STANDARD_DEVIATION 2.4 | 24.9 cm STANDARD_DEVIATION 2.5 |
| Birth length | 35.6 cm STANDARD_DEVIATION 3.5 | 35.6 cm STANDARD_DEVIATION 3.6 | 35.5 cm STANDARD_DEVIATION 3.4 |
| Birth weight | 1029 grams STANDARD_DEVIATION 299 | 1024 grams STANDARD_DEVIATION 304 | 1034 grams STANDARD_DEVIATION 294 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 80 Participants | 41 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 21 Participants | 19 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 34 Participants | 17 Participants | 17 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 85 Participants | 45 Participants | 40 Participants |
| Sex: Female, Male Female | 64 Participants | 31 Participants | 33 Participants |
| Sex: Female, Male Male | 56 Participants | 31 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 62 | 4 / 58 |
| other Total, other adverse events | 19 / 62 | 17 / 58 |
| serious Total, serious adverse events | 6 / 62 | 5 / 58 |
Outcome results
Primary
Growth Velocity
Rate of weight gain \[g x kg-1 x day-1\] and length velocity \[cm x week-1\]
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Growth Velocity | 13 g kg-1 day-1 | Standard Deviation 2.6 |
| Optimized Nutrition | Growth Velocity | 13.1 g kg-1 day-1 | Standard Deviation 2.1 |
Primary
Linear Growth Velocity
Increase in body length per week from birth to 36 weeks postmenstrual age or discharge
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Data were not available for patients transferred to another institution
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Linear Growth Velocity | 0.90 cm per week | Standard Deviation 0.23 |
| Optimized Nutrition | Linear Growth Velocity | 0.91 cm per week | Standard Deviation 0.18 |
Secondary
Blood Pressure
Systolic blood pressure (calm or sleeping)
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Blood Pressure | 69.4 mm Hg | Standard Deviation 7.2 |
| Optimized Nutrition | Blood Pressure | 69.7 mm Hg | Standard Deviation 6.9 |
Secondary
Body Composition
Percent fat mass measured by Dexascan
Time frame: at 1 year of age and 3 years of age
Secondary
Comparison of Head Size With Expected Value for Age and Gender
Comparison of head size with expected value for age and gender: Z score for fronto-occipital circumference Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Comparison of Head Size With Expected Value for Age and Gender | -1.06 Z-score | Standard Deviation 1 |
| Optimized Nutrition | Comparison of Head Size With Expected Value for Age and Gender | -1.24 Z-score | Standard Deviation 0.9 |
Secondary
Comparison of Length With Expected Value for Age and Gender
Comparison of length with expected value for age and gender: Z score for length Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero with concomitant zero for weight.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Comparison of Length With Expected Value for Age and Gender | -1.48 Z-score | Standard Deviation 0.9 |
| Optimized Nutrition | Comparison of Length With Expected Value for Age and Gender | -1.61 Z-score | Standard Deviation 0.9 |
Secondary
Comparison of Rate of Head Growth With Expected Value for Age and Gender
Change in z score for fronto-occipital circumference from birth to endpoint Expected mean for age and gender is zero. Normal is -2 to +2.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Comparison of Rate of Head Growth With Expected Value for Age and Gender | -.63 Z-score | Standard Deviation 1 |
| Optimized Nutrition | Comparison of Rate of Head Growth With Expected Value for Age and Gender | -.74 Z-score | Standard Deviation 1.1 |
Secondary
Comparison of Weight With Expected Value for Age and Gender
Comparison of weight with expected value for age and gender: Z score for weight Expected mean for age and gender is zero. Normal is -2 to +2. Best is zero with concomitant zero for length.
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Comparison of Weight With Expected Value for Age and Gender | -1.05 Z-score | Standard Deviation 0.9 |
| Optimized Nutrition | Comparison of Weight With Expected Value for Age and Gender | -1.18 Z-score | Standard Deviation 0.8 |
Secondary
Disproportionate Growth (Increased Fat Mass): BMI >90th Centile
Disproportionate growth (increased fat mass): BMI \> 90th centile for sex and age
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Total number is limited by need for accurate validated length and weight on the same day. This was not available in patients who were transferred.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized and Optimized Nutrition | Disproportionate Growth (Increased Fat Mass): BMI >90th Centile | 1 Participants |
| Optimized Nutrition | Disproportionate Growth (Increased Fat Mass): BMI >90th Centile | 1 Participants |
Secondary
Hypertension or High Systolic Blood Pressure
Systolic blood pressure \>90th centile defined by the SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN
Time frame: at 33-48 months adjusted age
Population: 33-48 months adjusted age Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized and Optimized Nutrition | Hypertension or High Systolic Blood Pressure | 7 Participants |
| Optimized Nutrition | Hypertension or High Systolic Blood Pressure | 3 Participants |
Secondary
Leptin
Serum levels of leptin (measure of adiposity)
Time frame: 33-48 months adjusted age
Population: 33-48 months adjusted age Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Leptin | 2.8 ng/ml | Standard Error 0.48 |
| Optimized Nutrition | Leptin | 1.9 ng/ml | Standard Error 0.32 |
Secondary
Neurodevelopment
Bayley Scale of Infant and Toddler Development, Third Edition (BSID-III): language composite score Higher scores mean a better outcome. The composite scaled score has a mean of 100 and a SD of 15, a floor of 47 and a ceiling of 153. Bayley, N. (2006). Bayley Scales of Infant and Toddler Development- Third Edition. San Antonio, TX: Harcourt Assessment. DOI: 10.1177/0734282906297199
Time frame: 18-41 months adjusted age (postnatal age corrected for prematurity) 18-41 months adjusted age (postnatal age corrected for prematurity) 18-41 months corrected age 18-41 months
Population: BSID-III assessment was performed at 18-38 months of age corrected for prematurity, scored for corrected age, and adjusted for age of administration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Individualized and Optimized Nutrition | Neurodevelopment | 74 score on a scale |
| Optimized Nutrition | Neurodevelopment | 74 score on a scale |
Secondary
Neurodevelopment
Bayley Scale of Infant and Toddler Development, Third Edition (BSID-III): cognitive composite score Higher scores mean a better outcome. The composite scaled score has a mean of 100 and a SD of 15, a floor of 55 and a ceiling of 145. Bayley, N. (2006). Bayley Scales of Infant and Toddler Development- Third Edition. San Antonio, TX: Harcourt Assessment. DOI: 10.1177/0734282906297199
Time frame: 18-41 months adjusted age (postnatal age corrected for prematurity)
Population: BSID-III assessment was performed at 18-38 months of age corrected for prematurity, scored for corrected age, and adjusted for age of administration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Individualized and Optimized Nutrition | Neurodevelopment | 85 score on a scale |
| Optimized Nutrition | Neurodevelopment | 85 score on a scale |
Secondary
Rate of Linear Growth
Rate of linear growth
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Rate of Linear Growth | .9 cm/week | Standard Deviation 0.23 |
| Optimized Nutrition | Rate of Linear Growth | .91 cm/week | Standard Deviation 0.18 |
Secondary
Rate of Weight Gain
Rate of weight gain
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Rate of Weight Gain | 13 g/kg/day | Standard Deviation 2.6 |
| Optimized Nutrition | Rate of Weight Gain | 13.1 g/kg/day | Standard Deviation 2.1 |
Secondary
Renal Function
Serum level of cystatin C. This value increases if renal glomerular filtration decreases.
Time frame: 33-48 months adjusted age
Population: 33-48 months adjusted age Not all participants entered follow-up and had data collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized and Optimized Nutrition | Renal Function | .79 mg/dl | Standard Deviation 0.14 |
| Optimized Nutrition | Renal Function | .83 mg/dl | Standard Deviation 0.14 |
Other Pre-specified
Mortality
Percent of infants who died from birth to endpoint (36 weeks post menstrual age or discharge from the neonatal intensive care unit if earlier than 36 weeks)
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized and Optimized Nutrition | Mortality | 3 Participants |
| Optimized Nutrition | Mortality | 1 Participants |
Other Pre-specified
Necrotizing Enterocolitis
Percentage of infants who developed necrotizing enterocolitis stage II or greater (using the modified Bell stage classification) in the neonatal intensive care unit
Time frame: 36 (range 35-37) weeks postmenstrual age or discharge (whichever comes first)
Population: Until 36 weeks postmenstrual age or discharge from the neonatal intensive care unit if earlier than 36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized and Optimized Nutrition | Necrotizing Enterocolitis | 6 Participants |
| Optimized Nutrition | Necrotizing Enterocolitis | 5 Participants |