Recruiting

Individualized Nutrition

Sponsor:

Children's National Research Institute

Code:

NCT06266455

Conditions

Very Preterm Maturity of Infant

Very Low Birth Weight Infant

Eligibility Criteria

Sex: All

Age: 0

Healthy Volunteers: Not accepted

Interventions

Standardized Fortification

Adjustable Fortification

Adjustable Fortification

Study Details

Brief summary:

Human milk has several well-established benefits but does not adequately meet the increased nutritional demands of the growing preterm infant, necessitating additional nutrient supplementation in a process known as fortification. In U.S. neonatal intensive care units (NICUs), human milk is primarily supplemented using standardized fortification, in which a multicomponent fortifier is added to human milk to achieve assumed nutrient content based on standard milk reference values. However, this method does not account for the significant variability in human milk composition or in preterm infant metabolism, and up to half of all very premature infants experience poor growth and malnutrition using current nutritional practices. Poor postnatal growth has adverse implications for the developing preterm brain and long-term neurodevelopment.

Recent advances allow for individualized methods of human milk fortification, including adjustable and targeted fortification. Adjustable fortification uses laboratory markers of protein metabolism (BUN level) to estimate an infant's protein requirements. In targeted fortification, a milk sample is analyzed to determine its specific macronutrient and energy content, with additional macronutrient supplementation provided as needed to achieve goal values. Emerging data suggest that both methods are safe and effective for improving growth, however information on their comparable efficacy and neurodevelopmental implications are lacking, particularly using advanced quantitative brain MRI (qMRI) techniques.

Through this prospective, randomized-controlled trial, the investigators will compare the impact of individualized human milk fortification on somatic growth and neurodevelopment in preterm infants. Infants will be randomized to receive one of three nutritional interventions: standardized (control group), adjustable, or targeted human milk fortification. Infants will undergo their assigned nutritional intervention until term-equivalent age or discharge home, whichever is achieved first. Brain qMRI will be performed at term-corrected age, and neurodevelopmental follow-up will be performed through 5 years of age.

Conditions

Very Preterm Maturity of Infant

Very Low Birth Weight Infant

Study ID

NCT06266455

Start date

Feb 8, 2024

Status verified date

Jul, 2025

Completion date

Jan, 2034

Anticipated

Primary completion date

Jan, 2034

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 0

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Birth gestational age (GA) of ≤32 weeks
  • Postnatal age ≤4 weeks at time of enrollment
  • Maternal plan to provide human milk to infant, and consent to providing donor human milk if insufficient maternal milk supply
  • Maternal age > 18 years old

Exclusion Criteria:

  • Formula feeding prior to 36 weeks PMA or discharge home (whichever achieved first), either secondary to parental preference or medical necessity
  • Dysmorphic features or congenital anomalies suggestive of a genetic syndrome, metabolic disorder, chromosomal abnormality, or congenital infection
  • Dysgenetic or major destructive brain lesions detected by head ultrasound before enrollment

Study Design

Enrollment

150 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Supportive Care

Interventions and Outcome Measures

Arms

active comparator: Standardized Fortification

All study participants will undergo feed advancement and fortification with liquid, bovine-based human milk fortifier (HMF) to an assumed human milk content of 24kcal/oz per the Children's National Hospital NICU standardized clinical feeding protocol. The same milk fortification recipes are utilized for mother's own milk (MOM) and donor human milk (DHM). Each infant's growth trajectory is monitored (weight, length, and head circumference) with dietary modifications performed as needed based on growth parameters.

Growth failure is defined as a decline in weight-for-age z-score by greater than 1 standard deviation (>1 SD) beginning 1 week after reaching goal fortified feeds. For infants who demonstrate growth failure, Step 1 will be to add medium chain triglyceride (MCT) oil. If growth remains sub-optimal, Step 2 will be to add liquid protein.

experimental: Adjustable

Adjustable fortification will begin 1 week after tolerating goal feeds of standardized fortification. Blood urea nitrogen (BUN) level as a marker of protein metabolism will be measured weekly, and supplementation with liquid protein will be adjusted as necessary to maintain a goal BUN level between 9-14mmol/dL, up to a maximum assumed protein intake of 4.5 g/kg/day. Liquid protein supplementation will be modified as follows:

  • BUN Level <9 mmol/dL: Increase by 0.5g/kg/day
  • BUN Level 9-14 mmol/dL: No change
  • BUN Level >14 mmol/dL: Decrease by 0.25g/kg/day
  • BUN Level >20 mmol/dL: Hold for 1 week and re-assess

Growth failure is defined as a decline in weight-for-age z-score by >1 SD beginning 1 week after achieving BUN within goal range from adjustable fortification. For infants who demonstrate growth failure, MCT oil will be added and increased weekly as needed.

experimental: Targeted

Targeted fortification will begin 1 week after tolerating goal feeds of standardized fortification. Additional supplementation with liquid protein and/or MCT oil will be provided based on twice weekly milk analysis using a mid-infrared human milk analyzer in order to meet macronutrient (carbohydrate, protein, lipid) and energy intake goals per pediatric nutrition guidelines (protein 4-4.5g/kg/day, fat 6-8g/kg/day, energy 120-130kcal/kg/day).

Growth failure is defined as a decline in weight-for-age z-score by >1 SD beginning 1 week after receiving macronutrient and energy intake within goal range from targeted fortification. For infants with growth failure, total energy intake will be increased with additional protein and/or MCT oil supplementation. Energy intake may be increased weekly as needed.

Interventions

Standardized Fortification

Fortification with liquid, bovine-based HMF to assumed human milk content of 24kcal/oz

Adjustable Fortification

Additional liquid protein supplementation to maintain serum BUN levels within goal range (9-14mmol/dL)

Adjustable Fortification

Additional liquid protein and/or MCT oil supplementation to maintain protein, fat, and energy intake within goal range based upon mid-infrared human milk analysis

Primary outcome measure

  • Weight Gain Velocity [ Time Frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first) ]
  • Length Growth Velocity [ Time Frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first) ]
  • Head Circumference Growth Velocity [ Time Frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first) ]
  • Total and Regional Brain Volumes [ Time Frame: Term-equivalent age (38 to 41 weeks postmenstrual age) ]
  • Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) [ Time Frame: Term-equivalent age (38 to 41 weeks postmenstrual age) ]
  • Mullen Scales of Early Learning (MSEL) [ Time Frame: 18 months corrected age ]
  • Mullen Scales of Early Learning (MSEL) [ Time Frame: 36 months (3 years) of age ]
  • Wechsler Preschool and Primary Scale of Intelligence (4th edition) (WPPSI-IV) [ Time Frame: 60 months (5 years) of age ]
  • Differential Abilities Scale (2nd edition)-(DAS-II) [ Time Frame: 60 months (5 years) of age ]

Central Contacts and Locations

Central contacts

Catherine Limperopoulos, Ph.D.

202-476-5293CLimpero@childrensnational.org

Katherine M. Ottolini, M.D.

202-476-8905KOttolin@childrensnational.org

Locations

Children's National Hospital

Recruiting

Washington D.C., District of Columbia, United States, 20010

Contacts

Catherine Limperopoulos, Ph.D.

202-476-5293CLimpero@childrensnational.org

Katherine M. Ottolini, M.D.

202-476-8905KOttolin@childrensnational.org

Principal Investigator:

Catherine Limperopoulos, Ph.D.

More Information

Sponsor

Children's National Research Institute

Last update posted

Jul 11, 2025

Last verified

Jul, 2025

Keywords

  • Magnetic Resonance Imaging
  • Neurodevelopment
  • Nutrition
  • Fortification

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Children's National Research Institute on 2025-07-11.