Targeting Human Milk Fortification to Improve Preterm Infant Growth and Brain Development

Study Overview
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Brief Summary
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This study is a randomized trial comparing 2 methods of human milk fortification for preterm infants in the neonatal intensive care unit (NICU). All participating infants will receive a human milk diet comprising maternal and/or donor milk plus multi-component and modular fortifiers. In one group (control), the milk will be fortified according to routine standard of care. In the other group (intervention), the fortification will be individually targeted based on the results of point-of-care human milk analysis. Outcomes include physical growth in the NICU and after discharge, brain structure by magnetic resonance imaging at term equivalent age, and neurodevelopment at 2 years.

Detailed Description
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Human milk is the recommended diet for preterm infants and it requires fortification to meet their high nutrient requirements. This study addresses a gap in knowledge about the optimal strategy for human milk fortification in the neonatal intensive care unit (NICU). Infants will be recruited from a single site (Brigham and Women's Hospital, Boston MA). Eligible infants are NICU inpatients born <31 weeks' gestation and enrolled within 21 days of birth, whose mothers are providing breast milk. Exclusion criteria include major congenital anomalies, severe fetal growth restriction (weight <3rd percentile), clinically significant gastrointestinal pathology, triplets or higher order multiples, and expected death or transfer. Infants who require fluid restriction <140 mL/kg/day will also be excluded. The study period begins when infants have reached full volume (150-160 mL/kg/day) human milk feedings fortified to 24 kcal per ounce. Participants will be randomized to one of two diet groups; twins will be randomized separately. The study diet will continue until 36 weeks' postmenstrual age or hospital discharge, whichever comes first. Available maternal milk will be pooled with donor milk (if needed) to reach the total daily fluid volume; this base milk will be analyzed with a point-of-care human milk analyzer (Miris, AB). All infants will receive at minimum the standard human milk fortification (multicomponent fortifier to 24 kcal/oz plus liquid protein 0.27 g/dL). In one group (control), we will follow the standard of care for milk fortification, only adding more protein and/or energy if weight gain is lagging. In the other group (intervention), we will individually target fortification with additional protein and/or energy so that the base milk always contains protein 1 g/dL and energy 67 kcal/dL. Outcome measures will include physical growth during the diet intervention period, including gain in weight, length, and head circumference and body composition with air displacement plethysmography at the end of the diet intervention. At term equivalent age, participants will undergo brain magnetic resonance imaging. At 2 years corrected age, outcomes include standard and novel neurodevelopmental tests including the Bayley-III and tests of emerging executive function; and physical size.

Official Title
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Targeting Human Milk Fortification to Improve Preterm Infant Growth and Brain Development

Conditions
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Preterm Birth, Breast Milk Expression, Nutrition Disorder, Infant, Brain Development Abnormality, Neurodevelopmental Disorders

Intervention / Treatment
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* Other: Individually targeted fortification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inpatient in Brigham and Women's Hospital NICU Gestational age 24 0/7 to 30 6/7 weeks Chronologic age <21 days Mother providing breast milk Exclusion Criteria: Major congenital anomaly Severe fetal growth restriction (birth weight <3rd percentile by Olsen reference) Necrotizing enterocolitis, intestinal perforation, other major gastrointestinal pathology Triplets or higher order multiples Plan for redirection of care and/or anticipated death Clinically significant renal or hepatic dysfunction Inborn error of metabolism Fluid restriction <140 mL/kg/day for 3 or more days Grade 3 or 4 intraventricular hemorrhage detected prior to enrollment Anticipated transfer <36 weeks' postmenstrual age Parents do not consent to use of pasteurized donor human milk Infant in non-parental custody

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 21 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard fortification<br>Standard of care fortification with multicomponent human milk fortifier (24 kcal/oz) and liquid protein (0.27 g/dL); additional protein and/or calories added only for growth faltering. | |
| Experimental: Individually targeted fortification<br>Standard of care fortification plus extra protein and/or calories to ensure that base milk has protein 1 g/dL and calories 67/dL. | Other: Individually targeted fortification<br>* Abbott liquid protein and/or medium chain triglyceride are added routinely to ensure that the base milk has protein 1 g/dL and calories 67/dL.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weight | Weight z-score | at study endpoint (36 weeks' postmenstrual age or discharge) | 
| Length | Length z-score | at study endpoint (36 weeks' postmenstrual age or discharge) | 
| Fat free mass | Fat free mass estimated with air displacement plethysmography (z-score) | at study endpoint (36 weeks' postmenstrual age or discharge) | 
| Total brain volume | Total brain volume by MRI | at term equivalent age (38 to 41 weeks' postmenstrual age) | 
| Cerebellar volume | Cerebellar volume by MRI | at term equivalent age (38 to 41 weeks' postmenstrual age) | 
| Bayley-III cognitive score | Scaled composite score (continuous), higher score indicates better performance, range of possible scores 55-145 | at 2 years' corrected age | 
| Bayley-III motor score | Scaled composite score (continuous), higher score indicates better performance, range of possible scores 46-154 | at 2 years' corrected age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fat mass | Fat mass estimated with air displacement plethysmography (z-score) | at study endpoint (36 weeks' postmenstrual age or discharge) | 
| Weight | Weight z-score | at 2 years' corrected age | 
| Height | Height z-score | at 2 years' corrected age | 
| Low Bayley-III cognitive score | Scaled composite score <85 (>1 standard deviation below the normative mean) | At 2 years' corrected age | 
| Low Bayley-III motor score | Scaled composite score <85 (>1 standard deviation below the normative mean) | At 2 years' corrected age | 
| Bayley-III language score | Scaled composite score (continuous), higher score indicates better performance, range of possible scores 46-154 | At 2 years' corrected age | 
| Bayley-III language score | Scaled composite score <85 (>1 standard deviation below the normative mean) | At 2 years' corrected age | 
| Spacial working memory | Spin the Pots task (number of trials, search time) | at 2 years' corrected age | 
| Behavioral inhibition | Mommies and Babies task (number of trials, errors) | at 2 years' corrected age | 
| Executive function | Behavioral Rating Inventory of Executive Function - Preschool Version, higher scores indicate more problems | at 2 years' corrected age | 
| Behavioral difficulties | Infant-Toddler Symptom Checklist - Long Version, higher scores indicate more problems | at 2 years' corrected age |