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

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.

Study Overview

• Status: Recruiting
• Conditions: Preterm Birth; Neurodevelopmental Disorders; Breast Milk Expression; Nutrition Disorder, Infant; Brain Development Abnormality
• Intervention / Treatment: Other: Individually targeted fortification

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kaitlin Drouin, MA; Phone Number: 617-732-8546; Email: kdrouin@bwh.harvard.edu
• Study Contact Backup: Name: Tina Steele, RN; Phone Number: 617-525-7376; Email: tdufresne@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Kaitlin Drouin, MA; Phone Number: 617-732-8546; Email: kdrouin@bwh.harvard.edu
      • Contact: Tina Steele, RN; Phone Number: 617-525-7376; Email: tdufresne@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 3 weeks (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard fortification; 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; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Mandy B Belfort, MD, MPH, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Belfort MB, Woodward LJ, Cherkerzian S, Pepin H, Ellard D, Steele T, Fusch C, Grant PE, Inder TE. Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial. BMC Pediatr. 2021 Apr 9;21(1):167. doi: 10.1186/s12887-021-02635-x.

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2020
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: June 5, 2019
• First Submitted That Met QC Criteria: June 5, 2019
• First Posted (Actual): June 6, 2019

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 27, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth; Nutrition Disorders; Neurodevelopmental Disorders; Infant Nutrition Disorders
• Other Study ID Numbers: 2019P000893

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No current plans to share individual patient data. Future data sharing would involve de-identified data only and would require a data use agreement in accordance with hospital policy.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No