Enrichment of Human Milk with Human and Bovine Milk-based Fortifiers for Very Preterm Infants: a Meta-analysis

Completed

• Conditions: Human Milk Fortification; Very Low Birth Weight Baby; Human Milk Nutrition; Human Milk Feeding; Necrotizing Enterocolitis (NEC); Late Onset Neonatal Sepsis; Growth; Feeding Intolerance in Preterm; Infant Mortality

• Registration Number: NCT06870318
• Lead Sponsor: The Hospital for Sick Children

Brief Summary

Research has shown that provision of mother's milk is the optimal way to feed very low birthweight (VLBW) infants. Many infants will require a supplement to mother's milk, pasteurized donor human milk (PDHM) compared to preterm formula is the most appropriate supplement as it has been shown to reduce the risk of necrotizing enterocolitis (NEC).

Most available evidence suggests neither mother's milk nor PDHM will meet the elevated nutritional requirements of VLBW infants without multi-nutrient fortification. Globally, the current standard of care is to use bovine protein-based nutrient fortifiers to meet these elevated nutrient requirements. Given the known benefits of mother's milk, the reduction in the risk of NEC with use of PDHM as a supplement, and the availability of human milk-based multi-nutrient fortifiers (HMBF), there has been considerable interest in the efficacy of HMBF over the less costly bovine milk-based fortifiers (BMBF).

This study is an analysis of individual participant data merged from randomized control trials that examined the efficacy of HMBF compared to BMBF during hospitalization, on the risk of death and severe morbidity or major feeding interruption. Participants of the trials included in the analyses were fed exclusively with human milk or a supplement of pasteurized donor human milk (PDHM).

Only two RCTs met this criteria -OptiMoM and the N-forte trial. In both studies the intervention aligned to commence upon randomization into the HMBF or BMBF groups. The difference between the OptiMoM and N-forte feeding protocols was that the later allowed for individualized fortification based on milk analysis whereas OptiMoM used standard fortification, predominant in Canada and globally.

For OptiMoM, the feeding intervention continued until infants were 84 days of age, discharge, or when the infant consumed ≥2 complete oral feeds daily. For N-forte trial, the feeding intervention ended when babies reached 34 weeks (zero days). Both studies followed participants and continued data collection if transferred to a level II NICU for convalescence (OptiMoM) or home care service followed closely by NICU nurses (N-forte) until discharge.

Detailed Description

Not available

Study Timeline

• Study Start: 2014-10-01
• Primary Completion: 2022-09-01
• Study Completion: 2022-09-01
• Study First Submitted: 2025-02-03
• Status Verified: 2025-03
• Study First Submitted QC: 2025-03-05
• Last Update Submitted: 2025-03-05
• Study First Posted: 2025-03-11
• Last Update Posted: 2025-03-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 355

Inclusion Criteria

• Infant is a participant of the OptiMoM or the N-Forte trial.

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Number of participants with composite of NEC (NEC II-III), culture-proven late-onset sepsis and mortality.	From study day 1 through hospitalization, approximately 60 days.	The first primary outcome is a binary (yes/no) composite of NEC (NEC II-III), culture-proven late-onset sepsis and mortality.
Percentage of infants with an interruption in enteral feeding.	Through feeding intervention, approximately 50 days.	The second primary outcome is the percentage of infants with an interruption in enteral feeding after commencement of the intervention (e.g. Study Day 1), unrelated to a clinical procedure, that lasted for ≥12 h or a \>50% reduction in volume over the same time-frame.

Secondary Outcome Measures

Name	Time	Method
Days from birth to full enteral feeding.	Approximately 10 days.	Full enteral feeding (defined as 150 ml/kg/d).
Number of participants with NEC II-III.	From study day 1 through hospitalization, approximately 60 days.	NEC II-III defined using Bell's staging criteria with Bell Stage \>II classification consisting of clinical symptoms and evidence of septic shock, pneumatosis, bowel perforation, or histologic evidence of bowel ischemia consistent with NEC on bowel resection.
Total deaths prior to discharge.	From study day 1 through hospitalization, approximately 60 days.	Total deaths prior to hospital discharge or discharge from home-care in Sweden.
Number of participants with late onset-sepsis.	From study day 1 through hospitalization, approximately 60 days.	Late-onset sepsis was defined as clinical symptoms and a positive culture in blood, cerebrospinal fluid, or suprapubic or catheter urine ≥5 days post-partum.
Number of participants with bronchopulmonary dysplasia.	Assessed at 36 weeks 0 days post-conceptional age.	Bronchopulmonary dysplasia defined as a need for oxygen support at 36 weeks 0 days.
Number of participants with severe retinopathy of prematurity (ROP).	From study day 1 through hospitalization, approximately 60 days.	Severe retinopathy of prematurity (ROP) that was treated (e.g. laser or intraocular antivascular injection).

Trial Locations

Locations (2)

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

Umeå University; 🇸🇪 Umeå, Sweden