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

Nutrient Enrichment of Human Milk with Human and Bovine Milk-based Fortifiers for Very Preterm Infants: an Individual Participant Data Meta-analysis

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.

Study Overview

• Status: Completed
• Conditions: Growth; Infant Mortality; Human Milk Nutrition; Very Low Birth Weight Baby; Human Milk Feeding; Late Onset Neonatal Sepsis; Necrotizing Enterocolitis (NEC); Feeding Intolerance in Preterm; Human Milk Fortification
• Intervention / Treatment: Other: No intervention; Observational study

• Study Type: Observational
• Enrollment (Actual): 355

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 0A4
      • The Hospital for Sick Children
• Sweden
  • Umeå, Sweden, SE-901 87
    • Umeå University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Participants of the OptiMoM and N-Forte trial are VLBW infants fed exclusively Human Milk.

Description

Inclusion Criteria:

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Human milk-based multi-nutrient fortifiers (HMBF) group; Infants born VLBW fed exclusively with Human Milk (parent milk or pasteurized donor milk) fortified with HMBF	Other: No intervention; Observational study; OptiMoM-NForte is meta-analysis study (observational secondary use of data), the investigators will analyze data from the OptiMoM and NForte trials. No interventions form part of this study.
Bovine milk-based fortifiers (BMBF) group; Infants born VLBW fed exclusively with Human Milk (parent milk or pasteurized donor milk) fortified with BMBF	Other: No intervention; Observational study; OptiMoM-NForte is meta-analysis study (observational secondary use of data), the investigators will analyze data from the OptiMoM and NForte trials. No interventions form part of this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with composite of NEC (NEC II-III), culture-proven late-onset sepsis and mortality.	The first primary outcome is a binary (yes/no) composite of NEC (NEC II-III), culture-proven late-onset sepsis and mortality.	From study day 1 through hospitalization, approximately 60 days.
Percentage of infants with an interruption in enteral feeding.	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.	Through feeding intervention, approximately 50 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days from birth to full enteral feeding.	Full enteral feeding (defined as 150 ml/kg/d).	Approximately 10 days.
Number of participants with NEC II-III.	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.	From study day 1 through hospitalization, approximately 60 days.
Number of participants with late onset-sepsis.	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.	From study day 1 through hospitalization, approximately 60 days.
Total deaths prior to discharge.	Total deaths prior to hospital discharge or discharge from home-care in Sweden.	From study day 1 through hospitalization, approximately 60 days.
Number of participants with bronchopulmonary dysplasia.	Bronchopulmonary dysplasia defined as a need for oxygen support at 36 weeks 0 days.	Assessed at 36 weeks 0 days post-conceptional age.
Number of participants with severe retinopathy of prematurity (ROP).	Severe retinopathy of prematurity (ROP) that was treated (e.g. laser or intraocular antivascular injection).	From study day 1 through hospitalization, approximately 60 days.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cause of death prior to discharge.	Cause of death prior to hospital discharge or discharge from home-care in Sweden (exploratory outcome).	From study day 1 through hospitalization, approximately 60 days.
Number of participants with surgical NEC.	NEC requiring surgical intervention (exploratory outcome).	From study day 1 through hospitalization, approximately 60 days.
Mortality and morbidity index.	A composite of death, NEC Bell´s II-III, culture-proven sepsis, treated ROP and BPD. (deemed exploratory given a similar composite used as the primary outcome)	From study day 1 through hospitalization, approximately 60 days.
Number of withdrawals.	Number of infants withdrawn from the intervention for any reason (exploratory outcome).	From study day 1 through hospitalization, approximately 60 days.
Days on parenteral nutrition.	Number of days on parenteral nutrition from birth/from Study Day 1. Defined as receiving amino acids and/or fat intravenously, not just a source of carbohydrate (exploratory outcome).	Through feeding intervention, approximately 50 days.
Percentage of enteral feeds fed as mother's versus PDHM.	Exploratory outcome.	Through feeding intervention, approximately 50 days.

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Umeå University; Region Östergötland
• Investigators: Principal Investigator: Deborah L O'Connor, PhD, RN, The Hospital for Sick Children; Principal Investigator: Magnus Domellöf, MD, PhD, Umeå University, Umeå (UMU)

Publications and helpful links

General Publications

• Jensen GB, Ahlsson F, Domellof M, Elfvin A, Naver L, Abrahamsson T. Nordic study on human milk fortification in extremely preterm infants: a randomised controlled trial-the N-forte trial. BMJ Open. 2021 Nov 23;11(11):e053400. doi: 10.1136/bmjopen-2021-053400.
• Corrigendum for O'Connor et al. Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants born weighing < 1250 g: a randomized clinical trial. Am J Clin Nutr 2018;108:108-16. Am J Clin Nutr. 2020 May 1;111(5):1112. doi: 10.1093/ajcn/nqaa042. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: February 3, 2025
• First Submitted That Met QC Criteria: March 5, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 5, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Bovine based vs human milk based fortifiers; RCTs meta-analysis; Human Milk Fortifiers (HMF)
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Body Weight; Intestinal Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Infections; Digestive System Diseases; Gastrointestinal Diseases; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Death; Gastroenteritis; Neonatal Sepsis; Premature Birth; Birth Weight; Enterocolitis; Enterocolitis, Necrotizing; Infant Death
• Other Study ID Numbers: 4784

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data transfer will take place via Secure File Transfer Protocol (SFTP). A sub-agreement which covers data sharing and confidentiality is in place.
• IPD Sharing Time Frame: February 2025 to February 2027

IPD Sharing Access Criteria

The Hospital for Sick Children (Lead Dr. Deborah L. O'Connor PhD, RD): Data analysis.

Umeå University - (Lead Dr. Magnus Domellöf MD, PhD): Data analysis.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No