Enteral High-dose DHA Supplementation on Bronchopulmonary Dysplasia in Very Preterm Infants: a Collaborative Study

NCT05915806 | Active Not Recruiting DMC

• 1 other identifier: MP-20-2015-2144; F1H-80784
• Study Type: interventional
• Target: 1,801
• Locations: 1 country
• Sites: 1

Brief Summary

This one-stage individual participant data (IPD) meta-analysis study will aim to determine whether high-dose docosahexaenoic acid (DHA) enteral supplementation during the neonatal period is associated with the risk for severe bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) compared to control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation. The association between high-dose DHA and severe BPD will also be explored in important subgroups according to sex, gestational age, small-for-gestational age and mode of delivery.

Conditions

Bronchopulmonary Dysplasia; Child Development; Neonatal and Perinatal Conditions

Keywords

Omega-3; Fatty acids; Preterm infants; Bronchopulmonary dysplasia; Individual participant data meta-analysis

Outcome Measures

Primary Outcomes (1)

• Severe BPD

  A priori defined based on a team consensus, grades of severity (no BPD, grade 1-, 2-, 3-BPD) are defined on the mode of respiratory support at 36 weeks' PMA, regardless of prior or current oxygen therapy according to Jensen's criteria. Infants will be classified as severe BPD (Yes) if they presented a "grade 2- or 3-BPD" at 36 weeks' PMA, the two most severe grades of BPD according to Jensen's classification. Grade 2 is defined as respiratory support with nasal cannula \>2 L/min ("high" flow) or noninvasive positive airway pressure (including nasal intermittent positive pressure ventilation or nasal continuous positive airway pressure). Grade 3 is defined as use of invasive mechanical ventilation. Infants will be classified as not severe BPD (No) if they presented "no BPD or grade 1-BPD" at 36 weeks' PMA. No BPD is defined as no support. Grade 1 is defined as respiratory support with nasal cannula ≤2 L/min ("low" flow).

  At 36 weeks' PMA

Secondary Outcomes (3)

• "Grade 2- or 3-BPD or death"

  At 36 weeks' PMA

• Severity grades of BPD

  At 36 weeks' PMA

• Mortality

  Up to 36 weeks' PMA

Other Outcomes (9)

• Rate of serious brain injury

  Up to 40 weeks' PMA

• Rate of severe retinopathy of prematurity (ROP)

  Up to 40 weeks' PMA

• Neonatal morbidity count

  Up to 40 weeks' PMA

Study Arms (2)

High-dose DHA

EXPERIMENTAL

Enteral supplementation with high-dose DHA in the neonatal period.

Dietary Supplement: High-dose DHA

Control

PLACEBO COMPARATOR

Control.

Dietary Supplement: Control

Interventions

High-dose DHA DIETARY_SUPPLEMENT

Direct enteral DHA supplementation at a dose of at least 40 mg/kg/day or DHA supplementation of breast milk or formula aiming for at least 0.4% of total fatty acids.

High-dose DHA

Control DIETARY_SUPPLEMENT

Control with no or low-dose DHA.

Control

Eligibility Criteria

• Age: Up to 14 Weeks
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

Trials included in our prior systematic review and traditional meta-analysis will be eligible for this IPD meta-analysis if they were registered randomized clinical trials of infants born preterm at less than 29 weeks of gestation and with adequate levels of blinding and allocation concealment. Moreover, eligibility will be restricted to trials conducted in a population of infants born after 2010 receiving contemporary respiratory care, similar to Jensen's cohort within which the severity-based definition of BPD was developed. The intervention has to involve enteral administration of high-dose DHA supplementation during the neonatal period. A high-dose DHA supplementation is defined as direct enteral DHA supplementation at a dose of at least 40 mg/kg/day or DHA supplementation of breast milk or formula aiming for at least 0.4% of total fatty acids. The intervention should be randomly assigned as either enteral administration of high-dose DHA supplementation OR a control with no or low-dose DHA. Trials evaluating intravenous DHA interventions or combined interventions (e.g. DHA combined to other nutrients or long-chain polyunsaturated fatty acids) are not considered for inclusion in this IPD meta-analysis to isolate the DHA effects and avoid heterogeneity in the intervention. The IPD meta-analysis will be conducted using a harmonized severity-based definition of BPD in eligible trials. This definition will be based on Jensen's criteria that adequately predict childhood outcomes in a contemporary cohort of infants born very preterm. To be included, prospectively collected data from eligible trials should allow BPD severity outcome classification and harmonization according to Jensen's severity-based BPD criteria at 36 weeks' PMA.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• CHU de Quebec-Universite Laval: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Laval University: collaborator
• South Australian Health and Medical Research Institute: collaborator
• McGill University Health Centre/Research Institute of the McGill University Health Centre: collaborator

Study Sites (1)

CHU de Québec-Université Laval

Québec, Quebec, G1V 4G2, Canada

Location

Related Publications (7)

• Marc I, Boutin A, Pronovost E, Guillot M, Bergeron F, Moore L, Makrides M. High doses of enteral docosahexaenoic acid omega-3 supplementation for prevention of bronchopulmonary dysplasia in very preterm infants: a protocol for a systematic review and meta-analysis. BMJ Open. 2022 Oct 17;12(10):e064515. doi: 10.1136/bmjopen-2022-064515.

  PMID: 36253040 BACKGROUND

• Marc I, Boutin A, Pronovost E, Perez Herrera NM, Guillot M, Bergeron F, Moore L, Sullivan TR, Lavoie PM, Makrides M. Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis. JAMA Netw Open. 2023 Mar 1;6(3):e233934. doi: 10.1001/jamanetworkopen.2023.3934.

  PMID: 36943265 BACKGROUND

• Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, Kirpalani H, Laughon MM, Poindexter BB, Duncan AF, Yoder BA, Eichenwald EC, DeMauro SB. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019 Sep 15;200(6):751-759. doi: 10.1164/rccm.201812-2348OC.

  PMID: 30995069 BACKGROUND

• Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978 Apr;92(4):529-34. doi: 10.1016/s0022-3476(78)80282-0.

  PMID: 305471 BACKGROUND

• Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003 Mar 5;289(9):1124-9. doi: 10.1001/jama.289.9.1124.

  PMID: 12622582 BACKGROUND

• Marc I, Lavoie PM, Sullivan TR, Pronovost E, Boutin A, Beltempo M, Guillot M, Gould JF, Simonyan D, McPhee AJ, Mohamed I, Moore L, Makrides M. High-dose docosahexaenoic acid for bronchopulmonary dysplasia severity in very preterm infants: a collaborative individual participant data meta-analysis. Am J Clin Nutr. 2025 Apr;121(4):826-834. doi: 10.1016/j.ajcnut.2025.01.004. Epub 2025 Feb 24.

  PMID: 40180500 DERIVED

• Marc I, Lavoie PM, McPhee AJ, Collins CT, Simonyan D, Pronovost E, Guillot M, Gould JF, Mohamed I, Beltempo M, Boutin A, Fortier I, Sullivan TR, Moore L, Makrides M. Enteral supplementation with high-dose docosahexaenoic acid on the risk of bronchopulmonary dysplasia in very preterm infants: a collaborative study protocol for an individual participant data meta-analysis. BMJ Open. 2023 Jul 30;13(7):e076223. doi: 10.1136/bmjopen-2023-076223.

  PMID: 37518076 DERIVED

MeSH Terms

Conditions

Bronchopulmonary Dysplasia

Condition Hierarchy (Ancestors)

Ventilator-Induced Lung Injury; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Isabelle Marc, MD, PhD

  CHU de Québec-Université Laval

  PRINCIPAL INVESTIGATOR

• Pascal M. Lavoie, MD, PhD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

• Andrew J. McPhee, MB, BS

  South Australian Health and Medical Research Institute

  PRINCIPAL INVESTIGATOR

• Carmel T. Collins, PhD

  South Australian Health and Medical Research Institute

  PRINCIPAL INVESTIGATOR

• David Simonyan, MSc

  CHU de Québec-Université Laval

  PRINCIPAL INVESTIGATOR

• Etienne Pronovost, BSc

  CHU de Québec-Université Laval

  PRINCIPAL INVESTIGATOR

• Mireille Guillot, MD

  CHU de Québec-Université Laval

  PRINCIPAL INVESTIGATOR

• Jacqueline F. Gould, PhD

  South Australian Health and Medical Research Institute

  PRINCIPAL INVESTIGATOR

• Ibrahim Mohamed, MD, PhD

  St. Justine's Hospital

  PRINCIPAL INVESTIGATOR

• Marc Beltempo, MD

  McGill University Health Centre/Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

• Amélie Boutin, PhD

  CHU de Québec-Université Laval

  PRINCIPAL INVESTIGATOR

• Isabel Fortier, PhD

  Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

• Thomas R. Sullivan, PhD

  South Australian Health and Medical Research Institute

  PRINCIPAL INVESTIGATOR

• Lynne Moore, PhD

  Laval University

  PRINCIPAL INVESTIGATOR

• Maria Makrides, PhD

  South Australian Health and Medical Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The prior systematic review included a meta-analysis of aggregated data of trials that examined the effects of an enteral supplementation with high-dose DHA during the neonatal period on the risk for BPD (any definition), death, BPD severity (any definition) and a combined outcome of BPD or death in preterm infants born less than 29 weeks of gestation. Information on data sources (searched up to August 1st, 2022), search strategy, selection process, data extraction and risk of bias assessment were detailed in the prior protocol and publication. All four trials included in the prior systematic review will be considered for inclusion in this IPD meta-analysis. Upon the early period of selecting studies for the prior systematic review, the principal investigator (IM) has contacted the primary author of trials for potential agreement to share de-identified IPD for the purpose of this participant-level meta-analysis. All IPD datasets will be harmonised and combined into one large dataset.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 30, 2023
• First Posted: June 23, 2023
• Study Start: July 30, 2023
• Primary Completion: November 15, 2023
• Study Completion: March 1, 2026
• Last Updated: July 14, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)