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

Enteral Supplementation With High-dose Docosahexaenoic Acid on the Risk for Bronchopulmonary Dysplasia in Very Preterm Infants: A Collaborative Study Protocol for an Individual Participant Data Meta-analysis

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Child Development; Bronchopulmonary Dysplasia; Neonatal and Perinatal Conditions
• Intervention / Treatment: Dietary supplement: High-dose DHA; Dietary supplement: Control

Detailed Description

Severe BPD is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose DHA supplementation on this short-term neonatal morbidity needs further investigations in infants born very preterm.

Therefore, based on previous systematic review findings and a known association between more severe BPD and unfavorable neurodevelopmental outcomes, a deeper understanding of the association between DHA and severe BPD needs further investigations. Harmonization of the severe BPD definition across the recent DHA trials, reclassified according to modern criteria will strengthen the results and allow their interpretation in balance with the potential efficacy of DHA on long-term neurodevelopmental outcomes. Moreover, inconsistent differential responses of DHA on BPD were previously reported according to subgroups such as sex, gestational age and mode of delivery and need to be further explored in this more vulnerable population.

• Study Type: Interventional
• Enrollment (Actual): 1801
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Québec, Quebec, Canada, G1V 4G2
      • CHU de Quebec-Universite Laval

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-dose DHA; Enteral supplementation with high-dose DHA in the neonatal period.	Dietary supplement: High-dose DHA; 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.
Placebo Comparator: Control; Control.	Dietary supplement: Control; Control with no or low-dose DHA.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
"Grade 2- or 3-BPD or death"	Mortality is defined as death from any cause before 36 weeks' PMA and "Grade 2- or 3-BPD" is defined using Jensen's classification as previously described.	At 36 weeks' PMA
Severity grades of BPD	Defined as no BPD, grade 1-, 2- or 3-BPD according to Jensen's criteria as previously described.	At 36 weeks' PMA
Mortality	Defined as death from any cause.	Up to 36 weeks' PMA

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of serious brain injury	Defined as intraventricular hemorrhage of grade 3 or 4 or periventricular leukomalacia.	Up to 40 weeks' PMA
Rate of severe retinopathy of prematurity (ROP)	Defined as unilateral or bilateral ROP of stages 4 or 5 or any stage of ROP requiring any treatment.	Up to 40 weeks' PMA
Neonatal morbidity count	Including "grade 2- or 3-BPD", serious brain injury and severe ROP. A score from 0 to 3 will be attributed according to the presence or absence of each morbidity.	Up to 40 weeks' PMA
Rate of patent ductus arteriosus	Defined as any patent ductus arteriosus requiring surgical treatment.	Up to 40 weeks' PMA
Rate of necrotising enterocolitis	Defined as any necrotising enterocolitis requiring surgery.	Up to 40 weeks' PMA
Rate of culture-proven sepsis	Defined as any episode of sepsis confirmed by positive blood culture and requiring antibiotics for therapeutic intent.	Up to 40 weeks' PMA
Child's weight	Child anthropometry (i.e. weight in grams).	Up to 36 weeks' PMA
Child's length	Child anthropometry (i.e. length in cm).	Up to 36 weeks' PMA
Child's head circumference	Child anthropometry (i.e. head circumference in cm).	Up to 36 weeks' PMA

Collaborators and Investigators

• Sponsor: CHU de Quebec-Universite Laval
• Collaborators: Canadian Institutes of Health Research (CIHR); McGill University Health Centre/Research Institute of the McGill University Health Centre; Laval University; South Australian Health and Medical Research Institute
• Investigators: Principal Investigator: Isabelle Marc, MD, PhD, CHU de Quebec-Universite 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 Quebec-Universite Laval; Principal Investigator: Etienne Pronovost, BSc, CHU de Quebec-Universite Laval; Principal Investigator: Mireille Guillot, MD, CHU de Quebec-Universite 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 Quebec-Universite 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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2023
• Primary Completion (Actual): November 15, 2023
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: May 30, 2023
• First Submitted That Met QC Criteria: June 20, 2023
• First Posted (Actual): June 23, 2023

Study Record Updates

• Last Update Posted (Actual): July 14, 2025
• Last Update Submitted That Met QC Criteria: July 10, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Omega-3; Bronchopulmonary dysplasia; Preterm infants; Fatty acids; Individual participant data meta-analysis
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Hyperplasia; Bronchopulmonary Dysplasia
• Other Study ID Numbers: MP-20-2015-2144; F1H-80784

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There are currently no plan to share IPD obtained during this IPD meta-analysis. However, principal investigators will examine request from any groups for future collaboration.

Drug and device information, study documents

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