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

Child Development Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05915806
• Other study ID #: MP-20-2015-2144; F1H-80784
• Status: Active, not recruiting
• Phase: N/A
• Start date: July 30, 2023
• Est. completion date: March 2024

Study information

• Verified date: September 2023
• Source: CHU de Quebec-Universite Laval
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1801
• Est. completion date: March 2024
• Est. primary completion date: September 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 14 Weeks

Eligibility

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.

Related Conditions & MeSH terms

• Bronchopulmonary Dysplasia
• Child Development
• Hyperplasia
• Neonatal and Perinatal Conditions

Intervention

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.
• Control
Control with no or low-dose DHA.

Locations

Country	Name	City	State
Canada	CHU de Québec-Université Laval	Québec	Quebec

Sponsors (5)

Lead Sponsor	Collaborator
CHU de Quebec-Universite Laval	Canadian Institutes of Health Research (CIHR), Laval University, McGill University Health Centre/Research Institute of the McGill University Health Centre, South Australian Health and Medical Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Rate of serious brain injury	Defined as intraventricular hemorrhage of grade 3 or 4 or periventricular leukomalacia.	Up to 40 weeks' PMA
Other	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
Other	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
Other	Rate of patent ductus arteriosus	Defined as any patent ductus arteriosus requiring surgical treatment.	Up to 40 weeks' PMA
Other	Rate of necrotising enterocolitis	Defined as any necrotising enterocolitis requiring surgery.	Up to 40 weeks' PMA
Other	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
Other	Child's weight	Child anthropometry (i.e. weight in grams).	Up to 36 weeks' PMA
Other	Child's length	Child anthropometry (i.e. length in cm).	Up to 36 weeks' PMA
Other	Child's head circumference	Child anthropometry (i.e. head circumference in cm).	Up to 36 weeks' PMA
Primary	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	"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
Secondary	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
Secondary	Mortality	Defined as death from any cause.	Up to 36 weeks' PMA