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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Bronchopulmonary Dysplasia, Child Development, Neonatal and Perinatal Conditions

Intervention / Treatment
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* Dietary Supplement: High-dose DHA
* Dietary Supplement: Control


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 14 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose DHA<br>Enteral supplementation with high-dose DHA in the neonatal period. | Dietary Supplement: High-dose DHA<br>* 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.<br>|
| Placebo Comparator: Control<br>Control. | Dietary Supplement: Control<br>* Control with no or low-dose DHA.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Omega-3, Fatty acids, Preterm infants, Bronchopulmonary dysplasia, Individual participant data meta-analysis