High-dose docosahexaenoic acid for bronchopulmonary dysplasia severity in very preterm infants: a collaborative individual participant data meta-analysis

Background: Neonatal supplementation with high-dose docosahexaenoic acid (DHA) omega-3 may benefit neurodevelopment in very preterm infants, but concerns remain regarding a potential increased risk and severity of bronchopulmonary dysplasia (BPD). However, the interpretation of evidence on the effect of DHA on severe BPD is challenging because of the heterogeneity in the BPD definitions used across trials. Objectives: This study aims to determine whether, compared with placebo, neonatal enteral supplementation with high-dose DHA, mimicking placental transfer, is associated with severe BPD in very preterm infants using an individual participant data meta-analysis of randomized controlled trials (RCTs). Methods: RCTs were eligible if recently conducted in infants born with gestational age (GA) <29 wk and compared enteral supplementation with high-dose DHA alone with a placebo. Using a harmonized data set, the primary outcome of severe BPD was defined as the need for “high-flow” nasal cannula >2 L/min, noninvasive positive airway pressure, or invasive mechanical ventilation at 36 wk postmenstrual age. Secondary outcomes (N = 15) included death, “death or severe BPD,” ordinal BPD severity grade, and common neonatal morbidities. Associations between high-dose DHA and outcomes were estimated using a one-stage meta-analysis approach. Results: Two RCTs were identified in a systematic review (searched up to August 1, 2022; N = 2304) that met inclusion criteria (N = 1801; 904 DHA and 897 placebo; GA 26.7 ± 1.5 wk). Severe BPD in survivors occurred in 290/843 (34.4%) infants in the DHA group and 268/841 (31.9%) infants in the placebo group {relative risk [RR], 1.06 [95% confidence interval (CI): 0.93, 1.21]; P = 0.36}. DHA was not associated with “death or severe BPD” [RR, 1.05 (95% CI: 0.94, 1.17); P = 0.41], the ordinal severity grade [odds ratio for a more severe grade, 1.20 (95% CI: 0.998, 1.45); P = 0.053], or other neonatal outcomes. There was limited evidence of heterogeneity for BPD-related outcomes. Conclusions: Neonatal enteral supplementation with high-dose DHA was not significantly associated with severe BPD in very preterm infants. Trial registration number: This study was registered at clinicaltrials.gov as NCT05915806, https://clinicaltrials.gov/study/NCT05915806. Meta-analysis registry number and website: PROSPERO, CRD42023431063, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=431063.