Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis

This systematic review and meta-analysis examines the association of daily omega-3 docosahexaenoic acid with bronchopulmonary dysplasia in randomized clinical trials involving preterm infants born at less than 29 weeks' gestation. Key Points QuestionIs enteral supplementation with high-dose docosahexaenoic acid (DHA) during the neonatal period associated with risk for bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age in preterm infants born at less than 29 weeks' gestation? Findings In this systematic review and meta-analysis of 4 randomized clinical trials involving 2304 infants, enteral supplementation with high-dose DHA during the neonatal period was not associated with BPD overall but was inversely associated with BPD in trials that used a more stringent, physiological BPD definition. Meaning Findings of this study suggest that high-dose DHA enteral supplementation should not be recommended for prevention of BPD in very preterm infants. Importance High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking. Objective To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation. Data Sources PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions. Study Selection Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death. Data Extraction and Synthesis Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses. Main Outcomes and Measures Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death. Results Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n=2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P=.53; I-2=72%) nor BPD or death (4 studies [n=2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P=.59; I-2=61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n=1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P=.04; I-2=48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n=1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P=.008; I-2=0%). Conclusions and Relevance Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.

Automated summary

This systematic review and meta-analysis examines the association between daily omega-3 docosahexaenoic acid (DHA) supplementation and bronchopulmonary dysplasia (BPD) in preterm infants born at less than 29 weeks' gestation. The study found that high-dose DHA supplementation during the neonatal period was not associated with BPD overall, but was inversely associated with BPD in trials that used a more stringent definition. These findings suggest that high-dose DHA supplementation should not be recommended for the prevention of BPD in very preterm infants.