Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants

The New England Journal of Medicine

Mar 2017

DOI: 10.1056/NEJMoa1611942

Citations:144

Influential Citations:13

Interventional (Human) Studies

Enhanced Details

Methods

Multicenter, randomized, double-blind, controlled trial conducted at 13 centers in Australia, New Zealand, and Singapore; included preterm infants born before 29 weeks' gestation who began enteral feeding within 3 days after birth; excluded: major congenital or chromosomal abnormalities, participation in another fatty-acid trial, receiving intravenous lipid emulsions containing fish oil before 36 weeks PMA, or maternal DHA supplementation >250 mg/day; randomization stratified by sex, gestational age (<27 weeks or 27 to <29 weeks) and center; intention-to-treat analysis.

Intervention

Enteral DHA emulsion at 60 mg/kg/day, started within 3 days after first enteral feeding, administered as 0.17 mL/kg per feeding, three times daily (total 0.5 mL/kg/day), continued until 36 weeks postmenstrual age or discharge home.

Results

Primary outcome: physiological BPD at 36 weeks PMA or discharge occurred in 291/592 (49.1%) with DHA vs 269/613 (43.9%) with control; adjusted RR 1.13 (95% CI 1.02–1.25), P = 0.02. Composite outcome of physiological BPD or death before 36 weeks PMA: 52.3% vs 46.4%; adjusted RR 1.11 (95% CI 1.00–1.23), P = 0.045. Death before 36 weeks: 6.2% vs 4.5% (not significant). Clinical BPD: 53.2% vs 49.7% (P = 0.06). Mild BPD lower with DHA: 13.5% vs 17.6% (P = 0.04). No significant differences in moderate/severe BPD, sepsis, NEC, IVH, ROP, or growth. Conclusion: Enteral DHA at 60 mg/kg/day did not reduce risk of physiologic BPD and may increase risk; no major safety concerns identified; results do not support routine DHA supplementation for BPD prevention in extremely preterm infants.

Limitations

Adherence to the DHA regimen in the first week after randomization was suboptimal (approximately 68–69% of planned doses given). Some primary-outcome data were missing and imputed; results may be affected by missing data and dosing-adherence issues; generalizability may be limited to high-income settings with similar neonatal care.

Abstract

BACKGROUND Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n‐3 long‐chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen‐saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.) show less