Does DHA Enteral Supplementation in Preterm Infants Prevent or Promote BPD?

In 2 RCTs using a physiological definition of BPD, the DHA intervention in preterm infants was associated with increased risk for BPD or death at 36 weeks PMA.

High-dose docosahexaenoic acid (DHA) enteral supplementation should not be used to prevent bronchopulmonary dysplasia (BPD) in very preterm infants, given that clinical trials using a stringent definition of BPD based on pulse oximetry have found that supplementation may be associated with the incidence of BPD and death. This was among the findings of systematic review and meta-analysis findings published in JAMA Network Open.

There is currently debate over whether DHA supplementation decreases or increases the risk for BPD in preterm infants. Moreover, the definition of BPD has been changing, with some randomized clinical trials (RCTs) using a “physiological” definition of BPD involving pulse oximetry. Investigators therefore undertook a systematic review and meta-analysis to evaluate the association between enteral supplementation with high-dose DHA during the neonatal period and the risk for BPD in preterm infants born at less than 29 weeks’ gestation.

Reviewers searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and from inception through August 1, 2022 for eligible RCTs; these included interventions that provided a high dose of enteral DHA omega-3 supplementation to infants through (1) direct administration of a minimum dose of 40 mg/kg/d or (2) supplementation of breast milk or formula to achieve a mean percentage of DHA of at least 0.4% of total fatty acids. Eligible studies also had to include data on BPD, death, BPD severity, or a combined outcome of BPD and death.

The researchers ultimately identified 4 RCTs with 2304 preterm infants born less than 29 weeks’ gestation for analysis (mean [SD] gestational age, 26.5 (1.6) weeks; 53.1% boys). Results were stratified based on how BPD and BPD severity were defined. All trials used trial-specific BPD definitions, but 2 of the 4 trials also used the more stringent physiological definition of BPD, in which pulse oximetry determined the need for supplemental oxygen and/or respiratory support. The 4 trials also used varying criteria for defining BPD severity.

These results suggest that high-dose DHA enteral supplementation should not be recommended for prevention of BPD in very preterm infants.

The primary outcomes of interest were incidence of BPD based on trial-specific BPD definitions and incidence of BPD when defined by the more stringent, physiological definition of BPD. Other outcomes of interest were BPD severity and death.

In all 4 trials, when the trial-specific definition of BPD was used, enteral supplementation with high-dose DHA in the neonatal period for very preterm infants was not associated with the outcome of “BPD” (n=2186 infants; risk ratio [RR], 1.07; 95% CI, 0.86-1.34; P =.53; I2 =72%), nor was it associated with the outcome of “BPD or death” at 36 weeks’ PMA (n=2299 infants; RR, 1.04; 95% CI, 0.91-1.18; P =.59; I2 =61%). No association between DHA supplementation and mortality was observed (n=2299 infants; RR, 1.08; 95% CI, 0.70-1.65; P =.73; I2 =37%).

However, in the 2 trials (n=1686 infants) that used the physiological definition of BPD, enteral supplementation with high-dose DHA was associated with a significantly increased risk of BPD at 36 weeks’ PMA compared with the control group (RR, 1.20; 95% CI, 1.01-1.42; P =.04; I2 =48%). The risk of physiologic BPD or death at 36 weeks’ PMA (assessed in 2 trials; n=1796 infants) also was associated with a high dose of DHA supplementation (RR, 1.11; 95% CI, 1.02-1.20; P =.02; I2 =0%).

Among 3 trials (n=1892 infants) that used a severity-based BPD definition, the risk of moderate-to-severe BPD at 36 weeks’ PMA also was associated with infants on high-dose DHA vs the control group (RR, 1.16; 95% CI, 1.04-1.29; P =.008; I2 =0%). The risk for severe BPD was also associated with the intervention, although it was not significant (RR, 1.17; 95% CI, 0.97-1.41; P =.11; I2 =35%).

In sensitivity meta-analyses in which risk ratios were calculated from frequencies for the included studies, similar results to those of the main analysis were observed. Interactions of sex and gestational age regarding the associations between DHA and BPD were not significant.

Limitations include the use of only 4 studies from industrialized countries with access to level 3 neonatal care units.

“These results suggest that high-dose DHA enteral supplementation should not be recommended for prevention of BPD in very preterm infants,” stated the study authors. “Further research is needed to understand the association between high-dose DHA supplementation and BPD as well as how this association affects other short-term and long-term outcomes.”

Disclosure: Some of the study authors declared affiliations with health and nutrition companies. Please see the original reference for a full list of authors’ disclosures.


Marc I, Boutin A, Pronovost E, et al. 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;6(3):e233934. doi:10.1001/jamanetworkopen.2023.3934