In children born at less than 29 weeks gestation, high-dose omega-3 docosahexaenoic acid (DHA) supplementation has improved IQ and augmented the risk of bronchopulmonary dysplasia (BPD).
It is unclear whether the heightened risk of BPD is associated with decreased benefits to IQ because BPD is associated with poorer cognitive outcomes.
Addressing this gap in the literature, a recent JAMA Network Open Study analyzed whether a reduction in IQ benefit was associated with the increased risk of BPD with DHA supplementation.
Study: Mediation Analysis to Untangle Opposing Associations of High-Dose Docosahexaenoic Acid With IQ and Bronchopulmonary Dysplasia in Children Born Preterm. Image Credit: Alexmalexra/Shutterstock.com
Children born at less than 29 weeks gestation have an IQ of 12 points lower than those born at term. They also are at a higher risk of BPD. DHA normally accumulates rapidly in the brain during the last trimester of pregnancy and has anti-inflammatory properties. Preterm children, therefore, have lower levels of DHA in their neural tissue.
In a previous randomized trial, it was observed that DHA supplementation of children born at less than 29 weeks gestation led to an increase in the risk of BPD from 43.9% to 49.1%.
Further, five years of corrected age highlighted a 3.45-point increase in mean full-scale IQ when administering DHA supplementation.
BPD occurs in about 50% of children born at less than 29 weeks gestation and continues to be a major challenge for clinical practice. High-dose DHA supplementation has been seen to minimize the longer-term burden facing these children and is a commonly used treatment in the neonatal unit.
About the study
This cohort study conducted an exploratory mediation analysis of results from the N3RO trial. The aim was to disentangle the opposing outcomes of DHA supplementation for BPD and IQ.
More specifically, the goal was to quantify the direct effect of DHA supplementation on IQ, independent of earlier effects on BPD risk, and the indirect impact of the DHA-related increase in BPD risk.
The present study used data collected in the N3RO trial, which was a blinded, randomized, and multicenter trial. 1,273 children, born at less than 29 weeks gestation, were recruited between 2012 and 2015 and were followed up until five years corrected age.
The children were randomized in a 1:1 ratio to either receive an enteral DHA emulsion (60 mg/kg/d) or a placebo emulsion without DHA. At 36 weeks postmenstrual age, children were assessed for physiological BPD (the main outcome of the initial phase of the trial).
It was observed that the higher BPD risk from neonatal DHA supplementation was not associated with a significant decrease in its benefit to IQ. The indirect effect estimate suggests that if DHA supplementation was administered to all children, a hypothetical intervention to lower the risk of BPD might be associated with little additional improvements to IQ.
The scarce evidence of the indirect effect on IQ via BPD hints at the possibility that the mechanisms by which DHA supplementation was associated with improved IQ and BPD differ.
Previous research has shown that DHA has functional and structural roles in neural tissues that potentially have cognitive benefits. Overall, the analysis suggests that if clinicians administer high-dose DHA to infants born very preterm, the resulting increase in BPD risk may not be associated with significant reductions in IQ benefits.
The mediation analysis's key strength is that it is based on data from a rigorously designed, large, and blinded trial with highly standardized measures of BPD, IQ, and compliance.
One study limitation is that the original trial showed high attrition rates by five years' corrected age due to the pandemic coronavirus disease 2019 (COVID-19). The precision of the direct and indirect effect estimates relied heavily on the proper specification of the underlying causal model linking DHA supplementation, IQ, and BPD together.
The presence of confounders is another key limitation. Although best efforts were made to account for confounders, it was not possible to rule out the effects of residual confounding.
Finally, the present study is silent on the trade-off between a higher risk of BPD and improved IQ associated with high-dose DHA supplementation. Future research could delve deeper into the association of the slight increase in the risk of BPD from DHA with long-term pulmonary function.
In sum, the present study documented that the higher risk of BPD from neonatal DHA supplementation was not associated with a reduction in the positive effect of DHA on IQ. This finding is important because clinicians could supplement children born preterm with high-dose DHA without lowering IQ benefits.