For the past several decades, it has been hoped that docosahexaenoic acid (DHA) and arachidonic acid supplementation to the preterm infant would improve cognitive outcomes. In this issue of Pediatrics, Boone et al1 present their findings regarding long-chain polyunsaturated fatty acid supplementation for 6 months to children between 10 and 16 months of age born <35 weeks’ gestation. Outcome measures, including caregiver reports of socioemotional development using the Brief Infant-Toddler Social and Emotional Assessment (BITSEA) and the Pervasive Developmental Disorders Screening Test–II, Stage 2 (PDDST-II), revealed no evidence of benefit on broad socioemotional development, although there was a decrease in risk of clinical concern for autism spectrum disorder (ASD) among those who received supplementation. The investigators suggest cautious interpretation of results given the short time frame and the post hoc analysis.
Cell, animal, and postmortem studies2,3 have shown that rates of DHA incorporation into the brain occur mainly from the last trimester of pregnancy until age 2. The study by Boone et al1 had only a narrow window of supplementation that did not begin until 10 months, which might have missed the therapeutic window of opportunity.
This study is a secondary analysis.4 In the report of the main outcomes, the same subjects as included in this study were administered the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) to measure developmental functioning. The Bayley-III and the way it was used for the primary outcomes has several advantages over BITSEA and PDDST-II that were used in this study, including the following: (1) results from Bayley-III can be directly compared to other similar trials that used the same instrument4,5 ; (2) Bayley-III is administered by a trained research assistant and consists of a structured clinical assessment to allow for a more objective assessment of functioning; and (3) Bayley-III was administered both at baseline and at study completion versus only at study completion for the BITSEA and PDDST-II, thereby allowing for change to be ascribed to the supplementation. In the previous report,4 no improvement in cognitive development or early measures of executive function were observed. Disturbingly, in the previous report,4 supplementation may have resulted in negative effects on language development and effortful control in some subgroups of children. This combination of findings led the investigators to “not support DHA supplementation in the second year of life for children who are born preterm.”4
The lack of significance in this study offers reason for caution. The only statistically significant results came about on subgroup analyses when looking at sex. The authors here found a statistically significant decreased risk of scoring above the cutoff and threshold for ASD-related concerns in girls with the BITSEA and in boys with the PDDST-II. This suggests that there may be some difference in how sex influences the effects of supplementation. However, without further analysis, it is not possible to make any meaningful conclusion beyond that a difference may exist. Previous studies have revealed both positive5 and negative6 effects of supplementation on female patients. At this time, it is unclear what relation sex has, if any, with DHA supplementation.
The authors’ overall conclusion that DHA supplementation resulted in decreased risk of clinical concern for ASD appears to be a more generous interpretation than the results show. As the authors noted, even with the statistically significant results, the magnitude was small. More accurately, they were able to show that caregivers’ perception of risk and/or concern in their child decreased, but it is unclear whether that risk would also be perceived or interpreted in the same way by an objective third party.
There are other concerns with the measures used in this study. For both the BITSEA and PDDST-II, there are concerns about a lack of validity or clinical efficacy in the sample population used in this study.7–9 For clinicians, neither tool is used extensively in practice settings, leading to caution in direct clinical applicability.
Regretfully, DHA supplementation did not improve developmental outcomes for preterm infants as the authors reveal in this report, in their previous publications,1,10 and as found in a Cochrane review.11 There may be small, inconsistent benefit on clinical concerns for ASD; however, there may also be negative consequences to supplementation during the second year of life. Supplementation of preterm infants with DHA and arachidonic acid after the first year of life should be approached with caution.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
FUNDING: No external funding.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2020-0284.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.