Effects of Omega-3-6-9 fatty acid supplementation on behavior and sleep in preterm toddlers with autism symptomatology: Secondary analysis of a randomized clinical trial

Early Hum Dev. 2022 Jun;169:105588. doi: 10.1016/j.earlhumdev.2022.105588. Epub 2022 May 19.


Background: Children born extremely preterm disproportionately experience sequelae of preterm birth compared to those born at later gestational ages, including higher prevalence of autism spectrum disorder (ASD) and associated behaviors.

Aim: Explore effects of combined dietary docosahexaenoic acid, eicosapentaenoic acid, gamma-linolenic acid, and oleic acid (omega 3-6-9) on caregiver-reported behavior and sleep in toddlers born at ≤29 weeks' gestation who were exhibiting symptoms commonly seen with ASD.

Study design: 90-day randomized (1:1), double blinded, placebo-controlled trial.

Subjects: Thirty-one children aged 18-38 months received omega 3-6-9 (n = 15) or canola oil placebo (n = 16).

Outcome measures: Mixed effects regression analyses followed intent to treat and explored treatment effects on measures of caregiver-reported behavior (Child Behavior Checklist 1.5-5, Toddler Behavior Assessment Questionnaire - Short Form, Vineland Adaptive Behavior Scales, 2nd Edition) and sleep (Children's Sleep Habits Questionnaire, Brief Infant Sleep Questionnaire).

Results: Twenty-nine of 31 (94%; ntx = 13, nplacebo = 16) children randomized had data available for at least one outcome measure, 27 (87%; ntx = 12, nplacebo = 15) had complete outcome data. Children randomized to omega 3-6-9 experienced a medium magnitude benefit of supplementation on anxious and depressed behaviors (ΔDifference = -1.27, d = -0.58, p = 0.049) and internalizing behaviors (ΔDifference = -3.41, d = -0.68, p = 0.05); and a large magnitude benefit on interpersonal relationship adaptive behaviors (ΔDifference = 7.50, d = 0.83, p = 0.01), compared to placebo. No effects were observed on other aspects of behavior or sleep.

Conclusions: Findings provide preliminary support for further exploration of omega 3-6-9 during toddlerhood to improve socioemotional outcomes among children born preterm, especially for those showing early symptoms commonly seen with ASD. Results need to be replicated in a larger sample.

Trial registration: Registered with ClinicalTrials.gov: NCT01683565.

Keywords: Behavior; Docosahexaenoic acid (DHA); Gamma-linolenic acid (GLA); Premature birth; Randomized clinical trial; Sleep.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Autism Spectrum Disorder* / drug therapy
  • Autistic Disorder*
  • Child, Preschool
  • Dietary Supplements
  • Docosahexaenoic Acids
  • Double-Blind Method
  • Fatty Acids, Omega-3* / therapeutic use
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Premature
  • Premature Birth*
  • Sleep


  • Fatty Acids, Omega-3
  • Docosahexaenoic Acids

Associated data

  • ClinicalTrials.gov/NCT01683565