Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years

N Engl J Med. 2022 Oct 27;387(17):1579-1588. doi: 10.1056/NEJMoa2206868.


Background: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood.

Methods: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI.

Results: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups.

Conclusions: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Australia
  • Bronchopulmonary Dysplasia* / prevention & control
  • Child
  • Child, Preschool
  • Cognition* / drug effects
  • Dietary Supplements / adverse effects
  • Docosahexaenoic Acids* / deficiency
  • Docosahexaenoic Acids* / pharmacology
  • Docosahexaenoic Acids* / therapeutic use
  • Emulsions
  • Enteral Nutrition
  • Follow-Up Studies
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Premature* / growth & development
  • Intelligence* / drug effects
  • Wechsler Scales


  • Docosahexaenoic Acids
  • Emulsions

Associated data

  • ANZCTR/ACTRN12612000503820