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Table.  
Developmental Outcomes From the Developmental Assessments and Parent Questionnaires Assessing Children at Age 7 Yearsa
Developmental Outcomes From the Developmental Assessments and Parent Questionnaires Assessing Children at Age 7 Yearsa
1.
Gould  JF, Smithers  LG, Makrides  M.  The effect of maternal omega-3 (n-3) LCPUFA supplementation during pregnancy on early childhood cognitive and visual development.  Am J Clin Nutr. 2013;97(3):531-544.PubMedGoogle ScholarCrossref
2.
Makrides  M, Gibson  RA, McPhee  AJ, Yelland  L, Quinlivan  J, Ryan  P; DOMInO Investigative Team.  Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children.  JAMA. 2010;304(15):1675-1683.PubMedGoogle ScholarCrossref
3.
Makrides  M, Gould  JF, Gawlik  NR,  et al.  Four-year follow-up of children born to women in a randomized trial of prenatal DHA supplementation.  JAMA. 2014;311(17):1802-1804.PubMedGoogle ScholarCrossref
4.
Gould  JF, Treyvaud  K, Yelland  LN,  et al.  Does n-3 LCPUFA supplementation during pregnancy increase the IQ of children at school age?  BMJ Open. 2016;6(5):e011465.PubMedGoogle ScholarCrossref
Research Letter
March 21, 2017

Seven-Year Follow-up of Children Born to Women in a Randomized Trial of Prenatal DHA Supplementation

Author Affiliations
  • 1Child Nutrition Research Centre, South Australian Health and Medical Research Institute, Adelaide, Australia
  • 2Department of Psychology and Counselling, La Trobe University, Melbourne, Australia
  • 3School of Public Health, University of Adelaide, Adelaide, Australia
  • 4Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia
  • 5Neonatal Services, Women’s and Children’s Hospital, Adelaide, Australia
 

Copyright 2017 American Medical Association. All Rights Reserved.

JAMA. 2017;317(11):1173-1175. doi:10.1001/jama.2016.21303

The sale of prenatal supplements with docosahexaenoic acid (DHA) continues to increase, despite little evidence of benefit to offspring neurodevelopment.1 We randomized pregnant women to receive 800 mg of DHA daily or a placebo during the last half of pregnancy and found no group differences in cognitive, language, and motor development at 18 months of age, although secondary analyses revealed less cognitive delay but lower language scores in the DHA group.2 At 4 years of age there was no benefit of DHA supplementation in general intelligence, language, and executive functioning, and a possible negative effect on parent-rated behavior and executive functioning.3 This follow-up was designed to evaluate the effect of prenatal DHA on intelligence quotient (IQ) at 7 years, the earliest age at which adult performance can be indicated.

Methods

Methodology for the trial2 and the 7-year follow-up4 have been published. Written informed consent was obtained and approval granted by the local institutional ethics review boards. Children selected for neurodevelopmental assessment who were alive or withdrawn were invited to attend an appointment at age 7 years (corrected age for children born preterm). Assessments were administered by trained psychologists blinded to group allocation (June 26, 2013, to September 12, 2015; for a description of the assessments, see the eAppendix in the Supplement). The primary outcome was full-scale IQ from the Wechsler Abbreviated Scale of Intelligence, Second Edition (mean, 100 [SD, 15]; delayed performance, full-scale IQ score <85). Language, academic abilities, and core components of executive functioning (memory, inhibition, and mental flexibility) were assessed as secondary outcomes (see Table for details).4 Parents completed standardized questionnaires about their child’s behavior and executive functioning and provided information on children’s DHA intake and neurodevelopmental diagnoses.

Analyses were performed using SAS (SAS Institute), version 9.3, and Stata: Release 13 (StataCorp) on an intention-to-treat basis. All families consenting to the follow-up were included in analyses using multiple imputation to handle missing data. Continuous data were analyzed using linear regressions and binary data using log binomial regression. A 2-sided P value less than .05 was considered significant. No adjustment for multiple comparisons was done. Therefore, secondary outcomes should be interpreted with caution. Analyses were adjusted for center, parity, child’s sex, mother’s secondary and further education, and smoking status at baseline.

Results

Of those eligible, 543 children (85.1%) participated in the 7-year follow-up (DHA group: 73.8%, 259 of 351 invited; control group: 75.7%, 284 of 375 invited) compared with 96% at 18 months and 89% at 4 years (eFigure in the Supplement). Baseline data did not significantly differ between participants and nonparticipants at 7 years. Mean IQ of the DHA and control groups did not differ (98.31 for the DHA group vs 97.32 for the control group; adjusted mean difference [AMD], 1.30 [95% CI, −0.47 to 3.08], P = .15) (Table). Performance on direct measures of language, academic functioning, and executive functioning did not significantly differ between groups, with the exception of slightly higher perceptual reasoning scores in the DHA group. Parents in the DHA group reported more behavior problems (total difficulties score, 9.71 for the DHA group vs 8.63 for the control group; AMD, 1.09 [95% CI, 0.18 to 2.00], P = .02) and executive dysfunction (Global Executive composite, 54.89 for the DHA group vs 52.54 for the control group; AMD, 2.38 [95% CI, 0.67 to 4.08], P = .01) in their children. Diagnosis of neurodevelopmental disorders and child DHA intake did not significantly differ between groups.

Discussion

This randomized clinical trial provides strong evidence for the lack of benefit of prenatal DHA supplementation on IQ at 7 years and cognition at 18 months2 and 4 years,3 despite higher numbers of preterm children in the control group. Direct assessments consistently demonstrated no significant differences in language,2,3 academic abilities, or executive functioning.3 Although perceptual reasoning was slightly higher in the DHA group, parent-reported behavioral problems and executive dysfunction were worse with prenatal DHA supplementation. Differences found in secondary outcomes may be chance findings due to the high number of comparisons made. The small but consistent negative effects of prenatal DHA on behavior and executive functioning at 7 and 4 years3 may reflect true effects, although effect sizes were small and neurodevelopmental diagnoses did not differ between groups. Differences are unlikely due to methodological issues as follow-up rates and variables after randomization were balanced between the groups.

Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Article Information

Corresponding Author: Maria Makrides, BSc, BND, PhD, Child Nutrition Research Centre, South Australian Health and Medical Research Institute, 72 King William Rd, North Adelaide SA 5006, Australia (maria.makrides@sahmri.com).

Author Contributions: Drs Gould and Yelland had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gould, Makrides.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Gould, Yelland, Makrides.

Obtained funding: Treyvaud, Yelland, Anderson, Smithers, McPhee, Makrides.

Administrative, technical, or material support: All authors.

Supervision: Gould, Makrides.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Makrides reports serving on scientific advisory boards for Nestle Nutrition Institute, Fonterra, and True Origins and associated honoraria are paid to her institution. Dr Gould reports honoraria paid to her institution from the Nestle Nutrition Institute. No other disclosures were reported.

Funding/Support: The original randomized trial of DHA in Pregnancy to Prevent Postnatal Depressive Symptoms and Enhance Neurodevelopment in Children (DOMInO) trial and the 7-year follow-up study were funded by National Health and Medical Research Council grants 349301 (DOMInO) and 1048493 (7-year follow-up). DOMInO trial treatment and control capsules were donated by Croda Chemicals. This work was supported by Australian National Health and Medical Research Council through senior research fellowship grants 1061704 (Dr Makrides) and 1081288 (Dr Anderson) and an early career fellowship grant 1052388 (Dr Yelland) and by a MS McLeod postdoctoral research fellowship grant from the Women’s and Children’s Hospital Foundation (Dr Gould).

Role of the Funder/Sponsor: The funding agencies and the company donating study products had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN1260500056906 and ACTRN12614000770662.

Additional Contributions: We thank the families for participation in the DOMInO study. We also thank Robert Gibson, PhD (University of Adelaide), for providing his expertise, and Jennie Louise, PhD (University of Adelaide), for her statistical assistance. Dr Louise received compensation for her contribution. Dr Gibson did not receive compensation for his contribution.

References
1.
Gould  JF, Smithers  LG, Makrides  M.  The effect of maternal omega-3 (n-3) LCPUFA supplementation during pregnancy on early childhood cognitive and visual development.  Am J Clin Nutr. 2013;97(3):531-544.PubMedGoogle ScholarCrossref
2.
Makrides  M, Gibson  RA, McPhee  AJ, Yelland  L, Quinlivan  J, Ryan  P; DOMInO Investigative Team.  Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children.  JAMA. 2010;304(15):1675-1683.PubMedGoogle ScholarCrossref
3.
Makrides  M, Gould  JF, Gawlik  NR,  et al.  Four-year follow-up of children born to women in a randomized trial of prenatal DHA supplementation.  JAMA. 2014;311(17):1802-1804.PubMedGoogle ScholarCrossref
4.
Gould  JF, Treyvaud  K, Yelland  LN,  et al.  Does n-3 LCPUFA supplementation during pregnancy increase the IQ of children at school age?  BMJ Open. 2016;6(5):e011465.PubMedGoogle ScholarCrossref
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