Randomized Controlled Trial

. 2024 Jan 1;178(1):45-54.

doi: 10.1001/jamapediatrics.2023.4924.

High-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial

Jacqueline F Gould^{1

2

3}, Rachel M Roberts³, Peter J Anderson⁴, Maria Makrides^{1

2}, Thomas R Sullivan^{1

5}, Robert A Gibson^{1

6}, Andrew J McPhee⁷, Lex W Doyle⁸, Jana M Bednarz¹, Karen P Best^{1

2}, Gillian Opie⁹, Javeed Travadi^{10

11}, Jeanie L Y Cheong¹², Peter G Davis¹², Mary Sharp¹³, Karen Simmer¹⁴, Kenneth Tan¹⁵, Scott Morris¹⁶, Kei Lui¹⁷, Srinivas Bolisetty¹⁸, Helen Liley¹⁹, Jacqueline Stack²⁰, Carmel T Collins^{1

2}

Affiliations

¹ SAHMRI Women and Kids, South Australian Health and Medical Research Institute, North Adelaide, South Australia, Australia.
² Discipline of Paediatrics, Faculty of Health and Medical Sciences, The University of Adelaide, North Terrace Adelaide, South Australia, Australia.
³ School of Psychology, Faculty of Health and Medical Sciences, The University of Adelaide, North Terrace Adelaide, Adelaide, South Australia, Australia.
⁴ Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia.
⁵ School of Public Health, Faculty of Health and Medical Sciences, The University of Adelaide, North Terrace Adelaide, South Australia, Australia.
⁶ School of Agriculture, Food and Wine, The University of Adelaide, Waite Campus, Glen Osmond, South Australia, Australia.
⁷ Neonatal Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
⁸ Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.
⁹ Neonatal Services, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.
¹⁰ Newborn Services, John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia.
¹¹ Neonatal Intensive Care Unit, Department of Paediatrics, Te Whatu Ora Waikato, Waikato Hospital, Hamilton, New Zealand.
¹² Neonatal Medicine, The Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.
¹³ King Edward Memorial Hospital, Perth, Western Australia, Australia.
¹⁴ The University of Western Australia, Perth, Western Australia, Australia.
¹⁵ Department of Paediatrics, Monash University, Monash Children's Hospital, Clayton, Victoria, Australia.
¹⁶ Neonatal-Perinatal Medicine, Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia, Australia.
¹⁷ School of Clinical Medicine, Discipline of Paediatrics and Child Health, University of New South Wales, Sydney, New South Wales, Australia.
¹⁸ Royal Hospital for Women, Randwick, New South Wales, Australia.
¹⁹ Mater Research - The Faculty of Medicine, The University of Queensland, South Brisbane, Queensland, Australia.
²⁰ Neonatal Intensive Care Unit, Liverpool Hospital, Elizabeth, Liverpool, New South Wales, Australia.

PMID: 37983037
PMCID: PMC10660239
DOI: 10.1001/jamapediatrics.2023.4924

Randomized Controlled Trial

High-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial

Jacqueline F Gould et al. JAMA Pediatr. 2024.

. 2024 Jan 1;178(1):45-54.

doi: 10.1001/jamapediatrics.2023.4924.

Authors

Affiliations

¹ SAHMRI Women and Kids, South Australian Health and Medical Research Institute, North Adelaide, South Australia, Australia.
² Discipline of Paediatrics, Faculty of Health and Medical Sciences, The University of Adelaide, North Terrace Adelaide, South Australia, Australia.
³ School of Psychology, Faculty of Health and Medical Sciences, The University of Adelaide, North Terrace Adelaide, Adelaide, South Australia, Australia.
⁴ Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia.
⁵ School of Public Health, Faculty of Health and Medical Sciences, The University of Adelaide, North Terrace Adelaide, South Australia, Australia.
⁶ School of Agriculture, Food and Wine, The University of Adelaide, Waite Campus, Glen Osmond, South Australia, Australia.
⁷ Neonatal Medicine, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
⁸ Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.
⁹ Neonatal Services, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.
¹⁰ Newborn Services, John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia.
¹¹ Neonatal Intensive Care Unit, Department of Paediatrics, Te Whatu Ora Waikato, Waikato Hospital, Hamilton, New Zealand.
¹² Neonatal Medicine, The Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.
¹³ King Edward Memorial Hospital, Perth, Western Australia, Australia.
¹⁴ The University of Western Australia, Perth, Western Australia, Australia.
¹⁵ Department of Paediatrics, Monash University, Monash Children's Hospital, Clayton, Victoria, Australia.
¹⁶ Neonatal-Perinatal Medicine, Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia, Australia.
¹⁷ School of Clinical Medicine, Discipline of Paediatrics and Child Health, University of New South Wales, Sydney, New South Wales, Australia.
¹⁸ Royal Hospital for Women, Randwick, New South Wales, Australia.
¹⁹ Mater Research - The Faculty of Medicine, The University of Queensland, South Brisbane, Queensland, Australia.
²⁰ Neonatal Intensive Care Unit, Liverpool Hospital, Elizabeth, Liverpool, New South Wales, Australia.

PMID: 37983037
PMCID: PMC10660239
DOI: 10.1001/jamapediatrics.2023.4924

Abstract

Importance: Children born at less than 29 weeks' gestation are at risk of behavioral difficulties. This may be due in part to the lack of transplacental supply of docosahexaenoic acid (DHA), a key fatty acid with structural and functional roles in the brain.

Objective: To determine whether meeting the neonatal DHA requirement through supplementation is associated with improved behavioral functioning of children born at less than 29 weeks' gestation.

Design, setting and participants: This was a follow-up of children from 10 Australian participating centers in a multi-center, blinded, parallel group randomized clinical trial of infants born at less than 29 weeks' gestation conducted from June 2012 and September 2015, excluding those with additional fatty acid supplementation or major congenital or chromosomal abnormalities. Follow-up took place from August 2018 to May 2021. Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age.

Interventions: Infants were randomized to receive daily enteral emulsions providing 60 mg/kg/d of DHA or a soy-oil emulsion (with no DHA) from within the first 3 days of enteral feeding until 36 weeks' postmenstrual age or discharge home, whichever occurred first.

Main outcomes and measures: The primary outcome of this follow-up was parent-rated behavior and emotional functioning as indicated by the Total Difficulties score of the Strengths and Difficulties Questionnaire. Parents also completed questionnaires about their child's behavioral manifestations of executive functioning, as well as a range of health outcomes to assess potential longer-term side effects of DHA intervention.

Results: Primary outcome data were available for 731 children (76% of 958 surviving eligible children; 361 in the intervention group and 370 in the control group). Of these 731, 452 (47%) were female, and the mean (SD) corrected age at follow-up was 5.4 (0.5) years. Following imputation for missing data, the mean Total Difficulties score was the same in both groups (intervention group, n = 465; mean [SD], 11.8 [6.3]; control group, n = 493; mean [SD], 11.8 [6.0]; mean difference adjusted for sex, gestational age stratum, and hospital, 0.01; 95% CI, -0.87 to 0.89; P = .98). There was no evidence for differences between the groups in any secondary outcomes of behavior, executive functioning, or health.

Conclusions and relevance: In this follow-up of a randomized clinical trial, enteral DHA supplementation at the equivalent of the estimated in utero dose for infants born at less than 29 weeks' gestation did not improve behavioral functioning at age 5 years. There were no indications of adverse effects with DHA supplementation.

Trial registration: Australian New Zealand Clinical Trial Registry: ACTRN12612000503820.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gould reported grants from Women and Children’s Hospital Foundation and the National Health and Medical Research Council Australia as well as nonfinancial support from NuMega Ingredients (donated study product) during the conduct of the study and grants from Fonterra and honoraria to support conference travel from NuMega Ingredients and Nestle Nutrition Institute outside the submitted work. Dr Roberts reported grants from Women’s and Children’s Hospital Foundation during the conduct of the study. Dr Makrides reported grants from the National Health and Medical Research Council (Project, Investigator, and Centre of Research Excellence) during the conduct of the study and nonfinancial support from NuMega Ingredients (donated study product for the original trial) and grants from Fonterra outside the submitted work; in addition, Drs Makrides and Gibson had a patent for methods and compositions for promoting the neurological development for preterm infants (2009201540) licensed to NuMega Ingredients. Dr Sullivan reported grants from the National Health and Medical Research Council and Women’s and Children’s Hospital Foundation during the conduct of the study. Dr Gibson reported grants from the National Health and Medical Research Council (Project and Centre of Research Excellence) as well as nonfinancial support from NuMega Ingredients (donated study product for the original trial) during the conduct of the study and grants from Fonterra outside the submitted work. Dr McPhee reported grants from the National Health and Medical Research Council Australia during the conduct of the study. Dr Doyle reported grants from the National Health and Medical Research Council of Australia Centre of Research Excellence Grant outside the submitted work. Dr Best reported grants from MS McLeod Post Doctoral Fellowship outside the submitted work. Dr Collins reported grants from Women’s and Children’s Hospital Foundation and the National Health and Medical Research Council as well as nonfinancial support from NuMega Ingredients (donation of study product for original trial) during the conduct of the study. No other disclosures were reported.

Figures

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References

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High-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial

Affiliations

High-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial

Authors

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Abstract

Conflict of interest statement

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