Enteral High-Dose Docosahexaenoic Acid and Neurodevelopment in Extremely Preterm Infants: A Systematic Review and Meta-analysis

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dc.contributor.authorShepherd, E.
dc.contributor.authorIkeda, N.
dc.contributor.authorSullivan, T.R.
dc.contributor.authorMarc, I.
dc.contributor.authorGuillot, M.
dc.contributor.authorMcPhee, A.
dc.contributor.authorGibson, R.
dc.contributor.authorMakrides, M.
dc.contributor.authorGould, J.
dc.date.issued2025
dc.description.abstractBackground: Enteral high-dose docosahexaenoic acid (DHA) may be required for neurodevelopment, including cognition, of extremely preterm infants. High-level summative evidence is lacking. Objectives: This study aims to examine associations between enteral high-dose DHA during the neonatal period and neurodevelopment in infants born ≤29 wk of gestation. Methods: The following databases were searched (from inception to 11 April, 2024): CINAHL, Cochrane Library, Embase, Medline, Scopus, and Web of Science. Eligible randomized controlled trials (RCTs) in infants born ≤29 wk, assessing direct enteral administration ≥ 40 mg/kg/d DHA, or breast milk/formula with DHA ≥ 0.60% total fatty acids, reporting neurodevelopmental outcomes. Two reviewers independently screened articles, extracted data, and assessed quality using the Cochrane Handbook guidance. Data were pooled using fixed or random-effect meta-analyses. The primary outcome was global cognitive scores from a standardized test. Results: We screened 1978 articles and included 3 high-quality RCTs (2028 infants born ≤29 wk). Enteral high-dose DHA was not associated with overall differences in global cognition scores at a corrected age (CA) of 18–36 mo [3 RCTs, 638 children, mean difference (MD) 0.67; 95% confidence interval (CI): –1.80, 3.15; P = 0.59; I² = 0%] or CA of 5–7 y (2 RCTs, 852 children; MD: 2.22; 95% CI: –0.14, 4.57; P = 0.06; I² = 33%); however, benefit was observed in the largest RCT with a direct enteral emulsion (656 children, CA of 5 y, MD 3.45; 95% CI: 0.38, 6.52; P = 0.03). Associations with most secondary outcomes were not seen; however, high-dose DHA was associated with reduced mild motor (3 RCTs, CA of 18–36 mo) and cognitive (2 RCTs, CA of 5–7 y) impairment. No negative impacts were observed. Conclusions: Enteral high-dose DHA in extremely preterm infants was not associated with differences in global cognition scores on metaanalysis; however, higher scores were observed with the use of a direct emulsion. Results support contemporary recommendations. This trial was registered at PROSPERO as CRD42022382744 (https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42022382744).
dc.description.statementofresponsibilityEmily Shepherd, Naho Ikeda, Thomas R. Sullivan, Isabelle Marc, Mireille Guillot, Andrew J. McPhee, Robert A Gibson, Maria Makrides, Jacqueline F. Gould
dc.identifier.citationCurrent Developments in Nutrition, 2025; 9(9):107510-1-107510-11
dc.identifier.doi10.1016/j.cdnut.2025.107510
dc.identifier.issn2475-2991
dc.identifier.issn2475-2991
dc.identifier.orcidShepherd, E. [0000-0002-9669-788X]
dc.identifier.orcidSullivan, T.R. [0000-0002-6930-5406]
dc.identifier.orcidMcPhee, A. [0000-0003-3820-5696]
dc.identifier.orcidGibson, R. [0000-0002-8750-525X]
dc.identifier.orcidMakrides, M. [0000-0003-3832-541X]
dc.identifier.orcidGould, J. [0000-0003-2810-6870]
dc.identifier.urihttps://hdl.handle.net/2440/148055
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2007800
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1173576
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT2016756
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT2033062
dc.rights© 2025 The Author(s). Published by Elsevier Inc. on behalf of American Society for Nutrition. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.source.urihttps://doi.org/10.1016/j.cdnut.2025.107510
dc.subjectinfant; premature; enteral nutrition; DHAs; cognition; systematic review
dc.titleEnteral High-Dose Docosahexaenoic Acid and Neurodevelopment in Extremely Preterm Infants: A Systematic Review and Meta-analysis
dc.typeJournal article
pubs.publication-statusPublished

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