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Lookup NU author(s): Dr Morag Andrew, Professor Nicholas EmbletonORCiD, Professor Janet Berrington, Penny Bradley, Dr Kate Court, Professor Jeremy Parr
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. Background: Infants born extremely preterm (EP; < 28 weeks of gestation) or term born infants with hypoxic-ischemic encephalopathy (HIE) have increased risk of long-term cognitive and learning deficits. Early supplementation with long chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA), choline, uridine-5′-monophosphate (UMP), and cytidine-5′-monophosphate (CMP), zinc, iodine, and vitamin B12 may improve cognitive and language outcomes in these populations. Methods: This multicentre, blinded, stratified, randomised controlled trial, including an economic evaluation, will investigate the impact of nutritional supplementation on cognitive development in infants born EP or term born infants with HIE. The planned sample size is 1010 (538 EP, and 472 HIE) infants from up to 40 National Health Service neonatal units in the UK. The trial patient populations are infants born EP (preterm stratum) and term infants (born at or more than 35 weeks of gestation) with HIE who received therapeutic hypothermia (HIE stratum). Patient strata were chosen to include infants at high risk of adverse neurodevelopmental outcomes by virtue of EP birth, or HIE requiring therapeutic hypothermia. Infants are randomly assigned, in a 1:1 allocation ratio, to receive either the active supplement or a matched control, in addition to standard care. Families, clinical teams, investigators, and Clinical Trials Unit staff are blinded to allocation. Only the Senior Trials Programmer and Trial Statisticians have access to allocation information. The active supplement is a nutrient powder formulated to be mixed with breast milk, infant formula, or food, containing LCPUFAs (including DHA, EPA, and ARA), choline, UMP, CMP, zinc, iodine, and vitamin B12. Supplementation commences once infants achieve full milk feeds and continues until 12 months post-estimated date of delivery (EDD), with a daily dosage of 1 g per kilogram of body weight. The primary outcome is the Parent Report of Children’s Abilities-Revised non-verbal cognitive scale at 24 months post-EDD. EP and HIE patient population comparisons have been appropriately powered and will be analysed separately. Discussion: Findings from the DOLFIN trial will inform international neonatal and infant nutritional and feeding policy and practice. Learnings from the trial will inform the design and delivery of future neonatal nutritional intervention trials. Trial registration: ISRCTN62323236. Registered 16 May 2022, https://www.isrctn.com/ISRCTN62323236.
Author(s): Andrew MJ, Embleton N, Hardy P, Johnson S, Juszczak E, Ledbury H, Pearson C, Rivero-Arias O, Francisco AA, Berrington J, Bradley P, Bradley PJ, Cole C, Court K, Hurd M, King A, Linsell L, Murray D, O'Connor HM, Roehr CC, Stalker V, Stanbury K, Wahengbam UD, Welsh R, Wiles J, Parr JR
Publication type: Article
Publication status: Published
Journal: Trials
Year: 2025
Volume: 26
Online publication date: 29/12/2025
Acceptance date: 21/10/2025
Date deposited: 12/01/2026
ISSN (electronic): 1745-6215
Publisher: BioMed Central Ltd
URL: https://doi.org/10.1186/s13063-025-09253-3
DOI: 10.1186/s13063-025-09253-3
Data Access Statement: Data requests should be directed to the corresponding author for review and consideration. Please be aware that exclusive access to the data will be maintained until after publication of the main trial findings. After this, access to anonymised data may be granted following a detailed review process.
PubMed id: 41462322
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