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Trial protocol: DOLFIN trial: Developmental Outcomes of Long-term Feed Supplementation in Neonates-A UK multicentre,

Morag J Andrew^1,2, Nicholas Embleton^3,4, Pollyanna Hardy⁵

¹Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK. morag.andrew@newcastle.ac.uk.

|December 30, 2025

Insights

This study investigates early nutritional supplementation for extremely preterm infants and those with hypoxic-ischemic encephalopathy to improve cognitive development. Findings will guide future infant nutrition policies and intervention trials.

Area of Science:

Neonatal Medicine
Developmental Pediatrics
Nutritional Science

Background:

Infants born extremely preterm (<28 weeks gestation) or with hypoxic-ischemic encephalopathy (HIE) face risks of long-term cognitive and learning deficits.
Early nutritional supplementation may mitigate these risks.

Purpose of the Study:

To investigate the impact of a specific nutritional supplement on cognitive development in high-risk infants.
To inform international neonatal nutritional and feeding policies.

Main Methods:

A multicentre, blinded, randomised controlled trial involving 1010 infants (extremely preterm and HIE).
Infants received either an active supplement (LCPUFAs, choline, UMP, CMP, zinc, iodine, vitamin B12) or a control.
Supplementation started post-full milk feeds until 12 months post-EDD; primary outcome assessed at 24 months post-EDD.

Main Results:

Primary outcome: Parent Report of Children's Abilities-Revised non-verbal cognitive scale at 24 months post-EDD.
Separate analyses for extremely preterm and HIE populations due to distinct risk profiles.
Trial is powered to detect significant differences in cognitive outcomes.

Conclusions:

Findings from the DOLFIN trial will inform international neonatal and infant nutritional and feeding policy and practice.
Learnings will guide the design and delivery of future neonatal nutritional intervention trials.

Read full analysis

Abstract

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 .

Keywords:

Brain Choline Cognition Docosahexaenoic acid Hypoxic ischaemic encephalopathy Neurodevelopment Nutrient Nutrition Preterm

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