Title: Investigating the clinical and cost-effectiveness of a nutrient enriched diet for babies with a brain injury: The Dolphin Randomised controlled trial
Funder: Department of Health and Social Care

Abstract: This trial aims to examine if giving a nutrient-rich fortifier (a powder that can be added to milk or food) to babies born very early and term babies with less oxygen around the time of birth improves their brain development_x000D_ _x000D_ Five of every 1,000 babies born in the UK is born very early or receives less oxygen around the time of birth. This can result in lifelong disability including special educational needs. Even without changes on a brain scan, events occurring before or around the time of birth can disrupt normal brain development causing later developmental problems and learning difficulties. The developing brain can repair injured areas and reduce disability by making new connections and nerve cells from specific nutrients present in low amounts in a healthy baby’s diet. These babies may need higher amounts of nutrients to support brain growth and repair. There is no research to guide how affected babies should be fed_x000D_ _x000D_ We ran a small study with 62 babies that compared a specially created fortifier, containing higher levels of some key nutrients needed for brain growth with another fortifier that did not contain these key nutrients. Babies received the fortifiers in their breast, formula milk or food until they were 2 years old. The results of the study were positive and showed that infants receiving the fortifier containing the key nutrients may have better brain development. But this was a small study; to know if the fortifier does truly help brain development, it needs to be tested in a much bigger study_x000D_ _x000D_ The trial aims to recruit 1,010 babies from UK hospitals. Preterm babies born less than 28 weeks' gestation, and term babies with less oxygen around the time of birth and who receive therapeutic cooling will be able to take part. Half the babies will receive a fortifier containing nutrients thought to aid brain development and the other half will receive a fortifier that does not contain these active ingredients. Parents will add the fortifier to their infants’ usual breast or formula milk or food every day for one year; reminders to add fortifer will be sent by online App or text. Support to promote and maintain breastfeeding will be provided. At 2 years of age, cognitive development will be assessed using a parent questionnaire. Economic cost, and emotional, behavioural and social outcomes will also be measured. Consent will be requested to assess children’s development up to school age_x000D_ _x000D_ The trial has been designed in partnership with parents, and a representative from the charity Bliss. They have contributed to the trial methods and materials. Through parent feedback from the initial study, we have made the fortifier easier to dissolve and have reduced the dosage needed to just once or twice a day. Our work with parents highlighted the importance of supporting breastfeeding in the trial. A number of initiatives will help promote and maintain breastfeeding, including guidance materials on the trial website and breastfeeding videos_x000D_ _x000D_ The results will be published in high impact journals and presented at parent networks and conferences. Results will be shared on the Bliss website. Parents who participated will receive a summary of the trial results; these will also be available on our website. The results will be shared with those developing guidelines for feeding babies born very early and term babies with less oxygen around the time of birth

Lay abstract: Research question_x000D_ In babies born very pre-term or with less oxygen around the time of birth (participants), does nutritional fortification with DHA, choline and uridine-5-monophosphate (intervention) plus usual care from birth to 12 months of age corrected for prematurity improve cognitive development (outcome) at 2 years of age corrected for prematurity, compared to babies receiving a matched control fortifier plus usual care (comparator)?_x000D_ _x000D_ Background_x000D_ Babies born pre-term or with less oxygen around the time of birth are at risk of neurodisability, and suboptimal long term neurodevelopmental outcomes and educational attainments. Adequate provision of key brain nutrients may support brain plasticity and development following perinatal brain injury, and improve neurodevelopmental outcomes_x000D_ _x000D_ Aims and objectives_x000D_ 1 Investigate, in a multicentre randomised placebo-controlled trial, the effect of nutritional fortification with DHA, choline and UMP on neurodevelopmental outcomes at 2 years corrected gestational age _x000D_ 2 Assess the safety of fortification_x000D_ 3 Conduct an internal pilot study to evaluate: recruitment, parental uptake and retention rates; clinician protocol adherence; safety; parent acceptability and adherence; completeness and quality of data collection_x000D_ 4 Determine the intervention’s impact on healthcare service use, parental health-related quality of life, parent employment, and value for money (NHS and society) using an economic evaluation_x000D_ 5 Facilitate a follow up study into the intervention’s effect on later developmental, health, healthcare resource use, and educational outcomes using routinely collected data_x000D_ _x000D_ Methods_x000D_ Multicentre blinded randomised placebo-controlled trial with an internal pilot and economic evaluation. Babies recruited from NHS Tertiary neonatal units will include: 1010 preterm babies born less than 28 weeks of gestation, and babies born at 35 weeks gestation or more receiving therapeutic hypothermia for HIE_x000D_ _x000D_ Intervention: Micronutrient breast milk/formula milk/food fortifier containing DHA, choline and UMP for newborns born pre-term or who receive less oxygen around the time of birth. Comparator: Matched control fortifier: identically packaged and delivered powder fortifier indistinguishable from the active treatment. Both groups will receive identical usual care (NHS breastfeeding, dietetic and other multidisciplinary team support) and clinical research team support_x000D_ _x000D_ Primary outcome (age 24 months, corrected for prematurity): PARCA-R Non-verbal Cognitive Scale score. Secondary outcomes: PARCA-R Language Development Scale score; motor, behavioural, attention, social and emotional outcomes. NHS data at 1 and 2 years for Safety, Health (necrotising enterocolitis, sepsis, chronic lung disease); Growth (height, weight, obesity, head circumference); need for social care. Parent acceptability of intervention and adherence. Economic evaluation_x000D_ _x000D_ Timeline_x000D_ Start 1.9.2021_x000D_ 0-6 mths Permissions, site set-up, create breastfeeding support and other materials in partnership with parents_x000D_ 7-33 mths Recruitment, internal pilot, community fortification_x000D_ 7-63 mths Community fortification, outcome measurement_x000D_ 64-69 mths Analysis, dissemination_x000D_ _x000D_ Impact and dissemination_x000D_ The pilot Dolphin neonatal trial showed a non-significant difference in neurodevelopmental outcomes between fortifier and control groups. This definitive trial will give clarity to parents and professionals on whether nutritional intervention improves outcomes, or not. If fortifier is effective, this may alter neonatal care pathways. We will disseminate to: professionals; parents, the public; and policymakers

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL