Effects of Nutrition Therapy on Growth, Inflammation and Metabolism in Immature Infants; a double-blind randomized trial

The ImNuT-study = Immature Infant, Nutrition Therapy We want to answer whether enhanced supply of the essential fatty acids arachidonic acid (AA) and docosahexaenoic acid (DHA) improves the severe outcomes related to very premature birth. Extremely preterm infants have increased mortality and a high disease burden (chronic lung disease, cerebral palsy, impaired cognitive function, reduced vision and hearing loss). Optimal nutrient supply from the first day of life is crucial in the care of these infants. The aim of the nutritional management is to mimic normal intrauterine growth. Premature infants have low energy reserves and are partly dependent on intravenous nutrient supply to cover their nutrient requirements. Additonally, most infants receive fortified human milk. The supply of DHA is however low, and many infants develop DHA deficiency during the first weeks of life. Recent studies suggest that AA and DHA may play a major role in improving brain growth and reducing the rate and severity of neonatal diseases. AA and DHA are essential for the structure and function of cells, as building blocks in the brain and retina, and as modulators of the immune system. The ImNuT-study will determine whether enhanced supply of AA and DHA during neonatal hospitalization 1) improves brain maturation and somatic growth and 2) reduces morbidity and cardiovascular disease risk. From April 2018 to January 2021, 121 Premature infants (born before 29 weeks of gestation) were randomly assigned to an intervention or a control group at birth. We have followed the children throughout neonatal hospitalization, 3, 6, 12 and 24 months corrected age. We have assessed nutritional intake, growth, clinical outcomes and several biomarkers of inflammation and metabolism to better understand which factors contribute to the damage of major organs such as brain, lung, eye and cardiovascular system of immature infants. By now, we have published 7 papers based on our results. This RCT suggests that the fatty acid supplement is safe and that is has beneficial effects on brain maturation and somatic growth up to term equivalent age. Our study also suggest that supplementation with AA and DHA reduces inflammation and may improve early lung function and reduce the risk of severe damage to the retinal vessels. We will now analyse data from the 2 year follow-up and apply funding for assessment of the children at 8 years of age. This study can be viewed as essential for the provision of evidence based guidelines for nutrition to preterm infants.

Målet med studien var å undersøke om enteralt tilskudd av de langkjedede flerumettede fettsyrene arakidonsyre (ARA) og dokosahesaensyre (DHA) under sykehusoppholdet ville føre til bedret kort- og langtidsutkomme hos premature nyfødte født før 29. svangerskapsuke sammenliknet med standard tilskudd av MCT-olje. Vi fant at tilskudd hadde flere potensielle positive effekter. Vi fant at barn som hadde fått ARA og DHA hadde tegn til bedret hjernemodning ved MR ved terminalder og bedret lengdetilvekst. Sekundære analyser fra studien tydet videre på at tilskudd av ARA og DHA ga mindre inflammasjon i første levemåned og bedre lungefunksjon under sykehusoppholdet, men vi fant ingen forskjeller i lungefunksjon eller kroppssammensetning ved 3 måneders korrigert alder. En tilsvarende studie utført i Sverige fant at ARA og DHA under sykehusoppholdet ga en halvering av risiko for alvorlige netthinneforandringer hos premature født før 28. svangerskapsuke. Vi fant samme trend i vår studie, men resultatene var ikke signifikante. Resultatene fra prosjektet tyder på tilskudd av ARA og DHA i doser svarende til intrauterin tilførsel er viktig for utviklingen av hjernen, netthinnen, lengdevekst og lungefunksjon og at tilskudd reduserer grad av postnatal inflammasjon, men oppføgingsstudier er nødvendig for å avklare om dette vil gi funksjonelle fordeler på lang sikt.

In recent years the survival of extremely premature infants (infants born < 28 weeks gestational age, GA) has increased markedly due to improved pre- and postnatal care. However, the risk of severe medical disabilities increases sharply with decreasing GA. Postnatal growth failure and inflammatory mediated diseases play an important role in the disease burden of these infants. Nutrition is a subject which has attracted much attention lately, since it is difficult to achieve optimal nutrition in these infants, and increasing evidence document that early nutrition has important short-term and long-term health effects. We and others have shown that enhanced supply of energy, protein, vitamin A and the essential fatty acids AA and DHA resulted in improved growth velocity, increased head circumference growth and improved brain maturation as compared to standard nutrient supply in infants with a birth weight below 1500g (the PRENU-study). Recent studies suggest that the fatty acid components play a major role in improving brain growth and reducing the rate and severity of neonatal morbidities. Based on this, we wish to conduct a double-blind RCT to determine whether early and prolonged supply of AA and DHA improves clinical outcomes and quality of growth in extremely premature infants as compared to our present nutrient supply. The main objectives are to evaluate the efficacy of this intervention on brain development, quality of growth, inflammation related comorbidities and long-term neurodevelopment and cardiovascular disease risk. By closely assessing nutritional intake, anthropometric measures, clinical outcomes and several biomarkers of inflammation and metabolism, we hope to elucidate mechanisms of inflammation and metabolic mediated damage to major organs such as brain, lung, eye and cardiovascular system of extremely premature infants. This study can be viewed as essential to provide results for establishing national guidelines for nutrition to preterm infants.