Metabolic mechanisms induced by enteral DHA and ARA supplementation in preterm infants

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Preterm birth indicates an end to the rich fetal supply of polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and Arachidonic Acid (ARA) which are a critical building blocks for brain and eye development and an important inflammatory modulator. Yet, for almost 40 years, enteral supplementation of DHA and ARA to replace lost fetal accretion has failed to translate into long-standing clinical benefit. The failure to understand the metabolism and induced molecular changes of fatty acid supplementation during the postnatal period has led to erroneous assumptions and replacement strategies that are, at best, not clinical beneficial and, at worst, harmful. The overall study objective of this proposal is to investigate the induced metabolism and downstream molecular mechanisms of enteral DHA and ARA supplementation from birth to 36 weeks' postnatal age in the extremely preterm infant. We have assembled a multidisciplinary team with expertise in neonatal-perinatal medicine and biostatistics/bioinformatics. The team of neonatologists are clinical and research leaders in nutrition, growth, and fatty acids and represents five level III/IV neonatal intensive care units with diverse demographic populations. We hypothesize that metabolism of DHA and ARA enteral supplementation is developmentally regulated and the impact of lipid derived metabolites on biology is dependent on the health state of the infant (context specificity). To interrogate our hypothesis, we propose a multi-center, randomized clinical trial to evaluate lipidomic actions of combined DHA and ARA supplementation from birth to 36 weeks postmenstrual age in 280 extremely low gestational age newborns born between 25 0/7 and 29 6/7 weeks of gestation. The following aims will be evaluated: Aim 1 – Identify the impact of combined enteral DHA and ARA supplementation on fatty acid metabolism including derivation of specialized pro-resolving mediators (SPMs) and oxylipin production and, Aim 2 – Determine the multisystemic change in circulating markers of inflammation and organ development and integrity as a function of enteral DHA/ARA supplementation. Successful completion of these aims will define developmentally regulated fatty acid metabolism in the immature host and impact of fatty acid supplementation on critical biological functions. Mechanistic data is required to bridge the scientific gap to appropriate clinical translation that is effective and safe. These data will inform a biologically rational approach to fatty acid delivery in preterm infants and identify molecular read-outs that may serve as biomarkers in future trials of clinical efficacy.