Randomized Controlled Trial of Enteral Vitamin D Supplementation (ViDES) in Infants <28 Weeks Gestational Age or <1000 Grams Birth Weight: Study Protocol.

Background Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear. Methods Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 grams birth weight at a large academic center in the United States. Infants are stratified by birth weight and randomized within 96 hours after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth. We hypothesize that the higher and early vitamin D dose (800 IU/d with early feeding) compared to placebo plus routine dose (400 IU/d with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at one month, reduce respiratory support at 36 weeks' postmenstrual age (on an ordinal scale predictive of later adverse outcomes) and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22-26 months' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes. The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability. Discussion Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterminfants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results. Trial registration ClinicalTrials.gov registered on July 14, 2022 (NCT05459298).