Effects of Earlier And Higher Vitamin D Supplementation in Extremely Preterm Newborns at 2 Years Of Age - PROJECT SUMMARY Extremely premature (EP) infants (<28 weeks gestation) often have vitamin D deficiency at birth that worsens in the first month after birth and may have lasting direct or indirect adverse effects on the developing lungs, bones, brain, and immune system, contributing to the high rate of chronic lung disease, osteopenia, infections, and neurodevelopmental impairment in EP infants. “Normal” vitamin D levels have been extrapolated from older children and adults, and the supplementation regimen & blood levels that result in the best health of EP infants are unknown, causing wide variation in official recommendations and clinical practice. This study builds on the ViDES trial (NCT05459298): a KL2-funded, phase IIB, blinded randomized trial comparing neonatal effects of two vitamin D supplementation regimens in EP infants (400 IU/day after feeds are established [the most used regimen in the U.S.] vs. 800 IU/day started in the first 96 h after birth [a more common regimen in Europe]) for the first month after birth. All infants then receive 400 IU/day. Our primary aim for the proposed R03 research is to test the hypothesis that the earlier and higher dosage regimen will improve pulmonary mechanics and wheezing at two years with similar, if not better, bone density, cognition, and infection rates. We also aim to identify vitamin D blood levels associated with the most favorable outcomes in EP infants and conduct exploratory analyses to assess whether race, ethnicity, sex, or gestational age are effect modifiers. We will use sophisticated assessments including: a) Liquid Chromatography-Tandem Mass Spectrometry to assess 25-hydroxyvitamin D and other vitamin D metabolites; b) non-invasive oscillometry to measure pulmonary mechanics during spontaneous breathing; c) the validated International Study of Asthma and Allergies questionnaire to assess wheezing; d) quantitative ultrasound to assess bone density by speed of sound transmission through the tibia. With our large population, NICHD Neonatal Research Network infrastructure, and high follow-up rate, we expect to assess at least 135 infants at 2 years (accounting for 15% mortality/ withdrawal of the study and a follow-up of 90%). We will assess the probability of benefit from the earlier, higher dosage regimen on pulmonary mechanics, wheezing, and bone density in conservative Bayesian analyses (using a neutral prior). The success of the ViDES trial to date, the expertise of our team of mentors and investigators (including Glenville Jones [Queen's University, Kingston Ontario], Anna Marie Hibbs [Case Western], Carol Wagner [South Carolina] and Matthew Rysavy [UT Heath]), and the commitment and resources of my primary mentor (Jon Tyson [UT Heath]) to cover cost overruns help to ensure the project's feasibility, execution, and validity. A better approach to vitamin D could prove to be a simple and inexpensive method to improve the outcomes of EP infants. Whatever the results, they will advance the understanding of vitamin D in EP infants and how best to prevent adverse multisystem disorders due to vitamin D deficiency in small preterm infants.
