Periconception Vitamin D Homeostasis and Reproductive Outcomes

Pregnancy complications such as early pregnancy loss, preeclampsia, preterm birth, and fetal growth restriction or low birthweight are common, distressing, and costly to individuals and society. While their etiologies are multifactorial, aberrations in implantation and placentation are a common pathway. Vitamin D has been proposed as a possible low-cost, widely accessible intervention to improve these outcomes, but randomized controlled trials have found no benefit to supplementation among vitamin D deficient patients. The study proposed in this application will address many of the limitations that have previously made definitive conclusions elusive. First, as fertility care provides access to patients very early in pregnancy, we will be able to measure periconception vitamin D in contrast to many studies which measure vitamin D in the second or third trimesters – long after implantation and placentation are complete and too late to intervene for meaningful benefits. Second, we will measure more than the storage form of vitamin D (25-hydroxyvitamin D, or 25(OH)D, which is most commonly used in prior studies), as emerging evidence from other fields indicates that more nuanced assessments such as the vitamin D metabolite ratio (VMR) and D binding protein (DBP) isoforms are more associated with clinical outcomes. Third, we will utilize different in vitro fertilization protocols as an experimental model for dynamic hormonal environments in which vitamin D metabolites and DBP are expected to vary, allowing for broader investigation of alterations in vitamin D homeostasis. Our central hypothesis is that due to its role in implantation and placentation, periconception VMR modulates the likelihood of establishing and sustaining pregnancy as well as developing placentally-mediated obstetric complications, with varying effects depending on DBP isoform. Supported by a team of mentors/collaborators and an advisory committee with diverse expertise as well as the well-established research infrastructure at Penn, I will conduct a prospective cohort study of patients seeking fertility care at our institution in order to test this hypothesis. Aim 1 will assess the effect of different periconception hormonal environments (unassisted conceptions, natural frozen embryo transfers, and programmed frozen embryo transfers) on VMR, with stratified analysis by DBP isoform. Aim 2 will assess the association between VMR and live birth, early pregnancy loss, and obstetric complications including hypertensive disorders of pregnancy, preterm birth, and low birthweight among patients undergoing frozen embryo transfer, again with stratified analysis by DBP isoform. In addition to answering critical questions on the role of vitamin D homeostasis in reproductive outcomes, this study will provide me with valuable experience in prospective reproductive outcomes data collection. Along with mentorship from renowned epidemiologists and reproductive endocrinologists, it will also prepare me for a career as a reproductive epidemiologist as well as my longer term goal of conducting clinical trials to improve reproductive outcomes in fertility and non-fertility patients alike. Project Number: 1K23HD114895-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Iris Lee | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $167,940 | Activity Code: K23 | Study Section: Reproduction, Andrology, and Gynecology Study Section[CHHD-R] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HD11489501A1