Vitamin D Binding Protein and Reproductive Outcomes.

Abstract

OBJECTIVE Little is known about whether D binding protein (DBP) plays a role in reproductive outcomes. The few existing studies have largely presumed that any effects of DBP are due to its modulation of vitamin D bioavailability per the "free hormone theory" despite its many vitamin D-independent functions. This study therefore aimed to comprehensively evaluate the association between DBP concentration/haplotype and reproductive outcomes in patients with polycystic ovary syndrome (PCOS) or unexplained infertility undergoing ovarian stimulation. DESIGN Retrospective cohort study, secondary analysis of randomized controlled trials Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). SUBJECTS 376 participants with PCOS (PPCOS II), 505 participants with unexplained infertility (AMIGOS). INTERVENTION OR EXPOSURE DBP concentration; DBP Gc1f, Gc1s, Gc2 haplotypes. MAIN OUTCOME MEASURES Primary: live birth. Secondary: early pregnancy loss; composite of preterm delivery, preeclampsia, and fetal growth restriction. RESULTS 881 participants were included. There was no association between DBP concentration, Gc1s, or Gc2 and live birth. When adjusting for age, race, BMI, 25(OH)D concentration, and treatment arm, the Gc1f haplotype was associated with increased odds of live birth (adjusted odds ratio [aOR] 1.49, 95% CI 1.06-2.09, p=0.02) and decreased odds of early pregnancy loss (aOR 0.46, 95% CI 0.25-0.86, p=0.02). There was no association with obstetric complications (aOR 0.76, 95% CI 0.39-1.47, p=0.42). CONCLUSIONS The Gc1f haplotype of DBP was associated with increased odds of live birth and decreased odds of early pregnancy loss independent of 25(OH)D and DBP concentration. As Gc1f results in the DBP variant with the greatest binding affinity for vitamin D, these findings challenge the current narrative that associations between DBP and reproductive outcomes are primarily due to modulation of vitamin D bioavailability. Additional studies are needed to investigate other mechanisms for the role of DBP in reproductive outcomes.