Target trial emulation of preconception serum vitamin D status on fertility outcomes: a couples-based approach

Objective: To evaluate associations between preconception 25-hydroxyvitamin D (25(OH)D) levels and biomarkers in female and male partners on live birth (LB), pregnancy loss, and semen quality. Design: Secondary analysis using the folic acid and zinc supplementation trial of couples seeking infertility treatment at four US centers (2013–2017). A target trial emulation framework was applied to estimate associations. Couples were observed for 9 months or through pregnancy. Subjects: Couples seeking infertility treatment. Intervention(s): Preconception concentrations of 25(OH)D (primary) and associated biomarkers: vitamin D binding protein, calcium, free vitamin D, bioavailable vitamin D. Main Outcome Measure(s): Live birth and pregnancy loss were ascertained via self-report and medical records. Semen quality was ascertained 6 months after enrollment. Log-binomial regression estimated risk ratios and 95% confidence intervals (CIs). Individual and joint models and effect measure modification by preconception body mass index were considered. Result(s): Among 2,370 couples, 19.5% of females and 29.9% of males were 25(OH)D deficient. Females with sufficient status had a 28%-higher likelihood of LB than deficient females (95% CI, 1.05–1.56). Female and male 25(OH)D status were associated with LB among those with normal body mass index (sufficient vs. deficient: female adjusted risk ratio [aRR], 1.39; 95% CI, 1.00–1.99; male aRR, 1.51; 95% CI, 1.01–2.25) and among obese female partners (sufficient vs. deficient: aRR, 1.33; 95% CI, 0.95–1.85). Couples whose both partners had higher 25(OH)D status had increased likelihood of LB (both not deficient vs. both deficient aRR, 1.26; 95% CI, 1.00–1.58). No associations were observed with pregnancy loss or semen quality. Similar results were found for all biomarkers except calcium. Conclusion(s): Preconception vitamin D status and bioavailability impact fertility among couples seeking infertility therapy, likely unrelated to semen quality. Body mass index stratified analyses demonstrated heterogeneous associations. Clinical Trial Registration Number: NCT01857310.