No evidence of a causal relationship between miscarriage and 25-hydroxyvitamin D: a Mendelian randomization study

Study question: Is there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage?

Summary answer: In this study, little evidence of a causal relationship was found between low serum 25OHD concentration or vitamin D deficiency and the risk of miscarriages.

What is known already: Associations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear.

Study design size duration: The latest and largest genome-wide association studies (GWAS) for serum 25OHD concentration (n = 417 580), vitamin D deficiency (426 cases and 354 812 controls), miscarriage (16 906 cases and 149 622 controls), and the number of miscarriages (n = 78 700) were used to explore the causal association between serum vitamin D levels and miscarriage by two-sample Mendelian randomization analysis.

Participants/materials setting methods: This study was based on summary GWAS results from the FinnGen database and the UK Biobank. The random-effect inverse-variance weighted method was regarded as the primary analysis; MR-Egger, weighted median, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were further employed as complementary methods. MR-Egger intercept analysis and MR-PRESSO were employed to test pleiotropy, and Cochran's Q statistic and leave-one-out sensitivity analysis were used to determine the heterogeneity and robustness of the overall estimates, respectively.

Main results and the role of chance: There was insufficient evidence of causal associations between serum 25OHD concentration and miscarriage (odds ratio (OR) = 0.995, 95% CI: 0.888 to 1.114, P = 0.927), or the number of miscarriages (β = -0.004, 95% CI: -0.040 to 0.032, P = 0.829). Furthermore, little evidence of causality between genetically determined vitamin D deficiency to miscarriage (OR = 0.993, 95% CI: 0.966 to 1.021, P = 0.624), or the number of miscarriages (β = 0.001, 95% CI: -0.009 to 0.011, P = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found.

Limitations reasons for caution: This study is limited by the absence of female-specific GWAS data and the limited amount of GWAS data available for this study, as well as the need for caution in generalizing the findings to non-European ethnic groups.

Wider implications of the findings: These findings enhance the current understanding of the intricate association between vitamin D and pregnancy outcomes, challenging prevailing beliefs regarding the strong association with miscarriage. The results provide a special perspective that may prompt further exploration and potentially offer insights for guiding future research and informing clinical guidelines pertaining to the management of miscarriage.

Study funding/competing interests: This project was supported by the Hubei Provincial Natural Science Foundation Program General Surface Project (2022CFB200), the Key Research & Developmental Program of of Hubei Province (2022BCA042), the Fundamental Research Funds for the Central Universities (2042022gf0007, 2042022kf1210), and the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001, JCRCYG-2022-009). All authors have no conflicts of interest to declare.

Trial registration number: N/A.