Zhang Feng, Huang Jingtao, Zhang Gangting, Dai Mengyang, Yin Tailang, Huang Chunyu, Liu Jue, Zhang Yan
Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Hum Reprod Open. 2024 Feb 19;2024(2):hoae011. doi: 10.1093/hropen/hoae011. eCollection 2024.
Is there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage?
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.
Associations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear.
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.
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, = 0.927), or the number of miscarriages (β = -0.004, 95% CI: -0.040 to 0.032, = 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, = 0.624), or the number of miscarriages (β = 0.001, 95% CI: -0.009 to 0.011, = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found.
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.
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.
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25-羟维生素D（25OHD）与流产之间是否存在因果关系？
在本研究中，未发现低血清25OHD浓度或维生素D缺乏与流产风险之间存在因果关系的明显证据。
已有报道称低维生素D水平与流产风险增加之间存在关联，但因果关系尚不清楚。
研究设计、规模、持续时间：利用最新且规模最大的全基因组关联研究（GWAS）数据，涉及血清25OHD浓度（n = 417580）、维生素D缺乏（426例病例和354812例对照）、流产（16906例病例和149622例对照）以及流产次数（n = 78700），通过两样本孟德尔随机化分析来探究血清维生素D水平与流产之间的因果关联。
参与者/材料、设置、方法：本研究基于芬兰基因数据库和英国生物银行的GWAS汇总结果。随机效应逆方差加权法被视为主要分析方法；MR-Egger、加权中位数、加权模式、简单模式以及MR-多效性残差和异常值（MR-PRESSO）被进一步用作补充方法。采用MR-Egger截距分析和MR-PRESSO来检验多效性，分别使用 Cochr an's Q统计量和留一法敏感性分析来确定总体估计值的异质性和稳健性。
没有充分证据表明血清25OHD浓度与流产（优势比（OR）= 0.995，95%置信区间：0.888至1.114，P = 0.927）或流产次数（β = -0.004，95%置信区间：-0.040至0.032，P = 0.829）之间存在因果关联。此外，也未观察到基因决定的维生素D缺乏与流产（OR = 0.993，95%置信区间：0.966至1.021，P = 0.624）或流产次数（β = 0.001，95%置信区间：-0.009至0.011，P = 0.828）之间存在因果关系的明显证据。敏感性分析结果稳健，未发现显著的异质性或水平多效性。
局限性、谨慎的原因：本研究受到缺乏女性特异性GWAS数据以及本研究可用的GWAS数据量有限的限制，并且在将研究结果推广到非欧洲种族群体时需要谨慎。
这些发现增进了当前对维生素D与妊娠结局之间复杂关联的理解，挑战了关于与流产有强关联的普遍观点。研究结果提供了一个独特视角，可能促使进一步探索，并有可能为指导未来研究以及为流产管理的临床指南提供见解。
研究资金/利益冲突：本项目得到湖北省自然科学基金面上项目（2022CFB200）、湖北省重点研发计划（2022BCA042）、中央高校基本科研业务费（2042022gf0007，2042022kf1210）以及武汉大学人民医院跨学科创新人才基金（JCRCWL - 2022 - 001，JCRCYG - 2022 - 009）的支持。所有作者均无利益冲突声明。
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