Vitamin D and Risk of Pregnancy-Related Hypertensive Disorders: Mendelian Randomization Study

Observational studies have found that women with lower levels of 25-hydroxyvitamin D are at greater risk of preeclampsia. Although some small trials of vitamin D supplementation in pregnancy have suggested a potential benefit of supplementation, a recent meta-analysis found no impact on preeclampsia from vitamin D supplementation. Therefore, it is unclear whether vitamin D levels are causally related to the development of preeclampsia. The current study usedmendelian randomization analysis to address this question.Mendelian randomization uses data from cohort studies and uses genetic variants as instrumental variables because they are generally randomly assigned in a population. A 2-sample mendelian randomization uses one population to examine the association between the genetic variant and the exposure (in this study, vitamin D level) and a second population to examine the genetic variant and the outcome (preeclampsia). The current study used data from 2 European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study). Participants included 7389 women in a 1-sample mendelian randomization analysis (751 with gestational hypertension and 135 with preeclampsia), and 3388 preeclampsia cases and 6059 controls in a 2-samplemendelian randomization analysis. Information on genetic variants, antenatal 25-hydroxyvitamin D levels, gestational hypertension, and preeclampsia were available in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Generation R Study. Participants excluded were women with multiple births, of non-European ethnicity, and with hypertension before pregnancy. Women of non-European ethnicity included those who were not of European ancestry based on self-reported information or principal component analysis of their genome. A total of 4066 women from ALSPAC and 3323 women from Generation R were available for analysis. Antenatal 25-hydroxyvitamin D levels were measured in serum (ALSPAC) or plasma (Generation R) using liquid chromatography- tandem mass spectrometry. This study found that, in the conventional multivariable analysis, the relative risk for preeclampsia was 1.03 (95% confidence interval, 1.00-1.07) per 10% decrease in 25-hydroxyvitamin D level and 2.04 (1.02-4.07) for 25-hydroxyvitamin D levels less than 25 nmol/L compared with greater than 75 nmol/L. The one sample mendelian randomization analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or preeclampsia: odds ratio of 0.90 (95% confidence interval, 0.78-1.03) and 1.19 (0.92-1.52) per 10% decrease, respectively. The 2 sample mendelian randomization similarly did not find a difference with an odds ratio for preeclampsia of 0.98 (0.89-1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80-1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level less than 75 nmol/L, and an odds ratio of 0.93 (0.73-1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels less than 50 nmol/L. No strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or preeclampsia. Future mendelian randomization studies with a larger number of women with preeclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels that could be studied are needed to better understand the causal relationship between vitamin D levels and preeclampsia.

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article Vitamin D and risk of pregnancy related hypertensive disorders: Mendelian randomisation study Magnus, M.C. (Maria C.), K. Miliku (Kozeta), Bauer, A. (Anna), Engel, S.M. (Stephanie M.), Felix, J.F. (Janine F.), V.W.V. Jaddoe (Vincent), Lawlor, D.A. (Debbie A.), S.J. London (Stephanie J.), P. Magnus (Per), McGinnis, R. (Ralph), et al. W. Nystad (Wenche), Page, C.M. (Christian M.), Rivadeneira, F. (Fernando), Stene, L.C. (Lars C.), Tapia, G. (German), Williams, N. (Nicholas), C. Bonilla (Carolina) and Fraser, A. (Abigail)