Vitamin D and risk of pregnancy related hypertensive disorders: mendelian randomisation study

Abstract

ObjectiveTo use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia.DesignOne and two sample mendelian randomisation analyses.SettingTwo European pregnancy cohorts (Avon Longitudinal Study of Parents and Children, and Generation R Study), and two case-control studies (subgroup nested within the Norwegian Mother and Child Cohort Study, and the UK Genetics of Pre-eclampsia Study).Participants7389 women in a one sample mendelian randomisation analysis (751 with gestational hypertension and 135 with pre-eclampsia), and 3388 pre-eclampsia cases and 6059 controls in a two sample mendelian randomisation analysis.ExposuresSingle nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables.Main outcome measuresGestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy.ResultsIn the conventional multivariable analysis, the relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels <25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension. The one sample mendelian randomisation 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 pre-eclampsia: odds ratio 0.90 (95% confidence interval 0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two sample mendelian randomisation estimate gave an odds ratio for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level <75 nmol/L, and an odds ratio of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels <50 nmol/L.ConclusionsNo strong evidence was found to support a causal effect of vitamin D status on gestational hypertension or pre-eclampsia. Future mendelian randomisation studies with a larger number of women with pre-eclampsia or more genetic instruments that would increase the proportion of 25-hydroxyvitamin D levels explained by the instrument are needed.

The Role of Vitamin D in Fertility and during Pregnancy and Lactation: A Review of Clinical Data

“…Several RCTs and meta-analyses of RCTs have been published on vitamin D supplementation during pregnancy and its effect on neonatal and maternal outcomes [ 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 ]. Amongst the many meta-analyses published, we focus on the findings of the most recent ones and/or the ones including the highest number of study participants.…”

Vitamin D – new insights into an old molecule

“…Recently, 2 small randomized controlled studies found a beneficial effect of vitamin D supplementation in the incidence of this entity 24,25 . However, a mendelian study with thousands of pregnant women did not find a clear causal effect between preeclampsia or hypertension during pregnancy with vitamin D deficiency 26 . This condition, preeclampsia, which is defined as the existence of de novo hypertension accompanied by proteinuria after 20 weeks' gestation, is associated with vasculitis and inflammation 27 .…”

The role of immunity in the pathogenesis and development of pre‐eclampsia

“…There are two studies showing that vitamin D supplementation in pregnancy reduced the risk of PE . In contrast, a recent study suggested that there was no strong evidence supporting a causal effect of vitamin D status on PE . Mirzakhani also reported that vitamin D supplementation (4400 vs 400 IU/d) initiated at 10‐18 gestational weeks of pregnancy did not reduce the risk of PE.…”