No vitamin D protection against gestational hypertension, pre-eclampsia

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There is no strong evidence that vitamin D protects against pregnancy-induced high blood pressure or pre-eclampsia, conclude researchers at the University of Bristol, Bristol Medical School, Norwegian Institute of Public Health, Erasmus MC –University Medical Centre Rotterdam, Gillings School of Global Public Health – University of North Carolina, Chapel Hill, University Hospitals Bristol NHS Foundation Trust, National Institute of Environmental Health Sciences – National Institutes of Health, Sanger Institute – University of Cambridge, Oslo University Hospital and Universidade de São Paulo.

The findings support current World Health Organisation guidance that evidence recommending vitamin D supplements for women during pregnancy to reduce adverse pregnancy outcomes is insufficient. However, in many countries, including the UK and the US, pregnant women are advised to take a daily dose of vitamin D.

It is common for pregnant women to have low levels of vitamin D, which can suppress the hormone that regulates blood pressure which may increase the risk of both hypertension and pre-eclampsia during pregnancy.

Previous population-based studies have found that women with lower levels of vitamin D are at greater risk of pre-eclampsia and some trials of vitamin D supplementation in pregnancy suggest a potential benefit. But it remains unclear whether vitamin D is a cause of pre-eclampsia.

So, an international team led by Maria Magnus at the University of Bristol, set out to investigate whether vitamin D has an effect on pregnancy induced hypertension or pre-eclampsia. Using a technique called Mendelian randomisation, they examined whether genetic variants associated with vitamin D production and metabolism also influenced the risk of pregnancy-induced hypertension and pre-eclampsia for 7,389 women (751 with gestational hypertension and 135 with pre-eclampsia) from two large European studies (Avon Longitudinal Study of Parents and Children, also known as Children of the 90s, and Generation R Study).

They also performed another (two sample) Mendelian randomisation analysis of 3,388 pre-eclampsia cases and 6,059 controls.

Analysing genetic information as proxies for the exposure of interest in this way avoids some of the problems that afflict traditional observational studies, making the results less prone to unmeasured (confounding) factors. An association that is observed using Mendelian randomisation therefore strengthens the inference of a causal relationship. Mendelian randomisation analysis showed no evidence to support a direct (causal) effect of vitamin D levels on risk of gestational hypertension or pre-eclampsia.

The researchers point to some study limitations. For example, the analyses were restricted to pregnant women. If vitamin D affects fertility, this may have resulted in selection bias.

In light of the uncertainty, they suggest further studies with a larger number of women with preeclampsia or more genetic variants that would increase the predictive power of vitamin D levels are needed.

“In combination with adequately powered clinical trials, this could help finally establish whether vitamin D status has a role in pregnancy related hypertensive disorders.” they conclude.

Objective: To use mendelian randomisation to investigate whether 25-hydroxyvitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia.
Design: One and two sample mendelian randomisation analyses.
Setting: Two 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).
Participants: 7389 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.
Exposures: Single nucleotide polymorphisms in genes associated with vitamin D synthesis (rs10741657 and rs12785878) and metabolism (rs6013897 and rs2282679) were used as instrumental variables.
Main outcome measures: Gestational hypertension and pre-eclampsia defined according to the International Society for the Study of Hypertension in Pregnancy.
Results: In 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.
Conclusions: No 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.

Maria C Magnus, Kozeta Miliku, Anna Bauer, Stephanie M Engel, Janine F Felix, Vincent W V Jaddoe, Debbie A Lawlor, Stephanie J London, Per Magnus, Ralph McGinnis, Wenche Nystad, Christian M Page, Fernando Rivadeneira, Lars C Stene, German Tapia, Nicholas Williams, Carolina Bonilla, Abigail Fraser

BMJ material BMJ abstract

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