#Grand Rounds

Is there a Causal Link between Vitamin D and Gestational Hypertension / Preeclampsia?

BACKGROUND AND PURPOSE:

Vitamin D, 1,25-dihydroxyvitamin D3 (Vitamin D) can suppress renin biosynthesis and regulate implantation
- Therefore, may impact gestational hypertension and/or preeclampsia
Previous literature on the relationship between low Vitamin D concentration and gestational hypertension/preeclampsia is inconclusive
‘Mendelian randomization’ is a technique that assesses genetic variants that impact pathways
- Genetic variants are random events at the time of conception, not likely to be impacted by bias
Magnus et al. (BMJ 2018) sought to determine whether low Vitamin D concentration has a causal effect on gestational hypertension or pre-eclampsia using knowledge of genetic variants that impact Vitamin D pathways

One and two sample mendelian randomization analysis
- Such analyses can be used to determine possible causal relationships
‘One Sample’ mendelian randomization analysis
- Assesses the genetic variants along the vitamin D pathway and outcomes (gestational hypertension and preeclampsia) in the same individual
‘Two Sample’ mendelian randomization analysis
- Results from genome studies are used to determine how the variants impact Vitamin D levels and assess whether variants that result in lower Vitamin D levels are associated with higher risk for gestational hypertension or preeclampsia
Vitamin D levels were measured in serum and plasma, and adjusted based on seasons and categorized based on Endocrine Society recommendations
- < 25 nmol/L | 25-49.9 nmol/L | 50-74.9 nmol/L | ≥75 nmol/L
Primary outcomes
- Gestational hypertension
- Preeclampsia
Definitions of preeclampsia and gestational hypertension were based on International Society for the Study of Hypertension in Pregnancy criteria

One sample analysis
- 7389 women were included
  - 751 with gestational hypertension
  - 135 with pre-eclampsia
Two sample analysis
- 3388 preeclampsia cases
- 6059 controls

In the conventional multivariable analysis comparing Vit D levels to outcomes

Pre-eclampsia
- Vitamin D levels <25 nmol/L compared with ≥75 nmol/L
  - RR 2.04 (95% CI, 1.02 to 4.07)
- Gestational hypertension: No association

One sample mendelian randomization analysis (using total genetic risk score)

There was no strong evidence for a linear effect (increase or decrease) of Vitamin D on the risk of gestational hypertension or pre-eclampsia

Two sample mendelian randomization analysis

Preeclampsia: Odds ratio (OR) 0.98 (95% CI, 0.89 to 1.07) per 10% decrease in Vitamin D level
Nor was there evidence of a causal linear effect

The authors did not “find any appreciable evidence of a causal effect of Vitamin D levels less than 75 nmol/L or less than 50 nmol/L on the risk of pre-eclampsia”
These results support the WHO guidance that currently, there is insufficient evidence to warrant vitamin D supplementation to prevent adverse pregnancy outcomes
Future studies are needed with larger number of women and more genetic instruments
- RCTs can assess the effect of supplements at particularly critical periods in time (e.g. around conception)

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