Response to Preeclampsia and Hypertensive Disease in Pregnancy: Their Contributions to Cardiovascular Risk
Valdiviezo C, et al. Clin Cardiol. 2012;35:160–165.
To the Editor:
The recent paper by Valdiviezo and colleagues reviewed the evidence linking preeclampsia and hypertension in pregnancy to increased risk of cardiovascular disease (CVD),1 and suggested that shared risk factors rather than a causative relationship could explain this detrimental association.
We suggest that hypovitaminosis D might in part explain the links between preeclampsia and hypertension during pregnancy and subsequent risk of CVD. Indeed, low serum 25-hydroxyvitamin D (25[OH]D) concentration represents a risk factor for preeclampsia. A study in Finland found that women who received regular vitamin D supplementation during the first year of life had half the risk of preeclampsia in their first pregnancy than those who did not.2 A nested case-control study in Pennsylvania found that a 50-nmol/L decline in 25(OH)D concentration doubled the risk of preeclampsia (adjusted odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.1-5.4).3 A subsequent nested case-control study in North Carolina found that midgestation maternal 25(OH)D of <50 nmol/L was associated with an unadjusted OR of preeclampsia of 3.63 (95% CI:1.52-8.65) compared with concentrations of at least 75 nmol/L.4
Furthermore, there is also evidence that hypertension during pregnancy is linked to low serum 25(OH)D concentration. Prevalence rates of hypertension during pregnancy are higher for winter delivery in nontropical regions or delivery during wet or humid periods in tropical climates5; those are the periods when solar ultraviolet-B doses and serum 25(OH)D concentrations are lowest. In addition, a study in Canada found inverse correlations between the highest blood pressure measured in pregnancy and serum 25(OH)D concentrations.6
Endothelial dysfunction is characteristic of preeclampsia.1 A rat model found that vitamin D deficiency was associated with endothelial vasodilator dysfunction, thus suggesting that hypovitaminosis D might contribute to the accompanying elevation in blood pressure and the subsequent increased CVD risk.7 In fact, there is mounting evidence that vitamin D deficiency represents a risk factor for CVD. A meta-analysis of observational studies found an OR of CVD incidence of 0.67 (95% CI: 0.56-0.81) for high vs low serum 25(OH)D concentration.8 An observational study found that low vitamin D concentrations were significantly associated with coronary artery disease, myocardial infarction, heart failure, and stroke, as well as with incident death.9 These findings were confirmed in another observational study, which also found that vitamin D supplementation conferred substantial survival benefit (OR for death: 0.39, 95% CI: 0.28-0.53, P < 0.0001).10
Finally, low serum 25(OH)D concentrations has been shown to be associated with increased risk of arterial calcification,11,12 which is considered another risk factor for CVD.1 he mechanism whereby vitamin D seems to reduce vascular calcification appears to be reduced osteoblastic gene expression.13 This gene is normally increased in chronic kidney disease.13
Thus, there is good evidence that hypovitaminosis D is associated with the risk for preeclampsia and hypertensive disease in pregnancy as well as CVD. Based on this evidence, it seems worthwhile to recommend to pregnant women that they supplement with vitamin D. A randomized controlled trial of vitamin D during pregnancy and lactation found that 4000 IU/d vitamin D3 was required for pregnant women to have sufficient 25(OH)D to control gene expression during fetal development and for nursing women to have sufficient unconverted vitamin D3 in their milk so the nursing infant can produce its own 25(OH)D.14 In addition, no adverse effects of this supplementation was found. In particular, there was no change in urine or serum calcium.14 It was therefore recommended that circulating 25(OH)D be 40 to 60 ng/mL (100–150 nmol/L) during pregnancy, and that a daily intake of 4000 IU vitamin D3 is required to attain that circulating concentration.15 These suggestions take strong issue with the recent Institute of Medicine (IOM) report on vitamin D requirements,16 and are based on a supplementation trial omitted by the IOM.
Controversy regarding supplementation with vitamin D is fueled by the different purposes of the IOM (guidance for food fortification and not to individualized patient care) and the Endocrine Society's (patient care) reports.17
As we have highlighted, there is a strong vitamin D requirement during pregnancy that is not fully recognized. Healthcare providers should formulate their own opinions with respect to vitamin D as it pertains to the care of their patients.18 Although the evidence presented is not fully supported by randomized controlled trials, it is mutually consistent, promises important health benefits for both mother and fetus, and apparently has no risk of adverse effects.