The role of hypovitaminosis D in pregnancy-related venous thromboembolism

Abstract

To the Editor: Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality during pregnancy (1). Strategies of pharmacological thromboprophylaxis are based on balancing the perceived risk of thrombosis with the adverse effects of thromboprophylaxis. We propose that an important risk factor for VTE, which is easily overlooked, and which needs to be checked in this setting is hypovitaminosis D. Mounting evidence has shown a high prevalence of vitamin D deficiency during pregnancy (2). Hypovitaminosis D during pregnancy not only is linked to maternal skeletal preservation and fetal skeletal formation, but is also vital to the fetal ‘imprinting’ that may affect chronic disease susceptibility later in life as well as soon after birth (3, 4). On the other hand, it has been found that active sun exposure lowers the risk of thrombotic events (5), thus suggesting that variation in vitamin D status, strictly related to sun exposure, might be a plausible cause for the seasonal variation in thromboembolic complications. 1,25-dihydroxyvitamin [1,25(OH)2D], the active form of the vitamin D, has been shown to have anticoagulant properties by upregulating thrombomodulin and downregulating tissue factor (6). Furthermore, levels of 25-hydroxyvitamin D [25(OH)D], the measurable form of vitamin D, which better represents vitamin D status, have been shown to be inversely related to plasminogen activator inhibitor 1 and tissue-type plasminogen activator antigen levels (7), thus indicating that vitamin D is related to fibrinolytic activity and to the integrity of the vascular endothelium. Interestingly, a randomised controlled study of 250 patients with prostate cancer, half of whom were given 45 micrograms of 1,25(OH)2D weekly, found an unexpected significantly lower risk of thrombotic events (2 vs. 11) (8). On the basis of this evidence, it seems worthwhile to recommend to pregnant women that they supplement with vitamin D for global health benefits, and for VTE prevention in particular. A randomised 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 (9). In addition, no adverse effects of this supplementation was found. In particular, there was no change in urine or serum calcium (9). It was therefore recommended that circulating 25(OH)D be 40–60 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 (10). Therefore, hypovitaminosis D should represent a potentially modifiable risk factor to be targeted at the beginning and during pregnancy, also to prevent thromboembolic complications. W.B.G. receives funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).