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Endocrinology, Diabetes and Hypertension Division Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Ellen W. Seely, M.D., Endocrinology, Diabetes and Hypertension Division, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: eseely{at}partners.org.
Preeclampsia complicates 3–5% of pregnancies in the United States and is a leading cause of maternal and neonatal morbidity and mortality. Despite this, its cause or causes are not known, and effective therapies, other than delivery, are lacking.
In this issue of JCEM, Bodnar et al. (1) report the intriguing finding that women who subsequently developed preeclampsia had lower levels of 25 hydroxyvitamin D [25(OH)D] at less than 22 wk of pregnancy than women who remained normotensive in pregnancy. It is of note, that many of these women had vitamin D deficiency despite the common use of prenatal vitamins in the study population. In addition, their 25(OH)D levels remained lower than normotensive controls at delivery, and their neonates had lower levels as well.
There is a long history of interest in the potential roles of calcium and hormones involved in calcium homeostasis in the pathogenesis of preeclampsia. Associations have been well recognized for over 25 yr between low calcium intake and the risk of hypertensive complications of pregnancy (2). Women with established preeclampsia have been reported to have lower urinary calcium excretion (3), lower 1,25 dihydroxyvitamin D [1,25 (OH)2 D] levels and ionized calcium levels, and higher PTH levels than normotensive controls (4). Because the placenta contributes approximately 50% of the circulating 1,25 (OH)2 D level in pregnancy, it was postulated that, in preeclampsia, the defective placenta is unable to produce sufficient levels of 1,25 (OH)2 D, resulting in inadequate gastrointestinal calcium absorption, low ionized calcium levels, and a secondary rise in PTH. How low circulating calcium levels and elevated PTH levels cause hypertension remains unclear. Although acute infusions of PTH are associated with a fall in blood pressure, chronic elevations have been reported to cause vasoconstriction and hypertension (5). Low calcium levels may also contribute to hypertension via stimulation of renin release from the kidney (6).
Based on the findings above, trials of calcium supplementation for the prevention of preeclampsia were undertaken. The Calcium for Preeclampsia Prevention (CPEP) Study performed in the United States showed no reduction in the risk for or severity of preeclampsia in over 4500 healthy nulliparous women supplemented, before 21 wk of pregnancy, with 2 g of calcium vs. placebo (7). This population of women may not have been calcium deficient before supplementation. However, an international study of calcium supplementation in 8325 pregnant women with low calcium intake (<600 mg/d) also did not demonstrate a reduction in rates of preeclampsia but did show a reduction in the secondary outcomes of severity of preeclampsia, maternal morbidity, and neonatal mortality (8).
The present report of Bodnar et al. (1) renews the interest in calciotropic hormones and their potential role in preeclampsia. Because the calciotropic hormone system involves the complex interaction of calcium with 25(OH)D and 1,25 (OH)2 D and their receptor and with PTH and its receptor, delineating which changes are primary and which are secondary is difficult. Unfortunately, the current report did not have information concerning calcium intake or levels of 1,25 (OH)2 D, vitamin D binding protein, calcium or PTH levels. Vitamin D-fortified milk is a major source of dietary vitamin D, so low vitamin D levels may reflect low calcium intake. In addition, women who go on to develop preeclampsia may have lower levels of vitamin D binding protein, and their free D levels may be no different from those who remain normotensive. It is also possible that low 25(OH)D levels reflect general nutritional status and that another associated dietary deficiency might explain the increased risk for preeclampsia.
It remains unclear how 25(OH)D insufficiency or deficiency would cause preeclampsia. The authors discuss the role of 1,25 (OH)2 D in the regulation of placental function and angiogenesis. However, low levels of 25(OH)D do not necessarily translate into low levels of 1,25 (OH)2 D. In fact, 1,25 (OH)2 D levels are often maintained in the normal range even with vitamin D deficiency (9, 10).
Vitamin D deficiency may be linked with preeclampsia through its actions outside of its traditional calcium regulatory role. An interaction between the renin-angiotensin system, a major regulator of blood pressure, and 1,25 (OH)2 D has been suggested in animal studies. Studies in mice have shown that 1,25 (OH)2 D inhibits renin expression in renal juxtagomerular cells (11). In addition, the vitamin D receptor is found in smooth muscle cells and juxtaglomerular cells (12), although its role is not well understood.
Results of human studies relating vitamin D to blood pressure are conflicting. A study of 308 women revealed an inverse relationship between reported vitamin D intake and blood pressure (13). However, this relationship between vitamin D intake and blood pressure was not seen in several larger studies (14, 15). Discrepancies among studies may be explained by differences in the accuracy of vitamin D intake recall and different ranges of vitamin D intake in the populations. Furthermore, these studies did not measure vitamin D levels. A recent study demonstrated that lower 25(OH)D levels were associated with an increased risk of hypertension (16).
Vitamin D also has immunomodulatory activities (17). The vitamin D receptor is present on activated T lymphocytes, and activation of this receptor inhibits T cell immune responsiveness. Pregnant women with lower vitamin D levels might have an increase in T cell activity. An exaggerated maternal immune response has been postulated as an etiology for preeclampsia (18).
Further studies are needed to confirm the intriguing findings of the present study. The next step would then be to determine whether vitamin D supplementation would decrease the risk of preeclampsia. Many studies of supplementation have been disappointing in regard to decreasing risk of disease. Calcium supplementation failed to decrease the risk for preeclampsia despite the observation that preeclampsia was associated with lower calcium intake as discussed above. Some studies of supplementation have even suggested harm. Vitamin E intake was reported to be inversely associated with death rates from ischemic heart disease (19). However, vitamin E supplementation did not lead to any reduction in cardiovascular events in high-risk individuals and was actually associated with an increase in the risk for heart failure over 7 yr (20).
The Food and Nutrition Board of the Institute of Medicine recommends a calcium intake of 1000–1300 mg/d for pregnant women. Adequate vitamin D intake is set at 200 IU/d for pregnant women—the same amount that is considered adequate for nonpregnant women of childbearing age (21). Given the high prevalence of vitamin D deficiency and insufficiency in the United States and worldwide and the increased recognition of the importance of vitamin D for bone health (22), there is a call for the reevaluation of the daily requirement for vitamin D (23) for both pregnant and nonpregnant individuals. As part of this process, the potential benefits of vitamin D beyond bone health will also need to be considered.
Increasing vitamin D intake to prevent deficiency is an important goal in both pregnant and nonpregnant individuals to promote skeletal health. Similar to most multivitamins, most prenatal vitamins contain only 400 IU of vitamin D, which may be insufficient to bring 25(OH)D levels into the normal range in many women. These women may require greater amounts of vitamin D supplementation. However, at this time, it would be premature to recommend vitamin D supplementation to pregnant women specifically for the prevention of preeclampsia.
Footnotes
Abbreviations: 1,25 (OH)2 D, 1,25 Dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D.
Received July 12, 2007.
Accepted July 13, 2007.
References
This article has been cited by other articles:
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  B. Novakovic, M. Sibson, H. K. Ng, U. Manuelpillai, V. Rakyan, T. Down, S. Beck, T. Fournier, D. Evain-Brion, E. Dimitriadis, et al. Placenta-specific Methylation of the Vitamin D 24-Hydroxylase Gene: IMPLICATIONS FOR FEEDBACK AUTOREGULATION OF ACTIVE VITAMIN D LEVELS AT THE FETOMATERNAL INTERFACE J. Biol. Chem., May 29, 2009; 284(22): 14838 - 14848. [Abstract] [Full Text] [PDF]
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 R. Bouillon, G. Carmeliet, L. Verlinden, E. van Etten, A. Verstuyf, H. F. Luderer, L. Lieben, C. Mathieu, and M. Demay Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice Endocr. Rev., October 1, 2008; 29(6): 726 - 776. [Abstract] [Full Text] [PDF]
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