Vitamin D deficiency during pregnancy: a risk factor not only for fetal growth and bone metabolism but also for correct development of the fetal immune system

Department of Dermatology
The Saarland University Hospital
66421 Homburg/Saar
Germany
E-mail: hajrei{at}uniklinik-saarland.de

Dear Sir:

We read with great interest the excellent article by Specker (1), who carried out a comprehensive review of studies that investigated maternal and neonatal outcomes of vitamin D deficiency or supplementation during pregnancy. We would like to add to this discussion an important topic that has become evident recently and that was not addressed by the clinical studies that Specker reviewed: the fact that extrarenal synthesis of 1,25-dihydroxyvitamin D [1,25(OH)₂D₃, or calcitriol] is of great importance for homeostasis in a multitude of tissues, including the immune system, and that this function of vitamin D is likely responsible for the numerous epidemiologic observations that persons who live at higher latitudes, who are more prone to vitamin D deficiency, are at increased risk of not only developing prostate, colon, breast, and other solid tumors; hypertension; and cardiovascular heart disease but also of developing autoimmune diseases, including multiple sclerosis and type 1 diabetes (2–5). Consequently, increasing evidence now indicates that vitamin D deficiency during pregnancy may represent for the fetus a predisposing factor for the future development of a broad variety of diseases, including diseases of the immune system, such as atopic dermatitis or autoimmune diseases (4, 6, 7).

During the past few years, important new immunomodulatory effects of vitamin D analogues have been characterized (4, 7–9). It has been shown that various cell types involved in immunologic reactions (eg, monocytes, T and B lymphocytes, and Langerhans cells) not only express the vitamin D receptor but also possess the enzymatic machinery (25-hydroxyvitamin D-1-hydroxylase) for the local synthesis of 1,25(OH)₂D₃ (4, 7–9). Today, the local synthesis of calcitriol in immune cells is considered to be of great importance for the regulation and control of immune responses. 1,25(OH)₂D₃ inhibits activation of T cells and induces the generation of CD25⁺/CD4⁺ regulatory T cells (4, 7, 9). In dendritic cells, 1,25(OH)₂D₃ inhibits maturation and induces a phenotype that promotes tolerance and inhibits immunity after stimulation with antigen (8, 9). In dendritic cells, calcitriol suppresses expression of major histocompatibility complex II molecules and of co-stimulatory molecules, including CD40, CD80, and CD86 (8, 9). In these cells, production of interleukin (IL) 10 is stimulated and production of IL-12 inhibited, which leads to suppression of T cell activation. At present, a connection between vitamin D and pathogenesis of atopic dermatitis is discussed. Epidemiologic studies have shown that patients with atopic dermatitis have a lower vitamin D intake than do control subjects (6). Vitamin D analogues suppress in vitro immunoglobulin E production and immunoglobulin E–mediated cutaneous reactions (10, 11).

In conclusion, a growing body of evidence now clearly indicates that adequate vitamin D concentrations during pregnancy are not only necessary to ensure appropriate maternal responses to the calcium demands of the fetus and neonatal handling of calcium, but also of great importance to guarantee the healthy development of a broad variety of tissues, including the immune system. Consequently, vitamin D deficiency during pregnancy may represent for the fetus a predisposing factor for the future development of a multitude of diseases not related to fetal growth and bone metabolism, including diseases of the immune system, such as atopic dermatitis, type 1 diabetes, and other autoimmune diseases.

ACKNOWLEDGMENTS

The authors had no conflicts of interest to report.

REFERENCES

1. Specker B. Vitamin D requirements during pregnancy. Am J Clin Nutr 2004;80(suppl):1740S–7S.
2. Garland CF, Comstock GW, Garland FC, et al. Serum 25-hydroxyvitamin D and colon cancer: eight year prospective study. Lancet 1989;2:1176–8.
3. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002;94:1867–75.
4. Zella JB, McCary LC, DeLuca HF. Oral administration of 1,25-dihydroxyvitamin D₃ completely protects NOD mice from insulin-dependent diabetes mellitus. Arch Biochem Biophys 2003;417:77–80.
5. Holick MF. Vitamin D deficiency: what a pain it is. Mayo Clin Proc 2003;78:1457–9.
6. Solvoll K, Soyland E, Sandstad B, Drevon CA. Dietary habits among patients with atopic dermatitis. Eur J Clin Nutr 2000;54:93–7.
7. Adorini L, Penna G, Giarratana N, Uskokovic M. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. J Cell Biochem 2003;88:227–33.
8. Griffin M, Kumar R. Effects of 1,25-dihydroxyvitamin D₃ and its analogs on dendritic cell function. J Cell Biochem 2003;88:323–6.
9. Van Etten E, Decallone B, Verlinden L, Verstuyf A, Bouillon R, Mathieu C. Analogs of 1,25-dihydroxyvitamin D₃ as pluripotent immunomodulators. J Cell Biochem 2003;88:223–6.
10. Heine G, Anton K, Henz BM, Worm M. 1,25-dihydroxyvitamin D₃ inhibits anti-CD40 plus IL-4-mediated IgE production in vitro. Eur J Immunol 2002;32:3395–404.
11. Katayama I, Minatohara K, Yokozeki H, Nishioka K. Topical vitamin D₃ downregulates IgE-mediated murine biphasic cutaneous reactions. Int Arch Allergy Immunol 1996;111:71–6.