Carol L. Wagner

Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents

Rickets in infants attributable to inadequate vitamin D intake and decreased exposure to sunlight continues to be reported in the United States. There are also concerns for vitamin D deficiency in older children and adolescents. Because there are limited natural dietary sources of vitamin D and adequate sunshine exposure for the cutaneous synthesis of vitamin D is not easily determined for a given individual and may increase the risk of skin cancer, the recommendations to ensure adequate vitamin D status have been revised to include all infants, including those who are exclusively breastfed and older children and adolescents. It is now recommended that all infants and children, including adolescents, have a minimum daily intake of 400 IU of vitamin D beginning soon after birth. The current recommendation replaces the previous recommendation of a minimum daily intake of 200 IU/day of vitamin D supplementation beginning in the first 2 months after birth and continuing through adolescence. These revised guidelines for vitamin D intake for healthy infants, children, and adolescents are based on evidence from new clinical trials and the historical precedence of safely giving 400 IU of vitamin D per day in the pediatric and adolescent population. New evidence supports a potential role for vitamin D in maintaining innate immunity and preventing diseases such as diabetes and cancer. The new data may eventually refine what constitutes vitamin D sufficiency or deficiency.

Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality—A review of recent evidence

BACKGROUND Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but also for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem are likely to be a risk for wide spectrum of acute and chronic illnesses. METHODS A review of randomized controlled trials, meta-analyses, and other evidence of vitamin D action on various health outcomes. RESULTS Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality. CONCLUSIONS Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for the spectrum of disorders. Supplementation guidance and population strategies for the eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers.

Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant

Scientific data pertaining to vitamin D supplementation during lactation are scarce. The daily recommended intake for vitamin D during lactation has been arbitrarily set at 400 IU/d (10 microg/d). This recommendation is irrelevant with respect to maintaining the nutritional vitamin D status of mothers and nursing infants, especially among darkly pigmented individuals. Our objective was to examine the effect of high-dose maternal vitamin D2 supplementation on the nutritional vitamin D status of mothers and nursing infants. Fully lactating women (n = 18) were enrolled at 1 mo after birth to 1 of 2 treatment arms, ie, 1600 IU vitamin D2 and 400 IU vitamin D3 (prenatal vitamin) or 3600 IU vitamin D2 and 400 IU vitamin D3, for a 3-mo study period. High-dose (1600 or 3600 IU/d) vitamin D2 supplementation for a period of 3 mo safely increased circulating 25-hydroxyvitamin D [25(OH)D] concentrations for both groups. The antirachitic activity of milk from mothers receiving 2000 IU/d vitamin D increased by 34.2 IU/L, on average, whereas the activity in the 4000 IU/d group increased by 94.2 IU/L. Nursing infant circulating 25(OH)D2 concentrations reflected maternal intake and the amount contained in the milk. With limited sun exposure, an intake of 400 IU/d vitamin D would not sustain circulating 25(OH)D concentrations and thus would supply only limited amounts of vitamin D to nursing infants in breast milk. A maternal intake of 2000 IU/d vitamin D would elevate circulating 25(OH)D concentrations for both mothers and nursing infants, albeit with limited capacity, especially with respect to nursing infants. A maternal intake of 4000 IU/d could achieve substantial progress toward improving both maternal and neonatal nutritional vitamin D status.

Vitamin D: Beyond bone

In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging.

The Role of the Parent Compound Vitamin D with Respect to Metabolism and Function: Why Clinical Dose Intervals Can Affect Clinical Outcomes

CONTEXT There is no doubt that vitamin D must be activated to the hormonal form 1,25-dihydroxyvitamin D to achieve full biological activity or that many tissues participate in this activation process-be it endocrine or autocrine. We believe that not only is 25-hydroxyvitamin D important to tissue delivery for this activation process, but also that intact vitamin D has a pivotal role in this process. OBJECTIVE In this review, evidence on the vitamin D endocrine/autocrine system is presented and discussed in relation to vitamin D-binding protein affinity, circulating half-lives, and enzymatic transformations of vitamin D metabolites, and how these affect biological action in any given tissue. CONCLUSIONS Circulating vitamin D, the parent compound, likely plays an important physiological role with respect to the vitamin D endocrine/autocrine system, as a substrate in many tissues, not originally thought to be important. Based on emerging data from the laboratory, clinical trials, and data on circulating 25-hydroxyvitamin D amassed during many decades, it is likely that for the optimal functioning of these systems, significant vitamin D should be available on a daily basis to ensure stable circulating concentrations, implying that variation in vitamin D dosing schedules could have profound effects on the outcomes of clinical trials because of the short circulating half-life of intact vitamin D.

Mother-child vitamin D deficiency: an international perspective

Perspective on the paper by Dijkstra et al (see page 750)

Host factors in amniotic fluid and breast milk that contribute to gut maturation.

The gut represents a complex organ system with regional differences, which reflect selective digestive and absorptive functions that change constantly in response to bodily requirements and the outside milieu. As a barrier to the external environment, gut epithelium must be renewed rapidly and repeatedly. Growth and renewal of gut epithelial cells is dependent on controlled cell stimulation and proliferation by a number of signaling processes and agents, including gut peptides—both endogenous and exogenous sources. This cascade of events begins during fetal development; with the ingestion of amniotic fluid, this process is enhanced and continued during infancy and early childhood through the ingestion of human milk. Events influenced by amniotic fluid during fetal development and those influenced by human milk that unfold after birth and early childhood to render the gut mature are presented.

Nutritional vitamin D status during pregnancy: reasons for concern

In this issue of CMAJ , Mannion and colleagues[1][1] report that women who restricted their intake of milk and vitamin D during pregnancy had smaller babies. In fact, each additional cup of milk per day was associated with a 41-g increase in birth weight; furthermore, each additional daily microgram

Vitamin D deficiency during pregnancy: an ongoing epidemic

In this issue of the Journal, van der Meer et al (1) report a high prevalence of vitamin D deficiency during pregnancy in nonWestern women in the Netherlands. These investigators found in their study that 50% of women with darker pigment were vitamin D deficient, whereas only 8% of Western women were defined as deficient. Even at first glance, this is a truly remarkable statistic. However, the actual percentage is far greater than reported. The reason for this is quite simple—the authors of this study were very conservative in their definition of vitamin D deficiency. They defined deficiency as circulating 25-hydroxyvitamin D [25(OH)D] concentrations 25 nmol/L (10 ng/mL). As far as we are concerned, this is an old definition of vitamin D deficiency, and many investigators now define deficiency as 80 nmol (32 ng/mL) circulating 25(OH)D/L (2, 3). This deficiency cutoff is now based on an array of biomarkers that are adversely affected by nutritional vitamin D deficiency rather than on Gaussian distributions of 25(OH)D concentrations in populations, as were used in the past (2). Why should anyone be concerned about vitamin D deficiency during pregnancy? After all, the skeletal problems encountered appear to be corrected simply by vitamin D supplementation after delivery. The answer is simple: the function of vitamin D is now known to extend well beyond skeletal integrity (2, 4–7), and thus it would be a tragedy to ignore this information. The next question is, how much vitamin D is required to correct this deficiency and achieve circulating 25(OH)D concentrations of 80 nmol/L? It is certain that, in the absence of meaningful sun exposure, the current adequate intake of 200 IU vitamin D/d is far less than enough. Such an intake will do nothing to maintain nutritional vitamin D status, let alone increase it (2, 8). To increase nutritional vitamin D to meaningful concentrations, dietary intakes of 2000 IU/d may be required (2, 8). Clearly, studies investigating the true vitamin D requirement during pregnancy are warranted. Indeed, we belive that these studies are essential. As mentioned earlier, we believe that they are important because vitamin D deficiency during pregnancy not only is linked to maternal skeletal preservation and fetal skeletal formation but also is vital to the fetal “imprinting” that may affect chronic disease susceptibility later in life as well as soon after birth (5). One need only review a recent report by Javaid et al (9) to appreciate the effect of maternal nutritional vitamin D status on childhood bone mineral accrual. The same may well be true for the risks of developing autoimmune diseases, such as multiple sclerosis (which has recently been linked to seasonality of birth; 10) and rheumatoid arthritis, or of conditions such as malignancy (4, 11). Most important is the role of nutritional vitamin D status in activating the human innate immune system that is reported by Liu et al (7). This seminal article described the way in which circulating 25(OH)D, through the induction of cathelicidin in macrophages, is able to contain Mycobacterium tuberculosis. This observation could have profound implications with respect to the treatment of a variety of infections. A final important point is that the induction of cathelicidin in this study did not occur when circulating concentrations of 25(OH)D were 20 nmol/L but, rather, occurred only when serum was repleted with 80 nmol 25(OH)D/L. This biomarker of nutritional vitamin D status clearly shows that higher circulating concentrations of 25(OH)D are beneficial to human health. Who would have thought that a “simple nutrient” could possess such global health potential?

Vitamin D and Its Role During Pregnancy in Attaining Optimal Health of Mother and Fetus

Despite its discovery a hundred years ago, vitamin D has emerged as one of the most controversial nutrients and prohormones of the 21st century. Its role in calcium metabolism and bone health is undisputed but its role in immune function and long-term health is debated. There are clear indicators from in vitro and animal in vivo studies that point to vitamin D’s indisputable role in both innate and adaptive immunity; however, the translation of these findings to clinical practice, including the care of the pregnant woman, has not occurred. Until recently, there has been a paucity of data from randomized controlled trials to establish clear cut beneficial effects of vitamin D supplementation during pregnancy. An overview of vitamin metabolism, states of deficiency, and the results of recent clinical trials conducted in the U.S. are presented with an emphasis on what is known and what questions remain to be answered.