Vitamin D Status during Pregnancy and the Risk of Subsequent Postpartum Depression: A Case-Control Study

Epidemiological studies have provided evidence of an association between vitamin D insufficiency and depression and other mood disorders, and a role for vitamin D in various brain functions has been suggested. We hypothesized that low vitamin D status during pregnancy might increase the risk of postpartum depression (PPD). The objective of the study was thus to determine whether low vitamin D status during pregnancy was associated with postpartum depression. In a case-control study nested in the Danish National Birth Cohort, we measured late pregnancy serum concentrations of 25[OH]D3 in 605 women with PPD and 875 controls. Odds ratios [OR) for PPD were calculated for six levels of 25[OH]D3. Overall, we found no association between vitamin D concentrations and risk of PPD (p = 0.08). Compared with women with vitamin D concentrations between 50 and 79 nmol/L, the adjusted odds ratios for PPD were 1.35 (95% CI: 0.64; 2.85), 0.83 (CI: 0.50; 1.39) and 1.13 (CI: 0.84; 1.51) among women with vitamin D concentrations < 15 nmol/L, 15–24 nmol/L and 25–49 nmol/L, respectively, and 1.53 (CI: 1.04; 2.26) and 1.89 (CI: 1.06; 3.37) among women with vitamin D concentrations of 80–99 nmol/L and ≥ 100 nmol/L, respectively. In an additional analysis among women with sufficient vitamin D (≥ 50 nmol/L), we observed a significant positive association between vitamin D concentrations and PPD. Our results did not support an association between low maternal vitamin D concentrations during pregnancy and risk of PPD. Instead, an increased risk of PPD was found among women with the highest vitamin D concentrations.     

More than metabolic: Considering the broader paleoepidemiological impact of vitamin D deficiency in bioarchaeology

Vitamin D deficiency has traditionally been viewed as a metabolic bone disease by bioarchaeologists and considered primarily in terms of the development of specific musculoskeletal changes used for diagnosis in paleopathological research. These skeletal manifestations are usually interpreted as representing general ill‐health. Clinical research shows that vitamin D is also integral to a number of extra‐skeletal physiological processes including immunoregulation, blood pressure homeostasis, cell division, and programmed cell death. Vitamin D deficiency and sub‐clinical insufficiency are thought to be risk factors for infectious and autoimmune diseases, as well as certain cancers and cardiovascular diseases. Epidemiological work indicates that the skeletal manifestations of vitamin D deficiency represent the extreme end of a spectrum of morbidity associated with negative health outcomes, including increased risk for secondary tuberculosis. This article provides a review of clinical research on the extra‐skeletal roles of vitamin D and the pathological consequences of poor vitamin D status. Additionally, it presents an interpretive model for bioarchaeological analyses of rickets and osteomalacia for consideration of the whole‐body impact of poor vitamin D nutriture and possible comorbidities that may have affected the wider population. Am J Phys Anthropol 160:183–196, 2016. © 2016 Wiley Periodicals, Inc.     

Vitamin D for Treatment and Prevention of Infectious Diseases; A Systematic Review of Randomized Controlled Trials

ObjectiveTo review the existing human controlled intervention studies of vitamin D as adjunctive therapy in settings of infection and provide recommendations for design and implementation of future studies in this field on the basis of the evidence reviewed.MethodsWe conducted a systematic review of randomized controlled clinical trials that studied vitamin D for treatment or prevention of infectious diseases in humans. Studies from 1948 through 2009 were identified through search terms in PubMed and Ovid MEDLINE.ResultsThirteen published controlled trials were identified by our search criteria. Ten trials were placebo controlled, and 9 of the 10 were conducted in a rigorous double-blind design. The selected clinical trials demonstrated substantial heterogeneity in baseline patient demographics, sample size, and vitamin D intervention strategies. Serious adverse events attributable to vitamin D supplementation were rare across all studies. On the basis of studies reviewed to date, the strongest evidence supports further research into adjunctive vitamin D therapy for tuberculosis, influenza, and viral upper respiratory tract illnesses. In the selected studies, certain aspects of study design are highlighted to help guide future clinical research in the field.ConclusionMore rigorously designed clinical trials are needed for further evaluation of the relationship between vitamin D status and the immune response to infection as well as for delineation of necessary changes in clinical practice and medical care of patients with vitamin D deficiency in infectious disease settings. (Endocr Pract. 2009;15:438-449)     

High prevalence of vitamin d deficiency in pregnant women: a national cross-sectional survey

An increasing number of studies suggest that vitamin D deficiency during pregnancy is associated with multiple adverse health outcomes in mothers, neonates and children. There are no representative country data available on vitamin D status of pregnant women in Europe. The aim of this study was to estimate the prevalence of vitamin D deficiency among Belgian pregnant women and to assess the determinants of vitamin D status in the first and third trimester of pregnancy. The women were selected via a multi-stage proportionate-to-size sampling design. Blood samples were collected and a questionnaire was completed face-to-face. 55 obstetric clinics were randomly selected and 1311 pregnant women participated in the study. The median serum 25-hydroxyvitamin D [25-(OH)D] concentration was significantly lower in the first trimester (20.4 ng/ml) than in third trimester (22.7 ng/ml). Of all women, 74.1% (95%CI = 71.8–76.5%) were vitamin D insufficient (25-(OH)D <30 ng/ml), 44.6% (95%CI = 41.9–47.3%) were vitamin D deficient (25-(OH)D <20 ng/ml), while 12.1% (95%CI = 10.3–13.8%) were severely vitamin D deficient (25-(OH)D <10 ng/ml). Of all women included, 62.0% reported taking vitamin D-containing multivitamins, of which only 24.2% started taking those before pregnancy. The risk of vitamin D deficiency (25-(OH)D <20 ng/ml) was significantly higher for less educated women and women who reported not going on holidays to sunny climates. The risk of severe vitamin D deficiency (25-(OH)D <10 ng/ml) decreased for women who reported alcohol consumption during pregnancy, decreased with more frequent use of sunscreen lotion and increased for smokers and women who reported preference for shadow. In conclusion, vitamin D deficiency is highly prevalent among pregnant women in Belgium and this raises concerns about the health consequences for the mother and the offspring. A targeted screening strategy to detect and treat women at high risk of severe vitamin D deficiency is needed in Belgium and in Europe.     

Preeclampsia and Blood Pressure Trajectory during Pregnancy in Relation to Vitamin D Status

Every tenth pregnancy is affected by hypertension, one of the most common complications and leading causes of maternal death worldwide. Hypertensive disorders in pregnancy include pregnancy-induced hypertension and preeclampsia. The pathophysiology of the development of hypertension in pregnancy is unknown, but studies suggest an association with vitamin D status, measured as 25-hydroxyvitamin D (25(OH)D). The aim of this study was to investigate the association between gestational 25(OH)D concentration and preeclampsia, pregnancy-induced hypertension and blood pressure trajectory. This cohort study included 2000 women. Blood was collected at the first (T1) and third (T3) trimester (mean gestational weeks 10.8 and 33.4). Blood pressure at gestational weeks 10, 25, 32 and 37 as well as symptoms of preeclampsia and pregnancy-induced hypertension were retrieved from medical records. Serum 25(OH)D concentrations (LC-MS/MS) in T1 was not significantly associated with preeclampsia. However, both 25(OH)D in T3 and change in 25(OH)D from T1 to T3 were significantly and negatively associated with preeclampsia. Women with a change in 25(OH)D concentration of ≥30 nmol/L had an odds ratio of 0.22 (p = 0.002) for preeclampsia. T1 25(OH)D was positively related to T1 systolic (β = 0.03, p = 0.022) and T1 diastolic blood pressure (β = 0.02, p = 0.016), and to systolic (β = 0.02, p = 0.02) blood pressure trajectory during pregnancy, in adjusted analyses. There was no association between 25(OH)D and pregnancy-induced hypertension in adjusted analysis. In conclusion, an increase in 25(OH)D concentration during pregnancy of at least 30 nmol/L, regardless of vitamin D status in T1, was associated with a lower odds ratio for preeclampsia. Vitamin D status was significantly and positively associated with T1 blood pressure and gestational systolic blood pressure trajectory but not with pregnancy-induced hypertension.     

Vitamin D: a hormone for all seasons--how much is enough?

Further understanding of its endocrine mechanisms and increased evidence for autocrine/paracrine actions has recently enhanced our knowledge of the biological activities of the vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D). The recognition of the contribution of vitamin D depletion to increased risk of osteoporosis, and most importantly the risk of hip fracture in the elderly, has increased the clinical significance of clinical laboratory testing for vitamin D status. Research has revealed that at least three genes contribute to vitamin D activity within tissues. These are the vitamin D receptor as well as two major vitamin D metabolising enzymes, CYP27B1, responsible for synthesis of 1,25(OH)2D and CYP24, responsible for catabolism of vitamin D metabolites. Current research focuses on the contribution of vitamin D metabolism to increasing vitamin D activity. This is of particular interest in bone forming cells where increased 1,25(OH)2D activity has been proposed to contribute to strengthening the skeleton. As well, solid tumours such as prostate, breast and colon cancers are another increasing area of vitamin D research. The major issues for the clinical laboratory in vitamin D testing include defining clinical decision limits for the interpretation of serum 25-hydroxyvitamin D (25OHD) levels and improving the precision and accuracy of this assay.     

Involvement of 1,25-dihydroxyvitamin D3 in regulating myocardial calcium metabolism: physiological and pathological actions

The role of the prohormone vitamin D3 in regulating calcium and phosphate metabolism in the intestine, kidney, and bone has been known for several decades. Recent studies have provided evidence that vitamin D3, may also play an important role in regulating metabolism in other organs, including heart. This role has been suggested by the identification of a specific receptor for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, in these tissues, as well as the presence of a 1,25(OH)2D3-dependent calcium binding protein. Although administration of excessive quantities of vitamin D3 has been shown in many studies to produce myocardial calcinosis and heart failure, the importance of vitamin D3 in regulating myocardial metabolism under normal conditions has only recently been demonstrated. The purpose of the present review is to assess the current status of research regarding the pathological and physiological actions of vitamin D3 on the heart. The initial section of this report will focus on the pathological effects of excessive vitamin D3 on cardiovascular function, while the latter sections will describe recent studies related to the involvement of 1,25(OH)2D3 in regulating calcium homeostasis in ventricular cells and the relationship between vitamin D3 and myocardial contractility.     

Vitamin A: a multifunctional tool for development

Extensive research carried out over the last 100 years has established that the fat-soluble organic compound vitamin A plays crucial roles in early development, organogenesis, cell proliferation, differentiation and apoptosis as well as in tissue homeostasis. Given its importance during development, the delivery of vitamin A to the embryo is very tightly regulated with perturbations leading to severe malformations. This review discusses the roles of vitamin A during human development and the molecular mechanisms controlling its biological effects, hence bridging the gap between human development and molecular genetic work carried out in animal models. Vitamin A delivery during pregnancy and its developmental teratology in humans are thus discussed alongside work on model organisms, such as chicken or mice, revealing the molecular layout and functions of vitamin A metabolism and signaling. We conclude that, during development, vitamin A-derived signals are very tightly controlled in time and space and that this complex regulation is achieved by elaborate autoregulatory loops and by sophisticated interactions with other signaling cascades.     

Vitamin D and osteoporosis-related fracture

The age-related decline in mass and quality of bone (osteoporosis) and muscle (sarcopenia) leads to an exponential increased risk for osteoporosis-related fracture with advancing age in older adults. As vitamin D inadequacy plausibly causally contributes to these declines, optimization of vitamin D status might reduce the deterioration of bone and muscle function with age. Putative mechanisms by which vitamin D inadequacy may increase fracture risk include both direct and indirect effects on bone and muscle. However, controversy currently clouds the role(s) of vitamin D in osteoporosis-related fracture, the amount of vitamin D required and the optimal 25-hydroxyvitamin D level. This review provides an overview of current knowledge and suggests a clinical approach to vitamin D status in older adults with, or at risk for, osteoporosis-related fracture. These recommendations are likely to evolve as additional data becomes available.     

The role of vitamin D in the prevention and the additional therapy of cancers

The active metabolite of vitamin D apart from a crucial role in maintaining mineral homeostasis and skeletal functions, has antiproliferative, apoptosis and differentiation inducing as well as immunomodulatory effects in cancer. It is well known that with increasing sunshine exposure the incidence of breast, prostate and colorectal cancer is decreasing. A number of in vitro and in vivo experiments documented the effects of vitamin D in the inhibition of the tumorigenesis. In studying the role of vitamin D in cancer, it is imperative to examine the potential pathways that control local tissue levels of vitamin D. The enzyme 24-hydroxylase converts the active vitamin D to inactive metabolite. Extra-renal production of this enzyme is observed and has been increasingly recognized as present in cancer cells. This enzyme is rate limiting for the amount of local vitamin D in cancer tissues and elevated expression is associated with an adverse prognosis. 24-hydroxylase may be a predictive marker of vitamin D efficacy in patients with cancer as an adjunctive therapy. There are many vitamin D analogs with no pronounced hypercalcemizing effects. Some analogs are in phase 1 and 2 clinical test, and they might have a role in the therapy of several types of cancer. At present our main task is to make an effort to decrease the vitamin D deficiency in Hungary. Speer G. The D-day. The role of vitamin D in the prevention and the additional therapy of cancers.     

Female athletes: A population at risk of vitamin and mineral deficiencies affecting health and performance

Adequate vitamin and mineral status is essential for optimal human health and performance. Female athletes could be at risk for vitamin and mineral insufficiency due to inadequate dietary intake, menstruation, and inflammatory responses to heavy physical activity. Recent studies have documented poor iron status and associated declines in both cognitive and physical performance in female athletes. Similarly, insufficient vitamin D and calcium status have been observed in female athletes, and may be associated with injuries, such as stress fracture, which may limit a female athlete's ability to participate in regular physical activity. This review will focus on recent studies detailing the prevalence of poor vitamin and mineral status in female athletes, using iron, vitamin D, and calcium as examples. Factors affecting the dietary requirement for these vitamins and minerals during physical training will be reviewed. Lastly, countermeasures for the prevention of inadequate vitamin and mineral status will be described.     

Neophobia, sensory and cognitive functions, and hedonic responses in vitamin D receptor mutant mice

Vitamin D is a seco-steroid hormone with multiple actions in the brain, mediated through the nuclear vitamin D receptor (VDR). We have recently shown that mutant mice lacking functional VDR demonstrate altered emotional behavior and specific motor deficits. Here we further examine phenotype of these mice, testing their novelty responses, as well as cognitive and sensory (olfactory and gustatory) functions in the novel food, two-trial Y-maze and tastant consumption tests. In addition, we study depression-like behavior in these mice, using anhedonia-based sucrose preference test. Overall, VDR mutant mice showed neophobic response in several different tests, but displayed unimpaired olfactory and gustatory functions, spatial memory and baseline hedonic responses. Collectively, these data confirm that mutation of VDR in mice leads to altering emotional/anxiety states, but does not play a major role in depression, as well as in the regulation of some sensory and cognitive processes. These results support the role of the vitamin D/VDR neuroendocrine system in the regulation of behavior, and may have clinical relevance, enabling a better focus on psychiatric and behavioral disorders associated with dysfunctions in this neuroendocrine system.     

Postpartum resolution of hypocalcemia in a lactating hypoparathyroid patient

A 24 year old woman with post-surgical hypoparathyroidism was studied during pregnancy and lactation. During pregnancy the patient required less vitamin D therapy for control of her hypoparathyroidism and, while lactating, maintained a normal serum calcium without any supplemental vitamin D. The serum parathyroid hormone concentration and plasma 1,25 (OH)2 vitamin D concentration were undetectable and low normal respectively at a time when the serum calcium concentration was normal and the patient was not on vitamin D therapy. Urinary calcium excretion was low during this period and may explain the normalization of the serum calcium. The mechanism by which the improvement in calcium metabolism occurred is unknown, but may be secondary to a direct effect of prolactin on calcium homeostasis.     

Synthesis and structure–activity relationship of p-carborane-based non-secosteroidal vitamin D analogs

1α,25-Dihydroxyvitamin D₃ [1α,25(OH)₂D₃: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure–activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure–activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.     

Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice

The vitamin D receptor (VDR) is present in mammary gland, and VDR ablation is associated with accelerated glandular development during puberty. VDR is a nuclear receptor whose ligand, 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] is generated after metabolic activation of vitamin D by specific vitamin D hydroxylases. In these studies, we demonstrate that both the VDR and the vitamin D 1-alpha hydroxylase (CYP27B1), which produces 1,25-(OH)(2)D are present in mammary gland and dynamically regulated during pregnancy, lactation, and involution. Furthermore, we show that mice lacking VDR exhibit accelerated lobuloalveolar development and premature casein expression during pregnancy and delayed postlactational involution compared with mice with functional VDR. The delay in mammary gland regression after weaning of VDR knockout mice is associated with impaired apoptosis as demonstrated by reductions in terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling staining, caspase-3 activation and Bax induction. Under the conditions used in this study, VDR ablation was not associated with hypocalcemia, suggesting that altered mammary gland development in the absence of the VDR is not related to disturbances in calcium homeostasis. Furthermore, in the setting of normocalcemia, VDR ablation does not affect milk protein or calcium content. These studies suggest that the VDR contributes to mammary cell turnover during the reproductive cycle, and its effects may be mediated via both endocrine and autocrine signaling pathways. Unlike many mammary regulatory factors that exert transient, stage-specific effects, VDR signaling impacts on mammary gland biology during all phases of the reproductive cycle.     

Protective and toxic effects of vitamin D on vascular calcification: clinical implications

The presence of vascular calcification (VC) is a predictor of poor survival in the general population. The development of VC is an active process that requires a pre-existing injury as an inducer and promoting factors such as hyperphosphatemia and hypercalcemia, as well as a deficiency in calcification repressor factors. Vascular smooth muscle cells possess an endogenous enzyme system for the biosynthesis of the vitamin D hormone calcitriol from its precursor 25-hydroxyvitamin D and also a cytosolic calcitriol receptor, indicating that the vasculature is an important target tissue for vitamin D. The toxic effects of supra-physiological vitamin D dosages on the vasculature have been known for several decades. Recent experimental data also demonstrate important physiological effects of vitamin D on factors that are protective for vascular health. This review article summarises the molecular basis of protective and toxic vitamin D actions on the vasculature. Chronic kidney disease can be considered as a human model of severe VC and poor survival. The disease is associated with calcitriol deficiency, hyperparathyroidism, and hyperphosphatemia. Evidence is increasing that phosphate overload plays a key role in the process of VC in chronic kidney disease. The first clinical studies indicate that vitamin D receptor activation can improve survival in these patients. Although less severe than in chronic kidney disease, vitamin D deficiency and secondary hyperparathyroidism are also frequent in the general population, especially in elderly and obese subjects. Future studies should focus on the impact of vitamin D deficiency on VC and clinical outcome in these groups.     

Vitamin D Deficiency in Early Pregnancy

Objective

Vitamin D deficiency is a common problem in reproductive-aged women in the United States. The effect of vitamin D deficiency in pregnancy is unknown, but has been associated with adverse pregnancy outcomes. The objective of this study was to analyze the relationship between vitamin D deficiency in the first trimester and subsequent clinical outcomes.

Study Design

This is a retrospective cohort study. Plasma was collected in the first trimester from 310 nulliparous women with singleton gestations without significant medical problems. Competitive enzymatic vitamin D assays were performed on banked plasma specimens and pregnancy outcomes were collected after delivery. Logistic regression was performed on patients stratified by plasma vitamin D concentration and the following combined clinical outcomes: preeclampsia, preterm delivery, intrauterine growth restriction, gestational diabetes, and spontaneous abortion.

Results

Vitamin D concentrations were obtained from 235 patients (mean age 24.3 years, range 18-40 years). Seventy percent of our study population was vitamin D insufficient with a serum concentration less than 30 ng/mL (mean serum concentration 27.6 ng/mL, range 13-71.6 ng/mL). Logistic regression was performed adjusting for age, race, body mass index, tobacco use, and time of year. Adverse pregnancy outcomes included preeclampsia, growth restriction, preterm delivery, gestational diabetes, and spontaneous abortion. There was no association between vitamin D deficiency and composite adverse pregnancy outcomes with an adjusted odds ratio of 1.01 (p value 0.738, 95% confidence intervals 0.961-1.057).

Conclusion

Vitamin D deficiency did not associate with adverse pregnancy outcomes in this study population. However, the high percentage of affected individuals highlights the prevalence of vitamin D deficiency in young, reproductive-aged women.