Spyridon N. Karras

Vitamin D in human reproduction: a narrative review

Background:  Special attention has been given to the effect of vitamin D supplementation on fertility outcomes in both sexes.

Do studies reporting ‘U’-shaped serum 25-hydroxyvitamin D–health outcome relationships reflect adverse effects?

ABSTRACT Several reports describe U-shaped 25-hydroxyvitamin D [25(OH)D] concentration–health outcomes, including musculo-skeletal disorders such as falls and fractures, several cancers, cardiovascular disease (CVD), cognitive function, all-cause mortality rates, birth outcomes, allergic reactions, frailty, and some other disorders. This paper reviews reports of U-shaped outcome associations with vitamin D status for evidence of underlying pathophysiological processes, or of confounding, finding that some U-shaped associations appear to be biologically meaningful, but that many could well reflect confounding by factors such as lifestyle, or hypovitaminosis D-related disease onset being masked by self-supplementation that was begun too late to correct developing health problems but before baseline vitamin D status assessment. However, the various U-shaped associations for allergic reactions may be due to vitamin D modulation of the phenotype of the immune response, shifting the Th1-Th2 balance toward Th2 formation. For prostate cancer, there seems to be little effect of 25(OH)D concentration on incidence; however, there is an inverse correlation between 25(OH)D concentration and mortality rates. Future observational studies, and randomized controlled trial data analyses, should include adjustment for data collected on prior long-term vitamin D supplementation and solar UVB exposure, as well as other potential confounders.

Maternal vitamin D status in pregnancy and offspring bone development: the unmet needs of vitamin D era

Data from animal and human studies implicate maternal vitamin D deficiency during pregnancy as a significant risk factor for several adverse outcomes affecting maternal, fetal, and child health. The possible associations of maternal vitamin D status and offspring bone development comprise a significant public health issue. Evidence from randomized trials regarding maternal vitamin D supplementation for optimization of offspring bone mass is lacking. In the same field, data from observational studies suggest that vitamin D supplementation is not indicated. Conversely, supplementation studies provided evidence that vitamin D has beneficial effects on neonatal calcium homeostasis. Nevertheless, a series of issues, such as technical difficulties of current vitamin D assays and functional interplay among vitamin D analytes, prohibit arrival at safe conclusions. Future studies would benefit from adoption of a gold standard assay, which would unravel the functions of vitamin D analytes. This narrative review summarizes and discusses data from both observational and supplementation studies regarding maternal vitamin D status during pregnancy and offspring bone development.

Hypovitaminosis D in pregnancy in the Mediterranean region: a systematic review.

Despite high levels of sunshine, maternal hypovitaminosis D during pregnancy is prevalent in the Mediterranean region. The aim of this study is to systematically review trials that investigated vitamin D concentrations during pregnancy in this region, in order to determine predictors of hypovitaminosis D and explain this phenomenon. After applying inclusion/exclusion criteria, 15 studies were entered into the systematic review involving 2649 pregnant women and 820 neonates. The main outcome was maternal vitamin D status, assessed by serum 25-hydroxy-vitamin D (25(OH)D) concentrations. Possible predictors of the outcome included maternal age, body mass index (BMI), race, socioeconomic status, skin type, gestational age, sun exposure, calcium and vitamin D intake and supplementation, smoking status, parity and season of delivery. Studies differed widely in vitamin D deficiency criteria, method of measurement and outcomes. The prevalence of vitamin D insufficiency ranges from 9.3 to 41.4%, whereas that of vitamin D deficiency from 22.7 to 90.3%. A positive association with 25(OH)D concentrations exists for light skin color, white race, uncovered dressing pattern, maternal vitamin D supplementation and season of gestation (spring/summer). An inverse association exists for BMI and gestational age, whereas data for smoking and socioeconomic status are controversial. We concluded that vitamin D deficiency in pregnancy seems to be quite common, even in the Mediterranean region. Racial, social and cultural habits, as well as the absence of preventive supplementation/dietary strategies, seem to negate the benefits of sun exposure.

Vitamin D administration during pregnancy as prevention for pregnancy, neonatal and postnatal complications

Pregnancy represents a time of rapid bodily change, which includes physical proportions, physiology and responsibility. At this context, maternal vitamin D stores have been the objective of extensive scientific research during the last decades, focusing on their potential effects on maternal an neonatal health. A growing body of observational studies indicated that maternal hypovitaminosis D (as defined by maternal 25-hydroxyvitamin D [25(OH)D] levels <20 ng/ml or <50 nmol/l) is a significant risk factor for adverse neonatal outcomes including asthma, multiple sclerosis and other neurological disorders. On that basis, this review aims to provide to the reader new insights into the vitamin D requirements and function during pregnancy supported by recent data and will not discuss the classical roles of vitamin D and skeletal function during pregnancy. In addition, we will focus on recent results that demonstrate that maternal vitamin D supplementation could reduce neonatal respiratory and neurological complications, suggesting that available guidelines should be updated, since it remains unclear why these recommendations are not updated according to recent results. Also, with regard to randomized controlled trials (RCT’s) for vitamin D, we consider that they are largely doomed to fail. The reasons for this are many and specific cases of this failure will be presented in this text.

Vitamin D and cardiovascular disease: From atherosclerosis to myocardial infarction and stroke

There continues to be interest in understanding the role of vitamin D in the pathogenesis, epidemiology and prevention of cardiovascular disease (CVD). In fact vitamin D deficiency has been associated to an increased risk of developing CVD given to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which vitamin D deficiency leads from endothelial dysfunction to myocardial infarction and stroke are not fully understood. Thus, the goal of this review is to provide an updated review of the literature on the basic science of how vitamin D may affect the cardiovascular system and in particular to analyze the role that vitamin D may have in the whole dynamic process from the initiation of endothelial dysfunction to the development of myocardial infarction and stroke.

Vitamin D during pregnancy: why observational studies suggest deficiency and interventional studies show no improvement in clinical outcomes? A narrative review

Abstract A considerable number of studies have examined vitamin D status during pregnancy. Although data from observational studies denote vitamin D hypovitaminosis (deficiency or insufficiency) during pregnancy is associated with a plethora of adverse maternal and neonatal outcomes, data from interventional (supplementation) trials fail to reveal a significant impact on maternal and offspring health. The aim of this narrative review was to critically appraise the methodology of the most representative published randomized controlled trials in an attempt to explain the difference between observational and supplementation results. We found that this difference could be attributed to a variety of factors, namely: (i) study design (lack of a specific outcome in conjunction with timing of supplementation, enrolment of participants with heterogeneous vitamin D status); (ii) pitfalls in the interpretation of vitamin D equilibrium (lack of determination of plasma half-life); (iii) supplementation regimen (administration of a wide range of regimens, in terms of dose, bolus and form); (iv) geographical characteristics (vitamin D needs could vary significantly within a country, particularly in areas with a wide range of latitude gradient); (v) adaptations of vitamin D metabolism during pregnancy (vitamin D and calcium equilibrium are changed during pregnancy compared with the non-pregnant state) and (vi) supplementation of populations with low baseline 25(OH)D values would likely manifest beneficial effects. All these parameters should be taken into consideration in the design of future vitamin D supplementation trials.

Maternal vitamin D levels during pregnancy and neonatal health: evidence to date and clinical implications.

Low maternal vitamin D levels during pregnancy have been associated with a plethora of adverse neonatal outcomes, including small for gestational age and preterm births, detrimental effect on offspring bone and teeth development, and risk of infectious diseases. Although most observational studies indicate a significant linear relationship between maternal 25-hydroxyvitamin D and the above outcomes, some randomized controlled trials to date are inconclusive, mostly due to differences in study design and supplementation regimen. The currently available results indicate that vitamin D supplementation during pregnancy reduces the risk of preterm birth, low birth weight, dental caries of infancy, and neonatal infectious diseases such as respiratory infections and sepsis. This narrative review aims to summarize available trial results regarding the effect of low maternal vitamin D levels during pregnancy, in conjunction with neonatal outcomes on the field, with a discourse on the appropriate clinical approach of this important issue.

Vitamin D supplements: a novel therapeutic approach for Alzheimer patients

Alzheimer disease (AD) is the main cause of dementia and loss of functional independence in the elderly (Aisen, 2010; Vellas and Aisen, 2010). AD is a chronic neurodegenerative disease characterized by a progressive decline of cognitive performance with a deleterious impact on social activities. AD is a worldwide big concern because of its adverse consequences and its expanding prevalence and incidence (Aisen, 2010; Vellas and Aisen, 2010). In order to reduce AD impact at an individual level and in terms of health and social costs, the development of efficient therapeutic strategies proves necessary. Regrettably, the development of all current specific medications is unsuccessful in clinical development phases (Birks, 2006; McShane et al., 2006; Anand et al., 2014). However, an interesting fact is that the prevalence of dementia in the general population might still be subject to changes. Indeed, a reduction in the prevalence of dementia is reported among English community-dwellers over the past two decades (Matthews et al., 2013). So, even if some factors, such as the increased life expectancy beyond 80 years, are unavoidable and augment the global prevalence of dementia, others may instead reduce its prevalence. For instance, efficient primary prevention of cardio-vascular disease is suspected to explain the reduced prevalence of dementia in England (Matthews et al., 2013). In the same vein, vitamin D, an “old” molecule primarily known for its effects on the bone, has been singled out in the last decade as an important biological component able to influence the natural history of AD. Here, we wish to highlight the difficulties experienced by the research on curative treatments and, in contrast, the prospects offered by multi-target drugs, especially those based on vitamin D.

Sarcopenia in post-menopausal women: Is there any role for vitamin D?

BACKGROUND Recently, special attention has been given to the role of vitamin D on the pathogenesis and therapy of sarcopenia in postmenopausal women. AIMS To elucidate the role of vitamin D with respect to sarcopenia in postmenopausal women, providing current evidence from both molecular and clinical studies. MATERIALS AND METHODS Systematic search to PubMed and Medline databases for publications reporting data on the role of vitamin D in sarcopenia. RESULTS Sarcopenia has a high prevalence in postmenopausal women, leading to mobility restriction, functional impairment, physical disability and fractures. Accumulating evidence from molecular and clinical studies suggest that vitamin D deficiency is associated with sarcopenic status in elderly women independent of body composition, diet and hormonal status. Current data, but not in a uniform way, provide evidence about the beneficial effect of vitamin D supplementation on muscle strength, physical performance and prevention of falls and fractures in elderly female populations. It is still unclear if and to what extent treatment modalities, such as dose, mode of administration and duration of supplementation, could influence treatment outcome. CONCLUSIONS Studies with superior methodological characteristics are needed in order to establish a role for vitamin D on the treatment of sarcopenia in postmenopausal women.