Vitamin D: The secosteroid hormone and human reproduction

Vitamin D is a secosteroid with an endocrine mechanism of action which is sequentially synthesized in humans in the skin, liver and kidneys. The active hormone, 1α,25-dihydrocholecalciferol [1,25(OH)₂D₃], is often considered only in terms of its role in controlling calcium and phosphorus homeostasis. However, cumulative evidence points to the presence of vitamin D receptors in many tissues. The present article summarizes key points regarding the participation of vitamin D in pregnancy and breastfeeding. During pregnancy, sufficient vitamin D concentrations are needed not only to address the growing demand for calcium on the part of the fetus, but also to participate in fetal growth, development of the nervous system, lung maturation and fetal immune system function. Hypovitaminosis D has been related to the development of diabetes, pre-eclampsia and fetal neurological disorders. During pregnancy and lactation, calcium from the maternal skeleton is mobilized, with a rise in bone turnover and a reduction in bone mass. It is advisable for pregnant and nursing women to maintain adequate levels of vitamin D, through small doses of solar exposure to facilitate natural formation of the hormone or by ingesting appropriate vitamin supplements. Further studies are needed to clarify the many gaps in knowledge and elucidate the role of vitamin D in the context of reproduction. Confirmation of experimental observations relating to the risks of hypovitaminosis D would have important public health implications.     

Inadequate vitamin D status in pregnancy: evidence for supplementation

The role of vitamin D in maintaining a healthy pregnancy has seen emerging interest among clinicians and researchers in recent years. The functions of this hormone are widespread and complex, and during pregnancy and breastfeeding it facilitates crucial transfer of calcium from mother to child for skeletal development. Aside from the role of vitamin D in bone development and health, a myriad of other physiological actions are now known, and it is hypothesized that maternal deficiency may increase susceptibility to adverse pregnancy events during pregnancy such as pre-eclampsia. The role of vitamin D in pregnancy and breastfeeding is summarized and applied to the knowledge from studies associating vitamin D deficiency with a range of adverse pregnancy outcomes, including pre-eclampsia and childhood asthma. Current clinical guidelines for vitamin D supplementation in pregnancy are discussed in the context of the available evidence. The need for robust randomized controlled trials to address areas of existing uncertainty is highlighted.     

钙在产科中的应用进展

钙是人体必需的矿物质之一,是机体骨骼系统的重要组成元素,尤其胎儿时期需要从母体摄入大量的钙以供其骨骼生长。近年来随着医学的不断发展,人们对于钙在妊娠期作用的认识不再局限于其仅仅为胎儿骨骼生长提供矿物质的单一层面,而是发现钙与胎儿生长发育、早产、妊娠期高血压疾病、产后出血和妊娠期糖尿病等产科情况存在关联,具有较好的应用价值。查阅国内外相关文献报道和最新研究资料,综述钙在产科中的应用进展,以期提高产科医师对钙在产科中的作用有更好的认识,为临床处理相关疾病提供参考。     

Vitamin D and pregnancy

Significant numbers of pregnant women do not meet the recommended levels of vitamin D. Neonates whose mothers had low vitamin D levels during pregnancy have a lower bone density at birth and are at risk of rickets. The consequences of vitamin D deficiency beyond calcium homoeostasis are not yet completely understood, however, there is growing evidence that vitamin D plays a role in the optimal function of many systems that influence pregnancy outcomes such as glucose homoeostasis, inflammation and vascular function.     

Renin–angiotensin systems and reproduction

Calcium and vitamin D supplementation have been shown to reduce secondary hyperparathyroidism and play a role in age-related osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion ,we compared the administration of a calcium-vitamin D supplement as a single morning dose with the administration of two divided doses at 6-hour intervals. Twelve healthy male volunteers were assigned to three investigational procedures ,which were alternated at weekly intervals. After a 'blank' control procedure ,when they were not exposed to any supplements ,they received one of two calcium-vitamin D supplement regimens: either two doses of Orocal^® D3 (500 mg calcium and 400 IU vitamin D3) with a 6-hour interval between doses ,or one water-soluble effervescent powder pack of Cacit^® vitamin D3 ,taken in the morning (1000 mg calcium and 880 IU vitamin D3). During the three procedures (control and the two calcium-vitamin D supplementation protocols) ,veinous blood was drawn every 60 minutes for up to 9 hours ,for serum calcium and parathyroid hormone measurements. The order of administration of the two calcium and vitamin D supplementation regimens was allocated by randomization. No significant changes in serum calcium were observed during the study. During the first 6 hours following calcium-vitamin D supplementation ,a statistically significant decrease in serum parathyroid hormone was observed with both regimens ,compared with baseline and the control procedure. During this first period ,no differences were observed between the two treatment regimens. However ,between the 6th and the 9th hour ,serum parathyroid hormone levels remained significantly decreased compared to baseline with the twice-daily Orocal D3 administration ,while they returned to baseline values with the once-daily Cacit D3 preparation. During this period ,the percentage decrease in serum parathyroid hormone relative to baseline was significantly greater with Orocal D3 than Cacit D3 (p = 0.0021). We therefore conclude that the twice-daily administration of 500 mg calcium and 400 IU vitamin D3 at 6-hour intervals provides a more prolonged decrease in serum parathyroid hormone levels than the administration of the same total amount of calcium and vitamin D ,as a single morning dose in young healthy volunteers. These results might have implications in terms of protection of the skeleton against secondary hyperparathyroidism and increased bone resorption and turnover in elderly subjects.     

Progesterone for the prevention of preterm birth in women with multiple pregnancies: the AMPHIA trial

Background

Adequate vitamin D concentrations during pregnancy are necessary to neonatal calcium homeostasis, bone maturation and mineralization. The aim of study is to evaluate serum vitamin D concentrations in mothers and their newborns and effect of vitamin D deficiency on pregnancy outcomes.

Methods

552 pregnant women were recruited from Tehran University educating hospitals in the winter of 2002. Maternal and cord blood samples were taken at delivery. The serum was assayed for 25-hydroxyvitamin D3, calcium, phosphorus and parathyroid hormone.

Results

The prevalence of vitamin D deficiency in maternal and cord blood samples were 66.8% and 93.3%, respectively (<35 nmol/l). There was significant correlation between maternal and cord blood serum concentrations of vitamin D. In mothers with vitamin D deficiency, cord blood vitamin D concentrations was lower than those from normal mothers (P = .001). Also, a significant direct correlation was seen between maternal vitamin D intake and weight gain during pregnancy.

Conclusion

Consideration to adequate calcium and vitamin D intake during pregnancy is essential. Furthermore, we think it is necessary to reconsider the recommendation for vitamin D supplementation for women during pregnancy.     

Calcium metabolism in pregnancy and the perinatal period: a review

Calcium homeostasis is a complex process involving calcium, other involved ions, and three calcitropic hormones, parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D3. The principal maternal adjustment during pregnancy is an increasing parathyroid hormone secretion which maintains the serum calcium concentration in the face of a falling albumin level, an expanding extracellular fluid volume, an increasing renal excretion, and placental calcium transfer. The placenta transports calcium ions actively, making the fetus hypercalcemic relative to its mother, which in turn stimulates calcitonin release and perhaps suppresses parathyroid hormone secretion by the fetus. A unique extrarenal system for 1 alpha-hydroxylation of 25-hydroxyvitamin D3 exists in the placenta and/or decidua, providing a source of 1,25-dihydroxyvitamin D3 for the fetus. With the abrupt cessation of the placental source of calcium at birth, the neonate's serum calcium level falls for 24 to 48 hours, then stabilizes and rises slightly. Hyperparathyroidism during pregnancy causes complications in both mother and infant and should usually be treated surgically as soon as diagnosed. Maternal hypoparathyroidism can be treated satisfactorily with high doses of supplemental calcium and vitamin D. Osteopenia accompanying long-term heparin administration may respond to 1,25-dihydroxyvitamin D3 (calcitriol) therapy. Diabetes in pregnancy is associated with disturbed neonatal calcium homeostasis, perhaps due to chronic hypomagnesemia. A possible etiologic role of calcium deficiency in pregnancy-related hypertension has been suggested. Dietary deficiency of calcium and/or vitamin D during gestation may lead to several adverse effects in the newborn infant.     

Influence of daily calcium and vitamin D supplementation on parathyroid hormone secretion.

Calcium and vitamin D supplementation have been shown to reduce secondary hyperparathyroidism and play a role in age-related osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we compared the administration of a calcium-vitamin D supplement as a single morning dose with the administration of two divided doses at 6-hour intervals. Twelve healthy male volunteers were assigned to three investigational procedures, which were alternated at weekly intervals. After a 'blank' control procedure, when they were not exposed to any supplements, they received one of two calcium-vitamin D supplement regimens: either two doses of Orocal D3 (500 mg calcium and 400 IU vitamin D3) with a 6-hour interval between doses, or one water-soluble effervescent powder pack of Cacit vitamin D3, taken in the morning (1000 mg calcium and 880 IU vitamin D3). During the three procedures (control and the two calcium-vitamin D supplementation protocols), veinous blood was drawn every 60 minutes for up to 9 hours, for serum calcium and parathyroid hormone measurements. The order of administration of the two calcium and vitamin D supplementation regimens was allocated by randomization. No significant changes in serum calcium were observed during the study. During the first 6 hours following calcium-vitamin D supplementation, a statistically significant decrease in serum parathyroid hormone was observed with both regimens, compared with baseline and the control procedure. During this first period, no differences were observed between the two treatment regimens. However, between the 6th and the 9th hour, serum parathyroid hormone levels remained significantly decreased compared to baseline with the twice-daily Orocal D3 administration, while they returned to baseline values with the once-daily Cacit D3 preparation. During this period, the percentage decrease in serum parathyroid hormone relative to baseline was significantly greater with Orocal D3 than Cacit D3 (p = 0.0021). We therefore conclude that the twice-daily administration of 500 mg calcium and 400 IU vitamin D3 at 6-hour intervals provides a more prolonged decrease in serum parathyroid hormone levels than the administration of the same total amount of calcium and vitamin D, as a single morning dose in young healthy.     

Knochenerkrankungen in Schwangerschaft und Stillzeit

At the German reference center for pregnancy-associated osteoporosis patients with osteological disorders during pregnancy and lactation are recorded. Approximately 75% suffered from pregnancy-associated osteoporosis with a leading symptom of back pain due to vertebral fractures and 25 % suffered from hip pain caused by bone marrow edema. Affected were mainly primigravida. Diagnostic imaging is essential, especially magnetic resonance imaging (MRI), as it is safe in pregnancy. Bone density measurements show a T-score ≤?2.5 according to the WHO criteria for patients with pregnancy-associated osteoporosis. Women with bone marrow edema often suffer from systemic osteopenia. Treatment should involve weaning, substitution of calcium and vitamin D is recommended. Analgesics therapy is essential. Pregnancy-associated osteoporosis usually requires a specific treatment, such as parathyroid hormone. Due to its self-limiting course in many cases bone marrow edema is sufficiently treated by weight load relief via crutches.     

The developmental origins of osteoporotic fracture

Undernutrition and other adverse influences arising in fetal life or immediately after birth have a permanent effect on body structure, physiology and metabolism. Evidence is now accumulating from human studies that programming of bone growth might be an important contributor to the later risk of osteoporotic fracture. Body weight in infancy is a determinant of adult bone mineral content, as well as of the basal levels of activity of the GH/IGF-1 and HPA axes, and recent work has suggested a central role for vitamin D. Epidemiological studies have suggested that maternal smoking and nutrition during pregnancy influence intrauterine skeletal mineralization. Finally, childhood growth rates have been directly linked to the risk of hip fracture many decades later. Further work is needed to use this approach to develop novel therapeutic and preventative strategies to reduce the burden of osteoporotic fractures in the population.     

Calcium supplementation during pregnancy and lactation: effects on the mother and the fetus

Calcium consumption is essential for bone development and maintenance throughout life, yet more than one half of the female population in the United States does not consume the recommended amount of calcium. Calcium intake is especially crucial during pregnancy and lactation because of the potential adverse effect on maternal bone health if maternal calcium stores are depleted. There is often a transient lowered bone mineral density and increased rate of bone resorption, with the greatest consequence during the third trimester and throughout lactation. Studies indicate that calcium consumption should be encouraged, especially during pregnancy and lactation, to replace maternal skeletal calcium stores that are depleted during these periods. Because the fetus in utero and the neonate through breast-feeding are dependent on maternal sources for the total calcium load, adequate maternal calcium intake also can affect fetal bone health positively. Proper calcium consumption can be attained through the diet by the consumption of dairy products or leafy greens (such as kale), the consumption of fortified foods, or by supplementation with widely available calcium-containing supplement products. Because many women experience heartburn during pregnancy, calcium-based antacids are ideal for providing heartburn relief, and they offer a calcium supplement to ensure maternal and fetal bone health, without the danger of adverse effects on the neonate.     

Vitamin D (soltriol), light, and reproduction

Evidence from autoradiographic studies with 1,25(OH)2-vitamin D3 (vitamin D, soltriol) labeled with tritium and from the literature indicates that the steroid hormone soltriol regulates and modulates reproductive processes in the female, as it does in the male. Nuclear receptors for soltriol have been discovered in the uterus, oviduct, ovary, mammary gland, placenta, and fetal membranes, as well as in the pituitary and hypothalamus. Soltriol is recognized as a transducer and hormonal messenger of sunlight, acting as a somatotropic activator and modulator of vital processes for the seasonal and estival adaptation of growth, development, and procreation. Its influence on calcium equilibrium is just one of its many functions to serve this goal. This article reviews experimental, clinical, and epidemiologic evidence that suggests the involvement of soltriol in the control of reproductive processes, noting its importance for the onset of puberty, fertility, pregnancy, lactation, and probably sexual behavior. Cooperative actions between soltriol and other steroid hormones, especially estradiol, are pointed out.     

Vitamin D and mineral metabolism in intrahepatic cholestasis of pregnancy

Serum concentrations of 25(OH)D, 24,25(OH)2D, 1,25(OH)2D, total protein, calcium, phosphorus, magnesium and alkaline phosphatase were measured in patients with intrahepatic cholestasis of pregnancy and in control subjects at the third trimester of pregnancy and at delivery. 25(OH)D levels of 40.5 +/- 21.5 nmol/l in the patient group were initially significantly (P less than 0.01) higher than the value of 26.3 +/- 9.5 nmol/l in the control group and decreased significantly (P less than 0.01) to 26.0 +/- 16.3 nmol/l at delivery. The levels of active 1,25(OH)2D and inactive 24,25(OH)2D did not alter in either group. Also the concentrations of calcium, phosphorus and magnesium remained unchanged in both groups. No significant differences in fetal vitamin D metabolites were observed between patients and controls, and the other analysed fetal parameters were similar in both groups. Cholestyramine and/or phenobarbital treatment had no influence on vitamin D metabolites. Since levels of 1,25(OH)2D and mineral parameters remained normal and a change in 25(OH)D concentrations was only transient, the clinical role of 25(OH)D variations cannot be substantial.     

The role of calcium in health and disease

Skeletal fragility at the end of the life span (osteoporosis) is a major source of morbidity and mortality. Adequate calcium intake from childhood to the end of the life span is critical for the formation and retention of a healthy skeleton. High intakes of calcium and vitamin D potentiate the bone loss prevention effects of hormone replacement therapy in postmenopausal women. Pregnancy and lactation are not risk factors for skeletal fragility, although lactation is associated with a transient loss of bone that cannot be prevented by calcium supplementation. Low calcium intake has been implicated in the development of hypertension, colon cancer, and premenstrual syndrome, and it is associated with low intakes of many other nutrients. Encouragement of increased consumption of calcium-rich foods has the potential to be a cost-effective strategy for reducing fracture incidence later in life and for increasing patients' dietary quality and overall health.     

Diagnosis,prevention, and treatment of osteoporosis in men

Though commonly seen as a disease afflicting only women, osteoporosis affects more than 5 million men in the United States with significant morbidity and mortality. Alcohol abuse, glucocorticoid excess, and hypogonadism are the principle risk factors for osteoporosis in men. Radiographs alone are insufficient in detecting the presence of the disease. Examining bone mineral density is the diagnostic standard used to detect the disease in both men and women. Unfortunately, diagnostic parameters and screening recommendations for bone mineral density testing have not been firmly established in men. The treatment and prevention of osteoporosis has been well studied in women, thus many of the treatments for men with the disease were extrapolated from studies predominantly involving women. Prevention of osteoporosis in men is best directed toward risk-factor modification and supplementation with calcium and vitamin D. The mainstay of treatment is bisphosphonates such as alendronate that have demonstrated both efficacy and safety in studies. Vitamin D and calcium supplementation also has some benefit in treating men with osteoporosis. Parathyroid hormone, thiazide diuretics, and calcitonin may also have a role in the prevention and treatment of osteoporosis in men, although this is not yet firmly established.     

A safe strategy to decrease fetal lead exposure in a woman with chronic intoxication

Abstract

During pregnancy skeletal lead is mobilized by maternal bone turnover and can threaten fetal development. The exact strategy suggested to women of childbearing age, who were chronically exposed to lead, and, thus, have high bone lead burden, is not well established. We describe 4 years of follow-up of a 29-year-old woman with chronic lead intoxication. We (a) advised her to delay conception until ‘toxicological clearance’, (b) treated her with multiple courses of lead chelator, DMSA, and (c) prescribed oral calcium. Patient had low blood lead and protoporphyrin level during pregnancy until delivery. Delaying conception, lead chelation, and calcium supplementation can decrease fetal exposure.     

Disorders of maternal calcium metabolism implicated by abnormal calcium metabolism in the neonate

Normal fetal and neonatal calcium homeostasis is dependent upon an adequate supply of calcium from maternal sources. Both maternal hypercalcemia and hypocalcemia can cause metabolic bone disease or disorders of calcium homeostasis in neonates. Maternal hypercalcemia can suppress fetal parathyroid function and cause neonatal hypocalcemia. Conversely, maternal hypocalcemia can stimulate fetal parathyroid tissue causing bone demineralization. We report two asymptomatic women, one with previously unrecognized hypoparathyroidism and the other with unrecognized familial benign hypercalcemia, who were diagnosed when their newborn infants presented with abnormalities of calcium metabolism. J.B. was born at 34 weeks' gestation with transient hyperbilirubinemia and thrombocytopenia. At 1 month of age he had severe bone demineralization, cortical irregularities, widening and cupping of the metaphyses, and lucent bands in the scapulae. The total serum calcium and phosphorus were normal with an ionized calcium of 5.4 mg/dL (4.6-5.4). His alkaline phosphatase, parathyroid hormone, and 1,25-dihydroxyvitamin D levels were all increased. P.B., mother of J.B., had no symptoms of hypocalcemia either prior to, or during this pregnancy. She had severe hypocalcemia and hyperphosphatemia, laboratory values typical of hypoparathyroidism. J.N. presented at 6 weeks of age with new onset of seizures and tetany secondary to severe hypocalcemia. The serum phosphorus, creatinine, alkaline phosphatase, and parathyroid hormone levels were normal. At 15 weeks of age his calcium was slightly elevated with a low fractional excretion of calcium. P.N., mother of J.N., had no symptoms of hypercalcemia either prior to, or during this pregnancy. Her serum calcium was 12.7 mg/dL and urine calcium was 66.5 mg/24 hr, with a low fractional excretion of calcium ranging from 0.0064 to 0.0073. P.N. has a brother who previously had parathyroid surgery. Both J.N. and P.N. meet the diagnostic criteria for familial benign hypercalcemia. These cases illustrate the important relationships between maternal serum calcium levels and neonatal calcium homeostasis. They emphasize the need to assess maternal calcium levels when infants are born with abnormal serum calcium levels or metabolic bone disease.     

Vitamin D,preeclampsia and prematurity: A systematic review and meta-analysis of observational and interventional studies

BackgroundVitamin D has important functions outside of bone metabolism. Deficiency has been associated with several adverse outcomes during pregnancy such as preeclampsia and prematurity. There is an increasing body of literature on this topic with studies performed to date having produced contradictory results.ObjectiveTo synthesize the literature about vitamin D deficiency and its association with preeclampsia and prematurity in order to determine if maternal vitamin D insufficiency and/or deficiency during pregnancy is associated with the prevalence of preeclampsia and prematurity.DesignA systematic review and meta-analysis of observational and interventional studies.MethodsTwo independent researchers reviewed the included studies according to PRISMA reporting guidelines. A protocol for this review was registered in PROSPERO with the registration number: “CRD42019136318”. Three electronic databases (PubMed, ScienceDirect and Web of Science); were searched in order to identify eligible studies. Observational and interventional studies were selected which had been published in the last 6 years, and analysed the association between maternal vitamin D concentrations during pregnancy and the development of preeclampsia and/or preterm birth. Data were extracted and presented in tables and figures. Fixed and random-effects meta-analyses were performed on the studies which provided enough sample data to calculate odds ratios. Results from both statistical methods were compared. Meta-analysis cut-off points for vitamin D insufficiency and deficiency were defined as <75nmol/L and <50nmol/L, respectively.ResultsFifty-five studies met the inclusion criteria. Fixed-effects meta-analysis of the interventional studies indicated that vitamin D supplementation acts as a prevention factor for preeclampsia and prematurity. Fixed-effects meta-analysis of observational studies concluded that vitamin D insufficiency and deficiency are associated with a higher risk of developing preeclampsia. However, prematurity and vitamin D were only associated when maternal vitamin D concentrations was <75 nmol/L. Random-effects meta-analysis found no significant association between vitamin D, preeclampsia and prematurity in either observational or interventional studies.ConclusionHigher vitamin D concentrations during pregnancy could be associated with a decreased risk of preeclampsia and prematurity but statistical significance of associations depends on the study design used. Well-designed clinical trials with vitamin D supplementation are needed in order to better define associations.     

Supplementation during pregnancy: beliefs and science

Pregnancy represents a challenge from a nutritional perspective, because micronutrient intake during the periconceptional period and in pregnancy affects fetal organ development and the mother’s health. Inappropriate diet/nutrition in pregnancy can lead to numerous deficiencies including iron deficiency and may impair placental function and play a role in miscarriage, intrauterine growth restriction, preterm delivery, and preeclampsia. This article reviews the risks associated with nutrient deficiencies in pregnant women and presents an overview of recommendations for dietary supplementation in pregnancy, focusing on oral iron supplementation. Risk factor detection, including dietary patterns and comorbidities, is paramount in optimal pregnancy management. Dietary habits, which can lead to deficiencies (e.g., iron, folate, vitamin D, and calcium) and result in negative health consequences for the mother and fetus/newborn, need to be investigated. Prenatal care should be personalized, accounting for ethnicity, culture, education, information level about pregnancy, and dietary and physical habits. Clinicians should make a plan for appropriate supplementation and prophylaxis/treatment of nutritional and other needs, and consider adequate intake of calcium, iodine, vitamin D, folate, and iron. Among the available oral iron supplements, prolonged-released ferrous sulfate (ferrous sulfate–polymeric complex) presents the lowest incidence of overall and gastrointestinal adverse events, with positive implications for compliance.