Abstract
Low vitamin D levels have been linked to conditions, including cardiovascular disease, certain malignancies, dementia, depression, diabetes, adverse pregnancy outcomes, and autoimmune diseases. Although vitamin D deficiency is a worldwide issue, it deserves specific attention in pregnant and nursing mothers due to the potential for unfavorable maternal–fetal outcomes. Vitamin D deficiency is increasingly prevalent among women of reproductive age and has been associated with gestational hypertension, preterm birth, and poorer offspring health. This chapter focuses on Vitamin D deficiency during gestation and its adverse effects on the fetal growth of neonates, during adolescence and adulthood of offspring. The role of epigenetic maternal–fetal adaptation mechanisms and vitamin D metabolism in the development of metabolic diseases is also explored.
Keyword
- Maternal vitamin D
- Gestation
- Fetal development
- Vitamin D metabolism
- Vitamin D in infancy and adolescent
- Programming
- Immune response
Background
Pregnancy is a critical period during which the developing fetus is very sensitive to damage caused by certain medications, alcohol, or other harmful exposures. Maternal nutrition and lifestyle play a major role where the right diet and lifestyle does not ensure a healthy life for the offspring. However, harmful diet and lifestyle are associated with increased frequency of birth defects and adverse pregnancy outcomes. Genetic heredity and the environment of an individual influence the risk of non-communicable disease. Growing evidence suggests maternal nutrition during preconception, pregnancy, and infancy has an everlasting effect on child health and also the risk of developing non-communicable diseases such as asthma, diabetes, obesity, and cardiovascular disease [1, 2].
The hypothesis of ‘early’ or ‘foetal’ origins of adult disease put forward by Barker et al. also referred as “Developmental origin of adult health and disease” state the importance of maternal nutrition during preconception and pregnancy [3]. Number of epidemiological, clinical and experimental animal studies has supported the hypothesis [4,5,6,7]. The most probable mechanistic framework that has been proposed is “developmental programming” which is the ability to form one or more alternative forms (behavior, physiological state, structure) from a single genotype in response to intrauterine environmental conditions [3]. During development, the cells are differentiating and tissues are forming hence if there are nutrient-limiting conditions and a toxic environment the fetus develops an adaptive response which may have the chances of disease risk in later life [1].
Vitamin deficiency is very common during pregnancy, childhood and adult life both in developed and developing countries. Adequate levels of Vitamin D are important during pregnancy and child development since it is necessary for many cellular and physiological processes. In this chapter we aim to review the importance of vitamin D during pregnancy, infancy, childhood and adolescence. Further, the role in fetal growth and neonatal anthropomorphic features and immune response is discussed. Lastly, we will discuss the risk of communicable disease in adulthood and effectiveness of vitamin D supplementation during pregnancy.
Why Vitamin D Matters?
Vitamin D includes vitamin D2 or ergocalciferol which is obtained from plants, and Vitamin D3 or cholecalciferol is obtained from animals. However both forms of vitamin D require UV light to catalyze the reaction [8]. The precursor epidermal 7-dehydrocholesterol is converted to previtamin D following Ultraviolet light (280–320 nm) exposure [9, 10]. If an individual is unexposed to sunlight he or she is solely dependent on the dietary source of Vitamin D [12]. Dietary source of Vitamin D mostly includes oily fish cod liver oil, egg yolks, shiitake mushrooms, and liver and organ meats [11, 12]. On an average the whole-body exposure to sunlight for a period of 10–15 min generates 10,000–15,000 IU vitamin D within 24 h whereas daily diet provides only 200 IU/day vitamin D [13, 14]. After a series of thermal reactions, previtamin D is converted to vitamin D and transferred to different organ by vitamin D-binding protein (VDBP) α-globulin. In the liver vitamin D is converted to 25(OH)D through the action of 25-hydroxylase [15]. 25(OH)D, is normally used to determine an individual’s vitamin D status [8, 16]. 25(OH)D also binds to VDBP and some of the unbound form is absorbed by kidney or extrarenal tissue and converted to dihydroxyvitamin D (1,25[OH]2D or calcitriol), the active form of vitamin D [17] (Fig. 17.1). Calcitriol main function is to maintain calcium homeostasis either by increasing intestinal absorption of calcium or urinary reabsorption of calcium or mobilization of calcium from bone [18]. Vitamin D has the ability to cross the blood brain barrier similar to many neurosteroids [19]. Hence the major body organs: heart, intestine, muscle and brain cannot function without adequate vitamin D.
Calcitriol function is mediated by binding to a vitamin D receptor which is in the nuclei of the cell. Vitamin D receptors belong to the [15] nuclear receptor superfamily of steroid/thyroid hormone receptors and its expression decreases with age. After binding of calcitriol to VDR it functions as a transcription factor which regulates the expression of gene cell specific manners [15]. In the intestine the expression of transport protein TRPV6 and calbindin is upregulated which are involved in calcium absorption [15]. Apart from expressing in the brain cells, muscle cells, cells of the cardiovascular system, vitamin D receptor is also expressed in immune cells including monocytes, Natural killer cells, macrophages activated T and B cells. In organs apart from the intestine the main role of VDR is cell survival, differentiation and prevention of apoptosis [20, 21].
Vitamin D Level During Pregnancy and Infancy
During pregnancy total calcitriol levels double during the first trimester and are maintained till term; however, free calcitriol levels do not increase until the third trimester [22, 23]. Intestinal absorption of calcium usually occurs during pregnancy and 80% calcium is obtained during the third trimester [23]. Fetuses usually have low levels of calcitriol in the circulation and high levels of calcium [23]. Calcium absorption in pregnancy is calcitriol independent [23]. However, decrease of intestinal calcium absorption rate from pregnant to the nonpregnant coincides with the calcitriol levels [24]. Studies in animal models have identified severe vitamin D deficiency, absent 1a-hydroxylase, or absent vitamin D receptors that do not affect the intestinal calcium absorption, fetus mineralized skeleton, and normal blood calcium level [25].
The placenta and maternal decidua expresses 1a-hydroxylase, an enzyme that converts 25(OH)D to calcitriol [26]. Placental uptake 25(OH)D3 by the process of endocytosis, which is later converted into 24,25-dihydroxyvitamin D3 and calcitriol, which is transferred into both the maternal and fetal circulation [27]. Ex Vivo maternal perfusion has provided the quantitative amount of metabolites transferred in maternal and fetal circulation after 25 (OH) D3 metabolism [27]. Placenta uptake 27% of 25 (OH)D3 from maternal circulation and transfer 5% into the fetal circulation. 25(OH) D3 converted to 24,25-dihydroxyvitamin D3 of these 17% is retained in placental tissue, 27% is transferred to placental circulation and 56% is transferred to the maternal circulation [27]. Placenta 25 (OD)D3 metabolized to 1,25-dihydroxyvitamin D [1,25(OH)2D3] retains 67% in placental tissue and around 28% is transferred back to maternal circulation and only 5% is transferred to fetal circulation [27]. Hence placenta play an important role in determining the amount to be transferred and amount to be stored with the placental tissue (Fig. 17.1). In placenta calcitriol functions as an autocrine regulator of hCG also differentially affects the expression of placental genes and proteins [28]. Epigenetic landscape determines the gene that will be expressed after calcitriol exposure [27]. Calcitriol is also known to act through VDR and the cAMP/protein kinase signaling pathway and regulates the expression and secretion of human chorionic gonadotropin [28]. In maternal decidua where implantation of embryo takes place the function of calcitriol is in immune tolerance [29]. The enzyme 1a-hydroxylase is expressed both in stromal and non-stromal cells including macrophages, uterine Natural Killer cells, T cells [29].
During neonatal period bone resorption provides calcium in breast milk and is calcitriol dependent [23]. It is only after 48 h but more often between 6 and 18 months of age that a neonate with severe vitamin D deficiency will have the sign of hypocalcemia and skeletal signs of rickets [23]. Genetic loss of VDR or absence of 1α-hydroxylase on calcium and bone metabolism more often appear later, in the first two years after birth. Clinically if infants and children have 25-D levels less than 30 nmol/l, especially < 20 nmol/l will have rickets (a condition that affects bone development) however if calcium intake is adequate then a 25-D level > 30 nmol/l will prevent rickets. Hence vitamin D is essential for neonates to maintain calcium homeostasis only after being born and not during pregnancy (Figs. 17.1 and 17.2).
Vitamin D Effect on Fetal Growth and Neonatal Anthropomorphic Features
There are many observational studies that have shown contradictory results on the associations between maternal 25(OH)D concentrations and fetal growth also on neonatal birth anthropometry. Several studies have found associations between maternal 25(OH)D level with birth weight [30,31,32,33]. Maternal vitamin D deficiency increases the risk of lower birth weight [30,31,32,33]. Some studies like [34] performed in a US multicentre cohort demonstrated no association vitamin D level ponderal index, placental weight, or the placental to fetal weight ratio. Another study identified the association of 25(OH) D level with increased risk of macrosomia [35]. A recent meta-analysis study has identified negative effect of vitamin-D-deficiency in mothers and birth of offspring with a lower birth weight and head circumference. [36]. Meta-analysis of randomized controlled trials has also identified the positive effect of maternal supplementation of vitamin D on birth weight, head circumference and length at birth [37]. However, studies showing the effect of vitamin D on birth size are confounded by several factors, including baseline maternal 25(OH)D levels, genetic factor and neonatal vitamin D status [37]. Hence further studies are required with proper statistical analysis to determine the association of Vitamin D effect on fetal growth and neonatal anthropomorphic features.
Vitamin D Effect on Immune Response During Pregnancy
During pregnancy maternal immune responses need to adapt to the semi-allogeneic fetus. Vitamin D is known to maintain tolerance and provide protective immunity to the developing fetus [38]. It modulates the proliferation and differentiation of immune B-lymphocytes, T-lymphocytes, dendritic cells (DCs) and macrophages [38]. Post-coitus the seminal fluid induces the proinflammatory response which contributes in the remodeling of endometrium for successful implantation of embryo [39]. However, as the embryo implants sufficient immune tolerance is maintained by the induction of Tregs and through repression of cytotoxic T cells, Th1 cells, macrophages, DCs and NK cells at maternal–fetal interface [40]. Studies have reported lower levels of Regulatory T cells in maternal and umbilical cord blood in a group of pregnant women deficient in vitamin D compared to vitamin D sufficient or insufficient pregnant women [41]. Downregulation of transcription factor of regulatory T cell (FOXP3) is also observed in placental cells of women deficient in vitamin D [42]. Throughout the pregnancy the correct balance of Th1 cytokines (TNF-α, INF-γ and IL-2) and Th2 cytokines (IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13) is very important [43]. In normal pregnancy there is predominance of Th2 cells and humoral immunity [44]. Calcitriol has been shown to selectively inhibit Th1 cells and to enhance Th2 differentiation which favor successful pregnancy. Decreased levels of TGF-β and IL-10 in maternal and cord blood are reported in vitamin D deficient and insufficient pregnant women [43, 45].
Aberrant inflammatory response in placental fetal cells has been reported CYP27B1 knockout and after VDR down regulation, suggesting that vitamin D plays a role in the immunological response at the fetal-placental interface during pregnancy [46]. Inflammatory response to bacterial infection of the placenta is also found to be associated with vitamin D signaling [47]. Innate immune cells like Neutrophils and macrophages showed more phagocytic activity when treated with a combination of bacterial lipopolysaccharide (LPS) and vitamin D [47]. However the epidemiological studies on placental inflammation and vitamin D levels, have been inconclusive [48, 49]. Calcitriol is found to increase the production of cathelicidin, an antimicrobial peptide in keratinocytes, macrophages, neutrophiles [50] and placental decidual cells [29, 51]. Cell death and infection rate are also found to be reduced in trophoblast cells pretreated with 25-(OH)D, 1,25-(OH)2D or both [51]. In vivo experiments showed LPS induced early pregnancy loss was reduced if mice were pretreated with vitamin D [52]. Hence it is believed that it might be possible to inhibit placental inflammation by supplementing women with vitamin D in early pregnancy.
Vitamin D Level During Adolescence
Vitamin D levels in adolescents have reduced dramatically over the past several decades and deficiency of vitamin D in serum have been documented in up to 54% of teens [53]. Recommendation for vitamin D intake is (200 IU/d or 5 mg/d) [54]. Decreasing consumption of dairy foods and minimum exposure to sun, application of sunscreen has partially contributed to this problem [53]. Mainly vitamin D is critically important for calcium homeostasis i.e., bone mineral gain during adolescence, and altered calcium homeostasis can have skeletal weakness [55]. Vitamin D receptors are expressed in most cell of colon, brain, small intestine, skin, heart, prostate, breast, gonads lymphocytes, osteoblasts, b-islet cells, and mononuclear cells and regulate many important biological functions. It has a positive effect on the immune system and also has been identified to decrease hypertension, cardiac disease, type 1 diabetes, various cancers, autoimmune and allergic diseases [56].
Maternal Vitamin D Deficiency and Risk of Communicable Disease in Adulthood
Vitamin D deficiency affects 70–80% of reproductive-aged women in India [57]. The presence of higher melanin pigment in skin, low intake of vitamin D and calcium-rich foods, limited availability and intake of vitamin D fortified foods, increasing sedentary and indoor lifestyles due to urbanisation, high rise buildings, increasing pollution that inhibits vitamin D synthesis, use of air conditioning and sunscreen, cultural practices of covering oneself can all lead to vitamin deficiency in Indians. Due to increased calcium needs and absorption, the fetus consumes around 250 mg of calcium each day. The placenta, similar to the kidneys, produces vitamin D receptors that activate 25(OH)D from previtamin D3 [58]. During pregnancy, circulating 1,25(OH)2D levels, the substrate of 25(OH)D, rise three to fourfold due to an increase in the serum vitamin D binding protein, which regulates the quantity of ‘free’ 1,25(OH)2D in the circulation. This process may be influenced by the placenta, calcium and phosphorus balance, and calcitonin, prolactin, and parathyroid hormone homeostasis [22]. There is also growing evidence that a higher maternal vitamin D status may aid the development of the fetal immunological, pancreatic, metabolic, cardiovascular, and brain systems. Vitamin D deficiency is associated with an increased risk of GDM and hypertension, pre-eclampsia, preterm birth, caesarean births, and postpartum depression, according to global data (Fig. 17.2). Maternal Vit D deficiency is also linked to poorer offspring health in the short and long term growth.
Although the most well-known consequences of vitamin D deficiency involve the musculoskeletal system, a growing body of research suggests that low levels of vitamin D may have a negative impact on the cardiovascular system [59]. Vitamin D receptors are found in a variety of tissues, including vascular smooth muscle, endothelium, and cardiomyocytes. In vitro, activated 1,25-dihydroxyvitamin D (1,25-OH D) reduces renin gene expression, regulates the growth and proliferation of vascular smooth muscle cells and cardiomyocytes, and inhibits lymphocyte cytokine production [60, 61]. The absence of vitamin D receptor activation causes tonic stimulation of the renin-angiotensin system, resulting in hypertension and left ventricular hypertrophy in knockout mice [62]. Several cross-sectional clinical studies have found links between low vitamin D levels and plasma renin activity, [63], blood pressure [64], coronary artery calcification [65], and prevalent cardiovascular disease [66].
There could be several explanations for the association between vitamin D insufficiency and cardiovascular disease. Experimental evidence suggests that 1,25-OH D has a role in the control of the renin-angiotensin axis by directly reducing renin gene expression. It is known that vascular smooth muscle cells and endothelial cells express vitamin D receptors and can convert circulating 25-OH D to 1,25-OH D. putative vascular effects of Vitamin D include regulation of smooth muscle cell proliferation, inflammation, and thrombosis. In addition, a lack of vitamin D causes secondary hyperparathyroidism. Myocyte hypertrophy and vascular remodeling are aided by parathyroid hormone (PTH) [67].
Several recent studies have found that women are at high risk for vitamin D insufficiency, which is linked to unfavorable pregnancy outcomes such as preeclampsia and gestational diabetes. It has been demonstrated that vitamin D supplementation is able to reduce adverse pregnancy outcomes when a higher level is achieved, with an increasing efficacy when the target level is raised from 20 to 40 ng/mL or 50 ng/mL [68].
Vitamin D Metabolism During Pregnancy
The metabolism of vitamin D is altered during pregnancy and lactation. At four weeks of gestation, the placenta begins to develop. From this point until term, 25(OH)D is transmitted across the placenta, and the mother’s level of 25(OH)D is associated with the concentration in the fetal cord blood [43]. However, 1,25(OH)2D, the active metabolite, does not easily cross the placenta. By expressing CYP27B1, the fetal kidneys and placenta supply 1,25(OH)2D to the fetal circulation [69]. Expression of all major mediators of vitamin D metabolism in the placenta facilitates trans-placental transfer of calcium to the fetus. Hormones involved in fetal growth, such as insulin-like growth factor 1 and human placental lactogen, may also have a synergistic effect [70]. Estradiol, prolactin, placental lactogen, and parathyroid hormone-related protein (PTHrP) may all affect CYP27B1 activity, and calcitonin increases CYP27B1 transcription. These metabolic alterations lead to a rise in 1,25(OH)2D levels, which are two times greater in third-trimester pregnant women’s serum than in non-pregnant or postpartum women. Normally, 1,25(OH)2D controls its own metabolism through a feedback loop, so that at-risk concentrations cause the production of CYP24A1 while simultaneously down-regulating CYP27B1. There is a decrease in 25(OH)D and 1,25(OH)2D as a result of this procedure. However, during pregnancy, this mechanism is uncoupled, leading to higher maternal 1,25(OH)2D concentrations in the blood Although the CYP24A1 promoter’s placental methylation was crucial to the gene’s functionality, there is no proof that it affects the levels of 25(OH)D in the blood of either pregnant women or newborns. Human breast milk and unfortified cow’s milk are both deficient in vitamin D [71]. Only after lactating women were given 4000–6000 IU of vitamin D per day was adequate vitamin D transmitted in breast milk to meet the infant’s needs [22].
Vitamin D Supplementation During Gestation
Several studies have recommended vitamin D supplementation as an early intervention for the prevention of associated illnesses. Epidemiological data have revealed a connection between fetal life events and a person’s susceptibility to disease in adulthood [72,73,74]. Infants in Finland who received at least 2000 IU/day of vitamin D3 during their first year of life lowered their chance of acquiring type 1 diabetes by 88% over the next 31 years, with no complaints of toxicity [75]. In comparison to placebo, Japanese children who got 1200 IU/day of vitamin D from December through March had a 42% lower chance of contracting influenza A. In a 16-week randomized controlled experiment, African-American children with normotension who received 2000 IU/day versus 400 IU/day had significantly greater serum 25(OH)D levels and significantly decreased arterial wall stiffness [76].
Fetal Programming and Vitamin D
Environmental factors during pregnancy cause the induction of particular genes and genomic pathways that regulate fetal development and eventual illness risk. This process is known as in utero epigenetic fetal programming. Recent research has examined how vitamin D affects epigenetic alteration during fetal programming and in adulthood. Epigenetic effects of vitamin D may be able to explain the most significant extra-skeletal and skeletal effects of vitamin D [77,78,79]. Post-translational modifications of histones’ amino acid tails, including as methylation, acetylation, and phosphorylation, as well as abnormal microRNA production, are examples of epigenetic alterations. There have been reports of early-life interactions between genetic and environmental factors that may be influenced by epigenetic variability [18]. Histone changes, particularly acetylation, are the main epigenetic effects of 1,25(OH)2D that are seen. Through its nuclear receptor (VDR),1,25(OH)2D controls vital cellular metabolic and differentiation pathways. Histone acetylation can alter the epigenetic activity of VDR. It interacts with other nuclear receptors that are affected by various types of histone deacetylases (HDACs) and histone acetyl transferases (HATs). Several studies on animals show that vitamin D influences epigenetics. Mice exposed to 1,25(OH)2D at a young age generate invariant natural killer T (iNKT) cells. Additionally, vitamin D deprivation caused epigenetic alterations in iNKT cells that were irreversible when treated with vitamin D3 or 1,25(OH)2D3 [80]. The epigenetic role of vitamin D in early life may explain adverse pregnancy outcomes associated with maternal vitamin D deficiency. Vitamin D may be important for germline epigenetic inheritance. The epigenetic control of the enzymes regulating vitamin D homeostasis at the fetomaternal interface is mostly unknown. Lowered 1,25-(OH)2D and altered calcium metabolism have been implicated in placental insufficiency, due to inadequate remodeling of the maternal vasculature in early pregnancy. Confirmation of epigenetic modulation of active vitamin D levels at the fetomaternal interface provides strong circumstantial evidence for the interaction of vitamin D and 1-carbon (folate or methyl donor) metabolism in regulating pregnancy outcome. Methyl groups are transferred from one donor molecule to another through a process known as one-carbon metabolism. S-adenosylmethionine is created during this cycle, and it donates its methyl group to cytosine to create methylated CpG [81, 82]. An investigation of diet-induced MHC examined the mRNA expression of lipid metabolic genes in the placenta that may predispose the offspring to early-onset atherosclerosis and related liver damage.
Conclusion
To summarize, understanding the processes that result in the establishment of epigenetic markings, their timing, and their susceptibility to environmental and genetic disruption may provide important insights into the evolution of various placental functions and may identify new risk pathways linked to unfavorable pregnancy outcomes and risk of offspring to chronic diseases. A vast body of research suggests that unfavorable prenatal and postnatal settings can predispose the fetus and newborn to lifetime health or disease. However, not all individuals exposed develop poor outcomes in adulthood. Several investigations demonstrate the need to examine how genetics, the environment, and their interactions interact to address the global problem of non-communicable diseases. Vitamin D supplementation is perhaps a significant, affordable, and safe adjuvant therapy for many diseases given its uncommon side effects and its relatively wide safety margin, but additional big, well-designed studies need assess this.
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Nair, R.R., Ramachandran, S. (2024). Maternal Vitamin D Levels During Gestation and Impact on Offspring’s Risk of Non-communicable Diseases in Adulthood. In: Tappia, P.S., Shah, A.K., Dhalla, N.S. (eds) Lipophilic Vitamins in Health and Disease. Advances in Biochemistry in Health and Disease, vol 28. Springer, Cham. https://doi.org/10.1007/978-3-031-55489-6_17
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