Impact of vitamin D on pregnancy-related disorders

Journal of Steroid Biochemistry and Molecular Biology 180 (2018) 51–64

Contents lists available at ScienceDirect

Journal of Steroid Biochemistry and Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb

Review

Impact of vitamin D on pregnancy-related disorders and on offspring outcome

T

Karoline von Webskya,b, Ahmed Abdallah Hasana,c, Christoph Reichetzedera,b, Oleg Tsuprykova,d, ⁎ Berthold Hochera,d,e, a

Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany Center for Cardiovascular Research, Charité—Universitätsmedizin Berlin, Berlin, Germany c Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Egypt d Institute for Laboratory Medicine, IFLB, Berlin, Germany e Department of Basic Medicine, Medical College of Hunan Normal University, Changsha, China b

A R T I C L E I N F O

A B S T R A C T

Keywords: Vitamin D deficiency Free vitamin D Vitamin D binding protein Epigenetics DNA methylation Single nucleotide polymorphism Preeclampsia Gestational diabetes mellitus Small for gestational age Long term health

Observational studies from all over the world continue to find high prevalence rates of vitamin D insufficiency and deficiency in many populations, including pregnant women. Beyond its classical function as a regulator of calcium and phosphate metabolism, vitamin D elicits numerous effects in the human body. Current evidence highlights a vital role of vitamin D in mammalian gestation. During pregnancy, adaptations in maternal vitamin D metabolism lead to a physiologic increase of vitamin D levels, mainly because of an increased renal production, although other potential sources like the placenta are being discussed. A sufficient supply of mother and child with calcium and vitamin D during pregnancy ensures a healthy bone development of the fetus, whereas lack of either of these nutrients can lead to the development of rickets in the child. Moreover, vitamin D insufficiency during pregnancy has consistently been associated with adverse maternal and neonatal pregnancy outcomes. In multitudinous studies, low maternal vitamin D status was associated with a higher risk for preeclampsia, gestational diabetes mellitus and other gestational diseases. Likewise, several negative consequences for the fetus have been reported, including fetal growth restriction, increased risk of preterm birth and a changed susceptibility for later-life diseases. However, study results are diverging and causality has not been proven so far. Meta-analyses on the relationship between maternal vitamin D status and pregnancy outcomes revealed a wide heterogeneity of studied populations and the applied methodology in vitamin D assessment. Until today, clinical guidelines for supplementation cannot be based on high-quality evidence and it is not clear if the required intake for pregnant women differs from non-pregnant women. Long-term safety data of vitamin D supplementation in pregnant women has not been established and overdosing of vitamin D might have unfavorable effects, especially in mothers and newborns with mutations of genes involved in vitamin D metabolism. Reliable data from large observational and interventional randomized control trials are urgently needed as a basis for any detailed and safe recommendations for supplementation in the general population and, most importantly, in pregnant women. This is of utmost importance, as ensuring a sufficient vitamin D-supply of mother and child implies a great potential for the prevention of birth complications and development of diseases.

1. Introduction A high prevalence of vitamin D deficiency has become of growing concern for scientists and societies worldwide because of potential adverse effects on human health. Importantly, pregnant women and

their children display high-risk groups for vitamin D deficiency and should therefore especially be in the focus of research. This review summarizes background information on vitamin D deficiency in the general population and in pregnant women. At first, a general overview of vitamin D biochemistry and physiology is given.

Abbreviations: 1,25(OH)2D, 1,25-dihydroxy vitamin D2/1,25-dihydroxyvitaminD3; 25OHD, 25-hydroxyvitamin D2/25-hydroxyvitamin D3; Calcitriol, 1,25-dihydroxyvitamin D3; CYP, cytochrome P450 enzyme; CYP24A1, 25-hydroxy vitaminD-24-hydroxylase; CYP27B1, 1α-hydroxylase; FGF-23, fibroblast growth factor 23; LC–MS/MS, liquid chromatography coupled to tandem mass spectrometry; PTH, parathyroid hormone; RMP, Reference Measurement Procedures; RXR, retinoid x receptor; SGA, small for gestational age; SNP, single nucleotide polymorphisms; DBP, vitamin D-binding protein; VDR, vitamin D receptor ⁎ Corresponding author at: Department of Basic Medicine, Medical College of Hunan Normal University, Changsha, China. E-mail address: [email protected] (B. Hocher). https://doi.org/10.1016/j.jsbmb.2017.11.008 Received 30 August 2017; Received in revised form 15 November 2017; Accepted 20 November 2017 Available online 21 November 2017 0960-0760/ © 2017 Elsevier Ltd. All rights reserved.


K. von Websky et al.

by a conformational change of the receptor that allows an obligate heterodimerization with the retinoid x receptor (RXR). The VDR/RXR complex is then able to bind vitamin D responsive elements in the promoter region of hormone sensitive genes, thus regulating their transcription and the respective protein biosynthesis [6]. Serum levels of 1,25(OH)2D are also controlled by a cytochrome P450 enzyme, the 25-hydroxyvitamin D-24- hydroxylase (CYP24A1). It is able to convert both, 25OHD and 1,25(OH)2D, into biologically inactive and water soluble metabolites, including 24,25-dihydroxyvitamin D and calcitroic acid [7]. 1,25(OH)2D is crucial for the maintenance of physiological serum calcium and phosphate levels as well as for bone growth and bone remodeling. 1,25(OH)2D increases the intestinal absorption of calcium and phosphorous and inhibits the secretion of parathyroid hormone. It facilitates renal tubular reabsorption of calcium and mobilizes calcium and phosphate from the bone [7]. Low 1,25(OH)2D serum concentrations activate the parathyroid glands and a subsequent increase in PTH, in turn, stimulates renal 1α-hydroxylase activity in the kidney. Via an enhanced conversion of 25OHD to 1,25(OH)2D, serum calcium and phosphate levels are restored. Another important regulator of vitamin D metabolism is fibroblast growth factor 23 (FGF-23). In concert with the transmembrane protein Klotho, FGF-23 balances concentration of 1,25(OH)2D via a negative feedback loop [8,9]. The VDR has been found to be expressed in a variety of tissues and CYP24A1 is present in all cells containing the VDR. Thus, organs like pancreas, breast, skin, lung, intestine, prostate and others are able to generate 1,25(OH)2D in a tissue-specific, auto-, and paracrine manner [10]. This locally produced 1,25(OH)2D apparently does not influence the concentration of circulatory 1,25(OH)2D and it does not depend so much on other calcium homeostasis regulators like PTH and calcium levels. Available levels of the substrate 25OHD seem to be more important though. In fact, higher concentrations of 25OHD are required for sufficient local production of 1,25(OH)2D in non-renal tissues compared to the requirements in the kidney [10,11]. Besides the classical impact on genes of mineral homeostasis, vitamin D allows a very selective control of genes involved in processes in skeletal muscle, skin, the cardiovascular system, glucose metabolism, and components of the immune system [7]. This multitude of biological processes influenced by the vitamin D metabolism underlines its important role in health and disease prevention. Fig. 1 gives an overview of the biologically relevant steps in the vitamin D metabolism.

Biological steps of the formation of active vitamin D are explained and different metabolites and enzymes of the vitamin D family and their possible actions are presented. In the following, data from clinical studies on deficiency prevalence in different populations are summarized. The second part of the review concentrates on vitamin D and pregnancy. It points out what is known about the physiologic role of vitamin D during pregnancy so far, and what still has to be investigated in the future. This is followed by a summary of studies on the prevalence of vitamin D deficiency in pregnant women and studies on the association of maternal vitamin D status and pregnancy outcomes. Current data on possible adverse effects of vitamin D deficiency on maternal and fetal outcomes like preeclampsia, gestational diabetes, and birth weight and the respective dietary guidelines are discussed. Additionally, epigenetic and genetic factors which might influence maternal and neonatal vitamin D status and challenges for measuring vitamin D are mentioned and in a final conclusion, important open questions and areas for future research are addressed. 1.1. Biochemistry and physiology of vitamin D Vitamin D is a general term for several related metabolites belonging to the vitamin D family. Because of diverse bioactive effects and a structural resemblance to steroid hormones, vitamin D is rather a hormone than a vitamin. It is a key nutrient which plays a major role in various metabolic processes in the human body, especially in calcium and phosphate homeostasis and bone metabolism [1]. Even though it is not a vitamin in the classical sense of the definition, specific amounts are required for many biological processes. Although vitamin D can be obtained from dietary intake, it is less available from food than other nutrients. Only a few foods are suitable sources, including fatty fish species, egg, beef and fish liver oils [1]. The major source in humans is the skin, where vitamin D is photochemically synthesized from a steroid precursor. Upon irradiation with ultraviolet light, pro-vitamin D3 (7dehydrocholesterol) turns into pre-vitamin D3 which then is converted to vitamin D3 (cholecalciferol). In plants, vitamin D2 (ergocalciferol) is synthesized in a comparable manner upon exposure to ultraviolet light out of the pro-vitamin D2 (ergosterol) [2]. Humans can metabolize both vitaminD2 and D3 but vitamin D2 is distinctively less potent than vitamin D3 and de novo synthesis in the skin is only possible for vitamin D3. VitaminD3 leaves the skin through small capillaries and enters the circulation. In the blood, it binds with high affinity to the vitamin Dbinding protein (DBP) and only a small fraction is carried by albumin and lipoprotein. When absorbed from the intestine and released into the blood stream, dietary vitamin D3 also binds to DBP. Either form of the vitamin D bound to DBP is then transported to the liver where it undergoes a first hydroxylation to 25-hydroxyvitamin D2 respective 25hydroxyvitamin D3 (25OHD). This metabolite is not particularly active, but it is the major circulating form of vitamin D. Notably, its concentration in the serum accounts as the most reliable marker to assess the vitamin D status [1]. The conversion to 25OHD by the 25-hydroxylases CYP27A1, CYP2R1 and other cytochrome P450 (CYP) enzymes is not highly regulated nor a rate limiting step [3]. The half-life of this relatively stable molecule is about two to three weeks [1,4]. In a next step, 25OHD bound to DBP is transported to the kidney where it binds to a cell surface receptor for DBP in the epithelial cells of the proximal tubule. Via the transmembrane protein megalin, the renal uptake for the concomitant hydroxylation of 25OHD in the cell is prepared [5]. This second hydroxylation is a crucial and highly controlled step in which the precursor 25OHD is turned into the functional, hormonally active forms 1,25-dihydroxy vitamin D2 respective 1,25-dihydroxy vitamin D3 (1,25(OH)2D), also known as calcitriol. The responsible cytochrome P450 enzyme for the conversion is 1α-hydroxylase (CYP27B1). In the kidney, 1α-hydroxylase is regulated by a number of factors including parathyroid hormone (PTH), serum calcium, phosphate, and by 1,25(OH)2D itself. The biological actions of 1,25(OH)2D are mediated by its binding to the vitamin D receptor (VDR) followed

1.2. Vitamin D deficiency – prevalence in the general population It has long been known that sustained vitamin D deficiency in children is associated with the development of rickets in the developing bone [12]. In adults, vitamin D deficiency classically is known for its manifestation as osteomalacia [13], osteoporosis [14], and fractures [15]. Such impairments in bone metabolism can be prevented or at least mitigated by adequate vitamin D and calcium supplementation [16]. More recently, a considerable amount of literature has been published on the association of vitamin D insufficiency with different diseases. Inverse associations with low serum levels of 25OHD have been observed for cardiovascular disease [17], multiple scleroses [18], chronic infections, autoimmune diseases [19], different types of cancer [20], and diabetes [21] in various studies. A systematic review and metaanalysis of observational cohorts and randomized intervention studies from 2014 investigated vitamin D status and risk of death due to cardiovascular disease, cancer, and other causes. It revealed that most of the studies, while indeed showing an inverse association of circulating 25OHD with cause specific death, did not give evidence for causality. Moreover, the meta-analysis found that supplementation with vitamin D reduced all-cause mortality only in a subpopulation of older adults [22]. Despite conflicting study results, a putative link between different diseases and vitamin D status is of crucial interest because vitamin D 52



Assay Challenges

Pro-vit. D (7-dehydrocholesterol) Skin

Free 25OHD

IrradiaƟon Vit. D (Cholecalcoferol) Skin

1,25(OH)2D (calcitriol)

and SNPs in the DBP gene

Very short t1/2, thus does not

2- Assays are sƟll not well

reŇect long-term vit. D status

established

Enters the circulaƟon

Dietary Vit. D

1- May vary acc. to genotype

Total 25OHD Vit. D (mainly DBP-bound)

(most reliable marker) 1- Measures both DBP-bound and free 25OHD

HydroxylaƟon by CYP enzymes in liver and back to circulaƟon

2- Need for a disƟnct reference method 3- Widespread variaƟon in measured results 4- Divergent results in response to vit. D

DBP-bound 25OHD

Free 25OHD

Renal 1ɲ-hydroxylase 24,25(OH)2D and calcitroic acid inacƟve and water soluble

24-OHase

supplementaƟon

Extrarenal 1ɲ-hydroxylase 1,25(OH)2D (Calcitriol) acƟve

Vit. D = Vitamin D, DBP = Vitamin D binding protein, CYP = Cytochrome P450, 25OHD = 25-hydroxy vitamin D, 1,25(OH)2D = 1,25-dihydroxy vitamin D, 24-OHase = 25-hydroxy vitamin D-24- hydroxylase, 24,25(OH)2D = 24,25-dihydroxyvitamin D , SNP = single nucleoƟde polymorphisms and t1/2 = half-life. Fig. 1. Vitamin D metabolism and assay challenges.

half of the dark winter [33]. Probable explanations are differences in sun seeking behavior, for example avoiding of sun exposure in sunny countries, differences in skin pigmentation, and differences in consumption of vitamin D containing food, such as codfish liver in the northern countries or fortified products in other countries [34].

insufficiency and deficiency are prevalent in most of the world’s populations [23,24]. An official global consensus on the definition of vitamin D deficiency does not exist, but most experts agree in defining vitamin D insufficiency as 21–29 ng/ml. While levels of < 20 ng/ml are considered to be indicative of vitamin D deficiency, a sufficient concentration of 25OHD is reached with ≥30 ng/ml [25]. Over the years, reference ranges for the “normal” human level of circulating 25OHD and recommendations for supplementation have changed. In their review on the topic, Hollis and Wagner give a summary of what recommendations were given at what times and on what basis and put their observations in the context of evolution and history [26]. By now, researches in the field, as well as clinicians, have acknowledged that basically everybody is at risk for a poor vitamin D status. Only few natural foods contain vitamin D, so the supply via the dietary intake is limited. The modern practice of avoiding sun exposure adds to season dependent variations in 25OHD serum concentrations, especially in countries in higher latitudes. As a result of inadequate exposure to sunlight, not enough vitamin D will be produced in the skin. Differences in skin-pigmentation [27], as well as air-pollution, time spent indoors, and aging are more factors leading to an insufficient cutaneous production of vitamin D [28]. In general, a higher serum 25OHD is easier to achieve in lower latitudes and with a lighter skin type. However, even living in a sunny Mediterranean climate is not a guarantor for sufficient production [29]. The European Euronut SENECA Study from 1995 found lower concentrations of mean serum 25OHD in Greece and Spain than in Norway [30]. Similar findings were shown in a large multicentre study in 2013 which found higher vitamin D levels with higher latitude in Europe [31]. A recent study aimed at quantifying the prevalence of vitamin D deficiency in Europe found it to be evident throughout different European populations at prevalence rates the authors claimed to be concerning [24]. Immigrants from Africa and the Middle East who live in northern Sweden were shown to have a very poor vitamin D status [32], whereas a large majority of a representative adult population living close to the Arctic Circle in Sweden displayed adequate vitamin D levels, even during the second

2. Vitamin D and pregnancy 2.1. Physiologic role of vitamin D in pregnancy During pregnancy the maternal metabolism undergoes multiple alterations of physiological processes to ensure a healthy development of the fetus. A close relationship between maternal and fetal vitamin D status during pregnancy underscores the importance of an optimal supply in this critical time. Maternal supply status could significantly affect the development and health of the offspring in utero and in later life [35]. In fact, observational studies from all over the world show a link between low vitamin D levels and adverse pregnancy-related outcomes for mother and child [36–39]. Adaptations in gestational vitamin D metabolism include a characteristic physiologic increase of 1,25(OH)2D in maternal blood. Serum concentrations of 1,25(OH)2D begin to rise early in gestation and highest levels are reached in the third trimester, usually being two- to threefold higher than in non-pregnant women [40,41]. The rise of 1,25(OH)2D induced by pregnancy may depend on substrate availability of 25OHD [42]. However, the reasons and the underlying mechanisms for this increase are not entirely understood. Evidently, renal production of active 1,25(OH)2D is accelerated and maternal renal 1αhydroxylase is up-regulated already in the first weeks of gestation [43]. Animal experiments with nephrectomised rats showed that the substantial rise in serum levels of 1,25(OH)2D during pregnancy is dependent on an intact kidney function [44] and human case reports from anephric mothers with comparable 1,25(OH)2D levels before and during pregnancy have been described [45]. Hollis and Wagner suggested that the increased renal production is uncoupled from feedback 53



Dutch study investigated maternal 25OHD at mid-gestation and fetal cord blood levels at term and found persistent vitamin D deficiency in 21% of the mother-infant pairs [61]. For other continents, results were in the range between 15% [62], and 35% [63] in Australia and roughly 50% in North American [64]. But also populations living in countries of lower latitudes are affected by a relatively high prevalence of vitamin D insufficiency during pregnancy which is shown by studies from Qatar [65], Nigeria [66], and Iran [67]. Risk factors associated with vitamin D deficiency delineated by several studies were physical inactivity, dietary vitamin D intake, vitamin D supplementation and non-European country of origin. Results between the studies are not directly comparable, as the time in pregnancy when measurements were taken differed from study to study. Moreover, variations in skin color, social and cultural habits concerning sun seeking behavior, diet, and other factors are evident. Importantly, most of the above cited studies found an association between vitamin D insufficiency and the onset of various pregnancy complications. In the following, potential adverse outcomes of vitamin D insufficiency in the mother and offspring will be presented.

control mechanisms of classic regulators like calcium, phosphorus, and PTH, but rather is triggered by a combination of several factors [26]. As an increase of 1,25(OH)2D levels in early pregnancy is already observed before PTH levels rise, it is assumed that PTH might not represent a major regulator of maternal renal 1α-hydroxylase during this stage [45]. The supraphysiologic 1,25(OH)2D concentrations could in part be mediated by calcitonin which was shown to stimulate renal 1α-hydroxylase gene expression independent of calcium levels [46]. Concentrations of pregnancy-related hormones like parathyroid hormonerelated protein (PTHrP), estradiol, prolactin, and placental lactogen are increased in the third trimenon and may also activate maternal renal 1α-hydroxylase [45]. Animal experiments showed that besides the kidney, the placenta is a potential source of 1,25(OH)2D [47]. Local production by 1α-hydroxylase was shown for decidual, placental, and fetal cells [48]. Also, the CYP24A1 gene is specifically hypermethylated in the placenta during pregnancy. The decreases in expression and activity of 24-hydroxylase in this organ may minimize the degradation of placental 1,25(OH)2D [49]. It is not clear, however, if the local production of 1,25(OH)2D from the placenta and other extrarenal sources substantially contributes to the drastic increase in systemic maternal 1,25(OH)2D plasma levels [45]. The origin and role of 1,25(OH)2D in the fetal circulation is not well understood until now. Expression of 1α-hydroxylase in the fetal kidneys suggest the potential of the fetus to generate 1,25(OH)2D [50]. It is known from rats that 1,25(OH)2D does not readily cross the placenta [51]. In contrast, a small study in chronically catheterized fetal and maternal sheep showed a transplacental crossing of 1,25(OH)2D [52]. Data regarding humans mostly derives from rather old studies with conflicting results. In a fairly recent study by Young et al. no association between maternal and fetal cord blood levels of 1,25(OH)2D was observed, corroborating the assumption that the fetus completely depends on sufficient levels of maternal 25OHD as the ultimate precondition for its own renal production of 1,25(OH)2D [53]. Interestingly, in contrast to rising 1,25(OH)2D levels, maternal plasma levels of 25OHD remain relatively stable during pregnancy, with only slight adaptations [54,55]. 25OHD readily passes the placenta [56], and even though it is not clear how a transplacental transport of 25OHD is mediated in humans, maternal values correlate well with cord blood values [54,55]. Because of a relatively long half-life of up to 3 weeks, cord blood 25OHD levels can serve as a useful measure of the maternal term vitamin D status on one hand and the neonatal vitamin D status on the other hand.

2.3. Impact of vitamin D deficiency on maternal and fetal outcomes 2.3.1. Impact of vitamin D deficiency on maternal outcome – preeclampsia Preeclampsia is a multifactorial syndrome specifically occurring during pregnancy, with the placenta being causal for the development of the disorder [68]. Symptoms may be present more frequently in the third trimester but an early-onset of the disease is known [68]. Accordingly, the pathogenesis has been described as a two-stage process [69], in which the first stage (in the first and early second trimesters) is characterized by maternal spiral artery remodeling and a disturbed placentation with poor trophoblast invasion [70]. In the second stage (after 20 weeks of gestation) placental and systemic endothelial cell dysfunction lead to the hallmark symptoms of hypertension and proteinuria [68]. An exaggerated inflammatory response is part of the complex pathophysiology of preeclampsia, as are widespread endothelial cell dysfunction and angiogenic imbalances disturbing the maternal-fetal exchange [68]. It is assumed that vitamin D plays an important role in controlling fetal–placental immune responses during pregnancy but the pathogenic mechanisms linking low vitamin D levels with preeclampsia are not well understood [71]. However, several immunomodulatory pathways and cardiovascular responses are modulated by vitamin D, consequently, low vitamin D has been postulated to be related to the onset of preeclampsia [71–73]. In vitro experiments showed that the expression of pregnancy-associated hormones in the placenta is influenced by molecules of the vitamin D metabolism [74–76] and that placental autocrine vitamin D exerts antibacterial and anti-inflammatory effects in maternal decidua and fetal trophoblast [77]. Ex vivo studies with placentas from VDR−/− mice and Cyp27b1−/− mice suggested that trophoblastic vitamin D is important for controlling placental inflammation [77]. Further data derives from animal models with vitamin D supplementation: in a rat model of reduced uterine perfusion pressure, vitamin D supplementation improved preeclampsia-associated pathologic characteristics like proinflammatory cytokine levels and hypertension [78]. Reduced inflammation and an improved angiogenic balance was observed after vitamin D supplementation in a rat model of pregnancy-induced hypertension [79]. An interesting mechanistic explanation for the overall increased risk of preeclampsia with male fetal gender was recently presented by Olmos-Ortiz et al. [80]. They were able to show that testosterone concentration was higher in the umbilical cord blood of male neonates, whereas levels of cathelicidin, an antimicrobial peptide in the placenta, were less compared to females. Simultaneously, they showed that testosterone significantly inhibited CYP27B1 and stimulated CYP24A1 gene expression in cultured trophoblasts of placental cotyledons from the same human cohort of term uncomplicated pregnancies. These results suggest that a shift in the placental CYP27B1/ CYP24A1 ratio might directly affect local calcitriol synthesis.

2.2. Prevalence of low vitamin D levels in pregnant women Increasing insight and a better understanding of the multiple physiological functions of vitamin D during pregnancy led to questions on potential adverse effects of vitamin D deficiency in this special period. Multiple causes like a reduced dietary intake, insufficient UV exposure, decreased endogenous synthesis, as well as factors and diseases affecting the absorption or the metabolism of vitamin D may account for a development of deficiency. However, the aetiology of vitamin D deficiency in pregnant women is not well understood so far [57]. In the last decades, a considerable number of observational studies have looked at the association between maternal vitamin D status and maternal and neonatal outcomes. The vitamin D status has been investigated in different populations of expecting women and nearly all studies showed a disturbingly high prevalence of vitamin D insufficiency [36–39]. A systematic review and meta-analysis summed up all studies on vitamin D status in maternal and newborn populations at a global level. Available data from the five global regions showed that vitamin D deficiency was present in more than half of pregnant women and newborns in nearly all regions [58]. Other European studies found prevalence rates for vitamin D insufficiency ranging from 10% in a multiethnic Swedish cohort [59], and 35% in an English cohort [60], until up to nearly half of the population in a German cohort [55]. A recent 54



sectional study from 2009 showed that vitamin D deficiency was associated with increased odds of primary cesarean section [107]. In contrast, an RCT assessing maternal vitamin D status showed no effect of vitamin D supplementation on the mode of delivery [42]. Overall, current evidence regarding the association between vitamin D deficiency and an increased risk for cesarean section remains contradictive [108–110,105,106]. One underlying reason for the observed differences in study results might be differing points in time of vitamin D status assessment during pregnancy. For future studies, serial measurements would be beneficial and vitamin D status close to the time of delivery may be important to look at.

Subsequently, less placental vitamin D might lead to less cathelicidin expression and therefore to a decreased antibacterial and anti-inflammatory activity in the placenta. In regards to human data, several studies [81–83] and meta-analyses [84,85], demonstrated association of low maternal vitamin D status with a higher risk for preeclampsia. A recent large prospective cohort study found an association between maternal serum 25OHD concentrations on the composite outcome of gestational age of the newborn and preeclampsia [86]. However, contradictory results from other studies limit the possibility to draw conclusions as to what extent vitamin D insufficiency is causal for the development of preeclampsia [87–89]. Nonetheless, multiple studies investigated vitamin D supplementation as a possible intervention strategy to improve preeclampsia outcomes. Some studies found a reduced risk [86,90,91], while others did not see an effect of interventions on the occurrence of preeclampsia [42,87,92,93]. According to Hollis and Wagner, a possible reason for this could be that the intervention was started too late in the course of pregnancy [35]. The authors claim that a putative protective effect of vitamin D on placental vascularization and angiogenesis takes places at a very early point in pregnancy and that therefore, entering pregnancy with an adequate vitamin D plasma level is crucial. If the role of low vitamin D for the development of preeclampsia will be substantiated by profound data, interventional strategies clearly need to be investigated more thoroughly, as they might offer a promising tool for the prevention of preeclampsia.

2.3.4. Impact of vitamin D deficiency on fetal outcome – fetal bone development The fetus completely relies on maternal 25OHD and calcium stores. Skeletal mineralization demands high amounts of calcium which have to be provided by the mother via an active transport towards the fetal bloodstream. 1,25(OH)2D is important for an efficient gastrointestinal calcium absorption in the mother [111,112]. Whereas only severe, long-standing calcium deficiency during pregnancy will lead to skeletal defects at birth [113], hypocalcemia and rickets in newborns due to vitamin D deficiency are not usually diagnosed at birth, but rather develop postnatally [114]. However, vitamin D deficiency may still affect offspring bone mineralization [115]. Evidence regarding associations between maternal vitamin D status and offspring intrauterine bone development is conflicting [115]. Interestingly, calcium metabolism and vitamin D are not so closely linked during pregnancy as it would be expected [35,41]. Vitamin D levels rise before the calcium demand of mother and child becomes important and they are back to normal during lactation, a time of high calcium demand [35]. Experiments with vitamin D deficient and insufficient animals indicated that vitamin D is not required to regulate serum mineral concentrations in the fetus, as the offspring displayed a normal skeletal mineral content [116–118]. On the other hand, a number of human studies showed correlations between maternal vitamin D levels and readouts of neonatal bone development, such as femoral volume, bone mineral content and tibial cross-sectional area [115]. Meanwhile, there is accumulating evidence of a link between maternal vitamin D status during pregnancy and bone development in later life of the offspring. Javaid et al. found in a study including 198 children that maternal vitamin D status at 34 weeks of gestation had an effect on skeletal development which was still observable in the offspring at the age of 9 years [119]. A large cohort study including 3960 mother-offspring pairs, however, found no association between maternal vitamin D status in pregnancy and offspring bone mass at 9–10 years of age [120]. Furthermore, supplementation of women with vitamin D during pregnancy did not lead to increased offspring whole-body bone-mineral content compared to placebo [121]. Conversely, another longitudinal prospective study investigating 341 mother and offspring pairs found a positive association between maternal gestational vitamin D status and offspring bone mass at 20 years.

2.3.2. Impact of vitamin D deficiency on maternal outcome – gestational diabetes mellitus Gestational diabetes mellitus (GDM) is a common pregnancy complication with substantial short- and long-term adverse health consequences for both mother and child [94]. Moreover, GDM is related to other obstetric problems like cesarean section rate and preeclampsia [95]. The role of maternal vitamin D status in GDM is not entirely clear but vitamin D may influence glucose tolerance during pregnancy [96]. Vitamin D is known to regulate insulin production by pancreatic betacells and improve insulin sensitivity [97,98] and it might influence insulin secretion and sensitivity of insulin-responsive tissues via its effects on intracellular calcium levels [96]. An interaction of vitamin D with insulin-like growth factors (IGF) could have an impact on glucose homeostasis [96]. Polymorphisms of the vitamin D receptor gene are discussed to play a role in GDM [99]. In several studies, maternal vitamin D deficiency in pregnancy was significantly associated with an elevated risk for GDM [100–103]. A recent meta-analysis from 20 observational studies in different populations found that insufficient vitamin D levels were associated with an increased GDM risk. However, large differences in study design and an insufficient consideration of confounding factors of the investigated studies may have affected the observed association in this meta-analysis [104]. Interestingly, a recent randomized controlled trial (RCT) investigating early pregnancy vitamin D status and maternal and infant outcomes among ethnically diverse women found a significant increase in risk for GDM with increasing serum 25OHD among Hispanic women [64]. Zhou et al. observed a similar association in a Chinese cohort [105], and related their surprising finding to older age and higher body mass index of the investigated group. The controversial findings show that large clinical trials in diverse cohorts are needed to clarify the role of vitamin D for GDM. Additionally, more well-designed RCTs investigating supplementation and its specific therapeutic potential for GDM are warranted.

2.3.5. Impact of vitamin D deficiency on fetal outcome – birth parameters and effects on long-term health Lack of vitamin D during pregnancy may be an important in utero cue which could have pronounced and irreversible effects on the longterm metabolic health of the offspring. Despite mounting evidence for this relation, study results remain inconsistent to a certain degree [122]. Early classical readouts for any potential adaption of the fetus to adverse environmental influences during gestation are a low birth weight, being small for gestational age (SGA) and preterm birth. Those parameters are especially important, as they are associated with increased disease susceptibility later in life [123]. Current studies describe a positive association between maternal vitamin D levels and birth weight [124,64,125,126]. Although some studies did not see any association [105,127], a recent systematic

2.3.3. Impact of vitamin D deficiency on maternal outcome – cesarean section There is a biological rationale for adverse labor and delivery outcomes with low vitamin D status in mothers, as vitamin D normally increases skeletal muscle function. Deficiency, therefore, might lead to poor uterine and skeletal muscle performance in labor [106]. A cross55



recommended ranges, could cause health problems in certain cases. The occurrence of adverse effects after vitamin D supplementation in about 200 children was observed in the 1950s, although not explainable back then. Hypercalcemia occurred in infants supplemented with vitamin D via fortified milk products [152]. As there were also children receiving the same supplementation but were not adversely affected, an underlying defect in the children with symptoms was suspected [152]. But only about 60 years later, Schlingmann et al. were able to identify different CYP24A1 mutations in children with idiopathic infantile hypercalcemia (IIH), which they assumed to be causative for the disease [153]. As symptoms of vitamin D intoxication were only seen after high-dose vitamin D prophylaxis in those previously healthy children with the mutation, it was suggested that vitamin D supplementation might be an important environmental trigger for the development of the full-on clinical phenotype of IIH. Meanwhile, a mutation in the SLC34A1 gene encoding the renal sodium-phosphate co-transporter NaPi-IIa has been identified as another important mutation in the complex and heterogeneous pathogenesis of IIH [154]. Mutation in this gene in concert with characteristic low circulating FGF23 levels lead to renal phosphate wasting, hypophosphatemia, high vitamin D levels, and the hallmark trait hypercalemia [154]. Since the first reports on the potential role of gene mutations in CYP24A1 for hypercalcemia, this relation has been confirmed in pediatric [155] and adult patients [156]. It became evident that longstanding symptomatic consequences of the genetic defects include nephrocalcinosis in childhood and nephrolithiasis in adults. Most of the data up to today comes from case reports and few small studies have been conducted [155–157]. In the light of the possibility that overt idiopathic infantile hypercalcemia and adult hypercalcemia might be provoked by vitamin D supplementation, the question arises what effects a supplementation might have during pregnancy in women with gene mutations of CYPs. As mentioned above, maternal vitamin D metabolism adapts during pregnancy. Despite the increase in 1,25(OH)2D, pregnant women do not develop symptomatic hypercalcemia under normal circumstances [35]. In pregnant women with CYP24A1 mutations, however, this could be different, but no clinical study data on the topic has been published. Importantly, the first cases of maternal hypercalcemia during pregnancy caused by a CYP24A1 mutation have recently been described. In these patients, recurrent hypercalcemia, nephrocalcinosis, as well as nephrolitiasis, were found [158,159]. These findings underline that supplementation with vitamin D during pregnancy could become a serious risk in women with (unidentified) genetic diseases of the vitamin D metabolism or the tightly linked mineral metabolism. Not only might mothers suffer from hypercalcemia and other sequelae as a result of excess vitamin D intake, but the health of the offspring could be compromised as well [160]. Ideally, a screening for CYP24A1 mutations and other genetic diseases should be incorporated into prenatal care regimens, if not for all pregnant women, at least in those presenting with clinical findings like hypercalcemia and hypercalciuria. An early genetic diagnosis in such patients would be important to adapt the diet and choose an appropriate therapy for mother and child.

review and meta-analysis highlighted a positive impact of increased maternal 25OHD concentrations due to vitamin D supplementation on birth weight and birth length. No impact of 25OHD supplementation on the incidence of SGA and preterm birth was found in the meta-analysis [87]. Some observational studies support this missing association [64], yet others demonstrated that lower maternal vitamin D levels during pregnancy are associated with a higher risk for SGA [128,125,98,86]. Regarding data on preterm birth and its association with vitamin D levels, study results are similarly conflicting [64,129,130]. A well-designed population-based prospective study on maternal vitamin D deficiency during pregnancy and fetal outcomes in 7098 mother and child pairs revealed that low maternal 25OHD concentrations were associated with proportional fetal growth restriction and with an increased risk of preterm birth and SGA at birth [122]. As the authors emphasize, all of these three outcomes are associated with perinatal mortality and later life diseases [122]. Evidence for a link between maternal vitamin D status and the risk for early postnatal overweight in the offspring was recently reported [131] and lower maternal vitamin D status may be linked to differences in offspring fat mass [60]. However, a study from a multi-ethnic Asian population did not find associations between maternal vitamin D levels during pregnancy and birth weight nor offspring adiposity outcomes in the first 2 years, possibly due to low prevalence of severe vitamin D deficiency in this mother-child cohort [132]. Besides the metabolic impact, vitamin D has several effects on the immune system and, as such, on inflammatory processes [35]. Therefore, vitamin D could influence the development of diseases in which inflammation is part of the pathogenesis [133]. Type 1 diabetes as an autoimmune disease is characterized by destruction of the beta cells which might be influenced by early environmental cues in utero [134]. The immunosuppressive effects of vitamin D could positively impact on the autoimmune destruction of pancreatic beta-cells during development of type 1 diabetes [135]. Studies demonstrated associations between lower 25OHD concentrations during pregnancy and an increased risk for type 1 diabetes in the offspring [136,137]. Yet again, other studies were not able to demonstrate these associations [134,135,138]. However, dietary vitamin D supplementation during pregnancy or infancy was shown to decrease the risk for type 1 diabetes [139,140]. Other possible interactions between vitamin D and the developing immune system were demonstrated, ranging from childhood allergic diseases like asthma, allergic rhinitis, and topic eczema to later life multiple sclerosis susceptibility [141–145]. Definite conclusions cannot be drawn from the available literature so far, as both low and high vitamin D levels were shown to be associated with an increased risk for immunologically mediated diseases in childhood or later life [141–145]. This notion is supported by a systematical review of current literature on the effects of in utero vitamin D exposure on childhood allergy and infection outcomes, which could not present consistent results [146]. Another connection between gestational vitamin D status and later life diseases susceptibility can be drawn for neurological disease. Vitamin D takes part in the regulation of cellular proliferation, differentiation, and survival of the developing brain [147]. Findings of seasonal variation in the prevalence of neuropsychiatric diseases such as schizophrenia and autism were shown to be related to maternal vitamin D deficiency [148–150]. Altogether, evidence indicates a positive association between maternal vitamin D status and fetal development [151] In the light of this relation, an adequate vitamin D status during pregnancy and in early childhood could help lower the risk for adverse birth outcomes and later life diseases [35].

2.4.2. Vitamin D and epigenetics, a mechanistic link between maternal vitamin D status and offspring long-term health Epigenetic mechanisms, like histone modifications, non-coding RNAs, and DNA methylation alter gene expression without changing the DNA base sequence. By now, epigenetic modifications are widely recognized as fundamental mechanisms during embryonic development. Epigenetic alterations of gene expression patterns can have consequences on the further development of the fetus and might affect the future adult health [98,123]. The complex system of vitamin D metabolism comprises many targets, including the VDR and enzymatic molecules whose function could be crucially changed by epigenetic modulation of the respective genes [161]. On the other hand, the vitamin D status itself may induce epigenetic alterations in various genes,

2.4. Genetic and epigenetic mechanisms affecting vitamin D status of mother and child 2.4.1. Rare genetic defects Low levels of vitamin D are a concern for health outcomes, but so are high levels. Potentially toxic effects of vitamin D can occur with overdosing [91]. Moreover, supplementation, even within the 56



standard technique however, is LC–MS/MS [176]. As correlation of the DiaSorin assay to LC–MS/MS in general is rather weak, there has been discussion on to what extent the current guidelines cut-off values for deficiency need to be reassessed [174]. Despite 25OHD currently being the best functional indicator of vitamin D status, its measurement still represents with several analytical (technical) challenges [177]. Specificity, precision, linearity and accuracy of immunoassays may vary a lot due to cross-reactivity with vitamin D molecules like C3-Epimers or 24,25(OH)2 vitamin D, and due to heterophilic antibodies and other complications [178]. Suggested sources of interference for binding assays include matrix effects and ion suppression effects of phospholipids [179]. Thus, there has been continuous effort of assay manufacturers and scientists to develop better assay robustness and performance. This includes development of assays with co-detection of 25OHD2, optimization of established sample preparation techniques as well as implementing novel sample preparation methods like magnetic particles and aptamers [170,178,179]. Another approach to widespread variations in measured 25OHD levels is standardization achieved by defining one distinct reference method procedure for 25OHD measurement and one standard reference material. In 2010, the Vitamin D Standardization Program (VDSP) was initiated as an international joint approach to standardize the laboratory measurement of vitamin D [23]. According to the aims of the program, certified assays would be accurate and comparable over time, location, and laboratory procedure to the Reference Measurement Procedures (RMPs) developed at the National Institute for Standards and Technology (NIST), the University of Ghent, and the Centers for Disease Control and Prevention. With comparable results across different methods and manufacturers, more reliable cross-sectional and international prevalence estimates of vitamin D deficiency could be realized in the future. Moreover, retrospective standardization of existing samples from epidemiological and clinical studies is a goal of the program [180]. Standardization efforts of VDSP have resulted in the certification of a number of university and commercial laboratories and companies so far [174]. However, independent from technical progress, biological influences may have a bigger impact on the observed variations in measured vitamin D levels than initially thought.

including genes of the vitamin D metabolism [161]. Zhou et al. showed that vitamin D supplementation changed the methylation levels in genes encoding for CYP enzymes [162]. However, so far only little is known about the interrelationship of vitamin D and epigenetic mechanisms. Vitamin D as an important micronutrient may influence the genome’s methylation status, comparable to other nutritional components of the maternal diet [163]. In fact, first indications of an association between maternal vitamin D status and epigenetic changes in the offspring come from animal experiments. In rat offspring of a vitamin Ddepleted parent generation, hypermethylation of a blood pressure-relevant gene was found in an array analysis of about 15 000 genes [164]. A mouse model of maternal vitamin D depletion even showed changes in DNA methylation in two generations of offspring, thus indicating transgenerational long term effects of the vitamin D status on the epigenome [165]. In a small human study, Jung et al. found significant differences in DNA methylation profiles in the cord blood of newborns with high versus low 25OHD levels [166]. However, a recent large genome wide study did not find associations between maternal 25OHD concentrations at midterm and cord blood DNA methylation [167]. Another study specifically looking at the influence of midterm maternal 25OHD levels on DNA methylation levels of crucial genes for fetal growth (in cord blood samples) did not see an association either [168]. Clearly, a relationship between the maternal vitamin D status and the methylation of genes in the offspring has to be further investigated. Epigenetic modifications could also affect the expression of genes involved in vitamin D synthesis and degradation and, as such, display a direct impact on vitamin D status. DNA methylation can essentially influence how a certain gene is expressed. In general, hypermethylation in the promoter region of a gene is usually linked to gene silencing and decreased gene expression [123]. In contrast, promoter hypomethylation in general leads to an increased gene expression [123]. Hypomethylation of hepatic CYP2R1, the gene encoding a crucial 25-hydroxylase for the production of 25OHD, could account for an increased expression of CYP2R1 enzyme and a subsequent increase in 25OHD levels [162]. Vice versa, hypermethylation and concomitant lower expression levels in the CYP24A1 gene, which encodes an important enzyme of vitamin D catabolism, would lead to an increase of 1,25(OH)2D. Interestingly, placental CYP24A1 is specifically hypermethylated during pregnancy [49]. A decreased expression of placental CYP24A1 could lead to a decreased local degradation of 1,25(OH)2D and might therefore serve for a better availability of 1,25(OH)2D for the fetus at the maternal-fetal interface. Genetic and epigenetic mechanisms affecting the vitamin D status are summarized in Fig. 2.

2.5.1. Total versus free vitamin D and variations in DBP Most vitamin D metabolites in the circulation are transported bound to proteins and free 25OHD represents only a very small fraction of less than 1%. In comparison, about 15% of all vitamin D metabolites are albumin-bound and about 85% are bound to the DBP [181]. Still, the small free 25OHD-fraction may be biologically relevant, especially in cases where the bound-to-free relationship of metabolites is shifted because of changes in the availability of the binding protein. Therefore, measurement of total 25OHD, as the currently widely accepted parameter, may not be the only and best method for determining vitamin D status, in particular for populations with altered DBP levels. 25OHD is bound to DBP in order to get into the renal cells to be activated by the 1α-hydroxylase in the kidney. However, for other than renal cells, binding to DBP would mean a decreased uptake, as the receptor for DBP, megalin, is not widely expressed in other tissues. Extrarenal, intracrine 1α-hydroxylase activity is suggested to be triggered by free 25OHD [182]. Accordingly, 1,25(OH)2D production in nearly all other tissues than the kidney would be dependent on the amount of circulating DBP, because with higher levels of DBP, more 25OHD is bound and less free 25OHD is able to enter the non-renal target cells [182]. This fits the free hormone hypothesis, according to which protein-bound hormones are relatively inactive while unbound hormones are more likely to exert biological activity and are therefore bioavailable. It is known that plasma levels of DBP may vary in different pathological conditions like infection [183], liver disease and nephropathy [184,185], and according to genotypes or single nucleotide polymorphisms (SNPs) in the DBP gene [186]. Differences in DBP levels

2.5. Determining the vitamin D status – still a challenge Methods for detection of vitamin D include physical detection with binding assays like high performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC–MS/MS) on one side, and immunoassays like chemiluminescence immunoassays (CLIA), radioimmunoassy (RIA) on the other side. Despite establishment of high-quality assays for vitamin D measurement [169,170], differences in analytical assays still lead to remarkable degrees of variation in obtained results [24]. Diverging results have also been observed for serum 25OHD in response to vitamin D supplementation in different populations [171–173] including pregnant women [87]. This represents a major challenge for the development of evidence-based clinical guidelines [23]. Most clinicians, researchers and laboratories use total 25OHD as the main readout for routine diagnostic testing as well as for clinical studies, and 25OHD is also the parameter recommended by health authorities and guidelines for measurement of the vitamin D status [174]. The 25-OHD cut-offs used in most guidelines have been defined on the bases of studies that used the DiaSorin radioimmunoassay RIA method [175]. Nowadays largely accepted gold 57



GeneƟc and EpigeneƟc Diīerences AīecƟng Vitamin D Status

DNA MethylaƟon

MutaƟons

Hypermethylated Promotor

SLC34A1

CYP24A1 Mutated CYP24A1

CYP24A1 TranscripƟon and TranslaƟon Serum 1,25(OH)2D

DefecƟve

ј Serum 1,25(OH)2D

Promotor

CYP2R1

Promotor

CYP2R1

Mutated SLC34A1

SLC34A1 TranscripƟon and TranslaƟon

Renal NaPi-IIa

Hypercalcemia, Hypercalciuria and Nephrolithiasis

DefecƟve

Renal NaPi-Iia >oss of funcƟon

TranscripƟon and TranslaƟon

Serum 25OHD

љ TranscripƟon and TranslaƟon

љ Serum 25OHD

Renal phosphate wasƟng, hypophosphatemia, ј Vit. D levels and Hypercalemia

Vit. D = Vitamin D, CYP = Cytochrome P450, 25OHD = 25-hydroxy vitamin D, 1,25(OH)2D = 1,25-dihydroxy vitamin, SLC34A1 = Solute carrier family 34 member 1 and NaPi-Iia = Na+-dependent Pi cotransporter type IIa Fig. 2. Genetic and epigenetic mechanisms affecting the Vitamin D status.

and extraskeletal health is still under debate. Existing national and international recommendations for gestational vitamin D supplementation do not yet comply with evidence-based medicine because of lacking high-quality evidence. Studies display great differences in regards to design, methodology and hardly contain information on adverse effects [91]. Moreover, the presence of confounding factors is a major limitation, not only within observational studies but also for the larger meta-analyses looking into vitamin D deficiency and pregnancy outcomes [194–196]. As the statistical approaches and definitions of the confounding factors vary from one study to another, it is complicated to provide conclusive evidence on the relations between vitamin D status and pregnancy and birth outcomes, even from meta-analyses [196]. Consequently, recommendations from public authorities differ globally, and even within one country. While the Institute of Medicine (IOM) and authorities in European countries recommend maintaining a serum 25OHD concentration of 20 ng/ml [197–199], The Endocrine Society suggests values of 40 ng/ml [200]. For pregnant and lactating women in particular, there are “still major gaps in our understanding of the importance of optimal vitamin D status” as recently stated by experts in the field [57]. According to a Cochrane Review from 2016 evaluating the effects of vitamin D supplementation during pregnancy, it is not clear if vitamin D should be given as standard prenatal care [91]. The European Food Safety Authority (EFSA) states that an adequate intake for pregnant women is the same as for non-pregnant women [201] and the IOM suggests 600 international units daily (IU/d) for adults including pregnant women to prevent deficiency [197]. Those recommendations are largely based on bone health and assume a minimal sun exposure. While the safe upper limit is set at 4000 (IU/d) for healthy adults [197], for pregnant women, doses higher than 600 (IU/d) are rather not recommended by American authorities due to safety concerns [200]. Above mentioned epigenetic and genetic factors may add to variations in supplementation response and environmental, nutrient, drug and other interactions with vitamin D metabolism could influence the individual reaction to high vitamin D exposure due to

may cause differences in the levels of free vitamin D [187], whereas vice versa, vitamin D supplementation apparently does not influence DBP serum levels [188]. During pregnancy, a state which is characterized by high estrogen concentrations, DBP production is increased [189–191], as hepatic synthesis of DBP is stimulated by steroid hormones. It is not clear however, if this naturally occurring increase of DBP levels during pregnancy may influence the bioavailability of vitamin D for mother and child. Whereas Kim et al. reported significantly lower levels of calculated bioavailable 25OHD (free plus albuminbound forms) in pregnant women compared to non-pregnant women [191], Schwartz et al. did not see any differences between pregnant women and non-pregnant women when comparing directly measured free 25OHD levels [192]. Notably, calculated values of free 25OHD, using serum total 25OHD, DBP and albumin concentrations for the calculation, seem to overestimate the directly measured actual values [188]. Bikle et al. suggested a lower affinity of DBP for its metabolites during pregnancy as a compensatory mechanism for the increased DBP concentrations, so that the level of free 25OHD would stay balanced [189]. Interestingly, Chun et al. recently showed that variations in maternal and cord blood vitamin D levels, due to genetic polymorphisms in the maternal DBP gene, could have effects on the newborns birth weight [193]. Taken together, total serum 25OHD may only incorrectly reflect the vitamin D status in certain ethnic groups and genetic backgrounds, in certain diseases and during pregnancy. Therefore, measurement of free 25OHD should be considered for states of varying serum DBP concentrations, including pregnancy. It is important to mention that the specific measurement of free 25OHD is comparably time- and labor-intensive. Fig. 1 addresses the challenges of measuring the vitamin D status.

2.6. Dietary recommendations for vitamin D Despite the recognition of vitamin D deficiency as a worldwide health issue, an optimal serum concentration of vitamin D for skeletal 58


[212] [87,212] [213] [214] [194,195,215] [195] [216]

Protects against low birth weight No impact on the incidence of being small for gestational age and pre-term birth Not associated with risk of type 1 diabetes Not associated with risk of allergic rhinitis Associated with lower risk of wheeze Not associated with asthma nor other atopic conditions Increased in utero exposure to vitamin D is inversely associated with the risk of asthma and wheeze in childhood - A higher risk of childhood asthma

supplementation. However, based on limited data from randomized controlled trials, some authors suggest that pregnant women can be supplemented with 1000–2000 (IU/d) during the second and third trimesters, and deficiency during pregnancy can be treated with daily doses of 4000 IU [42,202,203]. These discrepancies of current recommendations underscore the lack of a consensus on the required intake for pregnant women as the role of vitamin D supplementation in the preventive treatment of pregnancy-associated complications has remained uncertain. Importantly, the impact of extra oral vitamin D on maternal and neonatal health outcomes implies a great potential [35] and thus needs further elucidation with a special focus on efficiency and safety. Known meta-analysed associations between vitamin D status and supplementation during pregnancy and maternal and offspring’s longterm health outcomes are summarized in Table 1.

[209]

[208] - Reduces pre-term birth risk

3. Conclusion

-

Multiple effects of vitamin D on human health have been described and it has long been known that severe vitamin D and calcium deficiency can lead to rickets and osteoporosis. In the last decades, associations of vitamin D insufficiency with diseases like multiple sclerosis, diabetes, cancer, and others have been observed. Despite a plethora of studies on the topic, the relation of vitamin D deficiency and adverse health outcomes needs to be supported by more clinical data. It has been suggested that an adequate supply of vitamin D would prevent the development of these diseases, a concept which needs verification in large interventional trials. Vitamin D is especially important during pregnancy, as demonstrated by an impressive physiologic increase in maternal circulation. Observational studies from all over the world have found high prevalence rates of vitamin D insufficiency and deficiency in pregnant women. A poor vitamin D status of the mother may have negative consequences for the mother and potentially impair short and long term health of the offspring. Potential mechanisms for the observed associations include metabolic, immunomodulatory and anti-inflammatory effects of vitamin D and epigenetic modifications in crucial vitamin Dassociated genes. The concept of preventing and treating severe pregnancy complications with vitamin D is promising. However, until now, study results remain contradictive and do not unequivocally support therapeutic supplementation as a safe strategy for the prevention of pregnancy complications, as long-term safety data is missing. In women and newborns with genetic mutations of the vitamin D metabolism and associated pathways, vitamin D supplementation might lead to an accumulation of active metabolites and, therefore, pose a risk factor for the development of symptomatic hypercalcemia. Because of the remaining high prevalence of vitamin D insufficiency worldwide and even more so because of its potential negative consequences, scientific and medical interest in the use of vitamin D as a therapeutic option will still be growing. Currently available data of research in the field needs to be expanded with further observational studies and interventional randomized controlled trials. Ideally, a consensus on optimal vitamin D serum levels in different populations, including pregnant women, could be achieved. Future goals should comprise an establishment of new markers, a standardization of analytical assays and the implementation of evidence-based guidelines for the supplementation of vitamin D. Providing a sufficient vitamin D supply of mother and child could help to prevent birth complications and development of diseases.

High vitamin D levels in pregnancy

[87] - No effect on the incidence of preeclampsia or caesarian section rates

[210] [211] - An increased risk of childhood eczema but not for childhood asthma nor wheeze - Increases cord blood vitamin D conc. but not calcium conc. [89,204] Vitamin D intake during pregnancy

- Lower risk of preeclampsia

[196] [85,205] [209] - No association with risk of spontaneous abortion nor stillbirth - Increased risk of being small for gestational age - A higher risk of childhood asthma [87] [85,95,104,205,206] [85] - No effect on the incidence of preeclampsia - Elevated risk of gestational diabetes mellitus - Increased risk of bacterial vaginosis but not delivery by caesarian section

[196,205,207,208] - Increased risk of pre-term birth [84,85,204,205] - Higher risk of preeclampsia Vitamin D deficiency in pregnancy

Maternal outcomes

Table 1 Vitamin D status in pregnancy and maternal and offspring’s long-term health outcomes (meta-analyses).

Ref.

Offspring’s long-term health outcomes

Ref.


Declarations of interest The authors declared no competing interests.

59



Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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