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Vitamin D nutrition in pregnancy: current opinion

There is increasing interest in vitamin D nutrition during pregnancy because of widespread reports of a high prevalence of low vitamin D status in pregnant women. While vitamin D is important for calcium and phosphorus homeostasis and for bone health, it also plays important roles in many other physiologic functions in the body. Consistent with the expanded role of vitamin D, recent observational studies have demonstrated that low vitamin D status in pregnancy is associated with multiple potential adverse maternal, fetal, and infant outcomes and contributes to low vitamin D status in infants at birth. Therefore, an overview of the current understanding of vitamin D nutrition in pregnancy and a review of the results of studies to optimize vitamin D status during pregnancy and in the offspring is of public health importance and timely.


Introduction
Vitamin D deficiency in pregnancy is widespread in many parts of the world, 1 and there is an association between low vitamin D status and multiple potential adverse outcomes of pregnancy. [2][3][4][5] Therefore, vitamin D nutrition in pregnancy should be of global health interest. Although the synthesis and metabolism of vitamin D in the nonpregnant state is well known, its metabolism during pregnancy is less well understood. 3 The classical action of vitamin D is to maintain calcium homeostasis and bone health. In addition, it is now known to be involved in immunomodulation, cell proliferation, and cell differentiation, and in other physiologic functions in diverse tissues and organs, including the brain, pancreas, and heart. 6 Despite the reported high prevalence of vitamin D deficiency and its possible consequences, the criteria for defining an optimal level in the body, and hence the amount of vitamin D intake required to maintain adequate levels, is controversial. 3,7,8 This overview addresses the current information about vitamin D function, the global burden and potential consequences of low vitamin D status in pregnancy, and current strategies to optimize vitamin D status in pregnant mothers and their offspring.

Vitamin D sources and functions
The major source of vitamin D is endogenous synthesis from epidermal stores of 7-dehydrocholesterol following exposure of the skin to ultraviolet B radiation, resulting in formation of previtamin D 3 which is subsequently converted to vitamin D 3 (cholecalciferol). 9 Geographic location beyond latitude 35°, North or South, darker skin pigmentation due to melanin, winter season, and lifestyle factors, including avoidance of sun exposure, cloth-ing which covers most of the skin while outdoors, increased indoor activity, and the use of sunscreen, all reduce endogenous synthesis of vitamin D. 9,10 Endogenous synthesis accounts for about 90% of the body's vitamin D stores, while 10% is derived from dietary sources. Very few food items, including fatty fish, fortified dairy products, and egg yolk, contain vitamin D. 9,10 When exposure to sunlight is limited, individuals depend on dietary sources or vitamin D supplements to maintain adequate vitamin D status. Several reports in the literature have shown that inadequate or lack of sunlight exposure without appropriate corrective vitamin D intake or supplements accounts for the high prevalence of vitamin D deficiency in women. [11][12][13][14][15][16][17][18] After synthesis in the skin, vitamin D attaches to vitamin D-binding protein and is transported to the liver, where it undergoes a process of hydroxylation to form 25-hydroxyvitamin D [25(OH)D]. 9 The serum concentration of 25(OH)D is the most reliable marker of vitamin D nutritional status. A second hydroxylation takes place in the kidney, which converts 25(OH)D to the most biologically active metabolite, 1,25-dihydroxyvitamin D, the major classical physiologic function of which is to increase calcium and phosphorus absorption from the gut in order to maintain calcium homeostasis and promote mineralization of osteoid bone. 9 Although the renal 1-alpha hydroxylase (cytochrome P450 [CYP]27B1) enzyme is a major determinant of synthesis of 1,25-dihydroxyvitamin D, it is known that CYP27B1 is expressed in nonrenal tissues to produce 1,25 dihydroxyvitamin D. 6,19 In addition, vitamin D receptors are also expressed in a variety of organs, tissues, and cells (see Figure 1). 20 The 1,25-dihydroxyvitamin D locally produced in extrarenal tissues, such as immune cells, pancreatic beta cells, the intestine, prostate, breast, and other organs, controls multiple vitamin D-responsive genes, and thus plays an important physiologic role in cardiovascular health, 21,22 the adaptive and innate immune responses, 23,24 insulin secretion, 25,26 regulation of cell proliferation, differentiation, and apoptosis, and inhibition of angiogenesis. 27

Vitamin D homeostasis and functions during pregnancy
The classical function of vitamin D is to maintain calcium homeostasis. When serum vitamin D and calcium concentrations are low, there is increased synthesis of parathyroid hormone which further stimulates synthesis of 1,25-dihydroxyvitamin D [1,25(OH) 2 D] to correct calcium deficits through increased intestinal calcium absorption and mobilization of calcium from bone. Restoration of vitamin D status and calcium balance allows calcium accretion in the bones. However, sustained vitamin D deficiency results in rickets in children and osteomalacia in adults. 28   between 25(OH)D and parathyroid hormone, intestinal calcium absorption, and assessment of skeletal integrity. 29 While there is an inverse relationship between serum parathyroid hormone and 25(OH)D in nonpregnant states, this relationship has been shown in recent studies to be weak during pregnancy, 6,18,30,31 indicating that serum parathyroid hormone may be a less reliable biomarker of maternal vitamin D status during pregnancy than serum 25(OH)D. 32 The maternal 25(OH)D level does not vary significantly during pregnancy unless there is a change in vitamin D intake or endogenous synthesis. 2,33,34 However, serum 1,25(OH) 2 D levels increase by 100%-200% starting in the first trimester in both the mother and the fetus. [35][36][37] The increase in maternal 1,25(OH) 2 D, which originates mostly from the kidneys, accounts for increased intestinal calcium absorption during pregnancy. 38,39 The increase in fetal 1,25(OH) 2 D level seems to be related to synthesis in placental and fetal tissues. 39,40 An important aspect of vitamin D nutrition in pregnancy is that the vitamin D status of the infant at birth and in early infancy depends on the vitamin D status of the mother during pregnancy. 41 Vitamin D stores in the infant start with transplacental transfer of 25(OH)D in early pregnancy from mother to fetus. Physiologically active 1,25(OH) 2 D does not readily cross the placenta. 41 Many studies have shown that the vitamin D status of infants at birth as measured by cord blood 25(OH)D correlates positively with maternal vitamin D status. In general, cord blood 25(OH)D concentrations are approximately 60%-89% of the maternal value. 11,17,35,[41][42][43][44][45][46][47] Therefore, maintaining optimum vitamin D nutrition during pregnancy is essential for prevention of hypovitaminosis D in the fetus and vitamin D deficiency at birth and in early infancy.

High prevalence of low vitamin D intake in pregnancy
The vitamin D status in adults, including pregnant women, is based currently on measurement of serum 25(OH)D concentrations, but what constitutes the "normal" or "optimal" level is controversial. The Institute of Medicine in the US in its recent report recommends that a serum 25(OH)D concentration of 50 nmol/L (20 ng/mL) is adequate for calcium absorption and bone health in adults, including pregnant women, in the US and Canada. 7 However, new clinical guidelines from the Endocrine Society recommend maintaining a serum 25(OH)D concentration .75 nmol/L (30 ng/mL) in order to maximize calcium absorption and bone health, and for potential extraskeletal benefits noted in observational studies. 8 Many recent studies 13,[15][16][17][48][49][50][51][52][53][54][55][56][57] that evaluated vitamin D nutrition during pregnancy in different geographic locations reported wide variation in vitamin D status depending on latitude, season, sunlight exposure behavior, and vitamin D intake ( Table 1). The studies indicate that mean serum 25(OH)D concentrations during pregnancy or at delivery range from 12.8 nmol/L to 138.5 nmol/L. There is a high prevalence of vitamin D deficiency [serum 25(OH) D ,50 nmol/L], and as shown in Table 1, most women studied (.80%) have serum 25(OH)D concentrations ,75 nmol/L, which are considered "insufficient". 8 Mean serum 25(OH)D concentrations are highest and the prevalence of vitamin D deficiency is lowest in sun-enriched populations, 51,57 while the lowest mean serum 25(OH)D and the highest prevalence of vitamin D deficiency are reported in sunshine-deprived populations. 16,17,50,55,56 The high prevalence of low vitamin D associated with sunshine deprivation and inadequate corrective vitamin D intake should raise public health concern about the increased risk of adverse health effects of low vitamin D status for the mother and fetus and poor vitamin D nutrition in the infant at birth.

Implications of low vitamin D status during pregnancy Skeletal and calcemic complications
It is generally accepted that maternal vitamin D deficiency can result in osteomalacia. A serum 25(OH)D concentration ,25 nmol/L (10 ng/mL), which is associated with increased risk of osteomalacia in adults, 7 is common during pregnancy, as indicated by recent reports from many parts of the world. 1 For example, serum 25(OH)D , 25 nmol/L during pregnancy has been reported in 17%-18% of the Caucasian population in the UK, 48,49 61% of a mixed population in New Zealand, 54 32%-42% in the Indian population, 15,45 59%-84% of a nonwestern population in The Netherlands, 14 41% of the Kuwaiti population, 16 80% of the Iranian population, 17 and 75% of the Arab population in the United Arab Emirates. 1 However, there are limited studies on the association between such low levels of vitamin D status and skeletal integrity in pregnant women. In a recent study from northern India, 45 29 (14%) of 207 pregnant mothers showed biochemical evidence of osteomalacia (elevated heat-labile alkaline phosphatase, low phosphorus, and elevated parathyroid hormone), although none had demonstrable clinical evidence of the disease, ie, proximal muscle weakness, skeletal pain, or bone tenderness. Mothers with serum 25(OH)D , 25 nmol/L had elevated heat-labile alkaline phosphatase .125 IU/L and significantly lower phosphorus and higher parathyroid hormone levels than mothers with serum 25(OH)D . 25 nmol/L. Further, a recent study of the relationship between serum submit your manuscript | www.dovepress.com 25(OH)D and bone turnover in pregnant women in Istanbul, Turkey, found a negative correlation between the second and third trimester and postpartum 25(OH)D concentrations and serum cross-linked C-terminal telopeptide of type 1 collagen, which is a marker of bone resorption. 58 These studies seem to indicate a link between very low vitamin D status and subclinical osteomalacia in the mothers. There is controversy concerning the effect of maternal vitamin D deficiency on skeletal development of the fetus. From animal studies and some human data, it is suggested that mineralization of the fetal skeleton is independent of vitamin D and, therefore, maternal vitamin D deficiency has little effect on fetal skeletal development. 59 In contrast, some recent observational studies suggest that vitamin D nutrition during pregnancy may affect fetal bone development. High resolution three-dimensional ultrasound assessment in a study from the UK found greater splaying of the distal femoral metaphysis in the fetus when maternal serum 25(OH)D was ,50 nmol/L, 60 and the authors suggested that this finding is similar to radiologic features in vitamin D-deficient rickets.

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In a Finnish study, 50 bone mineral content of the fetal tibia was higher and the cross-sectional area was larger when maternal serum 25(OH)D concentrations during the first trimester were above the median (54.4 nmol/L). There was no significant difference in bone mineral density. Maternal 25(OH)D concentrations during pregnancy was shown in one UK study 48 to affect childhood bone mass at nine years of age, but this was not confirmed in a larger more recent study from the UK. 61 In populations where vitamin D deficiency is very severe, maternal vitamin D deficiency during pregnancy has been associated with neonatal craniotabes 62 and congenital rickets. [63][64][65] Taken together, the results from observational studies suggest a possible effect of low maternal 25(OH)D during pregnancy on fetal bone development, but the association with lower childhood bone mass is unproven. Randomized controlled trials with large sample sizes are needed to assess the effect of maternal vitamin D supplementation on fetal bone development. Severe hypocalcemia occasionally presenting as neonatal seizures is a known complication of maternal vitamin D deficiency during pregnancy. 66,67 submit your manuscript | www.dovepress.com

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Extraskeletal and noncalcemic complications of vitamin D deficiency during pregnancy Several extraskeletal complications of vitamin D deficiency during pregnancy have been reported in the mother, fetus, and infant. These include potentially increased risk of fetal growth restriction, a higher rate of cesarean section, increased risk of pre-eclampsia, gestational diabetes, and bacteria vaginosis, and a higher risk of lower respiratory tract infection, wheezing, and eczema in infants.

Fetal growth
The association between birth weight and maternal vitamin D status or intake remains inconclusive. 5 While some observational [68][69][70][71] and interventional 53,72,73 studies found improvement in birth weight with maternal vitamin D supplementation or improved vitamin D status, several other observational studies 31,74-76 and some interventional studies 18,33,77,78 showed no improvement with higher vitamin D status or supplementation. A recent Cochrane review 79 of five small-sized intervention trials of vitamin D supplementation concluded that mothers who were supplemented tended to have fewer babies weighing ,2500 g (relative risk 0.48; 95% confidence interval [CI] 0.23-1.01). Intervention trials and observational studies have also found an association between risk of small-for-gestational age infants and maternal vitamin D nutrition during pregnancy. In a study of 3730 women of variable ethnicity from Amsterdam in The Netherlands, those with serum 25(OH)D , 30 nmol/L had a higher risk of delivering a small-for-gestational age infant (odds ratio 2.4; CI 1.9-3.2) compared with those having a serum 25(OH) D $50 nmol/L. 68 Similarly, in another large study 80 of 1013 white and black mother-infant pairs from Boston, MA, second trimester serum 25(OH)D levels , 25 nmol/L were associated with an increased risk for delivery of a small-for-gestational age infant (odds ratio 3.93; CI 1.65-9.34). The relationship between maternal vitamin D status and small-for-gestational age infants was found to be U-shaped in a study from Pittsburgh in the US, 81 but this was not confirmed in the above studies. 68,80 The reasons for this difference are unclear. It is of note that the researchers from The Netherlands used a lower cutoff than the serum 25(OH)D value of ,75 nmol/L used in the Pittsburgh study, while the proportions of white women with serum 25(OH)D . 75 nmol/L were lower in the Boston study than in the Pittsburgh study. Randomized controlled studies including larger sample sizes and repeated vitamin D measurements during pregnancy will be needed to confirm the relationship between vitamin D supplementation and fetal growth. 82

Maternal complications
Observational studies reported an association between maternal vitamin D status during pregnancy and development of pre-eclampsia, which has both a genetic and an immunologic pathogenesis. A study from Pittsburgh showed an inverse relationship between vitamin D status and the risk of pre-eclampsia. 83 The authors found that the risk of pre-eclampsia was more than doubled (odds ratio 2. Diabetes is a major health issue globally. With increasing interest in the role of vitamin D in glucose homeostasis, the association between maternal serum 25(OH)D concentration in early pregnancy and the risk of gestational diabetes mellitus was investigated in a study from the National Institutes of Health, Bethesda, MD. 85 The authors found that maternal vitamin D deficiency [serum 25(OH)D , 50 nmol/L] was associated with a higher risk of gestational diabetes mellitus (adjusted odds ratio 2.66; CI 1.01-7.02). Consistent with this report, a systematic review and meta-analysis of seven observational studies performed between 2008 and 2011 found serum 25(OH)D , 50 nmol/L to be associated with gestational diabetes but with an overall lower odds ratio of 1.61 (CI 1.19-2.17). 86 Another meta-analysis of maternal vitamin D status and pregnancy outcomes, 87 which included 24 studies up to 2012, found an overall increased risk of preeclampsia (odds ratio 2.09; CI 1.50-2.90) and gestational diabetes (odds ratio 1.38; CI 1.12-1.70). It is of note that not all the individual studies provided adjusted odds ratios.
Recent studies have indicated a role for vitamin D in the innate immune response. Vitamin D has been shown to upregulate endogenous synthesis of cathelicidin, a potent antimicrobial peptide, in response to microbial invasion, via activation of toll-like receptors on microphages and monocytes. 6,24 Given that antimicrobial peptides provide rapid defense against invading pathogens, it is plausible that vitamin D plays a role in host defense against infections in both mother and offspring. In support of this premise is the finding that vitamin D deficiency is an independent risk factor for bacterial vaginosis in pregnant women. 88 A study from Pittsburgh showed an inverse dose-response relationship between serum 25(OH)D concentrations and the prevalence of bacterial vaginosis. 88 Compared with a serum concentration of 75 nmol/L, the prevalence of bacterial submit your manuscript | www.dovepress.com Dovepress Dovepress vaginosis increased 1.65-fold (CI 1.01-2.69) and 1.26-fold (CI 1.01-1.57) at serum concentrations of 20 nmol/L and 50 nmol/L, respectively. In another large study from New York in the US, 89 bacterial vaginosis was only associated with vitamin D deficiency (serum 25(OH)D , 75 nmol/L) in pregnant women (adjusted odds ratio 2.87; CI 1.13-7.28). Further, there is a suggestion of an association between vitamin D and periodontal disease, 90 and maternal serum 25(OH)D , 75 nmol/L during early pregnancy has been associated with a two-fold increased risk of periodontal disease. 91 In a recent randomized controlled trial of vitamin D supplementation from South Carolina, vitamin D supplementation of 4000 IU/day during pregnancy was associated with a reduction in the risk of combined morbidities, such as maternal infection, preterm labor, and preterm birth. 92 In view of the possible association between maternal vitamin D status and the pattern of fetal growth, pre-eclampsia, gestational diabetes mellitus, and maternal infection, and the significant potential for perinatal morbidities associated with these conditions, evaluation of vitamin D nutrition in early pregnancy and the effect of appropriate supplementation seems warranted.  76 However, another recent study with a larger sample size from the same institution did not find an association between maternal 25(OH)D . 75 nmol/L in late pregnancy and eczema or asthma at 12 months and three and six years of age. 97 There was no report on the association between maternal vitamin D status and respiratory infections in the latter study. Regarding neurocognitive development, while one study found no association between maternal vitamin D status during pregnancy and neurocognitive function, 76 a recent larger-sized study linked maternal serum 25(OH)D levels during pregnancy with language development in the offspring. 98 The results of the above studies suggest that childhood infections, atopy, and neurocognitive development need to be included as outcomes of interest following vitamin D supplementation in pregnancy, and that clinical trials should include a relevant group of subjects considered to be replete for vitamin D.

Impact on neonate and infant
Taken together, the high prevalence of vitamin D deficiency in pregnancy and the possible multiple potential adverse effects on mother and offspring identified in several epidemiologic studies underscore the urgent need for large randomized controlled trials to identify the amount of vitamin D supplementation that optimizes vitamin D status during pregnancy, and to determine the effect of supplementation on potential adverse conditions associated with vitamin D deficiency and any possible vitamin D excess.

Vitamin D requirement during pregnancy
In order to determine the vitamin D requirement during pregnancy, one needs to define the target serum 25(OH)D concentration considered as "normal" or "optimal". As noted previously, the recent Institute of Medicine report recommends that a circulating serum 25(OH)D concentration of 50 nmol/L is adequate to meet the needs for calcium homeostasis and bone health in adults. 7 The recommended dietary allowance of 600 IU/day for both pregnant and lactating women in the US and Canada would theoretically meet the daily requirement in 97.5% of the population for achieving the recommended target serum 25(OH)D concentration of 50 nmol/L. However, a committee of vitamin D experts 99 and the Endocrine Society 8 recommend a target serum concentration .75 nmol/L based on the available evidence in order to achieve optimal benefits for skeletal health as well as potential nonskeletal benefits. A target concentration of 75 nmol/L is consistent with the cord blood 25(OH)D level reported in some studies as being protective against lower respiratory infection, wheezing, and eczema in infants. [94][95][96] To achieve a target serum concentration .75 nmol/L, the society submit your manuscript | www.dovepress.com Dovepress Dovepress recommends a daily vitamin D intake of 1500-2000 IU. These recommendations are based mostly on studies from the US and may not be applicable worldwide due to differences in baseline vitamin D status, 100 particularly in populations where severe vitamin D deficiency is prevalent.
A review of the few previous randomized controlled trials of vitamin D supplementation during pregnancy indicates that doses of 400-1600 IU/day were insufficient in achieving a mean serum 25(OH)D concentration $50 nmol/L in most of the studies. 41 In a recent vitamin D supplementation trial from the UK, a multiethnic group of 180 pregnant women were randomized at 27 weeks' gestation to receive a single oral dose of 200,000 IU of vitamin D, daily supplementation of 800 IU, or no treatment. 33 The median serum 25(OH)D concentration in the 800 IU/day group at study entry was 26 nmol/L (interquartile range [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], and the median 25(OH)D concentration at delivery following supplementation was 42 nmol/L (interquartile range . Only 30% of the women treated with 800 IU/day of vitamin D achieved a serum 25(OH)D concentration .50 nmol/L. In another study from the UK, 101 the investigators recruited 80 consecutive pregnant women from minority ethnic backgrounds whose serum 25(OH)D concentrations at the first antenatal visit were ,20 nmol/L. These subjects with very low vitamin D status were started on 800 IU/day of vitamin D, increased to 1600 IU/day at 36 weeks' gestation if serum 25(OH)D was still low. The mean serum 25(OH)D concentration increased from 14.4 ± 2.3 nmol/L at enrollment to only 28.5 ± 15.8 nmol/L at delivery despite supplementation of 800-1600 IU/day. These two studies and older research 41 indicate that, in populations with a high prevalence of severe vitamin D sufficiency, supplementation up to 1600 IU/day may be inadequate to achieve the recommended target serum 25(OH)D concentration of 50 nmol/L. 7 In two recent studies from India, which used large single-dose supplementation of 120,000 IU at the fifth and seventh month of gestation 15 or at the second and third trimester, 69 only 25% and 62%, respectively, achieved a serum 25(OH)D concentration .50 nmol/L. The recent Cochrane review of vitamin D supplementation alone during pregnancy 79 considered five trials that compared the effects of supplementation with placebo or no supplementation. 33,73,77,78,102 The review concluded that vitamin D supplementation increases serum 25(OH)D concentrations during pregnancy. Of note, in two of the five studies, the mean concentration of 25(OH)D after supplementation was ,50 nmol/L, 33,78 and serum 25(OH)D was not measured in one study. 73 All these studies underscore the uncertainty about the amount of vitamin D supplementation required to optimize vitamin D status in pregnancy and which would be generalizable worldwide.
As mentioned earlier, the criteria for defining what constitutes "normal" vitamin D status are controversial. The Institute of Medicine 7 considers a serum 25(OH)D concentration .50 nmol/L as acceptable, while the Endocrine Society and vitamin D experts recommend .75 nmol/L. 8,99 A recent study among traditional populations in Tanzania with type VI (dark) skin color living in a sun-abundant environment recommended a mean serum 25(OH)D concentration of 115 nmol/L in nonpregnant adults and 139 nmol/L in pregnant women. 57 The question then is: what serum concentration of 25(OH)D is "normal" in adults, including during pregnancy? While the debate and studies to identify optimal serum 25(OH)D concentration continue, it is prudent to monitor vitamin D status and develop strategies to ensure at least a minimum serum 25(OH)D concentration of 50 nmol/L in pregnant women, especially in an environment where vitamin D deficiency is endemic.
In studies of adults and nonpregnant women, a vitamin D intake of up to 10,000 IU/day is associated with achievement of a serum 25(OH)D concentration $80 nmol/L without vitamin D toxicity. 103,104 From a review of previous studies, an additional daily intake of 100 IU of vitamin D increases the serum 25(OH)D concentration by 1-2 nmol/L. 7,105 Therefore, knowing the population baseline serum 25(OH)D concentration, it is possible to estimate the vitamin D intake required to replete body stores and achieve an expected target serum 25(OH)D concentration. Because of controversy surrounding vitamin D requirements during pregnancy, investigators from South Carolina performed a comprehensive, large, randomized controlled study of vitamin D supplementation in pregnancy to achieve optimal vitamin D status, defined as a serum 25(OH)D concentration $80 nmol/L at delivery. 18 Based on the pharmacokinetics of vitamin D, the authors investigated the safety and effectiveness of highdose vitamin D supplementation. They hypothesized that daily vitamin D 3 supplementation of 4000 IU/day would be more effective than 2000 IU and a standard dosing regimen of 400 IU in achieving a serum 25(OH)D concentration of .80 nmol/L without any safety issues referable to vitamin D supplementation. In this study, women of varied ethnicity were randomized at ,16 weeks' gestation into 4000 IU, 2000 IU, or 400 IU daily treatment groups, which were continued through to delivery. Subjects with an initial baseline 25(OH)D .100 nmol/L were allocated to vitamin D 3 2000 IU/day or 400 IU/day. Vitamin D status was monitored in the mother during pregnancy and in cord blood as submit your manuscript | www.dovepress.com Dovepress Dovepress a surrogate marker of infant vitamin D status at birth. The safety outcome measures monitored were serum 25(OH)D concentration, hypercalcemia, and hypercalciuria.
Of the 494 women enrolled in the study, 350 continued participation until delivery. The mean serum 25(OH)D concentrations at entry to the study were not significantly different between the groups. However, mean serum 25(OH)D concentrations at delivery were significantly different, with the highest level achieved by the group on 4000 IU/day. The mean serum 25(OH)D concentrations at delivery in the 4000 IU, 2000 IU, and 400 IU daily groups were 110 ± 40.4, 98.3 ± 34.2, and 78.9 ± 36.5 nmol/L respectively, (P = 0.0001). Similarly, 82%, 71%, and 50%, respectively, of the mothers on 4000 IU, 2000 IU, and 400 IU of vitamin D daily achieved a serum 25(OH)D concentration .80 nmol/L (P = 0.0001). The authors also found that supplementation with 4000 IU/day was associated with maximal 1,25(OH) 2 D production. Although the implications of this finding are unclear, they require exploration in future studies because of the possible role of 1,25(OH) 2 D in control of multiple gene expression. Neonatal serum 25(OH)D concentrations correlated significantly with maternal serum 25(OH)D at delivery and were significantly different by dosing group. If the Institute of Medicine's target of a serum 25(OH)D concentration $50 nmol/L 7 was adopted for neonatal vitamin D status, 79%, 58%, and 40%, respectively, of the infants of mothers on 4000, 2000, and 400 IU per day achieved adequate vitamin D status (P = 0.0001). There were no adverse events related to vitamin D supplementation during the study. Based on this protocol, the authors concluded that 4000 IU/day of vitamin D 3 supplementation is safe and most effective in achieving vitamin D sufficiency in mothers and adequate vitamin D status in their offspring, irrespective of ethnicity. The authors also found that maternal vitamin D supplementation with 4000 IU/day decreased the risk of combined comorbidities, including infection, preterm birth, gestational diabetes, and pre-eclampsia, 82 and suggested that additional studies with adequate power for assessment of other endpoints were needed. Another recent study from the United Arab Emirates among pregnant Arab women with a high prevalence of vitamin D deficiency also confirmed that 4000 IU/day of vitamin D supplementation was safe and more effective than 2000 IU/day and 400 IU/day in optimizing vitamin D status during pregnancy and in achieving vitamin D sufficiency at birth in mothers and offspring. 106 In the United Arab Emirates study, the increment from baseline to delivery was about four-fold higher than expected based on previous pharmacokinetic studies, possibly related to low baseline vitamin D status. 100 This indicates that baseline vitamin D status should be taken into consideration when evaluating vitamin D supplementation. 100,107 The findings of these recent intervention studies indicate an urgent need for more randomized controlled trials in diverse geographic locations with large sample sizes to identify the vitamin D intake required to optimize vitamin D status, and to assess the effect on pregnancy-related and infant-related complications. Based on biomarkers affected by vitamin D status, and findings from observational studies and recent randomized trials, future studies should include trial arms to achieve serum 25(OH)D concentrations that have been associated with potential extraskeletal benefits 8,82,84,[94][95][96] of vitamin D to understand better both the benefits and risks of vitamin D supplementation to mother and offspring.

Conclusion
The criteria for defining optimal vitamin D intake during pregnancy remain controversial. In view of the high prevalence of low vitamin D status in pregnancy worldwide, intervention trials to identify optimal vitamin D status and the required safe vitamin D intake could be an important part of public health strategy to improve the health of mothers, and the short-term and long-term outcomes for their offspring.

Disclosure
The authors report no conflicts of interest in this work.