The vitamin D endocrine system and parathyroid hormone (PTH) maintain bone and mineral homeostasis by acting on phosphate and calcium metabolism at the digestive, renal and skeletal sites. Vitamin D status is clinically studied by measuring circulating 25-hydroxyvitamin D [25(OH)D; calcidiol, calcifediol]. As pregnancy advances, the majority of women display a spontaneous reduction of circulating 25(OH)D maternal levels [1▪]. This occurs even in sunny regions and places without air pollution that are close to the seaside ; even when pregnant women receive a small amount of vitamin D supplementation (≤200 IU/day) .
It is hypothesized that during the first half of pregnancy vitamin D may contribute to fetal growth and to the ‘programming’ of some fetal functions and organs, including among others, the central nervous system, bone and dental enamel. Therefore, it seems reasonable to maintain sufficient maternal vitamin D and calcium levels that will cross the placenta to the fetus. Serum 25(OH)D levels are reported either as ng/ml or nmol/L, being 2.5 nmol/l = 1 ng/ml. In this manuscript 25(OH)D concentrations will be cited as ng/ml.
A meta-analysis of observational studies [4▪▪] found that vitamin D-deficient women [25(OH)D levels <12 ng/ml] had infants with lower birthweight (mean difference [MD] = −87.82 g; 95% CI, −119.7 to −55.91 g) and lower head circumference (MD −0.19 cm; 95% CI, −0.32 to −0.06 cm). Also, there was a higher risk of infants small-for-gestational-age and preterm birth (odd ratio (OR) = 1.59; 95% CI, 1.24–2.03). A similar trend was observed for vitamin D insufficiency (<20 ng/ml). Contrary to this, there was no association of low birthweight, small-for-gestational age or preterm birth in women with 25(OH)D levels at least 30 ng/ml. In addition, infants of vitamin D-insufficient mothers had lower scores in mental development scores and language developmental tests.
The Bi et al.[5▪▪] meta-analysis of randomized clinical trials (RCTs) regarding vitamin D supplementation (>400 IU/day) during pregnancy provides complementary information on offspring growth, morbidity, and mortality. Supplementation was performed with vitamin D3 in 22 RCTs and with vitamin D2 in three studies [Table 1]. Vitamin D supplementation was not associated to a higher risk of fetal or neonatal mortality, congenital malformations, and admission to a neonatal ICU. Neonates of supplemented women had higher calcium and 25(OH)D levels and a higher weight at birth and at 3, 6, and 12 months of follow-up [5▪▪]. Therefore, it seems reasonable to initiate vitamin D supplementation during the first trimester of pregnancy in order to maintain the physiology of PTH secretion and fetal requirements.
Despite the aforementioned, there are two large ‘discordant’ double-blind RCTs using high doses of vitamin D [6▪,7▪▪] that were published after the Bi et al. meta-analysis. The first, performed in Bangladesh [6▪] which assessed the effect of 3 different prenatal vitamin D supplementation doses (4200, 16 800 and 28 000 IU) administered weekly starting between 17 and 24 weeks of gestation and given until birth and the postpartum. As expected, maternal 25(OH)D levels increased and other expected changes occurred; however, there were no improvements in fetal or infant growth as assessed until 6 months of age. The second RCT, performed in Denmark [7▪▪], compared the effect on fetal growth of a maternal vitamin D3 dose of 2400 IU/day versus placebo given from gestational week 24 until 1 week postpartum. This supplementation dose had no effect on infant anthropometry; however, offspring growth restriction was more frequent among women displaying 25(OH)D levels less than 12.0 ng/mL. The lack of significant benefits on fetal growth and clinical outcomes might be related to the ‘late’ initiation of supplementation during pregnancy and other concomitant factors affecting all subgroups of pregnant women [8,9▪].
A Swedish study  pointed out that women with 25(OH)D levels at least 40 ng/ml had a significant lower risk of having infants small-for-gestational age and with low birth weight, when compared to gravids with serum 25(OH)D levels less than 12 ng/ml. Similar results have been reported in large studies from other latitudes such as China [11,12]. Despite this, the relationship between maternal 25(OH)D levels and fetal weight is nonlinear, suggesting that the spline regression model fitted the data better than the linear one .
Preterm birth is a worldwide highly prevalent complication of pregnancy, which has been related to maternal age, stress, ethnicity, economic factors, subclinical infections, and work conditions, among other factors. This obstetric problem has been linked to vitamin D status in different cohorts and multicentric studies. Gernand et al. studied 25(OH)D levels of pregnant women at 12–16 weeks’ gestation (n = 8222) who were included in a low-dose aspirin multicenter trial. After controlling for confounders such as prepregnancy body mass index and race they found a 1.8 fold (95% CI, 1.0–3.2) increase of preterm birth risk at less than 35 weeks in women with 25(OH)D levels less than 20 ng/ml as compared to those with 25(OH)D at least 30 ng/ml. The adjusted relative risk for preterm birth less than 35 weeks was 2.5 (95% CI, 1.1–5.8) in gravids with 25(OH)D less than 20 versus at least 30 ng/ml .
The Tous et al.[4▪▪] meta-analysis of observational studies comparing maternal 25(OH)D levels of less than 12 and at least 12 ng/ml demonstrates that there is no difference in preterm birth risk related to such cut-off value, although there was heterogeneity of studies. However, when two studies were deleted and homogeneity was demonstrated (I2 = 0%), there was a significant relationship between maternal vitamin D deficiency and PTB (OR = 1.23; 95% CI, 1.05–1.43). In addition, when the cut-off was fixed for levels of less than 20 versus at least 20 ng/ml, the risk of preterm birth was significantly increased for women with lower 25(OH)D levels (OR = 1.28; 95% CI, 1.08–1.52) . A Cochrane meta-analysis of RCTs reported that vitamin D supplementation has no difference/effect on the risk of preterm birth [15▪▪].
Several studies suggest an association between low vitamin D levels and the increased risk of preeclampsia. Some studies, based on 25(OH)D levels measured early in pregnancy, have not found such association. Contrary to this, the frequency of preeclampsia is reduced when vitamin D levels are maintained elevated during the last trimester of pregnancy by supplementing with 4000 IU/day . It seems that vitamin D may have a role at decreasing the risk of preeclampsia by downregulating some placental antiagiogenic factors .
In a RCT carried out by Ali et al.[18▪], pregnant women (6–12 weeks) with serum 25(OH)D levels less than 25 ng/ml were randomized to be supplemented with vitamin D3 400 IU/day (group 1) or 4000 IU/day (group 2) in order to compare the prevalence of preeclampsia. Maternal 25(OH)D increased in group 2 from 6.6 ± 2 ng/ml to 28.9 ± 30.9 ng/ml as compared to group 1 which increased from 7.0 ± 2.7 ng/ml to 14.1 ± 8.3 ng/ml, and the frequency of preeclampsia cases were, respectively, 1.2 and 8.6% (P < 0.05). In addition, group 2 reported less total number of intrauterine growth restrictions as compared to group 1 (9.6 vs. 22.2%; P = 0.027).
The recent meta-analysis of Fogacci et al.[19▪▪] reported that vitamin D administration during pregnancy was related to a significant reduction of preeclampsia risk (OR = 0.37; 95% CI, 0.26–0.52) with a high homogeneity of the trend. When the supplementation was initiated at the 20th week of gestation the risk was lower (OR = 0.35; 95% CI, 0.25–0.50; P < 0.001). Therefore, suggesting that vitamin D supplementation may be a useful clinical intervention to prevent or reduce the risk of preeclampsia.
Low maternal 25(OH)D levels have been associated to a higher risk of gestational diabetes mellitus (GDM). This risk is much greater in women with excessive body weight (overweight and obesity). Fat tissue has the capacity to retain 25(OH)D from the circulatory system, altering the equilibrium between PTH and calcium. Shao et al.[20▪▪] studied a very large population of pregnant women to whom an oral glucose tolerance test was performed in the first and second trimesters of pregnancy. They found that maternal vitamin D deficiency was associated with a higher risk of GDM and increased fasting blood glucose. In addition, the negative association between 25(OH)D deficiency (<20 ng/ml) and fasting blood glucose was stronger among women with excessive body weight. On the other hand, GDM prevalence fluctuates throughout the year, being lower in summer and fall and higher in winter/spring probably related with the circannual sun cycle.
A Cochrane meta-analysis [15▪▪] of RCTs and quasi-RCTs reported that vitamin D supplementation during pregnancy decreases the risk of GDM (Relative risk (RR) = 0.51; 95% CI, 0.27–0.97). A more recent prospective study [21▪] analyzed the association of vitamin D status and supplementation during the second trimester in 5984 gravids with GDM, to assess the threshold of 25(OH)D that could affect glucose metabolism and GDM risk. The prevalence of GDM was significantly lower when women had 25(OH)D levels between 20 and 30 ng/ml (RR = 0.74; 95% CI, 0.58–0.95) and more than 30 ng/ml (RR = 0.40; 95% CI, 0.22–0.70). In addition, GDM risk was significantly reduced only in women taking 400–600 IU vitamin D/day (RR = 0.83; 95% CI, 0.70–0.97) who achieved a mean 25(OH)D concentration of 20 ng/ml but not in those achieving levels of 16 ng/ml.
MATERNAL VITAMIN D STATUS AND OFFSPRING BONE AND ENAMEL HEALTH
Maternal vitamin D deficiency has been associated to lower infant bone mineral density and a smaller size at birth, suggesting the importance of vitamin D for fetal development. Boghossian et al.[22▪] have correlated maternal 25(OH)D levels, according to race, anthropometry and body composition as studied by dual energy X-ray absorptiometry. Deficient maternal 25(OH)D levels (<20 ng/ml) were associated to lower neonatal bone mineral density and smaller size. In addition, male infants also displayed lower lean mass and birthweight. A recent double-blinded RCT (Copenhagen Prospective Studies on Asthma in Childhood) [7▪▪] reported the results of comparing vitamin D supplementation at doses of 2800 IU/day (high-dose) versus 400 IU/day (standard-dose). Both groups started supplementation from the 24th week of pregnancy up to the first week after delivery [7▪▪]. The analysis of dual energy X-ray absorptiometries scanned at 3 and 6 years of age showed that children of mothers supplemented with the higher vitamin D dosage, as compared to the lower one, had higher adjusted whole-body bone mineral content. The largest effect was observed in children of vitamin D-insufficient mothers (<30 ng/ml). In addition, the authors reported borderline lower incidence of fractures in the vitamin D group [n = 23 vs. n = 36; incidence rate ratio: 0.62 (95% CI, 0.37–1.05); P = 0.08], and no differences in any anthropometric outcome.
Maternal vitamin D supplementation during pregnancy is also an effective intervention to reduce the rate of dental disease in later life. Indeed, intervention confers benefits on offspring enamel characteristics, in both milk teeth and the permanent teeth. Nørrisgaard et al.[23▪▪] reported results of a double blind RCT that assessed the effect of supplementing a high dose of vitamin D in pregnant women for the prevention of offspring enamel defects and caries. A daily high dose of vitamin D3 (2400 IU/day; n = 315) or matching placebo tablets (n = 308) was given from the 24th week of pregnancy to the first week postpartum. In addition, all women received 400 IU/day of vitamin D3 as part of standard care. The risk of enamel defects in permanent dentition was lower in offsprings of mothers treated with the high dose as compared to the standard dose (OR = 0.47; 95% CI, 0.27–0.81). A similar association was observed for the deciduous dentition (OR = 0.50; 95% CI, 0.28–0.87).
MATERNAL VITAMIN D STATUS AND OFFSPRING NEUROLOGICAL DISORDERS
There is evidence that maternal vitamin D status may influence early in gestation central nervous development. The attention deficit hyperactive disorder (ADHD) is a frequent problem that affects some 10% of children in the US and produces significant functional limitations. It seems that low 25(OH)D levels during the first trimester of pregnancy are associated with an increased risk of the offspring ADHD during the first years of life [24,25▪,26▪]. A recent meta-analysis has confirmed this association [27▪▪]. Low maternal 25(OH)D levels during the first trimester of pregnancy have also been associated with offspring autism  and the risk of depression in childhood and adolescence [29▪].
VITAMIN D SUPPLEMENTATION DURING PREGNANCY
The U.S. Institute of Medicine (IOM)  has recommended a serum 25(OH)D cut-off of more than 20 ng/ml to define sufficiency. Indeed, this level is associated with the prevention of bone manifestations of vitamin D deficiency (rickets and osteomalacia) in 97.5% of Canadians and Americans . The U.S. Endocrine Society  have set a serum 25(OH)D cut-off of more than 30 ng/ml as the target for optimal bone health.
The U.S. IOM recommends a vitamin D3 intake of 600 IU/day during pregnancy and lactation that will help maintain maternal bone health and ensure infant bone growth . The American College of Obstetricians and Gynecologists (ACOG)  and the International Federation of Gynecology and Obstetrics [34▪] recommend supplementing 250–600 IU/day cholecalciferol during pregnancy as a standard. They also recommend that vitamin D deficiency should be treated with vitamin D3 at doses of 1000–2000 IU/day. Data of recent trials and meta-analyses herein revised suggest that the prevention of some adverse obstetric and perinatal outcomes may require even higher vitamin D supplemental doses, although further RCTs are warranted to confirm this. The revised scientific information and meta-research analyses call for actions to update vitamin D intervention recommendations beyond bone health. As revised herein, vitamin D3 supplementation may benefit low vitamin status, fetal growth and reduce several obstetrical complications and adverse offspring outcomes. Hence, appropriate vitamin D supplementation may have a positive impact on pregnancy outcome. Current vitamin D supplementation requirements promoted by the IOM and ACOG may not be sufficient to reduce several maternal and offspring adverse outcomes.
Vitamin D3 is the preferred supplemental compound for pregnancy because of metabolic advantages over vitamin D2[35,36▪]. Oral calcifediol [25(OH)D] is more powerful than cholecalciferol, absorption by the intestine is higher, is least trapped into the fat tissue, and can be particularly useful during pregnancy [36▪,37▪▪].
The common recommendation of supplementing with 400–600 IU of vitamin D3/day may not be enough to maintain sufficient maternal circulating 25(OH)D levels, and thus prevent the discussed negative outcomes (maternal and offspring). Current evidence seems to suggest that supplementation should start in the first trimester of pregnancy. Finally, recent evidence regarding maternal vitamin D status and the risk of different offspring health conditions opens a new scenario concerning vitamin D supplementation as a preventive obstetric intervention. Nevertheless, this intervention requires further studies to better understand the role of vitamin D on fetal growth and development.
ORCID: FRPL https://orcid.org/0000-0002-2801-416X; SP: https://orcid.org/0000-0002-7959-1311; PC: https://orcid.org/0000-0002-1556-3979
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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