【Discussion】
Low vitamin D status is a global epidemic affecting people of all ages. It has attracted scholars of great interest in recent years. Although vitamin D is important for musculoskeletal health, increasing data suggest that vitamin D may also be important for fertility and pregnancy outcomes[18]. The number of research on the pleiotropic effects of vitamin D in pregnancy and the impact of low vitamin D status on maternal and infant outcomes has been expanding.
The main role of vitamin D during pregnancy is to promote calcium absorption and placental calcium transport. Existing evidence on maternal 25(OH)D concentrations during pregnancy is inconsistent, possibly due to small study samples, lack of adjustment for seasonal or ethnic variation and cross-sectional design[11].Some studies suggest that women are more likely to suffer from vitamin D deficiency or insufficiency during pregnancy and with a gradual decrease in the total amount of 25(OH)D from the first trimester to term[19] because the change of their hormone and metabolic conditions and the required nutrients increase significantly[20]. A meta-analysis carried out by Papapetrou, P. D.[21] reported no difference in the concentrations of 25(OH)D before, either during or after pregnancy. It’s unclear whether low vitamin D status is more frequent in pregnant women when compared to same-aged nonpregnant women. Therefore, pregnancy may not be a cause of low vitamin D status compared to nonpregnancy.
Risk factors associated with low vitamin D status delineated by several studies are: inadequate sun explore, low ambient UVR levels, physical inactivity, low dietary vitamin D intake, no or low vitamin D supplementation and medication[22]. Moreover, variations in skin color, social and cultural habits concerning sun seeking behavior, diet, and other factors are evident. However, there is no authoritative criteria for appropriate vitamin D status in pregnancy. Different criteria have been used for diagnosing vitamin D deficiency, but mostly referring to 50nmol/L and 75nmol/L. A high prevalence of vitamin D deficiency up to 62.34% was reported in South China[23]. Recent evidence showed that pregnant women in Shanghai are generally deficient in vitamin D, the results suggesting that 72.5% of the participants were vitamin D deficient[24]. At present, the classification standard for the determination of serum 25(OH)D concentration recommended by the IOM is still an indicator commonly used internationally to categorize vitamin D status in adults. A large number of studies[6, 11, 25, 26]published in recent years emphasize the relationship between low vitamin D status and several adverse pregnancy outcomes such as PE, GDM, preterm birth, etc according to IOM standard. Rostami et al[27] infer the ideal level of vitamin D during pregnancy based on pregnancy outcomes, they recommend a cutoff of 25(OH)D >37.5 nmol/L for the prevention of adverse pregnancy outcomes. In this study, vitamin D levels were measured in Asian pregnant women in South China on a normal diet during pregnancy. In contrast to many conclusions based on White British women and Pakistani women[28], the study found no significant association between low vitamin D status and adverse pregnancy outcomes. The reasons may be as follows: 1) The current vitamin D assessment is based on the upper limit of vitamin D level that satisfies 97.5% of the population to maintain normal bone health, instead of the “cut-off value” based on pregnancy outcomes. 2)The efficiency of vitamin D utilization was variable among people with different skin colors[11],3)Low vitamin D might affect pregnancy in the long term after delivery, consequently, women’s long-term outcomes and the development of children should be given as much attention as the adverse outcomes associated with vitamin D during pregnancy. These speculations still need to be confirmed by more studies.
At present, vitamin D screening during pregnancy has been increasingly used as a routine antenatal examination, which leads to additional vitamin D supplement distribution to pregnant women with low vitamin D status. In fact, studies on the association of vitamin D and pregnancy outcomes have not reached agreement. A Mendelian randomization study found no strong evidence to support an effect of vitamin D status on pregnancy related hypertensive disorders[29]. Observational studies have also not found that low vitamin D levels are associated with postpartum hemorrhage and showed an inverse relationship between vitamin D status and the occurrence of postpartum hemorrhage which remains unexplained [18, 25]. Agarwal, S et al[2] reviewed plenty observational and interventional studies, and they found that the role of vitamin D in GDM remains inconclusive, and this critical review showed that several observational studies reported an inverse relationship between vitamin D status in early pregnancy and the risk of GDM, conversely, there were also multiple studies failed to determine the role of vitamin D in the prevention of GDM. Large-scale prospective studies are still needed to assess the role of vitamin D in GDM. This prospective study demonstrated that low vitamin D status is not associated with adverse pregnancy outcomes, which was different from other researches[8, 30, 31].In other words, is low vitamin D status in pregnant women really matters, should we give positive medical intervention remains uncertain and requires further confirmation. Most experts agree that broad-based screening of serum 25(OH)D levels in the general population or during pregnancy is unnecessary[32]. In addition, the issue of vitamin D supplementation during pregnancy still needs to be further explored. Some high-quality RCT studies have failed to prove that vitamin D supplementation during pregnancy can reduce pregnancy complications and is beneficial to the development of fetus[33-35]. In France and in Belgium, women are not routinely supplemented with vitamin D before pregnancy[17]. A review also questioned whether vitamin D supplementation improved outcomes in osteoporosis prevention[36]. Research concludes that different populations in different regions have not been unified, neither RCTs nor observational trials have demonstrated that serum vitamin D levels are associated with pregnancy outcomes, nor have vitamin D supplementation improved pregnancy outcomes. This is because, on the one hand, vitamin D “deficiency” or “insufficiency” diagnosed by the IOM criteria is not necessarily applicable to all populations in all regions of the world, and on the other hand, low vitamin D status may not be correlated with most adverse outcomes.
It is important to clarify the meaning of IOM reference values for vitamin D, as they are related to both human health and clinical considerations. In fact, the use of “50nmol/L” and “30nmol/L” as a cut-off value is based on misinterpretation and misapplication of the IOM vitamin D reference values. The IOM developed these reference values, referred to as Dietary Reference Intakes (DRIs), for a range of nutrients. That is, the cause relationship of vitamin D and musculoskeletal health outcomes was used to inform dietary vitamin D requirements. Central to the DRI concept is the biologic reality that the requirements for any nutrient vary from person to person, and are usually normally distributed across the population. However, the exact nutritional requirements of an individual cannot be known. A common misconception is that the RDA functions as a “cut point” and that almost the entire population must have a serum 25(OH)D level above 50nmol/L to achieve good bone health[32]. Note that the values assume minimal to no sun. Vitamin D levels largely depend on exposure to the sun and are influenced by nutritional habits at only a minimal level[11].The reality is that most (about 97.5%) of the population has a requirement of vitamin D 50nmol/L or less[32]. Diagnosis of vitamin D “deficiency” or “insufficiency” itself presents a challenge due to the “diagnostic threshold” of vitamin D status in pregnancy cannot be equated with “nutrient supply”. A systematic review and meta-analysis published recent years [33] showed that, neither intermittent nor daily standard doses of vitamin D alone were associated with a reduced risk of fracture. Excessive concern about vitamin D “deficiency” or “insufficiency” can adversely affect patient care, including unnecessary vitamin D screening and supplementation, as well as rising health care costs.
Low vitamin D status may not relate to adverse pregnancy outcomes. However, the results bias caused by research samples cannot be ruled out. The etiology of various maternal and infant outcomes is complex and multifactorial, with many confounding factors. Determining the relationship of vitamin D levels during pregnancy requires further evaluation through large, multicenter, randomized controlled clinical trials focusing on specific adverse pregnancy outcomes.