Vitamin D deficiency is a costly health problem worldwide, and about one billion individuals in the world suffer from it Holick, 2010. Vitamin D is necessary agent for the regulation of mineral metabolism and skeletal health. Therefore, it plays a significant role in the health, growth, and fertility of humans Brown et al., 1999Hagenau et al., 2009.

Vitamin D deficiency during pregnancy can be accompanied by numerous maternal and fetal symptoms, including, inter alia, insulin resistance, gestational diabetes mellitus (GDM), increased risk of preeclampsia, bacterial vaginitis, and increased rate of cesareans among mothers and autism, Type I diabetes, increased rate of fetal growth delay, increased rate of respiratory infection, low birth weight, increased rate of HIV transmission from mother to fetus, asthma, and eczema in infants Aghajafari et al., 2013Palacios et al., 2016. The effect of vitamin D deficiency on the emergence of certain chronic diseases like autoimmune diseases Arnson et al., 2007, systemic lupus erythematosus (SLE) Amital et al., 2010, multiple sclerosis (MS) Ascherio et al., 2010, and malignancies Trump et al., 2010 has also been recognized.

A poor vitamin D status has been proposed as one risk factor associated with the incidence of GDM. The need for vitamin D is higher in some stages of life, including the period of rapid growth for fetuses in the embryonic stage, infancy, early stages of childhood, puberty, and pregnancy Shahgheibi et al., 2016. Vitamin D deficiency is common in pregnancy, and it significantly increases the risk for preeclampsia, cesarean section (C/S), and GDM in pregnancies Gernand et al., 2014Grant et al., 2014Merewood et al., 2009Robinson et al., 2010Yap et al., 2014.

Recent evidence suggests that vitamin D receptors are expressed in a large number of other tissues, including those involved in the regulation of glucose metabolism such as muscle and pancreatic beta cells Jain et al., 2015. These receptors have a direct effect on pancreatic beta cells and are required for the normal production and secretion of insulin by the endocrine pancreas Kramer et al., 2014Maghbooli et al., 2008. Thus, vitamin D deficiency is related to alterations in blood glucose and insulin concentrations and in target tissue sensitivity to insulin Shahgheibi et al., 2016. Vitamin D replenishment restores insulin secretion and sensitivity in patients with Type 2 diabetes with established vitamin D deficiency Muthukrishnan and Dhruv, 2015. Therefore, it was hypothesized that GDM might result from pregnancy-induced insulin resistance and impaired secretion to compensate for it.

There has been a rapidly growing interest in the association between vitamin D and the risk of gestational diabetes mellitus, and many studies with various populations and outcomes have been conducted on this topic. It is very important to have an overall estimation of its association. Also, understanding the breadth and quality of the conducted studies is critical. Recently some meta-analyses have found that vitamin D insufficiency is associated with increased GDM risk Aghajafari et al., 2013Lu et al., 2016Poel et al., 2012Zhang et al., 2015. Despite these findings, the knowledge and understanding of the clinical importance and implications of this association are limited. Moreover, since the publication of these meta-analyses, additional studies on this topic have been published. These studies have other clinically important outcomes that have not yet been effectively summarized. In order to authenticate these studies, an updated meta-analysis seems to be imperative. Thus, the current study aimed to quantitatively evaluate the association between vitamin D status and risk of gestational diabetes.

In the initial electronic search, a total of 278 potential articles were identified. A hand search of the bibliographies and reference lists of these articles identified 14 additional articles for a total of 292 articles identified through the literature search. After the initial screening of abstracts and titles, 224 papers were excluded based on the inclusion criteria, leaving 68 papers for a full text review. In a secondary screening and after the full text reviews, another 39 articles were excluded (four studies not in a pregnant population, eight studies in pregnant women with chronic disease, six studies for non-blood sampling, three studies for biological mechanisms, four studies for no outcome data, six studies for insufficient data, two studies for non-humans, and one study that was not in English). In total, 29 studies were selected for the final analysis ( Figure 1 ).

The literature on vitamin D insufficiency in pregnancy is growing rapidly.The current meta-analysis was conducted to comprehensively review the literature and explore possible correlations between vitamin D status and the risk of GDM.

In this systematic review and quantitative meta-analysis of 29 observational studies, an association was found between insufficient vitamin D levels and the incidence of GDM. Women with GDM appear to have a significant lower serum 25OHD than women with NGT. The current results suggest that vitamin D deficiency may be an independent risk factor for GDM. These results are consistent with those of previous meta-analyses Aghajafari et al., 2013Lu et al., 2016Poel et al., 2012Zhang et al., 2015. Since the publication of themeta-analyses included in this research, further studies have been published. Moreover, the previous meta-analyses did not include several important observational studies.The current study attempts to fill this gap.

Obesity as well as a high maternal age are risk factors for both vitamin D deficiency and gestational diabetes; thus, they are potential confounders of the association between vitamin D deficiency and the incidence of GDM Poel et al., 2012. Most of the studies included in the current meta-analysis had been adjusted for maternal age and BMI; however, the association between vitamin D status and GDM was statistically significant.

Recent evidence has suggested that vitamin D deficiency or insufficiency is more common among pregnant women with limited sun exposure (e.g., those who live in cold climates or in northern latitudes) which may affect their vitamin D status; Those women who wear sunscreen or protective clothing and those from ethnic minority groups with darker skin Bodnar et al., 2007Hollis and Wagner, 2004Lee et al., 2007. The majority of vitamin D is generated in the skin under the influence of ultraviolet B radiation, which makes serum 25OHD levels dependent on seasons, with higher levels seen in spring and summer Poel et al., 2012.

There are also other risk factors that could be associated with GDM risk, including smoking, alcohol intake, gestational weight gain, and socioeconomic status. In the current study, it was observed that the adjusted models differed across the included studies; some of them did not adjust for several important confounding factors. The contribution of these confounding factors to the risk of gestational diabetes can go some distance in explaining conflicting results among different studies.

Other important points noted were that the included studies used different methods and criteria for the diagnosis of GDM, serum 25OHD levels were measured in different trimesters of pregnancy, definitions of cut-offs for 25-OHD insufficiency varied, and different techniques were used. The studies suggest that the methods used to quantify 25-OHD levels and to diagnose GDM may be important factors which could influence the final results Agarwal et al., 2005Shirazian et al., 2008.

There were several limitations in the current meta-analysis. First, the included studies varied in their definitions of the cut-off for 25-OHD insufficiency and in diagnostic criteria of GDM, and that could have influenced the pooled effect. Secondly, the researchers were unable to evaluate the impact of some important factors such as gestational weight gain, skin tone, and socioeconomic status on the correlation between maternal vitamin D status and the risk of GDM because of insufficient data in some studies. Also, data on sunlight exposure and dietary vitamin D intake was not available. Thirdly, the most adjusted odds ratio was used in meta-analysis. However, the adjusted models differed across the included studies. In some studies, the potential confounding factors could not be adjusted for, and therefore, the findings could not be pooled by adjusting confounding factors. Furthermore, inherent to any meta-analysis is the possibility of publication bias which is an inevitable problem. Finally, some studies associated with vitamin D status and GDM were not accessible.

The present meta-analysis indicated that pregnant women with gestational diabetes had significantly lower vitamin D levels than did those with normal glucose tolerance. The results further demonstrated a statistically significant association between maternal vitamin D insufficiency and the incidence of gestational diabetes. In conclusion, these findings suggest that low levels of 25(OH)D may be a risk factor in pregnancy. However, given the variety of study designs and the heterogeneity between the included studies, it is not reasonable to derive a definite conclusion.Further clinical trials are needed to verify this association and determine the explicit effect of vitamin D supplementation on the prevention of gestational diabetes.

CIs: Confidence intervals

GDM: Gestational Diabetes Mellitus

NGT: Natural glucose tolerance

NR: Not reported

OR: Odds ratios

RR: Ratios risk

Shahin Nargesi and Mansour Amraei designed the study and participated in writing the paper, Ayub Ghorbani and Ehsan Shirzadpour performed the meta-analysis, Seyedeh Fatemeh Mousavi, Ehsan Shirzadpour and Mahmoud Mohamadpour participated in writing the paper, Mansour Amraei provided data analysis and participated in writing the paper. All authors read and approved the manuscript.