Background
Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance with onset or first recognition during pregnancy [
1]. Many risk factors, including obesity, gestational age and genetic background, contribute to the development of GDM [
2]. The prevalence of GDM was reported approximately 15 to 20% worldwide [
3]. Hyperglycemia during pregnancy is associated with adverse outcomes of both mother and offspring [
4]. Women with a history of GDM are at increased risk of developing insulin resistance syndrome (IRS) and cardiovascular disease (CVD) later in life [
4,
5].
Chronic low-grade inflammation is related to many known risk factors of GDM [
6]. Increased degrees of inflammation during early pregnancy are associated with increased risk of GDM and the development of hyperglycemia [
7]. In addition, the presence of oxidative stress has been reported in GDM [
8‐
10], and the antioxidant status in women with GDM was down-regulated [
11]. Oxidative stress plays important roles both in the pathogenesis and complications of GDM, supplementary therapy with antioxidants might help to reverse the oxidative status and improve the neonatal outcome [
12,
13]. Zinc deficiency [
14], hypomagnesemia [
15] are common features in diabetes, and low circulating levels of vitamin D [
16], vitamin E [
11], and magnesium [
17] have been found in women with GDM. Many reports showed that vitamin and mineral supplementation, such as vitamin D [
18], vitmin E [
13], magnesium [
15,
19], and selenium [
20] may regulate glucose metabolism and have beneficial roles in anti-inflammatory and anti-oxidative stress.
Nowadays, there is a growing interest to use vitamin and mineral supplementation during pregnancy, especially for women with GDM. Vitamin D is the most commonly used nutrient in the treatment of GDM, but the effect of vitamin D supplementation on glycemic control in GDM remains controversial. Some studies showed that vitamin D supplementation had beneficial effects on glycemia in women with GDM [
18]. However, other studies showed that vitamin D supplementation had no significant effect on fasting plasma glucose (FPG) or fasting blood glucose (FBG) level in patients with GDM [
21]. The role of selenium in glucose control in GDM was also inconsistent. A clinical trial showed that 200 μg selenium supplements for 6 weeks significantly reduced FPG and serum insulin levels in GDM patients [
20]. However, another clinical trial showed that 100 μg selenium supplements for 12 weeks has no significant effect in regulating glucose homeostasis in women with GDM [
22]. Studies on the effects of vitamin D and other nutritional supplementation on biomarkers of inflammation and oxidative stress in patients with GDM also have inconsistent results [
18,
23,
24]. It was reported that vitamin D supplementation had no significant effect on hs-CRP, plasma TAC, and total GSH [
18]. However, other studies showed that vitamin D or vitamin D-calcium co-supplementation had beneficial effects on biomarkers of inflammation and oxidative stress [
23,
24]. Thus, this meta-analysis was conducted to evaluate the effects of vitamin and mineral supplementation, especially vitamin and mineral co-supplementation, on glycemic control, inflammation and oxidative stress in GDM patients.
Methods
Search strategy and study selection
This systematic literature search was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [
25]. PubMed, Embase, Web of Science and Cochrane Library of RCTs were searched up to July, 2020. Search terms include Medical Subject Headings (MeSH) and keywords related to GDM, vitamins, minerals, micronutrients, glycemic control, inflammation and oxidative stress. The details of the search strategy are reported in the supplementary information. The search was limited to publications in English. DL and ZP did the literature searches, and discrepancies were resolved by discussion with a third author (ZC).
Eligibility criteria
Eligible articles were considered if they met the following criteria: (1) Participants: women with GDM; (2) Interventions: vitamin supplementation, or mineral supplementation, or vitamin and mineral co-supplementation; (3) Controls: placebo treatment; (4) Outcomes: at least one of the following outcomes was reported, FPG, serum insulin, homeostasis model assessment-insulin resistance (HOMA-IR), homeostasis model of assessment for β cell function (HOMA-B), high-sensitivity C-reactive protein (hs-CRP), total antioxidant capacity (TAC), glutathione (GSH), and malondialdehyde (MDA); (5) Studies: randomized controlled trials (RCTs). Trials were excluded if patients require substitute treatments (such as insulin and metformin et al.), or treatment was medications other than vitamins, minerals or placebo. We also excluded trials without accessible data or full text, or carried out after delivery.
Data extraction and analysis from included studies were performed by two authors independently (DL and ZP), and conflicts were resolved by a third author (YY). The following information was extracted: first author, publication year, agent, number of participants, dosage, follow-up duration, trial registration number, study location, clinical phase, and outcomes of interest.
Study quality and risk of Bias assessment
The Cochrane Collaboration’s risk of bias tool was used to assess the risk of bias, including the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. The risk of bias was judged as low, high, or unclear, according to the criteria of Cochrane Handbook.
Publication Bias assessment
Funnel plot and Egger’s test were used to assess the publication bias and tested for statistical significance. P value less than 0.1 was considered significant.
Statistical analyses
Results were presented as mean difference (MD) with 95% confidence interval (CI). Heterogeneity among studies was estimated by I-squared (I2) tests. P value < 0.1 and I2 > 50% indicated statistical heterogeneity, and random-effects models were used in meta-analysis; otherwise, fixed-effects models were used. Sensitivity analyses were also performed to examine the effect of each trial on the overall analysis. All statistical analyses were done with Review manager 5.3 and Stata 12.0.
Discussion
In this meta-analysis, we pooled the results of high-quality RCTs in women with GDM to assess the effects of vitamin and mineral supplementation vs placebo on glycemic control, biomarkers of inflammation and oxidative stress. Due to the close metabolism regulation between vitamins and minerals and data on the effects of vitamin and mineral co-administration on glucose regulation, inflammation and oxidative stress markers in women with GDM are scarce, we specifically included vitamin and mineral co-administration trails in this meta-analysis. And in order to have more reliable results and decrease the heterogeneity between different studies, we didn’t include trials if patients require substitute treatments (such as insulin and metformin et al.) or carried out after delivery, since both substitute treatments and delivery can affect glycemic status. Our findings demonstrated that vitamin and mineral supplementation, magnesium, zinc, selenium, calcium, vitamin D and E (alone or in combination), significantly improved glycemic control, attenuated inflammation and oxidative stress in women with GDM through decreasing serum FPG, insulin, HOMA-IR, HOMA-B, hs-CRP and MDA levels, and increasing TAC levels.
Vitamin and mineral supplementation improved glycemic control in GDM and related mechanism
Findings from this meta-analysis demonstrated that vitamin and mineral supplementation had a significant effect on serum insulin and blood glucose parameters. Subgroup analysis of the interventions showed that single mineral or vitamin D, or combined vitamin D/E and mineral supplementation all worked well on glycemic control. We found that vitamin D, magnesium and zinc has the potential role to promote glycemic control in diabetes patients. The dosages of vitamin D might be a reason of high heterogeneity of FPG in vitamin D and minerals group, 50,000 IU vitamin D every 3 weeks plus 1000 mg calcium per day worked better than 200 IU vitamin D supplementation plus minerals (100 mg magnesium, 4 mg zinc and 400 mg calcium) twice a day. Although different doses of vitamin D supplementation, ranging from 200 to 4000 IU daily for 12.5 days, had no effect on FPG level in women with GDM, higher doses of vitamin D significantly improved insulin resistance [
5]. Vitamin D can activate the transcription of insulin receptor gene to promote glucose oxidation through the phosphoinositide 3-kinase (PI3-K) pathway [
34]. Vitamin E plays an important role in regulating glucose metabolism through improve insulin action by upregulation GSH/GSSG ratio and magnesium concentration [
13]. Magnesium can regulate glucose and insulin metabolism by affecting the tyrosine kinase activity of insulin receptor, and help transport glucose into the cells via glucose transporter protein activity 4 (GLUT4) [
35]. Zinc can regulate insulin signaling through PI3-K/Akt pathway and help transport GLUT4 to the cell membrane [
14].
Vitamin and mineral supplementation relieves inflammation and possible mechanisms in GDM
Pregnant women with obesity or GDM have increased maternal inflammation and elevated hs-CRP compared to normal pregnant women, and suppression the inflammation helps improving pregnancy outcomes and maternal complications. Our meta-analysis showed that the supplementation of vitamin and mineral could significantly reduce the serum hs-CRP level in GDM patients. Subgroup analysis of treatments demonstrated that mineral supplementation, including zinc, magnesium, and selenium, was more significant than vitamin D and mineral supplementation in reducing hs-CRP level. Vitamin D, zinc and selenium can decrease the concentration of inflammatory cytokines through down-regulation of nuclear transcription factor κB (NF-κB), a key regulator of genes involved in inflammation [
14,
36]. Magnesium may decrease inflammatory response via regulation the intracellular calcium concentration and inhibition the NF-κB signaling pathway [
37,
38].
Underlying mechanisms of vitamin and mineral supplementation on oxidative stress in GDM
Oxidative stress plays a key role in the development of diabetes mellitus [
39]. Many kinds of vitamins and minerals have antioxidant activity and may have beneficial role in diabetes. Our meta-analysis showed a benefit effect of vitamin and mineral supplementation, including vitamin D, Calcium plus vitamin D, zinc and magnesium, on alleviating oxidative stress status in GDM patients through improving TAC levels, and reducing MDA levels. Vitamin D can increase GSH formation by upregulation of glutamate cysteine ligase (GCLC) and glutathione reductase (GR), which recycles oxidized GSSG to GSH to scavenge excessive ROS [
40]. Magnesium can influence the activities of mitochondrial electron transport chain and ROS production [
41]. Zinc is essential for the activity of superoxide dismutase (SOD), which plays an important role in redox balance, and may play antioxidant effect by decreasing ROS production [
14].
There are interactions between different vitamins and minerals. Zinc can regulate the release of calcium by acting on zinc-sensing receptor [
42], vitamin D affects insulin secretion by regulating plasma calcium [
43], vitamin E can improve glucose disposal through the upregulation of magnesium concentration [
13], magnesium is involved in the synthesis, transport and activation of vitamin D [
44]. Because of the possible interactions between different vitamins and minerals, further studies are necessary to assess whether the combination of vitamins and minerals is more effective than a single vitamin or mineral on GDM.
Limitations of our study
There are several limitations in our meta-analysis. First, the diversity of vitamin and mineral types and combinations make it challenging to perform subgroup analysis for all treatments. Second, all included trails were from Iran, and there was a lack of data from other countries. Finally, since GDM usually diagnosed between 24- and 28-week gestation, we didn’t include studies last more than 3 months to see the effect on postpartum outcomes.
Conclusion
In conclusion, our meta-analysis suggests a beneficial role of single or vitamin and mineral co-supplementation on biomarkers of glycemic control, inflammation and oxidative stress in women with GDM. In the future, more large-scale and longer duration studies of vitamin and mineral supplementation, especially vitamin and mineral co-supplementation, are needed to demonstrate their effect on glycemic control, anti-inflammatory and antioxidant effects in women with GDM.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.