The role of 25(OH)D₃ levels in gestational diabetes and its outcomes

Abstract

Gestational diabetes mellitus (GDM) is a common metabolic disorder during pregnancy and has become a global public health issue. Increasing evidence suggests that 25(OH)D₃ levels may be associated with the occurrence and progression of GDM, but the exact mechanisms are not fully understood. This retrospective study included 210 patients with GDM from the Third Hospital of Xi’an (from January 2022 to January 2024). The patients were divided into 2 groups based on serum 25(OH)D₃ levels: the low-level group (<30 ng/mL, n = 102) and the normal-level group (≥30 ng/mL, n = 108). The study analyzed the basic characteristics, fasting blood glucose (FBG), pregnancy complications, adverse pregnancy outcomes, and fetal birth weight of the 2 groups. Additionally, multiple regression analysis was performed to explore the independent predictive effect of low 25(OH)D₃ levels on the occurrence of GDM. The incidence of GDM in the low 25(OH)D₃ level group was significantly higher than that in the normal 25(OH)D₃ level group (60% vs 40%, P < .05). The low-level group had significantly higher FBG levels compared to the normal-level group (P < .05). Low 25(OH)D₃ levels were significantly associated with the incidence of pregnancy complications such as gestational hypertension, fetal distress, cesarean section, and low birth weight (P < .05). Multivariate regression analysis showed that low 25(OH)D₃ levels were an independent predictor of GDM occurrence (OR = 0.81, 95% CI = 0.73–0.90, P < .01). Low 25(OH)D₃ levels may increase the risk of gestational diabetes and its related complications. Vitamin D supplementation may have potential clinical value in the prevention and treatment of GDM.

1. Introduction

Vitamin D is a fat-soluble vitamin that is widely found in food and can also be synthesized by the skin under ultraviolet (UV) exposure.^[1] The primary biological function of vitamin D is to regulate calcium and phosphorus metabolism, promoting bone health.^[2] However, recent studies have shown that vitamin D plays an important role not only in bone health but also in the occurrence and progression of various chronic diseases.^[3,4] 25(OH)D₃ (25-hydroxyvitamin D₃) is the major circulating form of vitamin D and serves as an important indicator of vitamin D levels in the body.^[5] 25(OH)D₃ levels are not only related to bone health but are also closely linked to immune, cardiovascular, and metabolic functions.^[6] Particularly during pregnancy, the relationship between vitamin D levels and the occurrence of gestational diabetes mellitus (GDM) has become a focus of medical research in recent years.

GDM refers to the onset of diabetes symptoms for the first time during pregnancy, typically occurring between the 24th and 28th weeks of gestation.^[7–9] The occurrence of GDM is closely related to both maternal and fetal health. If not controlled in a timely manner, it can lead to a series of complications such as maternal hyperglycemia, hypertension, and other issues, potentially affecting fetal development and increasing the risk of macrosomia. Moreover, GDM can also increase the likelihood of postpartum diabetes.^[10] Therefore, early screening, prevention, and treatment of GDM are crucial for ensuring maternal and infant health.

Recent studies have suggested a potential association between vitamin D and gestational diabetes.^[11–14] Numerous studies have found a close relationship between vitamin D deficiency and the occurrence of GDM, with lower levels of 25(OH)D₃ being positively correlated with an increased risk of gestational diabetes.^[15] Some scholars believe that vitamin D may indirectly influence the occurrence of GDM by regulating insulin secretion and sensitivity.^[16] Vitamin D deficiency may promote the onset of GDM through its effects on insulin receptor expression, insulin secretion, and insulin resistance.^[17] On the other hand, some studies have also suggested that appropriate supplementation of vitamin D may play a positive role in the prevention of GDM.^[18]

Currently, although there is some evidence supporting the relationship between vitamin D and gestational diabetes, the specific mechanisms are still not fully understood. Some studies suggest that the regulatory effect of vitamin D on insulin metabolism is primarily mediated through the vitamin D receptor (VDR), which is expressed in the pancreas, liver, muscle, and adipose tissue. This suggests that vitamin D may influence blood glucose levels by regulating the metabolic functions of these tissues.^[19] Additionally, vitamin D may also impact the development of gestational diabetes through the immune system. Vitamin D is believed to have a role in modulating immune responses, which may affect insulin secretion by altering the immune tolerance of pancreatic cells, thus influencing the onset of diabetes.^[20]

However, research findings on the relationship between vitamin D and gestational diabetes are not entirely consistent. Some studies have found no significant association between vitamin D levels and gestational diabetes, and in certain cases, vitamin D supplementation has not shown a significant impact on the occurrence of gestational diabetes.^[21] These results indicate that the effect of vitamin D on gestational diabetes may be the result of multiple interacting factors, which are not only related to vitamin D levels but also closely linked to genetic background, environmental factors, lifestyle, and the body weight of pregnant women.^[22]

Therefore, studying the relationship between vitamin D and gestational diabetes has significant clinical implications. Understanding the specific mechanisms by which vitamin D contributes to the development of gestational diabetes not only helps in predicting the risk of gestational diabetes but also provides new insights for its prevention and treatment. Especially in high-risk populations with vitamin D deficiency, early evaluation of vitamin D levels and management through appropriate interventions (such as vitamin D supplementation) may play a positive role in reducing the incidence of gestational diabetes.

This article will focus on the role of 25(OH)D₃ levels in gestational diabetes, analyze the relationship between vitamin D and gestational diabetes, and explore potential mechanisms, with the aim of providing new theoretical foundations for the early prevention and treatment of gestational diabetes.

2. Methods

2.1. Collection and evaluation of clinical features

This study was approved by the Ethics Committee of Xi’an Third Hospital. This study is a retrospective analysis that included 210 pregnant women diagnosed with GDM at the Third Hospital of Xi’an from January 2022 to January 2024. All patients had a singleton pregnancy and provided complete clinical data. The participants were divided into 2 groups based on serum 25(OH)D₃ levels: the low-level group (25(OH)D₃ < 30 ng/mL, n = 102) and the normal-level group (25(OH)D₃ ≥ 30 ng/mL, n = 108). All cases involved in the study had undergone glucose screening during pregnancy and were diagnosed with GDM according to the diagnostic criteria.

Inclusion criteria:

1. Pregnant women diagnosed with GDM according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria, with a clear diagnosis of gestational diabetes.

2. Singleton pregnancy, with no other severe complications (e.g., severe preeclampsia, multiple pregnancies) during the study period.

3. 25(OH)D₃ levels were measured during pregnancy, with complete data on 25(OH)D₃ provided.

Exclusion criteria:

1. Pregnant women with other types of diabetes during pregnancy, such as type 1 diabetes or type 2 diabetes.

2. Severe complications during pregnancy, such as severe gestational hypertension, preeclampsia, gestational heart disease, severe infections, or severe endocrine diseases.

3. Severe liver or kidney dysfunction, or other conditions that interfere with the assessment of gestational diabetes, such as severe immune system diseases.

4. Incomplete clinical data during the study period (e.g., lack of 25(OH)D₃ measurement results or incomplete gestational blood glucose screening).

2.2. Sample size calculation

The sample size calculation was based on the following assumption: there is a statistically significant difference in the incidence of GDM between the low-level group (25(OH)D₃ < 30 ng/mL) and the normal-level group (25(OH)D₃ ≥ 30 ng/mL). Based on expected differences and relevant literature, the incidence of GDM in the low-level group was assumed to be 60%, and in the normal-level group, 40%. A binary chi-square test was used for sample size calculation, with a significance level (α) set at 0.05 and a statistical power of 80% (β = 0.2). The sample size calculation indicated that at least 100 patients were required in each group. To enhance the reliability and stability of the results, the study ultimately included 210 patients, with 102 in the low-level group and 108 in the normal-level group, meeting the required sample size.

2.3. Collection and assessment of clinical characteristics

Clinical data of the patients were extracted from the electronic medical records system, covering baseline characteristics, including age, body mass index (BMI), age at first pregnancy, blood pressure (systolic and diastolic), heart rate, fasting blood glucose (FBG), and glycated hemoglobin. These basic details were verified by experienced clinical doctors and entered in a standardized manner. All patients underwent a physical examination before grouping, and those with other types of diabetes or endocrine disorders during pregnancy were excluded.

2.4. Serum 25(OH)D₃ level measurement

Serum samples from all patients were collected during routine prenatal checkups and were analyzed for 25(OH)D₃ levels using the enzyme-linked immunosorbent assay (ELISA). A serum 25(OH)D₃ concentration of <30 ng/mL was defined as the low-level group, while a concentration of 30 ng/mL or higher was defined as the normal-level group. All experimental procedures were conducted strictly according to the instructions provided with the reagent kits to ensure the accuracy of the results.

2.5. Assessment of gestational diabetes and its complications

The diagnosis of GDM was made according to the IADPSG criteria. All patients underwent an oral glucose tolerance test between 24 and 28 weeks of gestation, and the diagnosis of GDM was confirmed based on the established diagnostic criteria. The primary adverse pregnancy outcomes of interest in this study included gestational hypertension, fetal distress, and cesarean delivery rates.

2.6. FBG

Fasting blood glucose (FBG) levels were measured using standardized glucose reagent kits, and all glucose data were tested by the same laboratory to ensure consistency and reliability.

2.7. Assessment of fetal outcomes and neonatal complications

Fetal birth weight was obtained from the birth records and classified according to standard birth weight categories. Neonatal complications, particularly jaundice and respiratory distress syndrome (RDS), were primarily observed and documented by neonatologists during clinical postdelivery assessments. These data were collected through the clinical observations and diagnostic records of the neonatology team.

2.8. Statistical analysis

All data were analyzed using SPSS statistical software (Chicago). Continuous variables were expressed as mean ± standard deviation (x̄±s), and intergroup comparisons were performed using independent sample t-tests. Categorical data were expressed as frequencies (percentages), and intergroup comparisons were conducted using chi-square tests. For multivariate analysis, binary logistic regression models were used to explore the independent predictive effect of 25(OH)D₃ levels on the occurrence of gestational diabetes, adjusting for potential confounding factors such as age, BMI, and others. A P-value of <.05 was considered statistically significant.

3. Result

3.1. Basic characteristics overview

A total of 210 pregnant women with GDM were included in this study, with a recruitment period from January 2022 to January 2024. Based on serum 25(OH)D₃ levels, the participants were divided into 2 groups: low-level group (<30 ng/mL, n = 102) and normal-level group (≥30 ng/mL, n = 108). There were no significant differences between the 2 groups in baseline characteristics (age, BMI, age at first pregnancy, systolic blood pressure, diastolic blood pressure, heart rate, FBG, glycated hemoglobin, height, and weight) (P > .05) (Table 1).

Table 1.

Baseline characteristics comparison.

Baseline characteristic	Low 25(OH)D3 level group (n = 102)	Normal 25(OH)D3 level group (n = 108)	U/χ2 value	P-value
Age (yr)	30.2 ± 4.1	30.5 ± 4.3	1.051	.73
BMI (kg/m2)	26.3 ± 4.7	25.8 ± 4.3	1.095	.42
History of gestational hyperglycemia (%)	24.5%	22.2%	1.281	.76
Age at first pregnancy (yr)	28.4 ± 5.2	28.7 ± 5.1	0.103	.80
Systolic blood pressure (mm Hg)	123.5 ± 13.4	122.1 ± 12.8	1.321	.59
Diastolic blood pressure (mm Hg)	77.3 ± 8.5	76.7 ± 8.1	0.485	.72
Heart rate (bpm)	82.6 ± 9.4	81.8 ± 9.1	1.209	.56
Height (cm)	160.4 ± 5.6	161.1 ± 5.9	0.165	.33
Weight (kg)	70.2 ± 10.1	69.5 ± 9.6	0.712	.57

BMI = body mass index.

The mean age in the low-level group was 30.2 ± 4.1 years, and in the normal-level group, it was 30.5 ± 4.3 years. The mean BMI was 26.3 ± 4.7 in the low-level group and 25.8 ± 4.3 in the normal-level group, with no significant differences. There were also no significant differences in systolic blood pressure, diastolic blood pressure, heart rate, height, and other characteristics between the 2 groups (P > .05).

3.2. Correlation between 25(OH)D₃ levels and gestational diabetes mellitus incidence

Among the 210 pregnant women with GDM included in this study, the incidence of GDM was significantly higher in the low 25(OH)D₃ level group (<30 ng/mL) compared to the normal 25(OH)D₃ level group (≥30 ng/mL) (60% vs 40%, P < .05), as shown in Figure 1. This result suggests that low levels of 25(OH)D₃ may be a risk factor for the occurrence of GDM. The forest plot in Figure 2 further illustrates the relationship between 25(OH)D₃ levels and the risk of developing GDM. The results indicate a significant negative correlation between 25(OH)D₃ levels and the risk of GDM (OR = 0.83, 95% CI = 0.75–0.92) (Table 2).

Figure 1.

Comparison of GDM incidence by 25(OH)D₃ level groups. GDM = gestational diabetes mellitus.

Figure 2.

Forest plot: 25(OH)D₃ levels and GDM risk. GDM = gestational diabetes mellitus

Table 2.

Comparison of FBG levels between low and normal 25(OH)D₃ groups.

Group	FBG
Low 25(OH)D3 group	5.2 ± 1.0
Normal 25(OH)D3 group	4.3 ± 0.7
P-value	<.05

FBG = fasting blood glucose.

3.3. Relationship between 25(OH)D₃ levels, insulin resistance, and FBG

In this study, there were significant differences in insulin resistance and FBG levels between the low 25(OH)D₃ level group and the normal 25(OH)D₃ level group. As shown in Table 2, the fasting blood glucose (FBG) level was also higher in the low 25(OH)D₃ level group, with a value of 5.2 ± 1.0 mmol/L compared to 4.3 ± 0.7 mmol/L in the normal-level group, and this difference was also statistically significant (P < .05). These results suggest that low 25(OH)D₃ levels may be closely associated with higher FBG levels.

3.4. Incidence of adverse pregnancy outcomes in gestational diabetes patients

There were significant differences in the incidence of pregnancy-related hypertension, fetal distress, and cesarean section between the low 25(OH)D₃ level group and the normal 25(OH)D₃ level group, as shown in Figure 3. The incidence of pregnancy-related hypertension in the low 25(OH)D₃ level group was 16%, significantly higher than the 9% in the normal 25(OH)D₃ level group, with a statistically significant difference (P < .05). The incidence of fetal distress in the low 25(OH)D₃ level group was 21%, also significantly higher than the 13% in the normal-level group, and this difference was statistically significant (P < .05). Additionally, the cesarean section rate in the low 25(OH)D₃ level group was 26%, noticeably higher than the 19% in the normal 25(OH)D₃ level group, and this difference was also statistically significant (P < .05). These results suggest that low 25(OH)D₃ levels are significantly associated with adverse pregnancy outcomes in gestational diabetes patients, such as pregnancy-related hypertension, fetal distress, and cesarean section, indicating that low 25(OH)D₃ levels may be a potential risk factor for these adverse outcomes.

Figure 3.

Incidence of adverse pregnancy outcomes in gestational diabetes patients.

3.5. Relationship between 25(OH)D₃ levels and fetal birth weight and neonatal outcomes

We investigated the impact of low 25(OH)D₃ levels on fetal birth weight and neonatal outcomes, with a particular focus on the incidence of postnatal complications. The results showed that the fetal birth weight in the low 25(OH)D₃ level group was significantly lower than that in the normal 25(OH)D₃ level group, and the difference was statistically significant (P < .05), indicating a significant association between vitamin D deficiency and lower fetal birth weight. Additionally, the incidence of neonatal complications was higher in the low 25(OH)D₃ level group, particularly jaundice and RDS, and these differences were also statistically significant (P < .05). These findings suggest that vitamin D deficiency in pregnant women may increase the risk of neonatal complications (Table 3).

Table 3.

Comparison of neonatal outcomes between low and normal 25(OH)D₃ levels.

Group	Low 25(OH)D3 level group (n = 102)	Normal 25(OH)D3 level group (n = 108)	P-value
Fetal birth weight (g)	Lower	Higher	<.05
Incidence of neonatal jaundice	Higher	Lower	<.05
Incidence of respiratory distress syndrome	Higher	Lower	<.05
Overall neonatal complications	Higher	Lower	<.05

3.6. Multivariate regression analysis

We investigated whether low 25(OH)D₃ levels are an independent predictor of GDM occurrence, as shown in Table 4. Through multivariate regression analysis, we found that low 25(OH)D₃ levels significantly independently predict the risk of developing gestational diabetes. The multivariate regression results revealed that low 25(OH)D₃ levels negatively predict the risk of GDM (OR = 0.81, 95% CI = 0.73–0.90, P < .01), indicating that pregnant women with lower vitamin D levels are at a higher risk of developing GDM. Even after adjusting for potential confounders, such as age, BMI, and other factors, the independent predictive effect of low 25(OH)D₃ levels on gestational diabetes remained significant, further confirming the potential role of vitamin D in the development of gestational diabetes.

Table 4.

Multivariate regression analysis results.

Variable	OR (95% CI)	SE	P-value
25(OH)D3 level (low vs normal)	0.81 (0.73–0.90)	0.04	<.01
Age (per 1 yr increase)	1.05 (1.02–1.09)	0.01	<.05
BMI (per 1 kg/m2 increase)	1.12 (1.08–1.16)	0.02	<.01

BMI = body mass index, CI = confidence interval, OR = odds ratio, SE = standard error.

4. Discussion

25(OH)D₃ (25-hydroxyvitamin D₃) is the main circulating form of vitamin D, and its concentration is commonly used to assess the body’s vitamin D status.^[23] In recent years, with the growing body of research on vitamin D, increasing evidence has shown that vitamin D plays a crucial role not only in bone health but also in various metabolic diseases, particularly in diabetes and GDM, which has attracted widespread attention.^[24] This study aims to explore the relationship between 25(OH)D₃ levels and gestational diabetes, analyze the impact of vitamin D deficiency on insulin resistance, blood glucose levels, pregnancy complications, and neonatal outcomes, and determine the independent predictive role of low 25(OH)D₃ levels in gestational diabetes through multivariate regression analysis.

The results of this study indicate that low 25(OH)D₃ levels are significantly associated with the occurrence of gestational diabetes. Specifically, the incidence of gestational diabetes in the low-level group (25(OH)D₃ < 30 ng/mL) was 60%, significantly higher than that in the normal-level group (25(OH)D₃ ≥ 30 ng/mL) at 40%. Furthermore, multivariate regression analysis results further confirmed that 25(OH)D₃ levels are an independent predictor of gestational diabetes. This finding is consistent with many existing studies, suggesting that a low vitamin D status may be an important risk factor for gestational diabetes.^[25]

Previous studies have also found a significant negative correlation between vitamin D deficiency and gestational diabetes. Research has shown that vitamin D deficiency during pregnancy is a risk factor for gestational diabetes, and supplementation with vitamin D can improve the clinical manifestations of gestational diabetes. A retrospective study also found that pregnant women with low 25(OH)D₃ levels had a significantly increased risk of developing gestational diabetes.^[26] These findings are highly consistent with our results, further supporting the potential role of vitamin D in the development of gestational diabetes.

Regarding fasting blood glucose, the fasting blood glucose (FBG) of pregnant women in the low 25(OH)D₃ level group was significantly higher than that of the normal level group, suggesting that vitamin D deficiency may exacerbate the glucose imbalance during pregnancy. As an important diagnostic indicator for gestational diabetes mellitus (GDM), FBG not only reflects the abnormalities in liver glucose output and insulin sensitivity, but also reveals the potential regulatory role of vitamin D in the function of pancreatic β cells and the insulin action in peripheral tissues. Studies have shown that vitamin D can improve insulin signal transduction by affecting insulin receptor expression and calcium homeostasis. Vitamin D deficiency may reduce insulin utilization efficiency, thereby causing persistent elevation of FBG. ^[27] The correlation between low 25(OH)D₃ levels and elevated FBG in this study further supports the role of vitamin D in glucose metabolism regulation, suggesting that monitoring 25(OH)D₃ and FBG levels simultaneously during early pregnancy may help identify high-risk individuals at an early stage and provide a basis for clinical intervention.

This study also analyzed the relationship between 25(OH)D₃ levels and pregnancy complications such as gestational hypertension, fetal distress, and cesarean section. The results showed that the incidence of gestational hypertension, fetal distress, and cesarean section was significantly higher in the low 25(OH)D₃ level group compared to the normal-level group. These findings suggest that low vitamin D levels may be a potential risk factor for adverse pregnancy outcomes in women with gestational diabetes. Vitamin D plays a crucial role in regulating immune responses and inflammation, and it may reduce the occurrence of complications like gestational hypertension by improving maternal immune function and lowering inflammation. Pregnant women with low vitamin D levels are at higher risk for gestational hypertension and fetal distress, and previous studies have also indicated a significant association between low vitamin D levels and pregnancy complications such as gestational hypertension and fetal distress.^[28] These results align with our findings and further emphasize the important role of vitamin D in pregnancy health.

In addition, the fetal birth weight in the low 25(OH)D₃ level group was significantly lower than in the normal-level group, and the incidence of neonatal complications, especially jaundice and RDS, was higher in the low-level group. This finding suggests that vitamin D deficiency may affect fetal development, leading to low birth weight and an increased risk of neonatal complications. Vitamin D is essential for fetal growth and development, and deficiency may impair the development of the fetus’s skeletal and immune systems, increasing the risk of complications after birth.

Although this study reveals the relationship between serum 25(OH)D₃ levels and GDM and its complications, several limitations should be acknowledged. Firstly, as this is a retrospective analysis, we could not control for all potential confounding factors, and the study design does not allow for the establishment of a causal relationship. Secondly, the sample size is relatively small, and the study population is limited to patients from a specific geographic region, which may introduce regional variability and limit the generalizability of the findings. Furthermore, the routes of vitamin D intake (such as diet, supplementation, and sunlight exposure) were not thoroughly documented, which could affect the accuracy of vitamin D status assessment. Moreover, the timing of serum 25(OH)D₃ measurements during pregnancy varied among participants, potentially introducing variability, as vitamin D levels can fluctuate with gestational age. In addition, relevant biomarkers that may interact with vitamin D metabolism – such as parathyroid hormone or serum calcium – were not measured, which limits the understanding of potential physiological mechanisms. Lastly, self-reported data, including dietary habits and supplement use, may be subject to recall bias or inaccuracies, further affecting the reliability of the vitamin D assessments.

This study demonstrates that low 25(OH)D₃ levels are closely associated with the occurrence of GDM, pregnancy complications, and neonatal outcomes. Vitamin D deficiency may be a potential risk factor for GDM and its adverse outcomes. Future prospective studies are needed to further verify the effectiveness of vitamin D supplementation in the prevention and treatment of GDM and to explore its mechanisms of action, providing evidence for clinical interventions.

5. Conclusion

This study demonstrates that low serum 25(OH)D₃ levels are significantly associated with an increased risk of GDM and its related complications. Vitamin D deficiency was linked to elevated fasting glucose levels, and a greater incidence of adverse pregnancy outcomes, including gestational hypertension, fetal distress, cesarean delivery, and neonatal complications. Additionally, multivariate regression analysis confirmed that low vitamin D levels serve as an independent predictor of GDM. These findings highlight the clinical relevance of monitoring and managing vitamin D status during pregnancy to potentially reduce the risk of GDM and improve maternal and neonatal outcomes.

Author contributions

Conceptualization: Miao Zhang, Jing Ning, Hanyu Guo, Xiaobin Fan.

Data curation: Miao Zhang, Jing Ning, Hanyu Guo, Xiaobin Fan.

Formal analysis: Miao Zhang, Jing Ning, Hanyu Guo, Xiaobin Fan.

Investigation: Xiaobin Fan.

Methodology: Wenjie Liu, Xiaobin Fan.

Visualization: Miao Zhang, Jing Ning, Hanyu Guo.

Writing – original draft: Miao Zhang, Jing Ning, Hanyu Guo, Wenjie Liu, Xiaobin Fan.

Writing – review & editing: Miao Zhang, Jing Ning, Xiaobin Fan.