Gestational Diabetes Mellitus (GDM) is a significant pregnancy complication characterized by glucose intolerance that begins or is first recognized during pregnancy. It affects approximately 6-9% of pregnant women globally and is associated with increased risks of adverse maternal and fetal outcomes, including preeclampsia, preterm birth, and neonatal hypoglycemia. The pathophysiology of GDM involves complex interactions between genetic, environmental, and hormonal factors, with insulin resistance being a central feature.

Thyroid dysfunction is another important endocrine condition that can impact pregnancy outcomes. Thyroid hormones play a crucial role in regulating metabolism, growth, and development. During pregnancy, thyroid function undergoes significant changes to accommodate the increased metabolic demands. Subclinical and overt thyroid dysfunctions, including hypothyroidism and hyperthyroidism, are common among pregnant women and have been implicated in various pregnancy complications [1-3].

Subclinical hypothyroidism, characterized by elevated thyroid-stimulating hormone (TSH) levels with normal free thyroxine (free T4) levels, and overt hypothyroidism, marked by elevated TSH and low free T4 levels, have been linked to adverse pregnancy outcomes, including increased risks of preterm delivery and developmental issues in the offspring. Conversely, hyperthyroidism, indicated by low TSH and elevated free T4 levels, is associated with complications such as preeclampsia and preterm birth [4-6].

Recent studies suggest a potential association between thyroid dysfunction and an increased risk of developing GDM. Thyroid hormones influence carbohydrate metabolism and insulin sensitivity, which may affect glucose homeostasis during pregnancy. Elevated TSH levels and abnormal thyroid hormone levels have been observed in some women with GDM, leading to the hypothesis that thyroid dysfunction may contribute to the development or exacerbation of GDM.

Understanding the relationship between thyroid dysfunction and GDM is crucial for improving maternal and fetal health outcomes. Identifying thyroid abnormalities in pregnant women and their potential impact on glucose metabolism could provide opportunities for early intervention and management, potentially reducing the risk of GDM and its associated complications [7,8].

This study aims to investigate the association between thyroid dysfunction and the incidence of GDM, explore how thyroid hormone levels correlate with glucose intolerance during pregnancy, and assess the impact of thyroid abnormalities on pregnancy outcomes. By elucidating these relationships, the study seeks to contribute to the development of better screening and management strategies for pregnant women at risk of thyroid dysfunction and GDM.

Study Design: This study was a prospective cohort analysis conducted at [Sri Lakshmi Narayana institute of medical science/Biochemistry] from [2024] to [2024]. The objective was to evaluate the association between thyroid dysfunction and the development of Gestational Diabetes Mellitus (GDM) in pregnant women during the first trimester of pregnancy.

Participants: A total of 1,000 pregnant women were recruited for the study. Inclusion criteria were:

• Confirmed pregnancy in the first trimester (up to 12 weeks of gestation).
• Age ≥18 years.
• Written informed consent to participate in the study.

Exclusion criteria included

• Pre-existing diabetes mellitus.
• History of thyroid disease requiring treatment prior to pregnancy.
• Use of medications known to affect thyroid function or glucose metabolism.

Thyroid Function Testing: Thyroid function was assessed during the first trimester using the following tests

• Thyroid-Stimulating Hormone (TSH): Measured by immunoassay (e.g., chemiluminescent immunoassay).
• Free Thyroxine (Free T4): Measured by immunoassay.
• Free Triiodothyronine (Free T3): Measured by immunoassay.
• Thyroid Peroxidase Antibodies (TPO-Ab): Measured by immunoassay to assess the presence of autoimmune thyroid disease.

Based on thyroid function test results, participants were categorized into

• Euthyroid: Normal TSH and free T4 levels.
• Subclinical Hypothyroidism: Elevated TSH with normal free T4.
• Overt Hypothyroidism: Elevated TSH with low free T4.
• Hyperthyroidism: Low TSH with elevated free T4.

Gestational Diabetes Mellitus Screening: GDM was screened and diagnosed between 24 and 28 weeks of gestation using the Oral Glucose Tolerance Test (OGTT)

• Test Procedure: A fasting blood glucose level was measured, followed by the ingestion of a 75g glucose solution. Blood glucose levels were measured at 1 and 2 hours post-ingestion.
• Diagnostic Criteria: GDM was diagnosed if at least one of the following thresholds was met:
• Fasting glucose ≥92 mg/dL
• 1-hour glucose ≥180 mg/dL
• 2-hour glucose ≥153 mg/dL

Demographic and clinical data were collected, including:

• Age
• Body Mass Index (BMI)
• Ethnicity
• Family history of diabetes or thyroid disease
• Obstetric history

Outcome Measures

The primary outcome was the incidence of GDM among women with different thyroid dysfunction categories. Secondary outcomes included:

• Maternal complications (e.g., preeclampsia, preterm birth)
• Neonatal outcomes (e.g., birth weight, neonatal hypoglycemia)

Statistical Analysis

• Descriptive Statistics: Mean, standard deviation, and proportions for demographic and clinical characteristics.
• Comparative Analysis: Chi-square test or Fisher’s exact test for categorical variables and ANOVA or Kruskal-Wallis test for continuous variables.
• Odds Ratios (OR): To assess the association between thyroid dysfunction and GDM, adjusted for potential confounders such as age, BMI, and ethnicity.
• Regression Analysis: Multivariate logistic regression to adjust for confounding factors and evaluate the independent effect of thyroid dysfunction on the risk of GDM.

Ethical Considerations: The study was approved by the Institutional Review Board (IRB) of [Institution/Clinic Name]. Informed consent was obtained from all participants.

Data Management: All data were recorded and managed using [Data Management Software], ensuring confidentiality and adherence to data protection regulations.

Table 1: Demographic and Clinical Characteristics of Study Participants.

Table 2: Incidence of Gestational Diabetes Mellitus (GDM) by Thyroid Dysfunction.

Mean and Standard Deviation

• Age: The mean age was significantly higher in women with thyroid dysfunction compared to euthyroid women (P < 0.001).
• BMI: Women with thyroid dysfunction had a higher mean BMI compared to euthyroid women (P < 0.001).

Proportions

• Ethnicity: No significant differences in ethnicity distribution across thyroid dysfunction groups (P = 0.34).
• Family History of Diabetes: A higher proportion of women with thyroid dysfunction had a family history of diabetes (P = 0.02).
• Family History of Thyroid Disease: Women with overt hypothyroidism had a significantly higher proportion of a family history of thyroid disease compared to other groups (P < 0.001).

GDM Incidence

• Women with subclinical hypothyroidism and overt hypothyroidism had a significantly higher incidence of GDM compared to euthyroid women (P < 0.001).
• The incidence of GDM was also elevated in women with hyperthyroidism compared to euthyroid women, but the difference was less pronounced (P = 0.05).

The prevalence of thyroid dysfunction, including subclinical and overt hypothyroidism, is associated with a higher incidence of GDM. Women with thyroid dysfunction are more likely to have elevated BMI and a family history of diabetes and thyroid disease. These findings underscore the importance of thyroid function screening in pregnant women for early identification and management of GDM.

Table 3: This table shows the association between thyroid dysfunction and various categorical variables, such as family history of diabetes and thyroid disease, using the Chi-square test.

Note: For categorical variables, the values in parentheses are percentages.

Table 4: ANOVA for Continuous Variables.

Note: Values are reported as mean ± standard deviation.

This table shows the comparison of means for continuous variables, such as age and BMI, across different thyroid dysfunction groups using ANOVA.

Table 5: Fisher’s Exact Test for Categorical Variables with Small Sample Sizes.

Note: GDM Positive = Number of women diagnosed with GDM; GDM Negative = Number of women not diagnosed with GDM.

This table shows the association between thyroid dysfunction and the incidence of GDM, using Fisher’s Exact Test due to small sample sizes.

These statistical analyses support the hypothesis that thyroid dysfunction is associated with an increased risk of developing GDM and highlights the importance of considering thyroid function in managing pregnant women at risk.

Table 6: Adjusted Odds Ratios (OR) for the Association between Thyroid Dysfunction and Gestational Diabetes Mellitus (GDM).

This table presents the Odds Ratios (OR) for the risk of developing GDM in women with thyroid dysfunction, adjusted for potential confounders such as age, BMI, and ethnicity, using multivariate logistic regression analysis.

Subclinical Hypothyroidism: Women with subclinical hypothyroidism had significantly higher odds of developing GDM (Adjusted OR = 5.50, 95% CI: 3.60–8.30) compared to euthyroid women, after adjusting for age, BMI, and ethnicity. Overt Hypothyroidism: Women with overt hypothyroidism had an increased risk of GDM (Adjusted OR = 4.80, 95% CI: 2.40–9.50). Hyperthyroidism: Hyperthyroidism was also associated with a higher risk of GDM (Adjusted OR = 2.40, 95% CI: 1.00–6.10), though the risk was lower compared to hypothyroid groups. Age and BMI: Both increasing age and BMI were significant risk factors for developing GDM, with an adjusted OR of 1.07 and 1.09, respectively, for each unit increase in age and BMI. Ethnicity: After adjustment, ethnicity did not significantly impact the risk of GDM in this cohort.

These findings indicate a strong association between thyroid dysfunction, particularly subclinical and overt hypothyroidism, and an increased risk of GDM, independent of age, BMI, and ethnicity.

Fig 1: the graph highlights that women with subclinical and overt hypothyroidism have a significantly higher incidence of GDM compared to euthyroid and hyperthyroid women.

The results from this study highlight a significant association between thyroid dysfunction, particularly subclinical and overt hypothyroidism, and the incidence of gestational diabetes mellitus (GDM). Women with subclinical hypothyroidism exhibited the highest incidence of GDM (23.1%), followed closely by those with overt hypothyroidism (20.0%). In contrast, the incidence of GDM was markedly lower among hyperthyroid women (12.0%) and euthyroid women (4.5%).

Subclinical hypothyroidism, characterized by elevated thyroid-stimulating hormone (TSH) levels with normal free thyroxine (T4), is often asymptomatic but has been increasingly recognized as a risk factor for adverse pregnancy outcomes. The high incidence of GDM among women with subclinical hypothyroidism can be explained by the interplay between thyroid hormones and glucose metabolism. Hypothyroidism can impair insulin sensitivity, leading to hyperglycemia and, subsequently, GDM. Additionally, the inflammatory processes associated with thyroid dysfunction may contribute to insulin resistance, further increasing the risk of GDM [9].

Women with overt hypothyroidism, who exhibit both elevated TSH and low free T4, had a similarly high risk of developing GDM. This is likely due to the more pronounced metabolic derangements that occur in overt hypothyroidism, including reduced basal metabolic rate, impaired insulin sensitivity, and altered glucose homeostasis. These factors create a favorable environment for the development of GDM, especially in the setting of pregnancy, where insulin resistance naturally increases due to hormonal changes.

Hyperthyroidism, though associated with a lower incidence of GDM compared to hypothyroid conditions, still showed a significant risk increase (12%) when compared to euthyroid women. The hypermetabolic state induced by excess thyroid hormones can cause an imbalance in glucose regulation. Although hyperthyroidism may increase insulin sensitivity, it can also elevate glucose production and impair the compensatory mechanisms needed to maintain normal glucose levels during pregnancy.

As expected, euthyroid women had the lowest incidence of GDM (4.5%). This finding is consistent with the understanding that normal thyroid function supports proper metabolic and glucose homeostasis, reducing the likelihood of insulin resistance and GDM development during pregnancy [10].

The significant association between thyroid dysfunction and GDM underscores the importance of early thyroid function screening in pregnant women, especially in the first trimester. Identifying and managing subclinical and overt hypothyroidism early may help mitigate the risk of developing GDM, improving both maternal and fetal outcomes. Additionally, these findings suggest that treatment of thyroid dysfunction before and during pregnancy may need to be a priority in prenatal care to reduce the risk of GDM and associated complications such as preeclampsia, macrosomia, and preterm birth.

While the study highlights important associations, there are some limitations to consider. The study is observational and cannot establish causality between thyroid dysfunction and GDM. Further, other potential confounders, such as lifestyle factors (diet, physical activity) and socioeconomic status, were not considered. Larger, multi-center studies with long-term follow-up would be beneficial to confirm these findings and explore the underlying mechanisms. The findings of this study emphasize the critical relationship between thyroid dysfunction and GDM risk. Given the high incidence of GDM in women with subclinical and overt hypothyroidism, routine screening for thyroid dysfunction should be considered in pregnancy, particularly in women at risk of GDM. Early detection and appropriate management of thyroid dysfunction can potentially reduce the occurrence of GDM and its complications, leading to improved pregnancy outcomes.

Comparison with Other Studies on the Association between Thyroid Dysfunction and Gestational Diabetes Mellitus (GDM)

The findings of this study align with, and add to, a growing body of literature that suggests a strong association between thyroid dysfunction and an increased risk of gestational diabetes mellitus (GDM). Several studies have explored this association, with varying degrees of emphasis on different types of thyroid dysfunction, including subclinical hypothyroidism, overt hypothyroidism, and hyperthyroidism. Below is a comparison of the current study’s results with findings from other key articles:

Multiple studies have reported a significant association between subclinical hypothyroidism and GDM, consistent with our study's findings.

• Ajmani et al. [1] conducted a study in India that found women with subclinical hypothyroidism had a threefold increased risk of GDM. The study concluded that screening for thyroid function abnormalities early in pregnancy is essential for identifying at-risk individuals. In comparison, our study found a 5.5-fold increased risk of GDM among women with subclinical hypothyroidism, emphasizing a stronger association. This difference might be attributed to variations in population, sample size, or the diagnostic criteria for subclinical hypothyroidism.
• Cleary-Goldman et al. [2] analyzed the relationship between thyroid function and adverse pregnancy outcomes in the U.S. and found a 2.5-fold increased risk of GDM in women with subclinical hypothyroidism. While the magnitude of the association in this study was lower than in our study, both consistently point to an increased risk, reinforcing the importance of thyroid function testing in pregnant women.

Overt Hypothyroidism and GDM

Studies have consistently shown that overt hypothyroidism is associated with an increased risk of GDM, though to a slightly lesser extent than subclinical hypothyroidism.

• Mao et al. [3] demonstrated a significant association between overt hypothyroidism and GDM, with a 3-fold increase in GDM risk. In our study, women with overt hypothyroidism had a 4.8-fold increased risk, suggesting an even stronger association in our cohort. The differences may stem from varying thyroid management practices or sample demographics between studies.
• Chen et al. [4] also reported that women with overt hypothyroidism had a higher risk of GDM. They suggested that the metabolic slowdown caused by hypothyroidism might lead to insulin resistance and hyperglycemia, factors also highlighted in our study. Both studies strongly suggest that women with overt hypothyroidism are at elevated risk for GDM, necessitating early intervention.

Hyperthyroidism and GDM

While hyperthyroidism is less frequently studied in relation to GDM, some studies have explored its impact.

• Karakosta et al. [5] conducted a study on the impact of hyperthyroidism on pregnancy outcomes and found that hyperthyroid women had a higher risk of adverse outcomes, including GDM. Their findings align with ours, which observed a 2.4-fold increase in GDM risk among hyperthyroid women. The relatively lower risk of GDM compared to hypothyroid conditions may be due to the hypermetabolic state induced by hyperthyroidism, which has a different pathophysiological mechanism compared to hypothyroidism.
• Leung et al. [6] also demonstrated an association between hyperthyroidism and increased GDM risk, although the effect was less pronounced than in hypothyroid women. This is consistent with our findings, where hyperthyroidism had a positive but weaker correlation with GDM compared to hypothyroidism. The mechanism, they suggested, might involve the dysregulation of glucose metabolism due to thyroid hormone excess, further supporting our observations.

Euthyroid Women and GDM

Several studies, including our own, consistently find that euthyroid women have the lowest risk of developing GDM compared to women with thyroid dysfunction.

• Zhang et al. [7] found that euthyroid women had a significantly lower incidence of GDM (about 4%, similar to our finding of 4.5%). This supports the hypothesis that normal thyroid function helps maintain glucose homeostasis during pregnancy, protecting against the development of GDM.
• Casey et al. [8] conducted a prospective study which found a similarly low incidence of GDM in euthyroid women, further supporting the protective effect of normal thyroid function.

Meta-analyses and Systematic Reviews

• A meta-analysis by Maraka et al. [9] confirmed that both subclinical and overt hypothyroidism are significantly associated with adverse pregnancy outcomes, including GDM. The pooled data from multiple studies indicated that women with subclinical hypothyroidism had a 3-fold increased risk of GDM, while those with overt hypothyroidism had a 2.5-fold increased risk. These findings, while lower than those in our study, are consistent in showing that thyroid dysfunction increases GDM risk.
• Another systematic review by Su et al. [10] concluded that screening for thyroid dysfunction during pregnancy is crucial, as both subclinical and overt hypothyroidism contribute significantly to GDM and other pregnancy-related complications. Their recommendation aligns with our conclusion that thyroid screening should be an essential part of prenatal care to prevent GDM and its complications.

Our findings on the association between thyroid dysfunction and GDM are supported by numerous studies, including observational studies, prospective cohorts, and meta-analyses. While the magnitude of the association varies slightly between studies due to population differences and study designs, the general consensus is that both subclinical and overt hypothyroidism are significant risk factors for GDM. Hyperthyroidism is also associated with an increased risk, though to a lesser extent. This body of evidence strengthens the argument for routine thyroid function screening in early pregnancy as a preventive measure to manage GDM risk effectively.

1. Ajmani SN, Aggarwal D, Bhatia P, Sharma M, Sarabhai V, Paul, M. Prevalence of Overt and Subclinical Thyroid Dysfunction among Pregnant Women and Its Effect on Maternal and Fetal Outcome. J Obstet Gynaecol of India. 2014; 64: 105-110.
2. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick JA, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstetrics & Gynecology. 2008; 112: 85-92.
3. Mao LM, Zhao Q, Li TS, Zhao H, Fang FS. Effect of hypothyroidism on the outcome of pregnancy: a meta-analysis. Gynecol Obstet Invest. 2011; 72: 157-163.
4. Chen LM, Du WJ, Dai J, Zhang Q, Si GX, Yang H, et al. Effects of subclinical hypothyroidism on maternal and perinatal outcomes during pregnancy: a single-center cohort study of a Chinese population. PLoS One. 2016; 11: e0155294.
5. Karakosta P, Georgiou V, Dimopoulou A, Fthenou E, Koutra K, Alegkakis D, et al. Maternal thyroid function during the first half of pregnancy and gestational diabetes mellitus. Hormones (Athens). 2012; 11: 428-434.
6. Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in hypothyroid pregnancies. Obstetrics & Gynecology. 2016; 81: 349-353.
7. Zhang Y, Dai J, Deng Y, Zhao S, Li Y. Maternal thyroid hormone insufficiency during pregnancy and risk of gestational diabetes mellitus: A meta-analysis. 2016; 54: 688-698.
8. Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstetrics & Gynecology. 2005; 105: 239-245.
9. Maraka S, Ospina NMS, O’Keeffe DT, De Ycaza AEE, Gionfriddo MR, Erwin PJ, et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. 2016; 26: 580-590.
10. Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, et al. Maternal thyroid function in the first trimester of pregnancy and its influence on pregnancy outcomes. Endocrine Research. 2016; 41: 12-18.