Gestational diabetes mellitus (GDM) is a common carbohydrate intolerance that may arise during pregnancy, with a prevalence rate of 17.5% in China.1 GDM is related to an increased risk of perinatal complications, such as preterm birth, miscarriage, neonatal macrosomia, pre-eclampsia, and birth defects.2,3 Moreover, the offspring of mothers with GDM have an elevated risk of glucose metabolism disorder.4 These adverse complications can be improved by proper diet, exercise, and insulin treatment. Some studies found that some factors were related to the development of GDM in early pregnancy, including Vitamin D, adiponectin, and placental growth factor.5–7 Pregnancy has a considerable impact on the thyroid gland and thyroid function.8,9 In the early pregnancy, the high circulation human chorionic gonadotropin level activates the thyroid-stimulating hormone (TSH) receptor and thus directly stimulate the thyroid to produce more thyroid hormone.10 It is believed that diabetes patients have a higher prevalence of thyroid disorders than the normal population.11 Thyroid disorders have been found in both Type 1 and Type 2 diabetes.12,13 The association between thyroid dysfunction and carbohydrate intolerance during pregnancy is mainly related to women with GDM. However, the association of GDM and thyroid disturbance remains controversial. Studies indicated no significant difference in TSH, free thyroxine (FT4) level, and thyroid peroxidase antibody (TPOAb) status between women with GDM and women without GDM,14,15 but Toulis et al.'s meta-analysis indicated that subclinical hypothyroidism may be a risk factor for GDM.16 Subclinical hypothyroidism can be divided into antibody-positive subclinical hypothyroidism and antibody-negative subclinical hypothyroidism according to thyroid autoantibody status. TPOAb is one of the thyroid autoantibodies, which positive is reported to increase the prevalence of subclinical hypothyroidism. So TPOAb status should be considered when the pregnant women's TSH level is high. This retrospective study found higher TSH was association with the risk of developing GDM, and we also evaluated the magnitude the problem of combination of TSH and TPOAb during pregnant women with carbohydrate intolerance.
Materials and methods
This study was a retrospective study, which conducted at the out-patient department of the First Affiliated Hospital, Sun Yat-sen University. All women who were undergoing prenatal test were recruited between January 2015 and December 2015. Exclusion criteria contain women who over 28 weeks pregnant and women who were not singleton pregnancy. Women who were on levothyroxine treatment or on insulin-dependent at conception were also excluded. Women who had the following situation were also excluded: personal history of Type 1 diabetes or other immune diseases, personal and family history of thyroid disease, current and past treatment with antithyroid drugs, levothyroxine, iodine-131, or thyroid surgery. According to last menstrual period and the results of first ultrasound exam, women were divided into first (<14 weeks) and second (≥14 and <28 weeks) trimesters of pregnancy. A total of 2333 women enrolled in this study. Five hundred and forty-six women were complicated with GDM, and 1787 were in the normal glucose tolerance group (NGT). Their demographic data and clinical details were collected by the obstetrician.
Methods of sampling and laboratory testing
Following an overnight fast, blood samples were collected in the morning for each subject. Serum was isolated by centrifugation and stored an −80°C until testing in the clinical laboratory. The concentration of serum TSH, free triiodothyronine (FT3), and FT4 were detected by chemiluminescent microparticle immunoassay. Maternal serum glucose levels were measured by standard enzymatic procedures. Serum hemoglobinA1c were measured via high-performance liquid chromatography using a Diabetes Control and Complications Trial aligned method in the clinical laboratory.
The diagnosis of GDM was based on a 75-g oral glucose tolerance test performed between 24 and 28 gestational weeks, according to the American Diabetes Association criteria17 (fasting ≥5.1 mmol/L, 1 h ≥10.0 mmol/L, 2 h ≥ 8.5 mmol/L). PGDM was defined as fasting plasma glucose ≥7.00 mmol/L at the first prenatal visit or the 75-g oral glucose tolerance test 2 h ≥11.10 mmol/L.17 In line with guidelines of the American Thyroid Association,10 this study established reference intervals of thyroid function at our institution. For the first trimester 0.22–4.53 mIu/L for TSH, 3.67–5.86 pmol/L for FT3, and FT4 8.62–15.7 pmol/L. For the second trimester, the respective reference intervals were 0.42–4.26 mIu/L for TSH, 3.33–5.55 pmol/L for FT3, and FT4 6.18–12.1 pmol/L. According to the trimester-specific population reference interval, the concentration of serum TSH and FT4 were categorized as high (serum concentration higher than the trimester-specific population reference interval), normal (serum concentration within the trimester-specific population reference interval), and low (serum concentration lower than the trimester-specific population reference interval). Overt and subclinical hypothyroidism was defined as increased TSH and decreased or normal FT4 levels. Overt and subclinical hyperthyroidism were defined as decreased TSH, and increased FT4 or normal FT4 levels, respectively.
Data were analyzed using SPSS 19.0. Continuous variables were described as mean ± standard deviation and compared by unpaired Student t test. The correlation was examined with Logistic regression. A P value of <0.05 was considered as statistically significant.
Demographic information of the patients enrolled in the study was shown in Table 1. The average age of the 2333 women in the study was 30.68 ± 4.246 years. Women in GDM were significantly older than women in NGT group [(32.39 ± 4.42) years vs. (30.15 ± 4.34) years, P < 0.001]. Serum FT4 concentration was significantly lower in GDM group [(9.34 ± 2.38) pmol/L vs. (10.05 ± 2.73) pmol/L, P < 0.001]; however, the TSH and FT3 concentration between the two groups showed no significantly difference (P > 0.05). The incidence of thyroid disease during pregnancy was 18.47%, and the incidence of subclinical hypothyroidism was 2.97%, of which 61.90% be TPOAb positive subclinical hypothyroidism. The incidence of TPOAb postive euthyroidism was 11.11% in pregnancy.
TSH and TSH combined TPOAb showed a positive correlation with the development of GDM (Table 2). Of those who met the inclusion criteria, the GDM incidence was 23.40%. The prevalence of GDM was 35.78% and 28.70% for the TSH (H) and TSH (L) pregnant women, respectively. Table 3 showed the TSH (H) women had a significant higher difference for the risk of GDM [P = 0.0015, odds ratio (OR): 2.09, 95% confidence interval (CI): 1.34–3.28]. The TSH (L) women showed no difference for the incidence of GDM (P = 0.1183, OR: 1.29, 95% CI: 0.94–1.78). Then we estimated the TSH level with the risk of GDM in the first and second trimester (Tables 4 and 5). In the second trimester, TSH (H) women had a significant higher prevalence of GDM (P = 0.001, OR: 2.14, CI: 1.36–3.37). However, there is no difference detected in the first trimester.
TPOAb status with TSH (H), TSH (N), and TSH (L) were combined to estimate the risk of GDM in pregnant women (Table 6). The prevalence of GDM was 51.72%, 29.31%, 23.02%, and 21.91%, 26.67%, and 29.87% for the TSH (H) TPOAb (+), TSH (H) TPOAb (−), TSH (N) TPOAb (+), TSH (L) TPOAb (+), and TSH (L) TPOAb (−) pregnant women, respectively. We found only the TSH (H) TPOAb (+) pregnant women had a significant higher incidence of GDM (P = 0.0018, OR: 3.63, CI: 1.62–8.16). Then we analyze the risk in the first and second trimester (Tables 7 and 8). The TSH (H) TPOAb (+) pregnant women had a significant women higher incidence of GDM (P = 0.0021, OR: 3.64, CI: 1.6–8.31), and TSH (H) TPOAb (−), TSH (N) TPOAb (+), TSH (L) TPOAb (+), TSH (L) TPOAb (−) did not increase the incidence of the risk of GDM in the second trimester. However, there is no difference detected in the first trimester.
GDM is defined as glucose intolerance that first detected during pregnancy. As altered thyroid hormone levels have been shown in diabetic patients without pregnant.11,12 For further understanding the relationship of thyroid dysfunction and GDM, we analyzed the maternal thyroid function, and assessed TSH and thyroid autoantibodies status to the risk of GDM. In the present study, GDM patients had significantly lower FT4 concentration but normal TSH and FT3 compared to NGT. Saunders et al.18 found that mean serum T4 levels were significantly lower between uncontrolled diabetics and normal control subjects; however, plasma T4 levels rose in these patients after insulin treatment. This study shows the prevalence of subclinical hypothyroidism was 2.97%, of which 61.90% be TPOAb positive subclinical hypothyroidism. The incidence of TPOAb positive euthyroidism was 11.11% in pregnancy, similar to previous reports.19–21 It also found the GDM prevalence was 23.40%, significantly higher than some reports.1 This may be because the patients’ age were elder than other studies, who was 30.15 ± 4.34 years for NGT, 32.39 ± 4.42 years for GDM. This may because our hospital is one of the GDM treatment center in our city.
In this study, the increased TSH level was correlated to higher risk of GDM in the later pregnancy were found. Karakosta et al.22 found a per-unit increase in TSH value was associated with an increased risk of GDM [relative risk (RR): 1.1, 95% CI: 1.0–1.2]. Positive TPOAb was correlated to subclinical hypothyroidism,23 so the impact of combination of TPOAb and TSH on the risk of developing GDM were analyzed. TSH (H) TPOAb (+) women were found to be with a higher risk of GDM (P = 0.0018, OR: 3.63, CI: 1.62–8.16). This is consistent with Ying et al.,21 who found the elevated TSH combined with positive TPOAb was associated with a three-fold increased risk of GDM. TSH and TPOAb were two important indicator for thyroid disease during pregnancy. However the difference between TSH (H) TPOAb (−) and TSH (N) TPOAb (+) was not showed, this may need further prospective study.
Reports found that the relationship between thyroid dysfunction and adverse outcome was not consistent with trimester7 Women had a higher incidence of developing GDM in the second trimester were found, who was TSH (H) TPOAb (+) (P = 0.0021, OR: 3.64, CI: 1.6–8.31). However in the first trimester, TSH level was not correlated to the incidence of GDM, after combine the TPOAb status, the risk of GDM do not show significant difference. This may due to a small subjects develop TSH (H), and TSH (H) TPOAb (+), TSH (H) TPOAb (−), TSH (N) TPOAb (+), TSH (L) TPOAb (+) and TSH (L) TPOAb (−) in the first trimester.
Elevated TSH and TPOAb status are important indicators for thyroid disease. Ying21 and our study found that the elevated TSH combined positive TPOAb is correlated with increased risk of GDM. Whether only TSH (H) or TPOAb positive correlated to increased risk of GDM is remains inconsistent. In this study TSH (H) is correlated to increased risk of GDM; however, TSH (H) TPOAb (−), and TSH (N) TPOAb (+) showed no association to the risk of GDM. This may due to the different diagnostic criteria for GDM in these studies. GDM incidence was significantly higher when International Association of Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria was used. Since older subjects enrolled in GDM group than the NGT group, the influence of age could not be excluded.
There are several limitations of the present study. First, the pregnancy outcomes of the pregnant women have not been analyzed, since both glucose intolerance and thyroid dysfunction during pregnancy were correlated with neuropsychiatric morbidity.24 Women with thyroid disorders complicate with glucose intolerance may aggravate the situation. Moreover, the thyroid autoantibodies had not been all evaluated, as previous studies demonstrated significant relationship between thyroid autoantibodies and miscarriage and preterm delivery.25 Finally, the small sample size in this study could affect the results.
It can be concluded that TPOAb positive subclinical hypothyroidism was correlated to development of GDM. Further study should be conducted to determine thyroid hormone levels before and after glycemic controlled in women with glucose intolerance.
Conflicts of Interest
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Keywords:© 2019 by Lippincott Williams & Wilkins, Inc.
Diabetes, gestational; Thyrotropin; Pregnancy trimester, first; Pregnancy trimester, second