European Journal of Endocrinology (2000) 143 741±747 ISSN 0804-4643

CLINICAL STUDY High frequency of antithyroid autoantibodies in pregnant women at increased risk of gestational diabetes mellitus A Olivieri, H Valensise2, F Magnani2, E Medda1, S De Angelis, M D'Archivio, M Sorcini, S Carta, S Baccarini and C Romanini2 Laboratory of Metabolism and Pathological Biochemistry, 1Laboratory of Epidemiology and Biostatistics, Istituto Superiore di SanitaÁ, Rome and 2Department of Gynecology and Obstetrics, Tor Vergata University, Rome, Italy (Correspondence should be addressed to A Olivieri, Laboratorio di Metabolismo e Biochimica Patologica, Istituto Superiore di SanitaÁ, Viale Regina Elena 299, 00161 Roma, Italy; Email: [email protected])

Abstract Background: Thyroid autoantibodies (ThyAb) and subclinical hypothyroidism occur more frequently in pregnant women with insulin-dependent diabetes mellitus than in healthy pregnant women. Few studies have investigated the presence of ThyAb in women with gestational diabetes mellitus (GDM), and no significant association between diabetes in pregnancy and thyroid function has been reported. Objective: To assess the thyroid biochemical profile and estimate the prevalence of ThyAb in a group of pregnant women at increased risk of GDM due to family and personal risk factors, and to investigate the relationship between a positive family history of diabetes or thyroid diseases and the eventual presence of ThyAb during pregnancy. Methods: Oral glucose tolerance, serum ThyAb and thyroid function were evaluated in 181 pregnant women with increased risk for GDM (study group). Seventeen healthy pregnant women without risk factors for GDM and with a normal glucose tolerance were recruited as controls. Results: The women who developed GDM showed a mean free thyroxine concentration significantly lower than that observed in the healthy pregnant women and in those with impaired gestational glucose tolerance and normal glucose tolerance. Twenty-nine of the 181 women in the study group (16%) were ThyAb positive. However, the risk of being ThyAb positive during pregnancy was three times greater in the women with positive family history of both diabetes mellitus and thyroid disease than in those with no family history of these conditions. Conclusions: This study showed that women with increased risk of GDM, mostly those with family history of diabetes mellitus and thyroid disease, also have an increased risk of being ThyAb positive during pregnancy. It also highlighted the importance of evaluating thyroid function in pregnant women with impaired glucose tolerance, in view of their increased risk of subclinical hypothyroidism.

European Journal of Endocrinology 143 741±747

Introduction ThyAb in women with GDM, and no significant association between diabetes in pregnancy and thyroid About 10% of women at 16 weeks gestation are function has been reported (8, 9). positive for thyroid peroxidase antibody (TPOAb), in GDM is defined as carbohydrate intolerance of line with what is found in the general population (1). variable severity that begins or is first diagnosed during The presence of TPOAb during pregnancy may be pregnancy. The prevalence of GDM varies from 0.15 to associated with hypothyroidism and it has been 12.8% (10±15). This wide range reflects racial or reported to be closely related to the increased risk of geographical differences in the distribution of genetic or developing postpartum thyroiditis (PPT) (2). Thyroid environmental risk factors. Women with GDM are autoantibodies (ThyAb) occur more frequently in characterized by a relatively diminished insulin secre- pregnant women with insulin-dependent diabetes tion, coupled with a pregnancy-induced insulin resis- mellitus (IDDM) than in healthy pregnant women (3± tance (16). Glucose tolerance returns to normal after 5). Moreover, an increased incidence of subclinical delivery in the majority of women, although several hypothyroidism has been reported in pregnant women studies have shown that women with previous GDM with IDDM (6). As regards gestational diabetes mellitus have a high risk of developing overt diabetes mellitus (GDM), various non-organ-specific autoantibodies have later in life (17±19). Furthermore, maternal hyper- been found to be associated with the condition (7). glycemia during pregnancy has been shown to However, few studies have investigated the presence of be associated with adverse perinatal and childhood q 2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org

Downloaded from Bioscientifica.com at 09/23/2021 03:25:59PM via free access 742 A Olivieri and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2000) 143 outcomes (20, 21), and possibly with obesity and and with a normal glucose tolerance after OGTT were diabetes in adult life (22). Screening for GDM is recruited as controls (mean age at conception 28:5 ^ recommended at present in all pregnant women, with 4:8 years; gestational age 24:7 ^ 5:0 weeks). The small the aim of reducing maternal and fetal morbidity size of the control group was due to the difficulty of during and after pregnancy. recruiting pregnant women without risk factors for The aims of this study were to assess the thyroid GDM who consented to have the standard OGTT. None biochemical profile and estimate the prevalence of of the patients and controls had a personal history of antithyroid autoantibodies in a group of pregnant thyroid disease and none was receiving any medication women at increased risk of GDM due to family and that could influence thyroid function. All the study personal risk factors, and to investigate the relationship group and control women were living in Rome or in between a positive family history of diabetes and/or other urban areas of the Latium region with marginally thyroid diseases and the presence of antithyroid sufficient iodine intake. All pregnant women taking autoantibodies during pregnancy. part in the study gave their written consent to be included. Thyroid function (free thyroxine (FT4), free tri- Patients and methods iodothyronine (FT3) and thyroid-stimulating hormone (TSH)), serum thyroxine binding-globulin (TBG) and Oral glucose tolerance, serum ThyAb and thyroid thyroglobulin (Tg) and antithyroglobulin (TgAb) and function were evaluated in 181 pregnant women TPOAb were assessed in the GDM risk group and in the (mean age at conception 31:2 ^ 4:2 years) with healthy pregnant controls, at the time of the OGTT. increased risk of GDM (study group). These women were considered to be at greater risk of GDM on the basis of a panel of risk factors concerning obstetric, family and personal history in addition to maternal age Postpartum thyroid function assessment and clinical problems regarding current pregnancy The thyroid hormone profile was assessed at the 3rd, (Table 1). The pregnant women were outpatients of the 6th, 9th and 12th months after parturition. PPT was Department of Obstetrics and Gynecology of the Tor diagnosed when two or more consecutive FT4,FT3 or Vergata University in Rome. TSH concentrations were outside the normal reference A standard 100-g 3-h fasting oral glucose tolerance ranges. Hypothyroidism was defined as increased TSH test (OGTT) was administered late in the second and serum concentrations with or without decreased FT4 early in the third trimester (mean gestational age concentrations; thyrotoxicosis was defined as increased 27:5 ^ 4:5 weeks). GDM was diagnosed if two or more serum concentrations of FT4 or FT3, or both, with of the four threshold plasma glucose values were met or suppressed TSH values. were exceeded, as described previously (23). Impaired glucose gestational tolerance (IGGT) was diagnosed if only one value was met or exceeded (23). Seventeen healthy pregnant women without risk factors for GDM In vitro tests Plasma glucose concentration was measured by the Table 1 Risk factors for GDM. glucose oxidase method (23). Radioimmunological kits for detection of total T3 (T3), total T4 (T4), Tg and TSH Obstetric history Parity $5 were purchased from Radim (Pomezia, Italy); serum Previous late abortion FT3,FT4, TgAb and TPOAb were detected using Previous preterm delivery Brahms RIA kits (Berlin, Germany); serum TBG RIA Previous macrosomic baby Previous perinatal death kits were supplied by Medical System (Genova, Italy). Previous pregnancy hypertension Previous GDM Previous fetopathy Previous polyhydramnios Statistical analysis

Family history Family history of diabetes The arithmetic mean and standard deviation of thyroid Family history of macrosomia biochemical parameters were calculated. The geometric mean and standard deviation of log values were Personal history Chronic hypertension estimated for the non-normally distributed TSH data. Recurrent infections of genitourinary tract Student's t-test was used to compare mean values Current pregnancy Maternal age .35 years between groups. Differences between proportions were 2 Pregravidic BMI $ 25 kg=m2 evaluated by x test or Fisher's exact probability test. Polihydramnios 2 Test for linear trend (xtrend) was also performed. Crude Excessive weight gain risk was estimated by odds ratio (OR) calculation. The Increased fetal biometry 95% confidence interval (CI) was also calculated. www.eje.org

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Table 2 Thyroid parameters observed in the healthy pregnant controls and the study group women classified on the basis of OGTT results. Prevalence of ThyAb is also shown.

T3 T4 FT3 FT4 TSH³ Tg TBG ThyAb+ve

Normal range 0.6±2.0 ng/ml 60±120 ng/ml 2.2±5.5 pg/ml 8±18 pg/ml 0.2±4 mUI/ml 0±25 ng/ml 15±32 mg/ml Healthy controls 2.6^0.3 134^49 4.1^0.41 7.6^1.5** 1.0^0.5 10^8.4 48^9.0 2 (11.7) n 17 NGT ˆn †144 2.4^0.4 128^37 4.0^0.5 7.4^1.9** 1.3^1.0 12^9.4 48^8.4 24 (16.7) IGGT nˆ 18 † 2.6^0.4 132^72 4.2^0.5 7.2^0.9²² 1.2^0.4 9.0^7.9 48^10 3 (16.7) GDM n ˆ 19† 2.4^0.5 144^21 4.0^0.6 6.2^1.2 1.3^0.6 15^14 45^11 2 (10.5) ˆ † Values are mean ^ S.D. or number (%). ³ A logarithmic transformation of TSH values was performed to normalize data for analysis. **P , 0:01 and ²²P 0:01; compared with FT in GDM group. ˆ 4 Results with TgAb and TPOAb; they had TSH and FT4 concentrations within the normal range. As assessed by the OGTT, 144 pregnant women To estimate the possible association of ThyAb in (79.5%) had normal glucose tolerance (NGT), 18 pregnancy and family history of diabetes mellitus, all (9.9%) had IGGT and 19 (10.5%) had GDM. Women the 181 patients were grouped on the basis of their with GDM and IGGT received a diet containing family history of diabetes mellitus. A positive history of 1600 kcal/day. Insulin treatment was started when the condition in first-degree relatives was reported in the 2-h postprandial plasma glucose concentration was 61 women (33.7%) (59 reported non-insulin-depen- greater than 130 mg/dl (23). dent diabetes mellitus (NIDDM) and two reported A significantly greater mean body mass index (BMI) IDDM). A significantly greater prevalence of ThyAb was found in the women with GDM than in the was observed in the group of women with familial healthy controls 27:7 ^ 6:9 compared with 20:8 ^ diabetes mellitus than in those without a family history 1:5kg=m2; P , 0: 01 : of diabetes mellitus (24.6% compared with 11.7%, Table 2 shows the† thyroid hormone profile in the P 0:04 : A greater risk of being ThyAb positive healthy pregnant controls n 17 and in the study ORˆ 2:47† ; 95% CI 1.03 to 5.96) was also group n 181 classified onˆ the† basis of the OGTT estimated ˆ in the group of women with a positive ˆ † results. Expected high values of T3,T4 and TBG were family history of diabetes mellitus. When present, a found in all groups of pregnant women. The women family history of thyroid disease was also taken into who developed GDM showed a mean FT4 concentration consideration in both the study group and the control significantly lower than that observed in the healthy women. A positive family history of thyroid disease was pregnant women 6:2 ^ 1:2 compared with 7:6 ^ present in 45 of the pregnant women of the study 1:5pg=ml; P , 0:01 and in those with IGGT and group (10 ThyAb positive, 22.2%) and in five of the 17 normal glucose tolerance† P 0:01 : Among the GDM controls (one ThyAb positive, 20.0%). The pregnant ˆ † pregnant women, 47.4% had FT4 concentrations women reported nodules, goiter, or both, in mothers or ,6.0 pg/ml (range 5.8±4.0 pg/ml). sisters. Frequencies of FT4 and TSH serum concentrations in In order to evaluate a possible combined effect of the women of the study group classified on the basis of positive family history of thyroid disease and diabetes the OGTT results and in the controls are illustrated in mellitus in the pregnant women, the distribution of Fig. 1. There was a significant trend towards very low ThyAb prevalence in the pregnant women in the study FT4 concentrations in the GDM women compared with group classified on the basis of their family history of 2 those in the healthy pregnant controls xtrend 8:09; diabetes mellitus or thyroid disease was investigated P , 0:01 : Greater TSH values were also foundˆ more (Fig. 2). Only those women who gave full information frequently† when the glucose tolerance was more (respondent women, n 169 were considered for this 2 ˆ † severely impaired xtrend 3:74; P 0:05 : analysis. Four groups were identified: group A included Twenty-nine of the 181ˆ womenˆ in the† study group 89 pregnant women without familial diabetes mellitus were ThyAb positive (ThyAb+ve), with a prevalence of and thyroid disease; group B comprised 22 women with 16% (95% CI 11.1 to 22.4). Of these 29 women, five had a positive family history of thyroid disease; group C TgAb, 18 had TPOAb and six had both antibodies. were 35 women with a positive family history of Among the TPOAb+ve women, two developed GDM and diabetes mellitus; group D included 23 women with a three showed IGGT. Furthermore, a significantly positive family history of both diabetes mellitus and greater mean BMI was found in the ThyAb1ve thyroid disease. A ThyAb prevalence of 13% was women with low serum FT4 compared with the observed in group A, 9% in group B, 20% in group controls 25:7 ^ 5:3 compared with 20:8 ^ C, and 35% in group D. The prevalence of ThyAb 1:5kg=m2; P , 0:01 : In the control group, two observed in this group was significantly greater pregnant women (11.7%)† were ThyAb positive, both P , 0:01 than that observed in the group of †

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Figure 1 Distribution of serum FT4 and TSH concentrations in the study group stratified on the basis of the OGTT, and in the pregnant controls. pregnant women without a family history of diabetes Postpartum thyroid function assessment mellitus and thyroid disease (group A). In addition, the risk of the presence of ThyAb during pregnancy in these At the time of the study, a complete postpartum follow- groups was estimated by calculation of OR values. up was obtained in 20 of the 29 patients who were OR 1 was established in group A as the reference ThyAb positive during pregnancy. Nine of the 20 value,ˆ OR 0:6 (95% CI 0.09 to 3.43) was found in patients (45%) developed PPT: four showed hypothy- ˆ group B, OR 1:6 (95% CI 0.51 to 4.97) in group C, roidism during the follow-up and five exhibited a and OR 3:4ˆ (95% CI 1.06 to 5.5) in group D. thyrotoxic phase followed by a hypothyroid phase. All ˆ www.eje.org

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Figure 2 Distribution of ThyAb prevalence in the study group women stratified on the basis of a family history of diabetes mellitus (DM), thyroid disease (TD), or both. nine of these women with PPT had normal glucose basis of the OGTT results (Fig. 1). The FT4 concentra- tolerance during pregnancy, and four of the nine were tions were more frequently lower than the lower limit still hypothyroid at the end of follow-up and then of normal when the glucose tolerance was more started L-thyroxine therapy. severely impaired. In addition, the distribution of TSH concentration was shifted towards greater TSH values in the women who developed GDM compared with that Discussion in the remainder of the study group and the controls. Carbohydrate intolerance is the most common meta- These results are consistent with a previous study in bolic complication of pregnancy. At present several risk which pregnant rats with streptozotocin-induced dia- factors have been recognized to identify pregnant betes mellitus are used as a model of maternal diabetes women at increased risk of GDM in their current (30). In that study, the effects of different degrees of pregnancy (18). The screening for GDM in women with diabetes mellitus on maternal and fetal circulating significant risk factors permits a prompt instigation of a thyroid hormones were investigated. It was reported diet, insulin treatment, or both, when necessary, and that impaired maternal thyroid hormone status was the reduction of maternal and fetal morbidity during related to the degree of the metabolic imbalance. and after pregnancy (23±26). Moreover, T4 and T3 concentrations in the fetal brain Generally, during pregnancy maternal thyroid func- were found to be lower than normal, and the expected tion remains normal. However, variations in serum T3, increase in the fetal brain type II 50 deiodinase activity T4 and TBG observed in pregnancy largely reflect (31, 32) was not observed. The low cerebral T3 associated changes in sex steroid production. In fact, improved only with adequate insulin treatment of the under the influence of estrogens, the production rate of dams. In humans before 12 weeks gestation, when TBG is increased and its peripheral degradation rate is the fetal thyroid gland becomes active, the mother is decreased because of its high sialic acid content. This the unique source of thyroid hormones. During the causes increased concentrations of serum TBG and a middle and last trimesters, thyroid hormones are high binding capacity of the protein for T4 and T3 (27, supplied by both the mother and the fetus, but mostly 28). Small changes are observed in FT4 serum by the mother (33). All this highlights the importance concentrations during pregnancy. Generally, these of adequate maternal thyroid secretion. Recently, an increase slightly during the first trimester and then increased risk for impaired cognitive development has decrease. These changes resemble those of `non- been reported, not only in children of women with thyroidal illness' and may contribute to the saving of undetected or inadequately treated thyroid deficiency energy during pregnancy (29). In this study, a during pregnancy (34), but also in children of significantly lower FT4 mean value was observed in pregnant women with increased titers of TPOAb and the women with GDM than in either the other women normal thyroid function (35). in the study group or the healthy pregnant controls. As regards the presence of ThyAb, our results Moreover, the increased risk of subclinical hypothyroid- showed that pregnant women with increased risk for ism in the women with GDM was also indicated by the GDM (study group) have a prevalence of ThyAb that is distribution of the serum FT4 and TSH concentrations greater (16%) than that observed in the general found in the women of the study group classified on the population of women (10%) within the first trimester

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Downloaded from Bioscientifica.com at 09/23/2021 03:25:59PM via free access 746 A Olivieri and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2000) 143 of pregnancy (36). This finding becomes more sig- increased ThyAb frequency (10.5%) was found in the nificant when it is noted that the pregnant women subgroup of pregnant women developing GDM. These were tested for ThyAb at the time of the OGTT ± late in results confirm the finding of Lapolla et al. (9) of a low the second or early in the third trimester. It is well prevalence of ThyAb in a group of patients with GDM known that circulating concentrations of thyroid who were tested for several organ-specific autoanti- antibodies decrease during pregnancy, both in patients bodies during the third trimester of pregnancy. Our with autoimmune thyroid disease and in women findings suggest that it is not impaired glucose without previously known thyroid diseases but who tolerance itself but rather a family history of diabetes are found to be positive at screening for ThyAb (37). mellitus that represents a risk factor for the presence of Furthermore, not only the incidence but also the titer of ThyAb in pregnancy. ThyAb have been reported to be greater in the first than At present, the usefulness of routine screening for in the third trimester of gestation (38). As regards ThyAb and thyroid function during pregnancy is thyroid function and the presence of ThyAb, a controversial (1, 32, 33, 35, 45, 46). A screening significantly greater BMI mean value was found in program should be at least introduced in `at risk' the ThyAb-positive women with low FT4 serum groups of pregnant women. The present study showed concentrations than in the controls. This finding may that women with increased risk of GDM, mostly those afford a clue as to a thyroid hypofunction actually with family history of diabetes mellitus and thyroid present in these women. disease, also have an increased risk of being ThyAb One of the most frequent risk factors for GDM is a positive during pregnancy. Moreover, attention was positive family history of diabetes mellitus. In this study drawn to the importance of evaluating thyroid function such a family history was present in 33.7% of the study in pregnant women with impaired glucose tolerance, in group women. Results showed that the women with a view of their increased risk of subclinical hypothyroid- positive family history of diabetes mellitus were twice ism. as likely to be ThyAb positive during pregnancy OR 2:47 as those without such a history. Never- ˆ † theless, to evaluate a possible combined effect of Acknowledgements positive family history of thyroid disease and diabetes mellitus in the pregnant women, we studied the The skilful technical assistance of Mrs F Latini is distribution of ThyAb in the pregnant women classified gratefully acknowledged. This study was supported by on the basis of their family history of diabetes mellitus, the Health Ministry Project No. ICS 110.1/RF99.109. thyroid disease, or both (Fig. 2). Our results showed that women with a positive family history of diabetes mellitus and thyroid disease (group C) had a signifi- References cantly greater risk of being ThyAb positive during 1 Ball S. Antenatal screening of thyroid antibodies. Lancet 1996 pregnancy OR 3:4 than those with no family 348 906±907. history of diabetes ˆ mellitus† and thyroid disease (group 2 Lazarus JH & Othman S. Thyroid disease in relation to pregnancy. A). 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