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Jesper Karmisholt Department of Medical Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Clinical Institute, Aalborg University, Aalborg, Denmark

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Allan Carlé Department of Medical Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Clinical Institute, Aalborg University, Aalborg, Denmark

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Stig Andersen Clinical Institute, Aalborg University, Aalborg, Denmark
Department of Geriatrics, Aalborg University Hospital, Aalborg, Denmark

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Background: Weight gain during treatment of hyperthyroidism is a frequent and for many patients unwanted outcome. With this repeated measurement study, we explored the timing of weight changes during the first year of antithyroid drug (ATD) treatment and assessed the correlation between body weight changes and changes in thyroid hormones, resting energy expenditure (REE), physical activity level, and energy efficiency. Methods: Patients with new onset hyperthyroidism were investigated every second month during the first year of ATD treatment. At each investigation, the following were measured: body weight, thyroid hormone concentrations, physical activity level, and daily number of steps, REE, and exercise performance. Results: Two men and eleven women, all sedentary, mean age 49(SD: 9.3) years were included. Significant changes after 1 year occurred for body weight (68.9–74.1 kg), thyroid hormones (free T3 [fT3] 17.5 to 4.42 pmol/L), REE (1,630–1,484 kcal/24 h), and energy efficiency at lower (50 W) workloads (16.0–17.6%). In individual patients, only REE and fT3 correlated to changes in body weight. Physical activity level did not change during treatment. Conclusion: In this study, treatment of hyperthyroidism was associated with marked increase in body weight in the patients. This increase correlated to a decrease in REE and only to a negligible extent to changes in energy efficiency and not at all to changes in physical activity level of daily living.

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Peter Laurberg Department of Endocrinology, Aalborg Hospital, Aalborg

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Nils Knudsen Medical Clinic I, Bispebjerg Hospital, Copenhagen, Denmark

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Stig Andersen Department of Endocrinology, Aalborg Hospital, Aalborg

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Allan Carlé Department of Endocrinology, Aalborg Hospital, Aalborg

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Inge Bülow Pedersen Department of Endocrinology, Aalborg Hospital, Aalborg

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Jesper Karmisholt Department of Endocrinology, Aalborg Hospital, Aalborg

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Important interaction exists between thyroid function, weight control, and obesity. Several mechanisms seem to be involved, and in studies of groups of people the pattern of thyroid function tests depends on the balance of obesity and underlying thyroid disease in the cohort studied. Obese people with a normal thyroid gland tend to have activation of the hypothalamic-pituitary-thyroid axis with higher serum TSH and thyroid hormones in serum. On the other hand, small differences in thyroid function are associated with up to 5 kg difference in body weight. The weight loss after therapy of overt hypothyroidism is caused by excretion of water bound in tissues (myxoedema). Many patients treated for hyperthyroidism experience a gain of more weight than they lost during the active phase of the disease. The mechanism for this excessive weight gain has not been fully elucidated. New studies on the relation between L-T<sub>3</sub> therapy and weight control are discussed. The interaction between weight control and therapy of thyroid disease is important to many patients and it should be studied in more detail.

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Allan Carlé Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Jens Faber Department of Endocrinology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Rudi Steffensen Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark

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Peter Laurberg Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Birte Nygaard Department of Endocrinology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Objectives: In previous studies, around half of all hypothyroid patients preferred levo-thyroxine (L-T4) + levo-triiodothyronine (L-T3) combination therapy, 25% preferred T4, and 25% had no preference. The reason for this is yet to be explored. Methods: A total of 45 overtly autoimmune, hypothyroid patients – now euthyroid on ≥6 months’ L-T4 therapy – participated in a prospective, double-blind, cross-over study. The patients were randomized into 2 groups of either 3 continuous months’ L-T4 therapy followed by 3 months’ combination therapy or vice versa. In all periods, 50 μg L-T4 was blindly replaced by either (identical) 50 μg L-T4 or by 20 μg T3. L-T4 was hereafter adjusted to obtain normal serum TSH values. We investigated 3 single nucleotide polymorphisms (SNPs) on the type II iodothyronine deiodinase (DIO2) gene (rs225014 (Thr92Ala), rs225015, and rs12885300 (ORFa-Gly3Asp)) and 1 SNP on the cellular membrane transport-facilitating monocarboxylate transporter (MCT10) gene (rs17606253), and asked in which of the 2 treatment periods patients felt better (i.e., which treatment was preferred). Results: 27 out of 45 patients (60%) preferred the combination therapy. Two polymorphisms (rs225014 (DIO2, Thr92Ala) and rs17606253 (MCT10)) were combined yielding 3 groups: none vs. 1 of 2 vs. both SNPs present, and 42 vs. 63 vs. 100% of our patients in the 3 groups preferred the combined treatment (Jongheere-Terpstra trend test, p = 0.009). Conclusion: The present study indicates that the combination of polymorphisms in DIO2 (rs225014) and MCT10 (rs17606253) enhances hypothyroid patients’ preference for L-T4 + L-T3 replacement therapy. In the future, combination therapy may be restricted or may be even recommended to individuals harbouring certain polymorphisms.

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Allan Carlé Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Institute, Aalborg University, Aalborg, Denmark

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Nils Knudsen Department of Endocrinology I, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark

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Torben Jørgensen Centre for Clinical Research and Prevention, Capital Region of Denmark, Copenhagen, Denmark
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Bettina Thuesen Centre for Clinical Research and Prevention, Capital Region of Denmark, Copenhagen, Denmark

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Jesper Karmisholt Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Institute, Aalborg University, Aalborg, Denmark

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Stine Linding Andersen Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Inge Bülow Pedersen Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Institute, Aalborg University, Aalborg, Denmark

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Objective: To investigate the association between reproductive history and later development of various nosological subtypes of overt hyperthyroidism. Study Design: From the Danish population, we included incident hyperthyroid women, and for each case we recruited 4 euthyroid age-sex-region-matched controls from the same sub-population. Hyperthyroid cases/controls were: Graves’ disease (GD, n = 232/928), multinodular toxic goitre (MNTG, n = 91/364), solitary toxic adenoma (STA, n = 21/84). Patients diagnosed with hyperthyroidism within 1 year after delivery including post-partum GD were excluded. In multivariate conditional regression models (reference: no reproductive events), we analysed the association between development of GD/MNTG/STA and reproductive factors such as age at menarche/menopause, reproductive span, number of pregnancies/childbirths/abortions, investigations for infertility, and years on oral contraceptives. We adjusted for possible confounders such as alcohol intake, smoking, co-morbidity, and education. Age was studied as a potential effect measure modifier. Results: GD patients diagnosed before the age of 40 years had given births more often than control subjects (OR [95% CI] for 1/2/3+ births [ref.: nulliparous] were 1.57 [0.80–3.11]/2.06 [1.001–4.22]/3.07 [1.50–6.26]), and they had induced abortions performed more often (OR for 1/2+ induced abortions [ref.: no: events] were 0.99 [0.54–1.84]/2.24 [1.12–4.45]). No associations were observed between any reproductive factor and the development of MNTG or STA. Conclusions: Childbirths and induced abortions may be followed by development of Graves’ hyperthyroidism after the post-partum period. This was not the case for the non-autoimmune subtypes of hyperthyroidism.

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Maja Hjelm Lundgaard Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Allan Carlé Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Ulla Birgitte Christiansen Department of Gynaecology and Obstetrics, Aalborg University Hospital, Aalborg, Denmark

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Anne Sørensen Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Gynaecology and Obstetrics, Aalborg University Hospital, Aalborg, Denmark

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Søren Risom Kristensen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Stine Linding Andersen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Introduction

Thyroid disorders have been linked to abnormalities in the coagulation system, and a hypocoagulant state has been proposed in hypothyroidism. The assessment of thyroid function is, however, not routinely recommended as part of the assessment for coagulation disorders.

Case presentation

We present a 32-year-old woman who had no history of thyroid disease and who recently gave birth preterm because of severe preeclampsia and intrauterine growth restriction. Due to severe placental dysfunction, she underwent a routine biochemical assessment of the coagulation system 6 months postpartum, and a prolonged activated partial thromboplastin time (APTT) (43 s) was identified along with a low level of coagulation factor VIII (0.44 IU/mL), and a low level of von Willebrand factor (vWF) antigen (0.35 IU/mL), vWF activity (0.38 IU/mL) as well as reduced generation of thrombin. The assessment of thyroid function in the patient identified autoimmune, overt hypothyroidism with a thyroid-stimulating hormone (TSH) concentration of 139 mIU/L, low levels of the peripheral thyroid hormones (total thyroxine: 43 nmol/L, total triiodothyronine: 0.9 nmol/L), and high levels of thyroid peroxidase antibodies (296 U/mL) as well as thyroglobulin antibodies (927 U/mL).

Conclusion

In this case, prolonged APTT provided a diagnostic clue for the assessment of thyroid function in a young woman with a recent history of severe placental dysfunction. The identification of autoimmune, overt hypothyroidism emphasizes that measurement of TSH may be of clinical importance in cases of unexplained prolonged APTT or other biochemical signs of abnormalities in the coagulation system.

Established facts

  • Hypothyroidism has been associated with alterations of the coagulation system suggesting a hypocoagulant state.

  • At present, measurement of thyroid-stimulating hormone is not routinely recommended as part of the assessment for coagulation disorders.

Novel insights

  • In this case, biochemical assessment of the coagulation system was routinely performed following a pregnancy complicated by severe placental dysfunction.

  • Overt hypothyroidism of autoimmune origin was identified secondary to prolonged activated partial thromboplastin time (APTT) postpartum along with low levels of coagulation factor VIII, von Willebrand factor, and thrombin generation.

  • Measurement of thyroid-stimulating hormone may be considered in cases of unexplained prolonged APTT.

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Line Tang Møllehave Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Nils Knudsen Department of Endocrinology, Bispebjerg University Hospital, University of Copenhagen, Denmark

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Allan Linneberg Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Inge Bülow Pedersen Department of Endocrinology and Medicine, Aalborg University Hospital, Aalborg, Denmark

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Gitte Ravn-Haren Research Group for Risk Benefit, National Food Institute, Technical University of Denmark, Lyngby, Denmark

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Anja Lykke Madsen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Allan Carlé Department of Endocrinology and Medicine, Aalborg University Hospital, Aalborg, Denmark

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Charlotte Cerqueira The Danish Clinical Quality Program – National Clinical Registries (RKKP), Denmark

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Anne Krejbjerg Department of Oncology, Aalborg University Hospital, Aalborg, Denmark

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Lone Banke Rasmussen Independent researcher, Klemensker, Denmark

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Lars Ovesen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Hans Perrild Department of Endocrinology, Bispebjerg University Hospital, University of Copenhagen, Denmark

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Lena Bjergved Sigurd Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Internal Medicine, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen, Denmark

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Betina Heinsbæk Thuesen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Pernille Vejbjerg Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark

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Torben Jørgensen Center for Clinical Research and Prevention, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Due to mild-to-moderate iodine deficiency in Denmark, health authorities initiated a voluntary iodine fortification (IF) program in 1998, which became mandatory in 2000. In line with recommendations from the World Health Organization, the Danish investigation on iodine intake and thyroid disease (DanThyr) was established to monitor the effect on thyroid health and disease. The program involved different study designs and followed two Danish sub-populations in the years before IF and up till 20 years after. Results showed that the IF was successfully implemented and increased the level of iodine intake from mild–moderate iodine deficiency to low adequacy. The level of thyroglobulin and thyroid volume decreased following IF, and there was an indication of fewer thyroid nodules. The incidence of hyperthyroidism increased transiently following IF but subsequently decreased below the pre-fortification level. Conversely, thyroid-stimulating hormone levels and the prevalence of thyroid autoimmunity increased along with an increase in the incidence of hypothyroidism. These trends were mirrored in the trends in treatments for thyroid disease. Most differences in thyroid health and disease between regions with different iodine intake levels before IF attenuated. This review illustrates the importance of a monitoring program to detect both beneficial and adverse effects and exemplifies how a monitoring program can be conducted when a nationwide health promotion program – as IF – is initiated.

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Stine Linding Andersen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Niels Henrik Bruun Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark

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Peter Astrup Christensen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Simon Lykkeboe Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Aase Handberg Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Annebirthe Bo Hansen Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Maja Hjelm Lundgaard Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

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Louise Knøsgaard Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Nanna Maria Uldall Torp Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

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Allan Carlé Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Jesper Karmisholt Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Inge Bülow Pedersen Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Peter Vestergaard Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Steno Diabetes Center North Jutland, Aalborg University Hospital, Aalborg, Denmark

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Stig Andersen Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
Department of Geriatrics, Aalborg University Hospital, Aalborg, Denmark

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Objective

Thyroid disease in women of reproductive age is mainly of autoimmune origin, and thyroid peroxidase antibodies (TPO-Ab) as well as thyroglobulin antibodies (Tg-Ab) are key markers. Adding to this, much focus in pregnancy is on euthyroid women who are thyroid antibody positive. Evidence to substantiate the cut-offs for the definition of thyroid autoantibody positivity in early pregnant women is warranted.

Methods

Stored serum samples from 14,030 Danish pregnant women were used for the measurement of TPO-Ab, Tg-Ab, TSH, and free thyroxine (ADVIA Centaur XPT, Siemens Healthineers). Among all women, a reference cohort of 10,905 individuals was identified for the establishment of antibody cut-offs. Percentile cut-offs for TPO-Ab and Tg-Ab were determined using regression on order statistics (the reference cohort). The established cut-offs were then applied (the full cohort), and frequencies of early pregnancy as well as later diagnosis of hypothyroidism were evaluated.

Results

The highest established cut-offs (95th, 97.5th, and 99th percentiles) were 59, 68, and 81 U/mL for TPO-Ab and 33, 41, and 52 U/mL for Tg-Ab. When the cut-offs were applied in the full cohort, 11.0, 10.2, and 9.7% were TPO-Ab positive, whereas 13.3, 12.3, and 11.2% were Tg-Ab positive. Antibody-positive women (TPO-Ab and/or Tg-Ab) had higher median TSH and were more likely to have hypothyroidism in early pregnancy and to be diagnosed with hypothyroidism during follow-up.

Conclusions

This large study established and evaluated pregnancy-specific cut-offs for TPO-Ab and Tg-Ab. The findings are important regarding the classification of exposure in pregnancy and assessment of thyroid autoimmunity per se.

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