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Flora Veltri Department of Endocrinology, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Kris Poppe Department of Endocrinology, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Variability in thyroid function in pregnant women is the result of 2 main determinants, each accounting for approximately half of it. The first is the genetically determined part of which the knowledge increases fast, but most remains to be discovered. The second determinant is caused by an ensemble of variables of which thyroid autoimmunity is the best known, but also by others such as parity, smoking, age, and BMI. More recently, new candidate variables have been proposed, such as iron, endocrine disruptors, and the ethnicity of the pregnant women. In the future, the diagnosis and treatment of thyroid (dys)function may be optimized by the use of each individual’s pituitary-thyroid set point, corrected with a factor taking into account the impact of nongenetically determined variables.

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Ringo Manta Department of Nuclear Medicine, CHU Saint Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Charlotte Martin Department of Infectious Diseases, CHU Saint Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Vinciane Muls Department of Gastroenterology and Endoscopy, CHU Saint-Pierre, University Libre de Bruxelles (ULB), Brussels, Belgium

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Kris G Poppe Department of Endocrinology, CHU Saint Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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A 22-year-old male with a history of ulcerative colitis and nephrotic syndrome treated with immunomodulatory agents including vedolizumab and mycophenolic acid developed hyperthyroidism 2 weeks following the first administration of BNT162b2 vaccine (Pfizer-BioNTech COVID-19 vaccine). Graves’ disease (GD) was diagnosed based on the elevated thyrotropin-receptor antibody, thyroid scintigraphy and ultrasound. To this day, four cases of new-onset GD following SARS-CoV-2 vaccine were reported in patients with no previous history of thyroid disease. Two cases of recurrence of GD following SARS-CoV-2 vaccine were also reported. Although the underlying mechanisms of vaccine-induced autoimmunity remain to be clarified, there is a rationale for the association between SARS-CoV-2 vaccination and the development of Th1-mediated diseases, at least in predisposed individuals. The BNT162b2 vaccine could be a trigger for GD in some patients. However, the benefit/risk ratio remains by far in favour of SARS-CoV-2 vaccination considering the potentially higher risk of severe infection in these patients.

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Kris Poppe Endocrine Unit, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Peter Bisschop Department of Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

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Laura Fugazzola Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

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Gesthimani Minziori Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

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David Unuane Department of Internal Medicine, Endocrine Unit, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium

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Andrea Weghofer Department of Gynecological Endocrinology & Reproductive Medicine, Medical University of Vienna, Vienna, Austria

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Severe thyroid dysfunction may lead to menstrual disorders and subfertility. Fertility problems may persist even after restoring normal thyroid function, and then an assisted reproductive technology (ART) may be a solution. Prior to an ART treatment, ovarian stimulation is performed, leading to high oestradiol levels, which may lead to hypothyroidism in women with thyroid autoimmunity (TAI), necessitating levothyroxine (LT4) supplements before pregnancy. Moreover, women with the polycystic ovarian syndrome and idiopathic subfertility have a higher prevalence of TAI. Women with hypothyroidism treated with LT4 prior to ART should have a serum TSH level <2.5 mIU/L. Subfertile women with hyperthyroidism planning an ART procedure should be informed of the increased risk of maternal and foetal complications, and euthyroidism should be restored and maintained for several months prior to an ART treatment. Fertilisation rates and embryo quality may be impaired in women with TSH >4.0 mIU/L and improved with LT4 therapy. In meta-analyses that mainly included women with TSH levels >4.0 mIU/L, LT4 treatment increased live birth rates, but that was not the case in 2 recent interventional studies in euthyroid women with TAI. The importance of the increased use of intracytoplasmic sperm injection as a type of ART on pregnancy outcomes in women with TAI deserves more investigation. For all of the above reasons, women of subfertile couples should be screened routinely for the presence of thyroid disorders.

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Kris Poppe Endocrine Unit, Department of Internal Medicine, University Hospital UZ Brussel (VUB), Brussels, Belgium

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Alicja Hubalewska-Dydejczyk Department of Endocrinology, Jagiellonian University Medical College, Kraków, Poland

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Peter Laurberg Department of Endocrinology and Medicine, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark

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Roberto Negro Division of Endocrinology, V. Fazzi Hospital, Lecce

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Francesco Vermiglio Cattedra di Endocrinologia, Policlinico Universitario, Messina, Italy

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Bijay Vaidya Department of Endocrinology, Royal Devon & Exeter Hospital, Exeter, UK

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Background: An optimal management of maternal hyperthyroidism is important for positive pregnancy outcome, and to this end, the Endocrine Society published their guidelines in 2007. This survey aimed to investigate to what extent the clinical practice relating to the management of hyperthyroidism during pregnancy in Europe is uniform and consistent with the guidelines. Materials and Methods: We e-mailed an online questionnaire survey based on clinical case scenarios to 605 members of the European Thyroid Association. We analysed 190 responses from 28 European countries. Results: For a woman with newly diagnosed Graves’ disease (GD) and wishing pregnancy, 78% of the responders would initiate antithyroid drugs (ATDs), while 22% would recommend definitive treatment with radioiodine or surgery. In case of a relapsed GD before pregnancy, 80% preferred definitive treatment. For a woman with newly diagnosed GD during pregnancy, 53% would treat with propylthiouracil, 12% with methimazole, and 34% with propylthiouracil initially and switch to methimazole after the first trimester. Responders used several combinations of tests to monitor the dose of ATDs, and the thyroid test results they targeted were inconsistent. For a lactating woman with GD, 68% would give ATDs without stopping lactation. Conclusions: Variation in the clinical practices surrounding the management of hyperthyroid pregnant women in Europe still exists.

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Emna Jelloul Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint Pierre, Université Libre de Bruxelles (ULB), Rue Haute, Brussels, Belgium

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Georgiana Sitoris Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint Pierre, Université Libre de Bruxelles (ULB), Rue Haute, Brussels, Belgium

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Flora Veltri Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint Pierre, Université Libre de Bruxelles (ULB), Rue Haute, Brussels, Belgium

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Pierre Kleynen Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint Pierre, Université Libre de Bruxelles (ULB), Rue Haute, Brussels, Belgium

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Serge Rozenberg Departement of Gynecology and Obstetrics, Centre Hospitalier Universitaire Saint Pierre, Université Libre de Bruxelles (ULB), Rue Haute, Brussels, Belgium

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Kris G Poppe Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint Pierre, Université Libre de Bruxelles (ULB), Rue Haute, Brussels, Belgium

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Objective

The aim of the study was to investigate the impact of suppressed serum TSH levels (sTSH) during early pregnancy on maternal and neonatal outcomes.

Methods

In this single-centre, retrospective cohort study 1081 women were screened at 11.8 ± 2.4 weeks of pregnancy for TSH, free T4 (FT4) and TPOAb. Exclusion criteria were twin- and assisted- reproduction pregnancies, women with TSH levels >3.74 mIU/L, severe hyperthyroidism, treated for thyroid dysfunction before or after screening and gestational blood sampling <6 or >16 weeks of pregnancy. The prevalence of adverse pregnancy outcomes was compared between the study group sTSH (TSH: < 0.06 mIU/L; n = 36) and euthyroid controls (TSH: 0.06–3.74 mIU/L; n = 1045), and the impact of sTSH on pregnancy outcomes verified in logistic regression analyses.

Results

Median (IQR) serum TSH level in women with sTSH was 0.03 (0.03–0.03) vs 1.25 (0.81–1.82) mIU/L in controls and FT4 levels 18.0 (14.4–20.3) vs 14.2 (12.9–15.4) pmol/L; both P < 0.001. None of the women with sTSH had thyrotropin receptor antibodies. Compared with controls, the prevalence of TPOAb positivity (TAI) was comparable between groups (5.6% vs 6.6%; P = 0.803). The prevalence of maternal and neonatal pregnancy outcomes was comparable between the study and control group. The logistic regression analyses with corrections for TAI, FT4 and demographic parameters confirmed the absence of an association between sTSH, and the following outcomes: iron deficient anaemia (aORs (95% CI)): 1.41 (0.64-2.99); P = 0.385, gestational diabetes: 1.19 (0.44–2.88); P = 0.713, preterm birth: 1.57 (0.23–6.22);P = 0.574 and low Apgar-1′ score: 0.71 (0.11–2.67); P = 0.657.

Conclusions

Suppressed serum TSH levels during the first to early second trimester of pregnancy were not associated with altered maternal or neonatal outcomes.

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Georgiana Sitoris Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Flora Veltri Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Pierre Kleynen Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Malika Ichiche Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Serge Rozenberg Department of Gynecology and Obstetrics, Centre Hospitalier Universitaire (CHU) Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Kris G Poppe Endocrine Unit Centre Hospitalier Universitaire (CHU) Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Objective

It is unknown if foetal gender influences maternal thyroid function during pregnancy. We therefore investigated the prevalence of thyroid disorders and determined first-trimester TSH reference ranges according to gender.

Methods

A cross-sectional study involving 1663 women with an ongoing pregnancy was conducted. Twin and assisted pregnancies and l-thyroxine or antithyroid treatment before pregnancy were exclusion criteria. Serum TSH, free T4 (FT4) and thyroid peroxidase antibodies (TPOAb) were measured at median (interquartile range; IQR) 13 (11–17) weeks of gestation. Subclinical hypothyroidism (SCH) was present when serum TSH levels were >3.74 mIU/L with normal FT4 levels (10.29–18.02 pmol/L), and thyroid autoimmunity (TAI) was present when TPOAb were ≥60 kIU/L.

Results

Eight hundred and forty-seven women were pregnant with a female foetus (FF) and 816 with a male foetus (MF). In women without TAI and during the gestational age period between 9 and 13 weeks (with presumed high-serum hCG levels), median (IQR range) serum TSH in the FF group was lower than that in the MF group: 1.13 (0.72–1.74) vs 1.24 (0.71–1.98) mIU/L; P = 0.021. First-trimester gender-specific TSH reference range was 0.03–3.53 mIU/L in the FF group and 0.03–3.89 mIU/L in the MF group. The prevalence of SCH and TAI was comparable between the FF and MF group: 4.4% vs 5.4%; P = 0.345 and 4.9% vs 7.5%; P = 0.079, respectively.

Conclusions

Women pregnant with an MF have slightly but significantly higher TSH levels and a higher upper limit of the first-trimester TSH reference range, compared with pregnancies with a FF. We hypothesise that this difference may be related to higher hCG levels in women pregnant with a FF, although we were unable to measure hCG in this study. Further studies are required to investigate if this difference has any clinical relevance.

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George J. Kahaly Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany

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Luigi Bartalena Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Lazlo Hegedüs Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark

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Laurence Leenhardt Thyroid and Endocrine Tumors Unit, Pitié Salpêtrière Hospital, Sorbonne University, Paris, France

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Kris Poppe Endocrine Unit, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Simon H. Pearce Department of Endocrinology, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

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Graves’ disease (GD) is a systemic autoimmune disorder characterized by the infiltration of thyroid antigen-specific T cells into thyroid-stimulating hormone receptor (TSH-R)-expressing tissues. Stimulatory autoantibodies (Ab) in GD activate the TSH-R leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with biochemically confirmed thyrotoxicosis, positive TSH-R-Ab, a hypervascular and hypoechoic thyroid gland (ultrasound), and associated orbitopathy. In GD, measurement of TSH-R-Ab is recommended for an accurate diagnosis/differential diagnosis, prior to stopping antithyroid drug (ATD) treatment and during pregnancy. Graves’ hyperthyroidism is treated by decreasing thyroid hormone synthesis with the use of ATD, or by reducing the amount of thyroid tissue with radioactive iodine (RAI) treatment or total thyroidectomy. Patients with newly diagnosed Graves’ hyperthyroidism are usually medically treated for 12–18 months with methimazole (MMI) as the preferred drug. In children with GD, a 24- to 36-month course of MMI is recommended. Patients with persistently high TSH-R-Ab at 12–18 months can continue MMI treatment, repeating the TSH-R-Ab measurement after an additional 12 months, or opt for therapy with RAI or thyroidectomy. Women treated with MMI should be switched to propylthiouracil when planning pregnancy and during the first trimester of pregnancy. If a patient relapses after completing a course of ATD, definitive treatment is recommended; however, continued long-term low-dose MMI can be considered. Thyroidectomy should be performed by an experienced high-volume thyroid surgeon. RAI is contraindicated in Graves’ patients with active/severe orbitopathy, and steroid prophylaxis is warranted in Graves’ patients with mild/active orbitopathy receiving RAI.

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Georgiana Sitoris Endocrine Unit Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Flora Veltri Endocrine Unit Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Malika Ichiche Endocrine Unit Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Pierre Kleynen Endocrine Unit Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Jean-Philippe Praet Department of Internal Medicine, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Serge Rozenberg Department of Gynecology and Obstetrics, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Kris G Poppe Endocrine Unit Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Objective

Pregnant women with autoimmune (subclinical) hypothyroidism have an increased risk of developing gestational diabetes mellitus (GDM). However, this association remains controversial in euthyroid women with thyroid autoimmunity (TAI). Therefore, the aim of the study was to determine the association between TAI and GDM in euthyroid women in a logistic regression analysis with adjustments for baseline/demographic parameters.

Methods

Cross-sectional study in 1447 euthyroid women who performed their entire clinical/biological workup and oral glucose tolerance test (OGTT) in our center. At median 13 (11–17) weeks of gestation, thyroid-stimulating hormone, free T4, and thyroid peroxidase antibodies (TPOAb) were measured, baseline characteristics were recorded, and an OGTT was performed between 24 and 28 weeks of pregnancy. Exclusion criteria were pre-pregnancy diabetes, assisted pregnancies, and women with (treated) thyroid dysfunction before or after screening. The diagnosis of GDM was based on 2013 World Health Organization criteria, and TAI was defined as TPOAb levels ≥60 kIU/L.

Results

Two hundred eighty women were diagnosed with GDM (19.4%), 26.1% in women with TAI, and 18.9% in women without TAI (P  = 0.096). In the logistic regression analysis, TAI was associated with GDM in women older than 30 years (adjusted odds ratio 1.68 (95% CI, 1.01–2.78); P  = 0.048). Maternal age >30 years, pre-pregnancy BMI ≥30 kg/m2, and other than Caucasian background were also associated with GDM; aOR 1.93 (95% CI, 1.46–2.56); P  < 0.001, 2.03 (95% CI, 1.46–2.81); P  < 0.001 and 1.46 (95% CI, 1.03–2.06); P  = 0.034, respectively.

Conclusions

In older pregnant women, the presence of TAI in euthyroid women was associated with GDM. In line with the literature data, (higher) age and BMI were strongly associated with GDM. Future investigations should focus on treatments that might prevent the development of GDM in euthyroid women with TAI.

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