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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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diagnostic clue for the assessment of thyroid function in this patient came across because unexplained prolonged APTT was identified during the testing for thrombophilia after severe pregnancy complications. Case presentation A 32-year-old woman was

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Paolo Cavarzere Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Laura Palma Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Lara Nicolussi Principe Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Monica Vincenzi Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Regional Center for Newborn Screening, Diagnosis and Treatment of Congenital Metabolic and Endocrinological Diseases, Verona, Italy

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Silvana Lauriola Neonatal Intensive Cure Unit, Department of Pediatrics, University Hospital of Verona, Verona, Italy

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Rossella Gaudino Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy
Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy

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Virginia Murri Pediatric Division, Hospital of San Bonifacio, Verona, Italy

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Luigi Lubrano Pediatric Division, Hospital of Legnago, Verona, Italy

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Giuliana Rossi Pediatric Division, Hospital of Mestre, Venezia, Italy

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Alessia Sallemi Pediatric Division, Hospital of Venezia, Venezia, Italy

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Ermanna Fattori Pediatric Division, Hospital of Negrar, Verona, Italy

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Marta Camilot Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Regional Center for Newborn Screening, Diagnosis and Treatment of Congenital Metabolic and Endocrinological Diseases, Verona, Italy

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Franco Antoniazzi Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy
Pediatric Section, Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy
Regional Center for the Diagnosis and Treatment of Children and Adolescents Rare Skeletal Disorders, Pediatric Clinic, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy

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Introduction During pregnancy, normal thyroid function is essential to ensure the regular development of the fetus ( 1 , 2 ). Overt or subclinical maternal hypothyroidism can modify, in fact, the course of pregnancy and the development of the

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Kamilla R Riis Department of Endocrinology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Camilla B Larsen Department of Endocrinology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Bjarke R Medici Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Denmark

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Christian Z Jensen Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Denmark

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Kristian H Winther Department of Endocrinology, Odense University Hospital, Odense, Denmark

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Emil L Larsen Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark

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Christina Ellervik Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Data and Data Support, Region Zealand, Sorø, Denmark

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Jeppe L la Cour Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Denmark

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Laszlo Hegedüs Department of Endocrinology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Thomas H Brix Department of Endocrinology, Odense University Hospital, Odense, Denmark

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Henrik E Poulsen Department of Endocrinology, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital, Denmark
Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
Department of Cardiology, University Hospital Nordsjælland, Hillerød, Denmark

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Filip K Knop Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Steno Diabetes Center Copenhagen, Herlev, Denmark
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

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Birte Nygaard Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Steen J Bonnema Department of Endocrinology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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the reference range of 0.3–4.0 mIU/L and total plasma thyroxine (TT4) below the reference range of 60–130 nmol/L) or mild (plasma TSH above the reference range, and plasma TT4 within the reference range). Exclusion criteria were pregnancy or planned

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Jorge Alberto Tapia-Martínez Laboratorio de Metabolismo I, Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Colonia Unidad Profesional Adolfo López Mateos, Delegación Gustavo A. Madero, Ciudad de México, México
Laboratorio 6, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Delegación Tlalpan, Ciudad de México, México

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Margarita Franco-Colín Laboratorio de Metabolismo I, Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Colonia Unidad Profesional Adolfo López Mateos, Delegación Gustavo A. Madero, Ciudad de México, México

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Vanessa Blas-Valdivia Laboratorio de Neurobiología, Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Colonia Unidad Profesional Adolfo López Mateos, Delegación Gustavo A. Madero, Ciudad de México, México

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Edgar Cano-Europa Laboratorio de Metabolismo I, Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Colonia Unidad Profesional Adolfo López Mateos, Delegación Gustavo A. Madero, Ciudad de México, México

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neonates, but we believe that it is crucial to have a thyroid state screening before or during pregnancy to avoid erroneous metabolic and thyroid gland programming and the development of cardiometabolic diseases in adulthood. The results presented allow

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Camilla Bøgelund Larsen Department of Endocrinology, Odense University Hospital, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Kristian Hillert Winther Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Per Karkov Cramon Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

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Åse Krogh Rasmussen Department of Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Institute of Clinical Medicine, Faculty of Health and Clinical Sciences, Copenhagen University, Copenhagen, Denmark

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

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Jakob Bue Bjorner Department of Public Health, Copenhagen University, Copenhagen, Denmark
QualityMetric Inc, Johnston, Lincoln, Rhode Island, USA

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Lutz Schomburg Institute for Experimental Endocrinology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Kamil Demircan Institute for Experimental Endocrinology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Thilo Samson Chillon Institute for Experimental Endocrinology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Jeppe Gram Medical Department, Endocrinology, University Hospital of South-West Jutland, Esbjerg, Denmark

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Stinus Gadegaard Hansen Medical Department, Endocrinology, University Hospital of South-West Jutland, Esbjerg, Denmark

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Frans Brandt Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Internal Medicine Research Unit, University Hospital of Southern Jutland, Aabenraa, Denmark

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Birte Nygaard Department of Endocrinology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

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Torquil Watt Department of Endocrinology and Metabolism, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Institute of Clinical Medicine, Faculty of Health and Clinical Sciences, Copenhagen University, Copenhagen, Denmark

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Laszlo Hegedüs Department of Endocrinology, Odense University Hospital, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Steen Joop Bonnema Department of Endocrinology, Odense University Hospital, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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surgery; antithyroid drug treatment; comorbidity rendering the participant unable to process patient-reported outcomes or receive intervention during the trial; immunomodulatory medication; other medications known to affect thyroid function; pregnancy

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Roberto Fiore Division of Endocrinology, Diabetes and Metabolism, University Hospital of Lausanne and University of Lausanne, Hôtel des Patients, Lausanne, Switzerland

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Stefano La Rosa Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Silvia Uccella Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Deborah Marchiori Unit of Pathology, Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Peter A Kopp Division of Endocrinology, Diabetes and Metabolism, University Hospital of Lausanne and University of Lausanne, Hôtel des Patients, Lausanne, Switzerland

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gradually during pregnancy, although total expression increases, in order to regulate maternal transfer of thyroid hormone to the fetus. The overexpression of D3 in tumor tissue can lead to hypothyroidism whenever its activity exceeds the maximal synthesis

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Jeppe Lerche la Cour Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Line Tang Møllehave Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Capital Region, Denmark

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Bjarke Røssner Medici Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Christian Zinck Jensen Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Anne Ahrendt Bjerregaard Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Capital Region, Denmark

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Birte Nygaard Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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-10: DC73.9) ever, and those who redeemed a prescription of antithyroid medication 2 years before redeeming T3 and/or DTE to exclude current block/replace treatment. Further, we chose a grace period with pregnancy or abortion ± 1 year. According to

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Irene Campi Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy

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Marco Dell’Acqua Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Elisa Stellaria Grassi Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Maria Cristina Vigone Department of Paediatrics, IRCCS San Raffaele Hospital, Milan, Italy

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Luca Persani Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Possible causes of refractory hypothyroidism. Mechanism Associated condition Poor compliance to levothyroxine therapy Unintentional Factitious disorders/malingering Increased thyroxine requirement Pregnancy and weight

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Ladan Mehran Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Atieh Amouzegar Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Hengameh Abdi Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Negar Delbari Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Elham Madreseh Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

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Maryam Tohidi Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Mohammad Ali Mansournia Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

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Fereidoun Azizi Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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iodine ( n = 2), pregnancy ( n = 145), TSH <0.1 and TSH >10 µ/L ( n = 279) as well as those with incomplete laboratory or missing data ( n = 211). Subsequently, 4,905 eligible participants remained to enter the current study (Fig.  1 ) . Fig. 1

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Salman Razvi Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Bronia Arnott Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Dawn Teare Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Shaun Hiu Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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Nicki O’Brien Department of Psychology, Northumbria University, Newcastle upon Tyne, United Kingdom

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Simon H. Pearce Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

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, vascular risk, pregnancy status, etc.) should be considered particularly when contemplating treatment [ 19 ]. The results of this survey suggest that most clinicians in our sample are aware of the relevant guidelines that recommend against treatment in

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