Keywords
Graves' disease
Pregnancy
antithyroids
methimazole
propylthiouracil
birth defects
How to Cite
Abstract
Background: Thyroid orbitopathy is a common manifestation of Graves' disease. In pregnancy, uncontrolled Graves' disease represents a challenge for treatment due of the risks it can cause to the mother and fetus.
Purpose: Updated review of Graves' disease and thyroid orbitopathy in pregnancy.
Methodology: Searching in the databases: PubMed, LILACS and Scielo, including literature published up to 2022, both in English and Spanish.
Discussion: Graves' disease affects up to 0.2% of pregnancies. Any serum TSH value below the limit of normality should be evaluated along with serum values of total T4 (TT4) or free T4 and anti-TSH receptor antibodies (TRAbs). PTU is the first-line therapy in the first 12 weeks of pregnancy. OT activity should be assessed with the clinical activity score (CAS) and severity with the EUGOGO classification. Mild cases require local management, while severe cases will require intravenous corticosteroid management. There is a risk of congenital defects with the use of ATD, being higher for MMI versus PTU.
Compared to nondisease controls, adjusted risk ratio (RR) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). The risk of CMZ/MMI was higher compared to PTU (RR, 1.20; 95% CI, 1.01-1.43).
Conclusion: Early diagnosis and treatment prevents catastrophic outcomes and reduces maternal and fetal morbidity and mortality.
References
Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol. 2013;1(3):238-49. https://doi.org/10.1016/S2213-8587(13)70086-X
Chen CH, Xirasagar S, Lin CC, Wang LH, Kou YR, Lin HC. Risk of adverse perinatal outcomes with antithyroid treatment during pregnancy: a nationwide population-based study. BJOG. 2011;118(11):1365-73. https://doi.org/10.1111/j.1471-0528.2011.03019.x
Alexander EK, Pearce EN, Brent GA, Brown R, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315-89. https://doi.org/10.1089/thy.2016.0457
Balucan FS, Morshed SA, Davies TF. Thyroid autoantibodies in pregnancy: their role, regulation and clinical relevance. J Thyroid Res. 2013;2013:182472. https://doi.org/10.1155/2013/182472
Davies TF, Andersen S, Latif R, Nagayama Y, Barbesino G, Brito M, et al. Graves’ disease. Nat Rev Dis Primers. 2020;6(1):52. https://doi.org/10.1038/s41572-020-0184-y
Andersen SL, Vestergaard P, Olsen J. Maternal thyroid function in early pregnancy and child neurodevelopmental disorders: a Danish nationwide case-cohort study. Thyroid. 2018;28(4):537-46. https://doi.org/10.1089/thy.2017.0425
Laurberg P, Andersen SL. Therapy of endocrine disease: antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk? Eur J Endocrinol. 2014;171(1):R13-20. https://doi.org/10.1530/EJE-14-0135
Diana T, Daiber A, Oelze M, Neumann S, Olivo P, Kanitz M, et al. Stimulatory TSH-receptor antibodies and oxidative stress in Graves disease. J Clin Endocrinol Metab. 2018;103(10):3668-77. https://doi.org/10.1210/jc.2018-00509
Wall JR, Lahooti H, Hibbert EJ, Champion B. Relationship between Clinical and Immunological Features of Thyroid Autoimmunity and Ophthalmopathy during Pregnancy. J Thyroid Res. 2015:698470. https://doi.org/10.1155/2015/698470
Smith TJ, Janssen J. Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy. Endocr Rev. 2019;40(1):236-67. https://doi.org/10.1210/er.2018-00066
Krieger CC, Sui X, Kahaly GJ, Neumann S, Gershengorn M. Inhibition of TSH/IGF-1 Receptor Crosstalk by Teprotumumab as a Treatment Modality of Thyroid Eye Disease. J Clin Endocrinol Metab. 2022;107(4):e1653-60. https://doi.org/10.1210/clinem/dgab824
Taylor PN, Zhang L, Lee RW, Muller I, Ezra D, Dayan C, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol. 2020;16(2):104-16. https://doi.org/10.1038/s41574-019-0305-4
Bucci I, Giuliani C, Napolitano G. Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance. Front Endocrinol. 2017;30:8. https://doi.org/10.3389/fendo.2017.00137
García Botina, HD, Córdoba Ramírez N, Builes Barrera CA. Diagnóstico y tratamiento de los trastornos tiroideos durante el embarazo: un enfoque para el cuidado integral del binomio madre-hijo. Iatreia.;26(2):172-84. https://doi.org/10.17533/udea.iatreia.14372
Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab. 1983;57(5):1036-40. https://doi.org/10.1210/jcem-57-5-1036
Meyer P, Das T, Ghadiri N, Murthy R, Theodoropoulou S. Clinical pathophysiology of thyroid eye disease: the cone model. Eye. 2019;33(2):244-53. https://doi.org/10.1038/s41433-018-0302-1
Kahaly GJ, Diana T, Olivo PD. TSH receptor antibodies: relevance & utility. Endocr Pract. 2020;26(1):97-106. https://doi.org/10.4158/EP-2019-0363
Botushanov NP, Botushanov AN, Botushanova AD. Graves’ Disease and Pregnancy. En: Gensure R. editor. Graves' Disease. Londres: IntechOpen; 2021. https://doi.org/10.5772/intechopen.97640
Wémeau L, Klein M, Sadoul JL, Briet C, Vélayoudom-Céphise FL. Graves’ disease: Introduction, epidemiology, endogenous and environmental pathogenic factors. Ann Endocrinol (Paris). 2018;79(6):599-607. https://doi.org/10.1016/j.ando.2018.09.002
Tagami T, Hagiwara H, Kimura T, Usui T, Shimatsu A, Naruse M. The incidence of gestational hyperthyroidism and postpartum thyroiditis in treated patients with Graves’ disease. Thyroid. 2007;17:767-72. https://doi.org/10.1089/thy.2007.0003
Korelitz JJ, McNally DL, Masters MN, Li S, Xu Y, Rivkees S. Prevalence of thyrotoxicosis, antithyroid medication use, and complications among pregnant women in the United States. Thyroid. 2013;23:758-65. https://doi.org/10.1089/thy.2012.0488
Yap YW, Onyekwelu E, Alam U. Thyroid disease in pregnancy. Clin Med (Lond). 2023;23(2):125-128. https://doi.org/10.7861/clinmed.2023-0018
Gargallo Fernández M. Hipertiroidismo y embarazo. Endocrinol Nutr. 2013 nov 1;60(9):535-43. https://doi.org/10.1016/j.endonu.2012.11.006
Laurberg P, Andersen SL. Endocrinology in pregnancy: Pregnancy and the incidence, diagnosing and therapy of Graves’ disease. Eur J Endocrinol. 2016;175:R219-30. https://doi.org/10.1530/EJE-16-0410
Lee RH, Spencer CA, Mestman JH, Miller E, Petrovic I, Braveman L, et al. Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol. 2009;200:260-7. https://doi.org/10.1016/j.ajog.2008.10.042
Lazarus JH. Management of hyperthyroidism in pregnancy. Endocrine. 2014;45(2):190-4. https://doi.org/10.1007/s12020-013-0086-9
Mourits MP, Koornneef L, Wiersinga WM, et al. Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73:639-44. https://doi.org/10.1136/bjo.73.8.639
Muller-Forell W, Kahaly GJ. Neuroimaging of Graves’ orbitopathy. Best Practice and Research: Clin Endocrinol Metab. 2012;26:259-71. https://doi.org/10.1016/j.beem.2011.11.009
Corvilain B, Hamy A, Brunaud L, Borson-Chazot F, Orgiazzi J, Bensalem Hachmi L, et al. Treatment of adult Graves’ disease. Ann Endocrinol (París). 2018 ;79(6):618-35. https://doi.org/10.1016/j.ando.2018.08.003
Andersen SL, Olsen J, Wu CS, Laurberg P. Severity of birth defects after propylthiouracil exposure in early pregnancy. Thyroid. 2014;24(10):1533-40. https://doi.org/10.1089/thy.2014.0150
Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab. 2001;86:2354-9. https://doi.org/10.1210/jcem.86.6.7573
Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab. 2013;98(11):4373-81. https://doi.org/10.1210/jc.2013-2831
Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, et al. Treatment of Graves’ disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab. 2012;97:2396-403. https://doi.org/10.1210/jc.2011-2860
Seo GH, Kim TH, Chung JH. Antithyroid drugs and congenital malformations: a Nationwide Korean cohort study. Ann Intern Med. 2018;168:405-13. https://doi.org/10.7326/M17-1398
Andersen SL, Knosgaard L, Olsen J, Vestergaard P, Andersen S. Maternal thyroid function, use of antithyroid drugs in early pregnancy and birth defects. J Clin Endocrinol Metab. 2019;104:6040-8. https://doi.org/10.1210/jc.2019-01343
Morales DR, Fonkwen L, Nordeng HME. Antithyroid drug use during pregnancy and the risk of birth defects in offspring: systematic review and meta-analysis of observational studies with methodological considerations. Br J Clin Pharmacol. 2021;87(10):3890-900. https://doi.org/10.1111/bcp.14805
Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis. Thyroid. 2016;26(10):1-272. https://doi.org/10.1089/thy.2016.0229
Li X, Liu G, Ma J, Zhou L. Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis. Clinics (Sao Paulo). 2015;70(6):453-9. https://doi.org/10.6061/clinics/2015(06)12
Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci M, et al. Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008;158:273-85. https://doi.org/10.1530/EJE-07-0666
Zhang D, Cai K, Wang G, Xu S, Mao X, Zheng A, et al. Trimester-specific reference ranges for thyroid hormones in pregnant women. Medicine (Baltimore). 2019 en.;98(4):e14245. https://doi.org/10.1097/MD.0000000000014245
Velasco I, Vila L, Goya M, Oleaga A, de la Calle M, Santamaria FJ. Resumen ejecutivo del documento de consenso SEEN-SEGO sobre el manejo de la disfunción tiroidea durante el embarazo. Endocrinol, Diabetes Nutr. 2022;70(supl. 1):38-50. https://doi.org/10.1016/j.endinu.2022.03.003
Lee SY, Pearce EN. Assessment and treatment of thyroid disorders in pregnancy and the postpartum period. Nature Rev Endocrinol. 2022;18(3):158-71. https://doi.org/10.1038/s41574-021-00604-z
Andersen SL, Andersen S. Antithyroid drugs and birth defects. Thyroid Res. 2020 jun. 27;13:11. https://doi.org/10.1186/s13044-020-00085-8
Nguyen CT, Mestman JH. Graves' hyperthyroidism in pregnancy. Curr Opin Endocrinol Diabetes Obes. 2019;26(5):232-240. https://doi.org/10.1097/MED.0000000000000492
Lo JC, Rivkees SA, Chandra M, Gonzalez J, Korelitz J, Kuzniewicz M. Gestational thyrotoxicosis, antithyroid drug use and neonatal outcomes within an integrated healthcare delivery system. Thyroid. 2015;25:698-705. https://doi.org/10.1089/thy.2014.0434
González EM, Melo LJ, Ramírez VC, Imitola A. Tiroidectomía en paciente embarazada con enfermedad de Graves sin respuesta a tratamiento médico: reporte de caso. Universitas Medica. 2020;61(3). https://doi.org/10.11144/Javeriana.umed61-3.grav
Gómez C, Imitola A, Taboada LB, Henao DC, Marín LF, Camargo J, et al. Thyroid orbitopathy: Management protocol based on review of the evidence. Rev Colomb Endocrinol, Diabet Metab. 2019;6(3):210-7. https://doi.org/10.53853/encr.6.3.535
Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodríguez Alvarez F, et al. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy: a randomized clinical trial. Am J Ophthalmol. 2018;195:181-90. https://doi.org/10.1016/j.ajo.2018.07.038
Bartalena L, Kahaly G, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur J Endocrinol. 2021;185(4):G43-67. https://doi.org/10.1530/eje-21-0479
Hamed Azzam S, Kang S, Salvi M, Ezra D. Tocilizumab for thyroid eye disease. Cochrane Database Syst Rev. 2018;11:CD012984. https://doi.org/10.1002/14651858.CD012984.pub2
Sanchez-Bilbao L, Martinez-Lopez D, Revenga M, et al. Anti-IL-6 receptor tocilizumab in refractory Graves’ orbitopathy: national multicenter observational study of 48 patients. J Clin Med. 2020;9(9):2816. https://doi.org/10.3390/jcm9092816
Perez-Moreiras JV, Varela-Agra M, Prada-Sanchez MC, Prada-Ramallal G. Steroid-resistant Graves’ orbitopathy treated with tocilizumab in real-world clinical practice: a 9-year single-center experience. J Clin Med. 2021;10(4):706. https://doi.org/10.3390/jcm10040706
Saito J, Yakuwa N, Kaneko K, Takai C, Goto M, Nakajima K, et al. Tocilizumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk and infant serum. Rheumatology. 2019;58(8):1505-7. https://doi.org/10.1093/rheumatology/kez100
Hoeltzenbein M, Beck E, Rajwanshi R, Gøtestam Skorpen C, Berber E, Schaefer C, et al. Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data. Semin Arthritis Rheum. 2016 oct. 1;46(2):238-45. https://doi.org/10.1016/j.semarthrit.2016.05.004
Córdoba Ramírez N, García Botina HD, Builes Barrera CA. Cambios fisiológicos de la función tiroidea en el embarazo: bases para la interpretación de las pruebas tiroideas. Iatreia. 2013;26(2):185-96. https://doi.org/10.17533/udea.iatreia.14373
Lalaguna Mallada P, Peralez Martínez JI, Congost Marín S, Odriozola M, Vara Callau M, Conde Barreiro S, et al. Hipertiroidismo neonatal. Rev Esp Endocrinol Pediatr. 2015;6(2):89-94. https://www.endocrinologiapediatrica.org/revistas/P1-E16/P1-E16-S598-A310.pdf
Caron P. Management of thyrotoxicosis and pregnancy: Review of the current literature and an update of the care pathway. Ann Endocrinol (París). 2022;83(4):226-31. https://doi.org/10.1016/j.ando.2022.01.006
Ashkar C, Sztal-Mazer S, Topliss DJ. How to manage Graves’ disease in women of childbearing potential. Clin Endocrinol (Oxford). 2022:1- 6. https://doi.org/10.1111/cen.14705
Kahaly GJ. Management of Graves Thyroidal and Extrathyroidal Disease: An Update. J Clin Endocrinol Metab. 2020;105(12):3704-20. https://doi.org/10.1210/clinem/dgaa646
Agrawal M, Lewis S, Premawardhana L, Dayan C, Taylor P, Okosieme O. Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis. Clin Endocrinol (Oxford). 2022 jun.;96(6):857-68. https://doi.org/10.1111/cen.14646
Tosounidou S, Gordon C. Medications in pregnancy and breastfeeding. Best Pract Res Clin Obstet Gynaecol. 2020;64:68-76. https://doi.org/10.1016/j.bpobgyn.2019.10.007
Rashad R, Pinto R, Li E, Sohrab M, Distefano AG. Thyroid Eye Disease. Life. 2022;12(12):2084. https://doi.org/10.3390/life12122084
Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce S. 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J. 2018;7(4):167-86. https://doi.org/10.1159/000490384
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright (c) 2023 Revista Colombiana de Endocrinología, Diabetes & Metabolismo