Thyroid dysfunction during pregnancy: when and whom to treat?

The thyroid gland is an important organ of the endocrine system. Its hormones influence all human organs and systems. Among thyroid dysfunctions, the most common variant is primary hypothyroidism. Since during pregnancy the mother's thyroid gland undergoes changes and the need for thyroid hormones increases, the risk of hypothyroidism increases. Particular attention should be paid to women who are carriers of antithyroid antibodies, as they are more likely to have thyroid dysfunction during pregnancy. In this regard, such patients should have their thyroid function examined in each trimester of pregnancy. It is known that hypothyroidism, both manifest and subclinical, has a negative impact on pregnancy outcomes and the subsequent psycho-physical development of the child. With obvious hypothyroidism, the risk of premature birth, arterial hypertension, preeclampsia and other complications increases. Therefore, treatment for hypothyroidism during pregnancy should begin immediately. The basis of treatment for this pathology is the prescription of replacement therapy with L-thyroxine immediately in a full replacement dose. For women who were already taking the drug before pregnancy, the dose of L-thyroxine increases by 20-30% with the onset of gestation. Also during pregnancy, there may be a decrease in thyroid hormones, usually thyroxine (T4w), with normal TSH. This condition is called isolated hypothyroxinemia. Its causes may be insufficient iodine intake, as well as increased levels of thyroxine-binding globulin. Its increase leads to an increase in the concentration of the total fractions of the hormones T4 and T3, but at the same time the true level of T4fr is underestimated. Isolated hypothyroidism does not require treatment if TSH levels are normal.

1. Gaberšček S, Zaletel K. Thyroid physiology and autoimmunity in pregnancy and after delivery. Expert Rev Clin Immunol. 2011;7(5):697-706. https://doi.org/10.1586/eci.11.42.

2. Moleti M, Trimarchi F, Vermiglio А. Thyroid physiology in pregnancy. Endocr Pract. 2014;20(6):589-596. https://doi.org/10.4158/EP13341.RA.

3. Baba KA, Azar ST. Thyroid dysfunction in pregnancy. Int J Gen Med. 2012;5:227-230. https://doi.org/10.2147/IJGM.S27009.

4. Marqusee E, Braverman LE, Lawrence JE, Carroll JS, Seely EW. The effect of droloxifene and estrogen on thyroid function in postmenopausal women. J Clin Endocrinol Metab. 2000;85(11):4407-4410. https://doi.org/10.1210/jcem.85.11.6975.

5. Krassas G, Karras SN, Pontikides N. Thyroid diseases during pregnancy: a number of important issues. Hormones (Athens). 2015;14(1):59-69. https://doi.org/10.1007/BF03401381.

6. Maciel LM, Magalhaes PK. Thyroid and pregnancy. Arq Bras Endocrinol Metabol. 2008;52(7):1084-1095. https://doi.org/10.1590/s0004-27302008000700004.

7. Loubiere LS, Vasilopoulou E, Bulmer JN, Taylor PM, Stieger B, Verrey F et al. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta. 2010;31(4):295-304. https://doi.org/10.1016/j.placenta.2010.01.013.

8. de Escobar GM, Obregon MJ, del Rey FE. Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab. 2004;18(2):225-248. https://doi.org/10.1016/j.beem.2004.03.012.

9. Williams GR. Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol. 2008;20(6):784-794. https://doi.org/10.1111/j.1365-2826.2008.01733.x.

10. Alexander EK, Pearce EN, Brent GA, Brown RS, 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):315-389. https://doi.org/10.1089/thy.2016.0457.

11. Lazarus JH. Screening for thyroid dysfunction in pregnancy: is it worthwhile? J Thyroid Res. 2011;2011:397012. https://doi.org/10.4061/2011/397012.

12. Teng W, Shan Z, Patil-Sisodia K, Cooper DS. Hypothyroidism in pregnancy. Lancet Diabetes Endocrinol. 2013;1(3):228-237. https://doi.org/10.1016/S2213-8587(13)70109-8.

13. Dieguez M, Herrero A, Avello N. Suarez P. Delgado E, Menendez E. Prevalence of thyroid dysfunction in women in early pregnancy: does it increase with maternal age? Clin Endocrinol (Oxf). 2016;84(1):121-126. https://doi.org/10.1111/cen.12693.

14. Yazbeck CF, Sullivan SD. Thyroid disorders during pregnancy. Med Clin North Am. 2012;96(2):235-256. https://doi.org/10.1016/j.mcna.2012.01.004.

15. Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011;25(6):927-943. https://doi.org/10.1016/j.beem.2011.07.010.

16. Brenta G, Vaisman M, Sgarbi JA, Bergoglio LM, Andrada NC, Bravo PP et al. Task Force on Hypothyroidism of the Latin American Thyroid Society (LATS). Clinical practice guidelines for the management of hypothyroidism. Arq Bras Endocrinol Metabol. 2013;57(4):265-291. https://doi.org/10.1590/s0004-27302013000400003.

17. Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94. https://doi.org/10.1159/000362597.

18. Glinoer D, Soto MF, Bourdoux P, Lejeune B, Delange F, Lemone M et al. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab. 1991;73(2):421-427. https://doi.org/10.1210/jcem-73-2-421.

19. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid. 2002;12(1):63-68. https://doi.org/10.1089/105072502753451986.

20. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Role of thyroid hormone during early brain development. Eur J Endocrinol. 2004;151(3):25-37. https://doi.org/10.1530/eje.0.151u025.

21. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341(8):549-555. https://doi.org/10.1056/NEJM199908193410801.

22. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R et al. American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081-1125. https://doi.org/10.1089/thy.2011.0087.

23. Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, Cunningham FG. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol. 2005;105(2):239-245. https://doi.org/10.1097/01.AOG.0000152345.99421.22.

24. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol. 2007;109(5):1129-1135. https://doi.org/10.1097/01.AOG.0000262054.03531.24.

25. Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T et al. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab. 2011;96(10):3234-3241. https://doi.org/10.1210/jc.2011-0274.

26. Nazarpour S, Ramezani Tehrani F, Simbar M, Tohidi M, Alavi Majd H, Azizi F. Effects of levothyroxine treatment on pregnancy outcomes in pregnant women with autoimmune thyroid disease. Eur J Endocrinol. 2017;176(2):253-265. https://doi.org/10.1530/EJE-16-0548.

27. Leon G, Murcia M, Rebagliato M, Alvarez-Pedrerol M, Castilla AM, Basterrechea M et al. Maternal thyroid dysfunction during gestation, preterm delivery, and birthweight. The Infancia y Medio Ambiente Cohort, Spain. Paediatr Perinat Epidemiol. 2015;29(2):113-22. https://doi.org/10.1111/ppe.12172.

28. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf). 2003;59(3):282-288. https://doi.org/10.1046/j.1365-2265.2003.01822.x.

29. Pop VJ, Brouwers EP, Wijnen H, Oei G, Essed GG, Vader HL. Low concentrations of maternal thyroxin during early gestation: a risk factor of breech presentation? BJOG. 2004;111(9):925-90. https://doi.org/10.1111/j.1471-0528.2004.00213.x.

30. Craig WY, Allan WC, Kloza EM, Pulkkinen AJ, Waisbren S, Spratt DI et al. Mid-gestational maternal free thyroxine concentration and offspring neurocognitive development at age two years. J Clin Endocrinol Metab. 2012;97(1):22-28. https://doi.org/10.1210/jc.2011-1772.

31. Korevaar TI. Evidence-Based Tightrope Walking: The 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):309-311. https://doi.org/10.1089/thy.2017.2904O.tko.

32. Yassa L, Marqusee E, Fawcett R, Alexander EK. Thyroid hormone early adjustment in pregnancy (the THERAPY) trial. J Clin Endocrinol Metab. 2010;95(7):3234-3241. https//doi.org/10.1210/jc.2010-0013.

33. Yan YQ, Dong ZL, Dong L, Wang FR, Yang XM, Jin XY et al. Trimester- and method-specific reference intervals for thyroid tests in pregnant Chinese women: methodology, euthyroid definition and iodine status can influence the setting of reference intervals. Clin Endocrinol (Oxf). 2011;74(2):262-269. https//doi.org/10.1111/j.1365-2265.2010.03910.x.

34. Marwaha RK, Chopra S, Gopalakrishnan S, Sharma B, Kanwar RS, Sastry A et al. Establishment of reference range for thyroid hormones in normal pregnant Indian women. BJOG. 2008;115(5):602-606. https://doi.org/10.1111/j.1471-0528.2008.01673.x.

35. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de Muinck Keizer-Schrama SM et al. Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J Clin Endocrinol Metab. 2013;98(11):4382-4390. https//doi.org/10.1210/jc.2013-2855.

36. Moon HW, Chung HJ, Park CM, Hur M, Yun YM. Establishment of trimester-specific reference intervals for thyroid hormones in Korean pregnant women. Ann Lab Med. 2015;35(2):198-204. https//doi.org/10.3343/alm.2015.35.2.198.

37. Li C, Shan Z, Mao J, Wang W, Xie X, Zhou W et al. Assessment of thyroid function during first-trimester pregnancy: what is the rational upper limit of serum TSH during the first trimester in Chinese pregnant women? J Clin Endocrinol Metab. 2014;99(1):73-79. https//doi.org/10.1210/jc.2013-1674.

38. Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-825. https://doi.org/10.1056/NEJMoa1606205.

39. Rybakova AA, Platonov NM, Malysheva NM, Nikankina LV, Elfimova AR, Troshina EA. Reference intervals of thyroidstimulating hormone in pregnant women living in the central regions of the Russian Federation. Problemy Endokrinologii. 2022;68(6):43-48. (In Russ.) https://doi.org/10.14341/probl13151.

40. Fadeev VV, Morgunova TB, Melnichenko GA, Dedov II. Draft of the clinical recommendations for diagnosis and treatment of hypothyroidism. Clinical and Experimental Thyroidology. 2021;17(1):4-13. (In Russ.) https://doi.org/10.14341/ket12702.

41. Schroeder AC, Privalsky ML. Thyroid hormones, t3 and t4, in the brain. Front Endocrinol (Lausanne). 2014;5:40. https://doi.org/10.3389/fendo.2014.00040.

42. Bernal J, Guadano-Ferraz A, Morte B. Thyroid hormone transporters - functions and clinical implications. Nat Rev Endocrinol. 2015;11(7):406-417. https://doi.org/10.1038/nrendo.2015.66.

43. Carosa E, Lenzi A, Jannini EA. Thyroid hormone receptors and ligands, tissue distribution and sexual behavior. Mol Cell Endocrinol. 2018;467:49-59. https://doi.org/10.1016/j.mce.2017.11.006.

44. Abdulkhabirova FM, Bezlepkina OB, Brovin DN, Vadina TA, Melnichenko GA, Nagaeva EV et al. Clinical practice guidelines “Management of iodine deficiency disorders”. Problemy Endokrinologii. 2021;67(3):10-25. (In Russ.) https://doi.org/10.14341/probl12750.

45. Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004;351(3):241-249. https://doi.org/10.1056/NEJMoa040079.

46. Fan X, Wu L. The impact of thyroid abnormalities during pregnancy on subsequent neuropsychological development of the offspring: a meta-analysis. J Matern Fetal Neonatal Med. 2016;29(24):3971-3976. https://doi.org/10.3109/14767058.2016.1152248.

47. Yang J, Liu Y, Liu H, Zheng H, Li X, Zhu L et al. Associations of maternal iodine status and thyroid function with adverse pregnancy outcomes in Henan Province of China. J Trace Elem Med Biol. 2018;47:104-110. https://doi.org/10.1016/j.jtemb.2018.01.013.

48. Nassie DI, Ashwal E, Raban O, Ben-Haroush A, Wiznitzer A, Yogev Y et al. Is there an association between subclinical hypothyroidism and preterm uterine contractions? A prospective observational study. J Matern Fetal Neonatal Med. 2017;30(8):881-885. https://doi.org/10.1080/14767058.2016.1191065.

49. Arbib N, Hadar E, Sneh-Arbib O, Chen R, Wiznitzer A, Gabbay-Benziv R. First trimester thyroid stimulating hormone as an independent risk factor for adverse pregnancy outcome. J Matern Fetal Neonatal Med. 2017;30(18):2174-2178. https://doi.org/10.1080/14767058.2016.1242123.

50. Korevaar TIM, Steegers EAP, Chaker L, Medici M, Jaddoe VWV, Visser TJ et al. Thyroid function and premature delivery in TPO antibody-negative women: the added value of hCG. J Clin Endocrinol Metab. 2017;102(9): 3360-3367. https://doi.org/10.1210/jc.2017-00846.

51. Zhao L, Jiang G, Tian X, Zhang X, Zhu T, Chen B et al. Initiation timing effect of levothyroxine treatment on subclinical hypothyroidism in pregnancy. Gynecol Endocrinol. 2018;34(10):845-848. https://doi.org/10.1080/09513590.2018.1451836.

52. Nazarpour S, Ramezani Tehrani F, Simbar M, Tohidi M, Minooee S, Rahmati M et al. Effects of levothyroxine on pregnant women with subclinical hypothyroidism, negative for thyroid peroxidase antibodies. J Clin Endocrinol Metab. 2018;103(3):926-935. https://doi.org/10.1210/jc.2017-01850.

53. Maraka S, Mwangi R, McCoy RG, Yao X, Sangaralingham LR, Singh Ospina NM et al. Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ. 2017;356:i6865. https://doi.org/10.1136/bmj.i6865.

54. Galofre JC, Haber RS, Mitchell AA, Pessah R, Davies TF. Increased postpartum thyroxine replacement in Hashimoto's thyroiditis. Thyroid. 2010;20(8):901-908. https://doi.org/10.1089/thy.2009.0391.

55. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011;342:d2616. https://doi.org/10.1136/bmj.d2616.

56. Busnelli A, Paffoni A, Fedele L, Somigliana E. The impact of thyroid autoimmunity on IVF/ICSI outcome: a systematic review and meta-analysis. Hum Reprod Update. 2016;22(6):793-794. https://doi.org/10.1093/humupd/dmw034.

57. Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y et al. Effect of levothyroxine on miscarriage among women with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial. JAMA. 2017;318(22):2190-2198. https://doi.org/10.1001/jama.2017.18249.

58. Rao M, Zeng Z, Zhao S, Tang L. Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmuneity undergoing in vitro fertilization/intracytoplasmic sperm injection: an updated meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2018;16(1):92. https://doi.org/10.1186/s12958-018-0410-6.

59. Asik M, Gunes F, Binnetoglu E, Eroglu M, Bozkurt N, Sen H et al. Decrease in TSH levels after lactose restriction in Hashimoto's thyroiditis patients with lactose intolerance. Endocrine. 2014;46(2):279-284. https://doi.org/10.1007/s12020-013-0065-1.