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Thyroid disease in pregnancy: new insights in diagnosis and clinical management

Key Points

  • Studies published during the past decade have enabled researchers to gain new insights into the diagnosis, physiology and treatment of thyroid disease during pregnancy.

  • The previously recommended TSH cut-offs of 2.5 mU/l or 3.0 mU/l are too low and are likely to lead to overdiagnosis and overtreatment of thyroid disease during pregnancy.

  • The combination of thyroid peroxidase-antibody positivity and a high concentration of TSH seems to synergistically increase the risk of adverse pregnancy outcomes.

  • Substantial new evidence supports the important role of thyroid hormone for fetal neurodevelopment.

  • New studies indicate that in patients treated with levothyroxine, titration to thyroid hormone concentrations in the higher end of the normal range might carry a risk of overtreatment.

  • Particularly during early pregnancy, treatment with methimazole (thiamazole) or propylthiouracil might increase the risk of fetal anomalies, and clinicians should consider the cessation of low-dose regimens.

Abstract

Adequate thyroid hormone availability is important for an uncomplicated pregnancy and optimal fetal growth and development. Overt thyroid disease is associated with a wide range of adverse obstetric and child development outcomes. An increasing number of studies now indicate that milder forms of thyroid dysfunction are also associated with these adverse pregnancy outcomes. The definitions of both overt and subclinical thyroid dysfunction have changed considerably over the past few years, as new data indicate that the commonly used fixed upper limits of 2.5 mU/l or 3.0 mU/l for thyroid-stimulating hormone (TSH) are too low to define an abnormal thyroid function. Furthermore, some studies now show that the reference ranges are not necessarily the best cut-off for identifying pregnancies at high risk of adverse outcomes. In addition, data suggest that thyroid peroxidase autoantibody positivity and high or low concentrations of human chorionic gonadotropin seem to have a more prominent role in the interpretation of thyroid dysfunction than previously thought. Data on the effects of thyroid disease treatment are lacking, but some studies indicate that clinicians should be aware of the potential for overtreatment with levothyroxine. Here, we put studies from the past decade on reference ranges for TSH, determinants of thyroid dysfunction, risks of adverse outcomes and options for treatment into perspective. In addition, we provide an overview of the current views on thyroid physiology during pregnancy and discuss strategies to identify high-risk individuals who might benefit from levothyroxine treatment.

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Figure 1: Changes in thyroid physiology during pregnancy.
Figure 2: Thyroidal response to human chorionic gonadotropin (hCG) stimulation in women who are thyroid peroxidase antibody (TPOAb) negative and women who are TPOAb positive.
Figure 3: Proposed longitudinal effects of the differences in the thyroidal response to human chorionic gonadotropin (hCG) stimulation.
Figure 4: Association between maternal free T4 concentrations during early pregnancy and child IQ and cortical volume as well as postulated treatment strategies.
Figure 5: Thyroid-related substances and crossing of the placental barrier.

References

  1. 1

    Krassas, G. E., Poppe, K. & Glinoer, D. Thyroid function and human reproductive health. Endocr. Rev. 31, 702–755 (2010).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Hershman, J. M. The role of human chorionic gonadotropin as a thyroid stimulator in normal pregnancy. J. Clin. Endocrinol. Metab. 93, 3305–3306 (2008).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Medici, M., Korevaar, T. I., Visser, W. E., Visser, T. J. & Peeters, R. P. Thyroid function in pregnancy: what is normal? Clin. Chem. 61, 704–713 (2015).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Pop, V., Broeren, M. & Wiersinga, W. The attitude toward hypothyroidism during early gestation: time for a change of mind? Thyroid 24, 1541–1546 (2014).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Abalovich, M. et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 92, S1–S47 (2007).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Lazarus, J. et al. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur. Thyroid J. 3, 76–94 (2014).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  7. 7

    Lazarus, J. H. et al. Antenatal thyroid screening and childhood cognitive function. N. Engl. J. Med. 366, 493–501 (2012).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Stagnaro-Green, A. et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21, 1081–1125 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Blatt, A. J., Nakamoto, J. M. & Kaufman, H. W. National status of testing for hypothyroidism during pregnancy and postpartum. J. Clin. Endocrinol. Metab. 97, 777–784 (2012).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Casey, B. M. et al. Subclinical hyperthyroidism and pregnancy outcomes. Obstet. Gynecol. 107, 337–341 (2006).

    Article  PubMed  Google Scholar 

  11. 11

    Korevaar, T. et al. Stimulation of thyroid function by hCG during pregnancy: a risk factor for thyroid disease and a mechanism for known risk factors. Thyroid 27, 440–450 (2017).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Cooper, D. S. & Laurberg, P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol. 1, 238–249 (2013).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Korevaar, T. I. et al. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol. 4, 35–43 (2016).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Cooper, D. S. & Rivkees, S. A. Putting propylthiouracil in perspective. J. Clin. Endocrinol. Metab. 94, 1881–1882 (2009).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Laurberg, P. & Andersen, S. L. Antithyroid drug use in pregnancy and birth defects: why some studies find clear associations, and some studies report none. Thyroid 25, 1185–1190 (2015).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Andersen, S. L., Olsen, J., Wu, C. S. & Laurberg, P. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J. Clin. Endocrinol. Metab. 98, 4373–4381 (2013).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Takata, K. et al. Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid 19, 559–563 (2009).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Taylor, P. N. & Vaidya, B. Side effects of anti-thyroid drugs and their impact on the choice of treatment for thyrotoxicosis in pregnancy. Eur. Thyroid J. 1, 176–185 (2012).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  19. 19

    De Groot, L. et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 97, 2543–2565 (2012).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Dashe, J. S. et al. Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet. Gynecol. 106, 753–757 (2005).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Lambert-Messerlian, G. et al. First- and second-trimester thyroid hormone reference data in pregnant women: a FaSTER (First- and Second-Trimester Evaluation of Risk for aneuploidy) Research Consortium study. Am. J. Obstet. Gynecol. 199, 62e1–62e6 (2008).

    Article  CAS  Google Scholar 

  22. 22

    Harris, E. K. & Boyd, J. C. Statistical Bases of Reference Values in Laboratory Medicine (Marcel Dekker, 1995).

    Book  Google Scholar 

  23. 23

    Geffre, A. et al. Reference values: a review. Vet. Clin. Pathol. 38, 288–298 (2009).

    Article  PubMed  Google Scholar 

  24. 24

    Medici, M. et al. Maternal early pregnancy and newborn thyroid hormone parameters: the Generation R study. J. Clin. Endocrinol. Metab. 97, 646–652 (2012).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Li, C. 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. 99, 73–79 (2014).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Alexander, E. K. et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease during Pregnancy and the Postpartum. Thyroid 27, 315–389 (2017).

    Article  PubMed  Google Scholar 

  27. 27

    Anckaert, E. et al. FT4 immunoassays may display a pattern during pregnancy similar to the equilibrium dialysis ID-LC/tandem MS candidate reference measurement procedure in spite of susceptibility towards binding protein alterations. Clin. Chim. Acta 411, 1348–1353 (2010).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Berta, E. et al. Evaluation of the thyroid function of healthy pregnant women by five different hormone assays. Pharmazie 65, 436–439 (2010).

    CAS  PubMed  Google Scholar 

  29. 29

    Lee, R. H. et al. Free T4 immunoassays are flawed during pregnancy. Am. J. Obstet. Gynecol. 200, 260e1–260e6 (2009).

    Article  CAS  Google Scholar 

  30. 30

    Kahric-Janicic, N. et al. Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy. Thyroid 17, 303–311 (2007).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  31. 31

    Christofides, N. D., Wilkinson, E., Stoddart, M., Ray, D. C. & Beckett, G. J. Assessment of serum thyroxine binding capacity-dependent biases in free thyroxine assays. Clin. Chem. 45, 520–525 (1999).

    CAS  PubMed  Google Scholar 

  32. 32

    Sapin, R. & d'Herbomez, M. Free thyroxine measured by equilibrium dialysis and nine immunoassays in sera with various serum thyroxine-binding capacities. Clin. Chem. 49, 1531–1535 (2003).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Bliddal, S. et al. Gestational age-specific reference ranges from different laboratories misclassify pregnant women's thyroid status: comparison of two longitudinal prospective cohort studies. Eur. J. Endocrinol. 170, 329–339 (2014).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Glinoer, D. et al. Regulation of maternal thyroid during pregnancy. J. Clin. Endocrinol. Metab. 71, 276–287 (1990).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Korevaar, T. I. et al. Maternal total T4 during the first half of pregnancy: physiologic aspects and the risk of adverse outcomes in comparison with free T4. Clin. Endocrinol. (Oxf.) 85, 757–763 (2016).

    CAS  Article  Google Scholar 

  36. 36

    Oken, E. et al. Neonatal thyroxine, maternal thyroid function, and child cognition. J. Clin. Endocrinol. Metab. 94, 497–503 (2009).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Zimmermann, M. B. The effects of iodine deficiency in pregnancy and infancy. Paediatr. Perinat Epidemiol. 26 (Suppl. 1), 108–117 (2012).

    Article  PubMed  Google Scholar 

  38. 38

    Shi, X. et al. Optimal and safe upper limits of iodine intake for early pregnancy in iodine-sufficient regions: a cross-sectional study of 7190 pregnant women in China. J. Clin. Endocrinol. Metab. 100, 1630–1638 (2015).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Benhadi, N. et al. Ethnic differences in TSH but not in free T4 concentrations or TPO antibodies during pregnancy. Clin. Endocrinol. (Oxf.) 66, 765–770 (2007).

    CAS  Article  Google Scholar 

  40. 40

    La'ulu, S. L. & Roberts, W. L. Second-trimester reference intervals for thyroid tests: the role of ethnicity. Clin. Chem. 53, 1658–1664 (2007).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    La'ulu, S. L. & Roberts, W. L. Ethnic differences in first-trimester thyroid reference intervals. Clin. Chem. 57, 913–915 (2011).

    Article  PubMed  Google Scholar 

  42. 42

    Walker, J. A., Illions, E. H., Huddleston, J. F. & Smallridge, R. C. Racial comparisons of thyroid function and autoimmunity during pregnancy and the postpartum period. Obstet. Gynecol. 106, 1365–1371 (2005).

    Article  PubMed  Google Scholar 

  43. 43

    Dhatt, G. S. et al. Thyrotrophin and free thyroxine trimester-specific reference intervals in a mixed ethnic pregnant population in the United Arab Emirates. Clin. Chim. Acta 370, 147–151 (2006).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Korevaar, T. I. et al. Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J. Clin. Endocrinol. Metab. 98, 4382–4390 (2013).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Pop, V. J., Biondi, B., Wijnen, H. A., Kuppens, S. M. & L. Vader, H. Maternal thyroid parameters, body mass index and subsequent weight gain during pregnancy in healthy euthyroid women. Clin. Endocrinol. 79, 577–583 (2013).

    Article  Google Scholar 

  46. 46

    Knight, B. A., Shields, B. M., Hattersley, A. T. & Vaidya, B. Maternal hypothyroxinaemia in pregnancy is associated with obesity and adverse maternal metabolic parameters. Eur. J. Endocrinol. 174, 51–57 (2016).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  47. 47

    Han, C. et al. High body mass index is an indicator of maternal hypothyroidism, hypothyroxinemia, and thyroid-peroxidase antibody positivity during early pregnancy. Biomed. Res. Int. 2015, 321831 (2015).

    Google Scholar 

  48. 48

    Mannisto, T. et al. Early pregnancy reference intervals of thyroid hormone concentrations in a thyroid antibody-negative pregnant population. Thyroid 21, 291–298 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Laurberg, P., Andersen, S. L., Hindersson, P., Nohr, E. A. & Olsen, J. Dynamics and predictors of serum TSH and fT4 reference limits in early pregnancy: a study within the Danish national birth cohort. J. Clin. Endocrinol. Metab. 101, 2484–2492 (2016).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Mosso, L. et al. Early pregnancy thyroid hormone reference ranges in Chilean women: the influence of body mass index. Clin. Endocrinol. (Oxf.) 85, 942–948 (2016).

    CAS  Article  Google Scholar 

  51. 51

    Korevaar, T. I. et al. Risk factors and a clinical prediction model for low maternal thyroid function during early pregnancy: two population-based prospective cohort studies. Clin. Endocrinol. (Oxf.) 85, 902–909 (2016).

    CAS  Article  Google Scholar 

  52. 52

    Haddow, J. E. et al. Variability in thyroid-stimulating hormone suppression by human chorionic [corrected] gonadotropin during early pregnancy. J. Clin. Endocrinol. Metab. 93, 3341–3347 (2008).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  53. 53

    Korevaar, T. I. et al. Thyroid autoimmunity impairs the thyroidal response to human chorionic gonadotropin: two population-based prospective cohort studies. J. Clin. Endocrinol. Metab. 102, 69–77 (2017).

    Article  PubMed  Google Scholar 

  54. 54

    Romero, R. et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J. Matern Fetal Neonatal Med. 21, 9–23 (2008).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  55. 55

    Kamba, T. et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am. J. Physiol. Heart Circ. Physiol. 290, H560–H576 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Yang, Y. et al. Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proc. Natl Acad. Sci. USA 110, 12018–12023 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Korevaar, T. I. et al. Placental angiogenic factors are associated with maternal thyroid function and modify hCG-mediated FT4 stimulation. J. Clin. Endocrinol. Metab. 100, E1328–E2334 (2015).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    van den Boogaard, E. et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum. Reprod. Update 17, 605–619 (2011).

    Article  PubMed  Google Scholar 

  59. 59

    Haddow, J. E. et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N. Engl. J. Med. 341, 549–555 (1999).

    CAS  Article  PubMed  Google Scholar 

  60. 60

    de Escobar, G. M., Obregon, M. J. & del Rey, F. E. Role of thyroid hormone during early brain development. Eur. J. Endocrinol. 151, U25–U37 (2004).

    Article  Google Scholar 

  61. 61

    Calvo, R., Obregon, M. J., Deona, C. R., Delrey, F. E. & Deescobar, G. M. Congenital hypothyroidism, as studied in rats - crucial role of maternal thyroxine but not of 3,5,3′-Triiodothyronine in the protection of the fetal brain. J. Clin. Invest. 86, 889–899 (1990).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  62. 62

    Sheehan, P. M., Nankervis, A., Araujo Junior, E. & Da Silva Costa, F. Maternal thyroid disease and preterm birth: systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 100, 4325–4331 (2015).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Maraka, S. et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid 26, 580–590 (2016).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  64. 64

    Negro, R. & Stagnaro-Green, A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ 349, g4929 (2014).

    Article  PubMed  Google Scholar 

  65. 65

    Henrichs, J. et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J. Clin. Endocrinol. Metab. 95, 4227–4234 (2010).

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Henrichs, J., Ghassabian, A., Peeters, R. P. & Tiemeier, H. Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin. Endocrinol. (Oxf.) 79, 152–162 (2013).

    Article  Google Scholar 

  67. 67

    Julvez, J. et al. Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 24, 150–157 (2013).

    Article  PubMed  Google Scholar 

  68. 68

    Karakosta, P. et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J. Clin. Endocrinol. Metab. 97, 4464–4472 (2012).

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Liu, H. et al. Maternal subclinical hypothyroidism, thyroid autoimmunity, and the risk of miscarriage: a prospective cohort study. Thyroid 24, 1642–1649 (2014).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  70. 70

    Ying, H. et al. Maternal TSH level and TPOAb status in early pregnancy and their relationship to the risk of gestational diabetes mellitus. Endocr 54, 742–750 (2016).

    CAS  Article  Google Scholar 

  71. 71

    Maraka, S. et al. Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ 356, i6865 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Thangaratinam, S. et al. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 342, d2616 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73

    He, X. et al. Thyroid antibodies and risk of preterm delivery: a meta-analysis of prospective cohort studies. Eur. J. Endocrinol. 167, 455–464 (2012).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Biro, E. et al. Association of systemic and thyroid autoimmune diseases. Clin. Rheumatol 25, 240–245 (2006).

    Article  PubMed  Google Scholar 

  75. 75

    Nakamura, H. et al. Prevalence of interrelated autoantibodies in thyroid diseases and autoimmune disorders. J. Endocrinol. Invest. 31, 861–865 (2008).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Negro, R. et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J. Clin. Endocrinol. Metab. 91, 2587–2591 (2006).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Nazarpour, S. et al. Effects of levothyroxine treatment on pregnancy outcomes in pregnant women with autoimmune thyroid disease. Eur. J. Endocrinol. 176, 253–265 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    ISRCTNregistry Thyroid AntiBodies and LEvoThyroxine study (TABLET) trial registration. ISRCTNregistry http://www.isrctn.com/ISRCTN15948785 (2017).

  79. 79

    Nederlands Trialregister T4LIFE trial registration. Trialregister http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3364 (2017).

  80. 80

    Berbel, P. et al. Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 19, 511–519 (2009).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Pop, V. J. & Vulsma, T. Maternal hypothyroxinaemia during (early) gestation. Lancet 365, 1604–1606 (2005).

    Article  PubMed  Google Scholar 

  82. 82

    Zimmermann, M. B. The adverse effects of mild-to-moderate iodine deficiency during pregnancy and childhood: a review. Thyroid 17, 829–835 (2007).

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Zimmermann, M. B. & Boelaert, K. Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol. 3, 286–295 (2015).

    CAS  Article  PubMed  Google Scholar 

  84. 84

    Pedersen, K. M. et al. Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. J. Clin. Endocrinol. Metab. 77, 1078–1083 (1993).

    CAS  PubMed  Google Scholar 

  85. 85

    Negro, R., Soldin, O. P., Obregon, M. J. & Stagnaro-Green, A. Hypothyroxinemia and pregnancy. Endocr. Pract. 17, 422–429 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86

    Yu, X. et al. Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China. J. Clin. Endocrinol. Metab. 100, 1594–1601 (2015).

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Medici, M. et al. Maternal thyroid hormone parameters during early pregnancy and birth weight: the Generation R Study. J. Clin. Endocrinol. Metab. 98, 59–66 (2013).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Ghassabian, A. et al. Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children. J. Clin. Endocrinol. Metab. 99, 2383–2390 (2014).

    CAS  Article  PubMed  Google Scholar 

  89. 89

    Roman, G. C. et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann. Neurol. 74, 733–742 (2013).

    CAS  Article  PubMed  Google Scholar 

  90. 90

    Gyllenberg, D. et al. Hypothyroxinemia during gestation and offspring schizophrenia in a national birth cohort. Biol. Psychiatry 79, 962–970 (2016).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Finken, M. J., van Eijsden, M., Loomans, E. M., Vrijkotte, T. G. & Rotteveel, J. Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. J. Clin. Endocrinol. Metab. 98, 1417–1426 (2013).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Modesto, T. et al. Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit/Hyperactivity disorder symptoms in children. JAMA Pediatr. 169, 838–845 (2015).

    Article  PubMed  Google Scholar 

  93. 93

    Pakkila, F. et al. Maternal and child's thyroid function and child's intellect and scholastic performance. Thyroid 25, 1363–1374 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94

    European Thyroid Association Abstracts: Hales, C. et al. (p59) and Taylor, P. et al. (p128) Eur. Thyroid J. 5 (Suppl. 1), 57–176 (2016).

  95. 95

    Hales, C. et al. The second wave of the Controlled Antenatal Thyroid Screening (CATS II) study: the cognitive assessment protocol. BMC Endocr. Disord. 14, 95 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Casey, B. M. et al. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N. Engl. J. Med. 376, 815–825 (2017).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  97. 97

    ClinicalTrials Thyroid therapy for mild thyroid deficiency in pregnancy (TSH). ClinicalTrials https://clinicaltrials.gov/ct2/show/NCT00388297 (2017).

  98. 98

    Attina, T. M. et al. Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. Lancet Diabetes Endocrinol. 4, 996–1003 (2016).

    Article  PubMed  Google Scholar 

  99. 99

    Power, C., Kuh, D. & Morton, S. From developmental origins of adult disease to life course research on adult disease and aging: insights from birth cohort studies. Annu. Rev. Publ. Health 34, 7–28 (2013).

    Article  Google Scholar 

  100. 100

    Casey, B. M. et al. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet. Gynecol. 109, 1129–1135 (2007).

    Article  PubMed  Google Scholar 

  101. 101

    Mannisto, T. et al. Thyroid dysfunction and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life. J. Clin. Endocrinol. Metab. 95, 1084–1094 (2010).

    CAS  Article  PubMed  Google Scholar 

  102. 102

    Haddow, J. E. et al. Implications of High Free Thyroxine (FT4) concentrations in euthyroid pregnancies: the FaSTER trial. J. Clin. Endocrinol. Metab. 99, 2038–2044 (2014).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  103. 103

    Pakkila, F. et al. The impact of gestational thyroid hormone concentrations on ADHD symptoms of the child. J. Clin. Endocrinol. Metab. 99, E1–E8 (2014).

    Article  PubMed  Google Scholar 

  104. 104

    Dosiou, C. & Medici, M. Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns. Eur. J. Endocrinol. 176, R21–R38 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Medici, M. et al. Maternal early-pregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the generation R study. J. Clin. Endocrinol. Metab. 99, E2591–2598 (2014).

    CAS  Article  PubMed  Google Scholar 

  106. 106

    Tudela, C. M., Casey, B. M., McIntire, D. D. & Cunningham, F. G. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet. Gynecol. 119, 983–988 (2012).

    CAS  Article  PubMed  Google Scholar 

  107. 107

    Tong, Z. et al. The effect of subclinical maternal thyroid dysfunction and autoimmunity on intrauterine growth restriction: a systematic review and meta-analysis. Med. (Baltimore) 95, e3677 (2016).

    Article  CAS  Google Scholar 

  108. 108

    Carle, A. et al. Epidemiology of subtypes of hyperthyroidism in Denmark: a population-based study. Eur. J. Endocrinol. 164, 801–809 (2011).

    CAS  Article  PubMed  Google Scholar 

  109. 109

    Springer, D., Zima, T. & Limanova, Z. Reference intervals in evaluation of maternal thyroid function during the first trimester of pregnancy. Eur. J. Endocrinol. 160, 791–797 (2009).

    CAS  Article  PubMed  Google Scholar 

  110. 110

    Sheffield, J. S. & Cunningham, F. G. Thyrotoxicosis and heart failure that complicate pregnancy. Am. J. Obstet. Gynecol. 190, 211–217 (2004).

    Article  PubMed  Google Scholar 

  111. 111

    Sahu, M. T., Das, V., Mittal, S., Agarwal, A. & Sahu, M. Overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome. Arch. Gynecol. Obstet. 281, 215–220 (2010).

    Article  PubMed  Google Scholar 

  112. 112

    Luewan, S., Chakkabut, P. & Tongsong, T. Outcomes of pregnancy complicated with hyperthyroidism: a cohort study. Arch. Gynecol. Obstet. 283, 243–247 (2011).

    Article  PubMed  Google Scholar 

  113. 113

    Millar, L. K. et al. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet. Gynecol. 84, 946–949 (1994).

    CAS  PubMed  Google Scholar 

  114. 114

    Davis, L. E., Lucas, M. J., Hankins, G. D., Roark, M. L. & Cunningham, F. G. Thyrotoxicosis complicating pregnancy. Am. J. Obstet. Gynecol. 160, 63–70 (1989).

    CAS  Article  PubMed  Google Scholar 

  115. 115

    Pillar, N., Levy, A., Holcberg, G. & Sheiner, E. Pregnancy and perinatal outcome in women with hyperthyroidism. Int. J. Gynaecol. Obstet. 108, 61–64 (2010).

    Article  PubMed  Google Scholar 

  116. 116

    Aggarawal, N. et al. Pregnancy outcome in hyperthyroidism: a case control study. Gynecol. Obstet. Invest. 77, 94–99 (2014).

    Article  PubMed  Google Scholar 

  117. 117

    Mannisto, T. et al. Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. J. Clin. Endocrinol. Metab. 98, 2725–2733 (2013).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  118. 118

    Andersen, S. L., Laurberg, P., Wu, C. S. & Olsen, J. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG 121, 1365–1374 (2014).

    CAS  Article  PubMed  Google Scholar 

  119. 119

    Andersen, S. L., Olsen, J., Wu, C. S. & Laurberg, P. Low birth weight in children born to mothers with hyperthyroidism and high birth weight in hypothyroidism, whereas preterm birth is common in both conditions: A danish national hospital register study. Eur. Thyroid J. 2, 135–144 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  120. 120

    Andersen, S. L., Olsen, J., Wu, C. S. & Laurberg, P. Spontaneous abortion, stillbirth and hyperthyroidism: a danish population-based study. Eur. Thyroid J. 3, 164–172 (2014).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  121. 121

    Laurberg, P. et al. TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur. J. Endocrinol. 158, 69–75 (2008).

    CAS  Article  PubMed  Google Scholar 

  122. 122

    Zakarija, M. & McKenzie, J. M. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. J. Clin. Endocrinol. Metab. 57, 1036–1040 (1983).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    Barbesino, G. & Tomer, Y. Clinical review: Clinical utility of TSH receptor antibodies. J. Clin. Endocrinol. Metab. 98, 2247–2255 (2013).

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  124. 124

    Yoshihara, A. et al. Substituting potassium iodide for methimazole as the treatment for graves' disease during the first trimester may reduce the incidence of congenital anomalies: a retrospective study at a single medical institution in Japan. Thyroid 25, 1155–1161 (2015).

    CAS  Article  PubMed  Google Scholar 

  125. 125

    Nedrebo, B. G. et al. Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves' disease. Eur. J. Endocrinol. 147, 583–589 (2002).

    CAS  Article  PubMed  Google Scholar 

  126. 126

    Momotani, N., Noh, J., Oyanagi, H., Ishikawa, N. & Ito, K. Antithyroid drug therapy for Graves' disease during pregnancy. Optimal regimen for fetal thyroid status. N. Engl. J. Med. 315, 24–28 (1986).

    CAS  Article  PubMed  Google Scholar 

  127. 127

    Korevaar, T. I. et al. Maternal and birth characteristics are determinants of offspring thyroid function. J. Clin. Endocrinol. Metab. 101, 206–213 (2016).

    CAS  Article  PubMed  Google Scholar 

  128. 128

    Korevaar, T. I. et al. The risk of pre-eclampsia according to high thyroid function in pregnancy differs by hCG concentration. J. Clin. Endocrinol. Metab. 101, 5037–5043 (2016).

    CAS  Article  PubMed  Google Scholar 

  129. 129

    Ashoor, G., Maiz, N., Rotas, M., Kametas, N. A. & Nicolaides, K. H. Maternal thyroid function at 11 to 13 weeks of gestation and subsequent development of preeclampsia. Prenat Diagn. 30, 1032–1038 (2010).

    Article  PubMed  Google Scholar 

  130. 130

    Wilson, K. L., Casey, B. M., McIntire, D. D., Halvorson, L. M. & Cunningham, F. G. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet. Gynecol. 119, 315–320 (2012).

    Article  PubMed  Google Scholar 

  131. 131

    Korevaar, T. I., Taylor, P. N., Dayan, C. M. & Peeters, R. P. An invitation to join the consortium on thyroid and pregnancy. Obstet. Gynecol. 128, 913 (2016).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors' research work was supported by a clinical fellowship from The Netherlands Organisation for Health Research and Development (ZonMw), project number 90700412 to R.P. Peeters.

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T.I.M.K. and R.P.P. wrote the first draft of the manuscript, after which all authors contributed equally to researching the data for the article, discussion of content, writing the article and reviewing and/or editing the manuscript.

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Correspondence to Tim I. M. Korevaar.

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Competing interests

T.I.M.K. has received lecture fees from Berlin-Chemie, Goodlife Healthcare and Excemed. R.P.P. has received lecture fees from Goodlife Healthcare. The other authors declare no competing interests.

Supplementary information

Supplementary information S1 (table)

Reference ranges for TSH and FT4 during early pregnancy worldwide. (PDF 148 kb)

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Glossary

Subclinical hypothyroidism

Defined as a high TSH concentration (>97.5th percentile) with a normal free T4 concentration (2.5th to 97.5th percentiles).

Hypothyroxinaemia

Defined as a normal TSH concentration (2.5th to 97.5th percentiles) with a low free T4 (<2.5th percentile; but in some cases <5th percentile).

Mental score

Determined by the outcome of standardized neurodevelopment tests, such as the WISC, and is a reflection of child IQ.

Psychomotor score

The outcome of standardized neurodevelopment tests, such as the WISC, and reflects the psychomotor development of the child, including the child's achievement of developmental milestones.

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Korevaar, T., Medici, M., Visser, T. et al. Thyroid disease in pregnancy: new insights in diagnosis and clinical management. Nat Rev Endocrinol 13, 610–622 (2017). https://doi.org/10.1038/nrendo.2017.93

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