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  1. Outline • Transient thyrotoxicosis of pregnancy • Graves disease during pregnancy • Hypothyroidism and pregnancy • Iodine nutrition and pregnancy

  2. Thyroid disease and pregnancy

  3. Changes in thyroid physiology in pregnancy

  4. Transient thyrotoxicosis of pregnancy (TTP)

  5. TTP: Prevalence • Close to 20%of pregnant women have a suppressed TSH and normal free T4 • In about 2.4% pregnant women had low TSH ( less than 0.20 mU/liter) and high free T4 index concentration.

  6. TTP:Racial differences • In some studies (Yeo et al., 2001) the frequency of transient gestational hyper thyroid-ism reached 11% for Asian women • Gestational thyrotoxicosis is at least 10-fold more frequent than hyperthyroidism due to graves disease

  7. TTP: natural history

  8. Mirror curve of TSH and HCG concentrations Glinoer et al., 1990,The Endocrine Society

  9. TTP:Role of HCG • In normal pregnancy, when hCG levels are highest at 10–12 wk gestation, there is suppression of serum TSH levels, presumably due to slight increases in free thyroxine concentration driven by high hCG values • These abnormalities are exaggerated in twin pregnanciesandhyperemesis gravidarum

  10. Role of HCG quality • Elevations of thyroid hormone and suppression of TSH are not entirely correlated with hCG levels • An increase in acidic forms of hCGhave demonstrated in hyperemesis gravidarum. unusual glycosylation patterns of hCG are common in hydatidiform moles which frequently present as hyperemesis gravidarum • A mutant TSH receptor

  11. TTG: TSH receptor mutation Rodien et al. Human Reproduction Update,2004, 95-105

  12. Hyperemesisgravidarum and hyperthyroidism

  13. Definition of HG • Hyperemesis gravidarum, defined as severe vomiting in early pregnancy that causes more than 5% weight loss, dehydration, and ketonuria and occurs in 0.5–10 cases per 1000 pregnancies • Gestational transient thyrotoxicosis has been observed in up to two thirds of women suffering from hyperemesis gravidarum JCEM

  14. Distinction between gestational transient thyrotoxicosis andGraves' disease

  15. Distinction between gestational transient thyrotoxicosis and Graves' disease 1.charachteristics of hyperemesis gravidarumare present in former . 2.Goitre is usually but not necessarily absent in the former 3.No past history of thyroid disease is reported by the patient or her family. 4.Ophthalmic examination reveals no abnormality, in contrast to half of patients with graves disease. Graves' disease. 5.Gestational age

  16. Distinction between gestational transient thyrotoxicosis andGraves' disease:TFT • Antithyroid antibodies are usually absent in gestational transient thyrotoxicosis. In particular, TSHR antibodies are absent • Serum free T3 is elevated less frequently in GTT compared with graves disease

  17. Treatment • Clinical symptoms usually are mild • Close observation of the course of the clinical presentation and thyroid hormone abnormalities is indicated. • Beta blockers such as metoprololmay be helpful and may be used with obstetrical agreement De Groot et al. JCEM,2012: 2543–2565

  18. Key massges • Transient thyrotoxicosis of pregnancy should differentiated from hyperthyroidism solely based on clinical judgment • Subjects with TTP should be observed carefully and treated with appropriate beta blockers if have sever symptoms of thyrotoxicosis

  19. Graves disease during pregnancy

  20. Prevalence • Prevalence of hyperthyroidism in pregnancy 0.1 to 0.4% • About 85% of cases are Graves’disease De Groot et al. JCEM,2012: 2543–2565

  21. Clinical course of Graves in pregnancy • First trimester • Second and third trimester • Puerperium

  22. Clinical manifestations • Symptoma are non specific and may be mimicked by normal pregnancy. • Significance of goiter • TFT must be interpreted in the context of the normal gestational changes of decreased serum TSH and increased T4and T3 levels De Groot et al. JCEM,2012: 2543–2565

  23. Maternal complications of hyperthyroidism in pregnancy Manissto etal.JCEM, 2013, 2725-2733

  24. Fetal complications • Low birth weight • Fetal hypothyroidism (overtreatment of mother) • Fetal central congenital hypothyroidism (undertreatmentof maternal hyperthyroidism) • Fetal thyrotoxicosis placental passage of TSI • Fetal death De Groot et al. JCEM,2012: 2543–2565

  25. Neonatal Graves

  26. Treatment:Goal • Goal of therapy : maintaining free T4 or FTI upper limit of the non pregnant reference range. evidence level :B (1QQEE) De Groot et al. JCEM 2012, 2543–2565,

  27. Treatment:Choosing ATD • PTU is recommended as the first-line drug for treatment of hyperthyroidism during the first trimester of pregnancy • Monitoring liver function is recommended every 3–4 wkand encourage patients to promptly report any new symptoms of hepatitis level: C; evidence, poor (2QEEE) • MMI may also be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse response to PTU. De Groot et al. JCEM 2012, 2543–2565,

  28. Treatment:Choosing ATD • AACE recommend clinicians change treatment of patients from PTU to MMI after the completion of the first trimester. • After switching from PTU to MMI, thyroid function should be assessed after 2 wk and then at 2- to 4-wk intervals ( level: B; evidence, fair (1QQEE) . De Groot et al. JCEM 2012, 2543–2565,

  29. Aplasia cutis

  30. Thyroidectomy Indications : • patients with severe adverse reaction to ATD therapy • persistently high doses of ATD are required over 30mg/d of MMI or 450 mg/d of PTU • Non adherence to ATD. • Optimal timing of surgery: second trimaster level: C; evidence, fair (2QEEE) De Groot et al. JCEM 2012, 2543–2565,

  31. Subclinical hyperthyroidism • No evidence of benefit of treatment of subclinical hyperthyroidism during pregnancy • Treatment could potentially adversely affect fetal outcome level: C; evidence, fair (2QEEE) De Groot et al. JCEM 2012, 2543–2565,

  32. Key massages • Goal of treatment in maternal hyperthyroidism is achieving free T4 or FTI in upper limit normal • TFT should be carry out at least monthly and stepwise decreasing antithyroid drugs during pregnancy is recommended to achieve above goal • PTU is recommended in firs trimester • Methimazole is recommended in second and third trimester

  33. Hypothyroidism in pregnancy

  34. Epidemiology • The prevalence of overt hypothyroidism in pregnancy is estimated at 0.3 – 0.5 respectively . • Endemic iodine deficiency and chronic autoimmune thyroiditis in iodine repleted areas are the most common cause of hypothyroidism in pregnant women worldwide. Mandel et al. Clin Endocrinol Metab 2004 ; 18 : 213 -24

  35. Epidemiology • Thyroid autoantibodies are found in 5–15% of women during childbearing age. • Subclinical hypothyroidism occurs in 2–3% of pregnant women . DeVivo et al. Thyroid 2010 20:633–637

  36. Clinical manifestations • A high index of suspicion is therefore required, especially in women with a predisposition to thyroid disease such as a personal or family history of thyroid disease, the presence of goiter or the coexistence of other autoimmune disorders like type 1 diabetes. Expert Opin. Pharmacother. (2008) 9(13):2281-2293

  37. Complications

  38. Maternal complications Manissto etal.JCEM, 2013, 2725-2733

  39. Fetal complications

  40. JE Haddow et al., N Engl J Med.1999;341:529-555

  41. Maternal thyroid failure and average child IQ scores1 • The IQ scores of children whose mothers had untreated hypothyroidism during pregnancy were significantly lower than those of the control children. • IQ scores for children whose mothers were being treated for hypothyroidism during pregnancy were similar to those of the control children. Control Untreated (p = 0.005) Control, n = 124 Untreated hypothyroidism, n = 48 1. Adapted from: JE Haddow et al., N Engl J Med. 1999;341:529-555

  42. Other fetal complications Untreated maternal overt hypothyroidism is associated with low birthand more fetal and perinatal death Haddow et al. N Engl J Med 1999, :549–555

  43. Subclinical hypothyroidismduring pregnancy • Definition : Serum TSH concentration above the upper limit of the trimester-specific reference range with a normal free T4 or FTI • In the first trimester, the “normal” range is reduced to 0.1–2.5 mIU/liter . De Groot et al. JCEM 2012, 2543–2565,

  44. Subclinical hypothyroidismduring pregnancy • Women with gestational SCH have more preterm deliveries • Effect on long term neurological development in the offspring are controversial. Casey et al.ObstetGynecol 2005, 105:239–245

  45. Anti TPO positive euthyroid women