Hyperthyroid in Pregnancy

1. Hyperthyroid in Pregnancy Dr. n mohammadi Fellowship of fetal medicine

4. Normal physiology • The hypothalamic pituitary axis • Thyrotropin-releasing hormone (TRH) • Produced in a tonic fashion in the paraventricular nucleus of the hypothalamus. • TSH has an α and β subunit;β subunit confers specificity. • TSH secretion regulated by negative feedback from circulating thyroid hormone, dopamine, and somatostatin. • TSH then stimulates the thyroid gland to produce, as well as secrete, thyroxine(T4) and triiodothyronine (T3).

6. Physiologic adaptation during pregnancy • increase in thyroid-binding globulin • secondary to an estrogenic stimulation of TBG synthesis and reduced hepatic clearance of TBG ;two to threefold • levels of bound proteins, total thyroxine, and total triiodothyronine are increased and resin triiodothyronine uptake (RT3U) is decreased • begins early in the first trimester, plateaus during midgestation, and persists until shortly after delivery • decrease in its hepatic clearance,estrogen-induced sialylation • free T4 and T3 increase slightly during the first trimester in response to elevated hCG. decline to nadir in third trimester

7. human chorionic gonadotropin (hCG) • intrinsic thyrotropic activity • begins shortly after conception, peaks around gestational week 10,declines to a nadir by about week 20 • directly activate the TSH receptor • partial inhibition of the pituitary gland (by cross-reactivity of the α subunit) • transient decrease in TSH between Weeks 8 and 14 • mirrors the peak in hCG concentrations • 20% of normal women, TSH levels decrease to less than the lower limit of normal

8. hCG TSH

9. A decrease in basal TSH of 0.1 mU/L was observed for every 10,000 IU/L increment in hCG • reduction in plasma iodide • fetal :monodeiodinase types II and III in the placenta • increased maternal glomerular filtration rate-- increased renal clearance of iodide throughout pregnancy • transplacental passage of T4 and iodide and placental metabolism of iodothyronines • stimulate the maternal thyroid ; depleting the maternal circulation of thyroid hormone and its precursors

10. EFFECTS OF PREGNANCY ON THYROID PHYSIOLOGY

12. Screening for Thyroid Disease in Pregnancy A 24-year-old woman was just diagnosed withher first pregnancy. She enjoys good generalhealth. There is no h/o thyroid disease or Rx. Q: Should she have screening TFT? Thyroid 21:1081-1125, 2011

13. Screening for Thyroid Disease in Pregnancy Although the benefits of universal screening for thyroid dysfunction may not be justified at this time, selected screening for the following should be done: • Positive FHxthyroid disease • Goiter • TPOAb+ • Symptoms • Type 1 DM • Miscarriage • Other autoimmunedisease • Infertility • Morbid obesity • >30 years Thyroid 2011

14. TSH in Pregnancy A 28-year-old woman who is 6 weekspregnant has a routine serum TSHlevel of 4.1 mIU/L & FT4 1.3 ng/dL Q: Is this TSH normal?

15. Guidelines for Serum TSH During Pregnancy • Recommendation 1Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake,should be applied • Recommendation 2If trimester-specific reference ranges for TSH are not available in the laboratory, the following references ranges are recommend:1st trimester, 0.1-2.5 mIU/L; 2nd trimester,0.2-3.0 mIU/L; 3rd trimester, 0.3-3.0 mIU/L

16. Hyperthyroidism and pregnancy • 0.2% of pregnancies • prevalence 0.1% to 0.4%, with 85% Graves’ disease • Single toxic adenoma, multinodular toxic goiter, and subacute thyroiditis • gestational trophoblastic disease,viral thyroiditis and tumors of the pituitary gland or ovary (struma ovarii) • TSH is depressed and fT4 and fT3 are increased. • The RT3U that normally is decreased in pregnancy is increased in hyperthyroidism.

17. Hyperthyroidism and pregnancy • serum TSH value <0.01 mU/L and also a high serum free T4 value • may be difficult to determine the cause • thyroid radionuclide imaging is contraindicated in pregnant women. • Measurement of thyrotropin receptor antibody (thyroid stimulating immunoglobulins)  Graves' disease during pregnancy • transient hyperthyroidism in hyperemesis gravidarum and gestational transient thyrotoxicity (GTT)

19. Hyperthyroid manifestations • Nonspecific symptoms; • _Tachycardia • _Heat intolerance • _Increased perspiration • Additional symptoms: • _Anxiety • _Hand tremor • _Weigh loss despite a normal or increased appetite

20. Specific findings: • Goiter • ophthalmopathy

21. Hyperthyroidism and pregnancy • Severe maternal hyperthyroidism • increased risk of stillbirth • preterm delivery • intrauterine growth restriction • Preeclampsia • heart failure • spontaneous abortion • Fetal thyroid hyperfunction or hypofunction caused by TSHRAbs • Fetal goiter from excessive antithyroid drug treatment • Neonatal thyrotoxicosis • Increased perinatal and maternal mortality • Decreased IQ of offspring because of excessive use of antithyroid drugs

22. Transient hyperthyroidism during pregnancy & gestational transient thyrotoxicity (GTT) • hyperemesis gravidarum • severe nausea and vomiting leading to a 5% loss of body weight, dehydration, and ketosis. • absence of goiter and ophthalmopathy, and absence of the common symptoms and signs of hyperthyroidism • higher serum hCG and estradiol concentrations • 60% have a subnormal serum TSH level (< 0.4 mU/L),50% have an elevated serum free T4 concentration • Severity positively correlated with maternal free T4 levels but not to thyroid function. • 12% elevated free T3 index • believed to be related to hCG stimulation of the thyroid gland • Normalization of T4 levels by midgestation. • Treatment is supportive care

23. GTT • first trimester • related to hCG stimulation of the thyroid gland • symptoms of hyperthyroidism and elevated free T4 levels. • The thyroid gland usually is not enlarged • resolution of symptoms parallels the decline in hCG levels • usually resolves spontaneously by 20 weeks’ gestation • beyond 20 weeks,repeat evaluation for other causes

24. Trophoblastic hyperthyroidism • hydatidiform mole (molar pregnancy) & choriocarcinoma. • high serum hCG concentrations and abnormal hCG isoforms • 55 to 60 percent had clinically evident hyperthyroidism • normal thyroid gland and few symptoms of thyroid hormone excess. • some :findings of hyperthyroidism and a diffuse goiter • ophthalmopathy is not present • Nausea and vomiting may predominate

25. Trophoblastic hyperthyroidisem • Women with symtomatic moderate to severe hyperthyroidisem due to trophoblastic diseases require treatment. • This include women with total T4 and total T3> 1.5 times the upper limit of nonpregnant women, require antithyroid therapy.

26. subclinical hyperthyroidism • Low TSH and normal free T4. • associated with osteoporosis cardiovascular morbidity, and progression to overt thyrotoxicosis and thyroid failure. • not associated with adverse pregnancy outcomes • does not warrant treatment.

27. Graves’ disease • 95% of thyrotoxicosis during pregnancy. • activity level fluctuate during gestation, with • exacerbation during the first trimester • gradual improvement during the latter half. • exacerbation shortly after delivery • clinicalscenarios. • stable Graves’ disease receiving thionamidetherapy with exacerbation during early pregnancy. • in remission with a relapse of disease. • without prior history diagnosed with Graves’ disease de novo duringpregnancy.

28. Graves’ disease • Diagnosis • difficult :hypermetabolic symptoms in normal pregnancy • thyroid examination: goiter (with or without bruit) • suppressed serum TSH level and usually elevated free and total T4 serum concentrations. • TSH receptor antibodi • autoantibodies mimic TSH can cross the placenta and cause neonatal Graves’ disease

29. Graves’ disease • Pregnancy outcome • preterm labor • untreated (88%)/partially treated(25%) /adequately treated (8%) [ • preeclampsia • untreated twice • stillbirth • untreated (50%) /partially treated (16%) /adequately treated (0%) • small for gestational age • congenital malformations unrelated to thionamide therapy • Mother may have thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII), • cause transient neonatal hypothyroidism • fetal bradycardia, goiter,and growth restriction

30. Graves’ disease • Neonatal thyrotoxicosis : • 1% of infants • occur in euthyroid mother or has had surgical or radioactive 131I treatments before pregnancy • fetal ultrasound to exclude evidence of fetal thyrotoxicosis (eg, an anterior fetal neck mass) or fetal tachycardia. • fetal goiter, advanced bone age, poor growth, and craniosynostosis, Cardiac failure and hydrops • Fetal blood sampling — Fetal blood for thyroid function tests by percutaneous umbilical vein sampling after 20 weeks of gestation • High maternal TSH receptor-stimulating antibody levels Fetal signs suggestive of thyroid disease History of a prior baby with hyperthyroidism

31. Thyroid storm • obstetric emergency • extreme metabolic state • 10% of pregnant women with hyperthyroidism • high risk of maternal cardiac failure. • fever, change in mental status, seizures, nausea, diarrhea, and cardiac arrhythmias. • inciting event (eg, infection, surgery, labor/delivery) and a source of infection • treatment immediately, even if serum free T4, free T3, and TSH levels are not known. • untreated thyroid storm can be shock, stupor, and coma.

32. Guidelines for clinical management of maternalhyperthyroidism during pregnancy • 1. Use the lowest dosage of thionamide (preferably PTU) to maintain maternal total T4 concentrations in the upper one third of normal to slightly elevated range for pregnancy. • Normal range of total T4 during pregnancy is estimated to be 1.5 times the nonpregnant state • 2. Monitor maternal total T4 serum concentration every 2–4 weeks, and titrate thionamide as necessary. • Monitoring serum TSH may become useful later.

33. Guidelines for clinical management of maternalhyperthyroidism during pregnancy • 3. Measure TSH receptor antibodies (thyroid-stimulating immunoglobulins or TSH receptor binding inhibitory immunoglobulins) at 26–28 weeks to assess risk of fetal/neonatal hyperthyroidism. • TSH receptor antibody measurement is crucial in hypothyroid levothyroxine-treated women with a prior history of Graves’ disease, who do not appear thyrotoxic. • 4. Perform fetal ultrasound at weeks 26–28 to assess potential fetal response to thionamide treatment and effect of TSH receptor antibodies on fetal thyroid function

34. Treatment Thionamides propylthiouracil (PTU) and methimazole(MMI) Both cross the placenta with equal transfer kinetics. Both can cause fetal goiter and hypothyroidism, usually mild and transient & dose-dependent median time to normalization of maternal thyroid function 7 weeks with PTU and 8 weeks with MMI PTU more highly bound to albumin theorize that MMI crosses the placenta in higher concentrations

35. Treatment Thionamides maternal :rash rare birth defects in MMI: aplasia cutis, choanal atresia,esophageal atresia, and minor dysmorphic features Low thyroid function at birth ½ neonates whose mothers received PTU or MMI and had serum T4 concentrations within the normal (non-pregnant) range normal IQ scores Graves’ disease may ameliorate thionamide discontinued in 30% during the final weeks fall in serum TSH receptor-stimulating antibody concentrations and a rise in TSH receptor-blocking antibodies. Graves' hyperthyroidism can worsen postpartum do not recommend the use of T4 with thionamide therapy during pregnancy.

36. Treatment β-Adrenergic blockers weaned as soon as the hyperthyroidism is controlled occasional cases of neonatal growth restriction, hypoglycemia, respiratory depression, and bradycardia increased frequency of first-trimester miscarriages avoiding in the first trimester Iodides past reports of neonatal hypothyroidism after exposure to iodine low-dose potassium iodide may be considered Preparation for thyroidectomy thionamide-intolerant patients refusing surgery.

37. Treatment Surgery Subtotal thyroidectomy : persistently high dosages of thionamides (PTU > 600 mg/d, MMI > 40 mg/d) are required to control maternal disease allergic or intolerant of both thionamides noncompliant with medical therapy compressive symptoms second trimester, before gestational week 24 prepared with a β-adrenergic blocking agent and a 10- to 14-day course of potassium iodide

38. Treatment Radioactive iodine therapy contraindicated fetal thyroid gland begins to concentrate iodine after gestational week 10, Fetal thyroid tissue is present by 10 to 12 weeks predisposing to congenital hypothyroidism Nursing Breast feeding in mothers taking PTU or MMI is safe Thyroid function in newborn infants is unaffected PTU is preferred because it is less concentrated in breast milk

39. Up to date_ATA • Suggest that PTU use be limited to first trimester only. • In the second trimester,switching from PTU to MMI • Initial lowest dose: PTU 50 mg two or three times daily and MMI 5 to 10 mg daily.

40. PTU associated liver failure: • Sudden onset- rapidly progressive • Routine monitoring of LFT is not recommended. • Malaise weakness nausea vomiting jundice dark urine light-colored stools.

41. A 32-year-old woman pregnant 10 weeks presents with nausea, vomiting, and a 2 kg weight loss; her first pregnancy 2 years earlier was uncomplicated On exam she is dehydrated, euthyroid, without a goiter and has normal eyes TSH 0.01 (<2.5) FT4 2.1 (0.8-1.8) FT4I 20 (5-12) Q: Does she require antithyroid Rx?

42. Hyperthyroidism & PregnancyConclusions • Hyperemesis gravidarum is HCG-induced, reversible, and dosent requires ATD. • Measure TSH receptor Ab (TRAb),TBII assay • and TOTAL T3 to distinguish from Graves’ disease.

43. Hyperthyroidism & Pregnancy • Recommendation 22When serum TSH is suppressed (<0.1) inthe 1st trimester, FT4 should be obtained;TT3 & TRAb may also be helpful • Recommendation 26ATDs are not recommended for Rx of gestational hyperthyroidism

44. Hyperthyroidism & Pregnancy A 32-year-old woman is 8 weeks pregnant; she reports palpitations, anxiety, heat intolerance and an 8 lb weight loss for 6 months On exam she is nervous, slightly hyperthyroid, has lid lag, and thyroid is x2 enlarged TSH 0.01FT4 2.8 FT4I 16 (5-12)TRAb 75% (<16%) Q: How do you manage?

45. Postpartum thyroid disease • Postpartum thyroiditis • Dx: documenting abnormal TSH (elevated or suppressed) levels during the first year postpartum in the absence of positive TSI or a toxic nodule • hypo- or hyperthyroidism • classic presentation : • transient hyperthyroid phase that occurs 6 weeks to 6 months postpartum • followed by a hypothyroid phase that lasts for up to 1 year postpartum

46. Postpartum thyroiditis • autoimmune disorder with a self-limited hyperthyroid phase • within one year after parturition. • Presentations • Transient hyperthyroidism alone • Transient hypothyroidism alone • Transient hyperthyroidism followed by hypothyroidism and then recovery. • can also occur after spontaneous or induced abortion • 3 to 16 percent • higher, up to 25 percent, in women with type 1 diabetes mellitus ,and in women with positive antithyroid antibodies (normal thyroid function)

47. Postpartum thyroiditis • like painless thyroiditis • variant form of chronic autoimmune thyroiditis (Hashimoto's thyroiditis). • high serum concentrations of anti-peroxidase antibodies • many eventually become hypothyroid or have a goiter • high serum antithyroid antibody concentrations early in pregnancy • decline later (as immunologic tolerance increases during pregnancy) • rise again after delivery • subclinical thyroid autoimmune disease early in pregnancy and soon after • Progression to permanent hypothyroidism • related to higher TSH concentrations and the antiperoxidase antibody titer • maternal age and female sex of the infant • Postpartum thyroiditis is likely to recur after subsequent pregnancies

48. distinguished from Graves' hyperthyroidism, • hyperthyroidism in postpartum thyroiditis is usually mild (both clinically and biochemically), • thyroid enlargement is minimal • Graves' ophthalmopathy is absent. • by reevaluation in three to four weeks: postpartum thyroiditis improved • lymphocytic hypophysitis, • TSH normal or low, low free T4 • postpartum thyroiditis, TSH elevated with decreased FT4.

49. Postpartum thyroiditis • antithyroids :no role. • Hypothyroid :may require treatment and some • significant rate of residual hypothyroidism • Recommend:maintain thyroxine until childbearing is complete, with an attempt to wean off medication 1 year after the last delivery • Postpartum--signs/symptoms of thyroid dysfunction • symptoms mimic normal postpartum changes • TSH, free T4, and antithyroid antibodies levels • postpartum depression and postpartum thyroiditis

50. Postpartum Graves’ disease • 60% Graves’ disease in the reproductive years; postpartum onset • euthyroid patients with Graves’ disease with TSI • increased risk of developing recurrent Graves’ disease if antithyroid medication was withheld • TSIs differentiate postpartum Graves’ disease from postpartum thyroiditis with a hyperthyroid component.