Thyroid Disease in Pregnancy

1. Thyroid Disease in Pregnancy ChantarojanasiriT. ,MD.

2. OUTLINE • Normal physiology& changes during pregnancy • Hyperthyroid • Hypothyroid • Postpartum thyroid disease • Thyroid cancer • Euthyroid with autoimmune thyroid disease • Practice guidelines

5. 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. The rate-limiting step is iodide trapping • mediated by TSH. • nonpregnant state, 80 mg/d to 100 mg/d of iodine taken up • 20% of the intake is cleared by the thyroid gland; remainder renally

8. 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

9. 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

10. hCG TSH

11. 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

12. Hypothyroid;25% to 47% average dosage increase during pregnancy • increased serum thyroid stimulating hormone (TSH) and thyroglobulin concentrations, relative hypothyroxinemia, and occasional goiter formation • Esp. from area with borderline iodine sufficiency • associated with increase in thyroid gland size in 15%

13. EFFECTS OF PREGNANCY ON THYROID PHYSIOLOGY

15. 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 fTI are increased. • The RT3U that normally is decreased in pregnancy is increased in hyperthyroidism.

16. 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 (GET)

17. 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

18. Transient hyperthyroidism during pregnancy & gestational transient thyrotoxicity (GET) • 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

19. GET • 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

20. 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

21. subclinical hyperthyroidism • associated with osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis and thyroid failure. • not associated with adverse pregnancy outcomes • does not warrant treatment.

22. 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.

23. 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 antibodies • complications related to the duration and control of maternal hyperthyroidism • autoantibodies mimic TSH can cross the placenta and cause neonatal Graves’ disease

24. 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

25. 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

26. 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.

27. 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. Shane O. LeBeau, Endocrinol Metab Clin N Am 35 (2006) 117–136

28. 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

29. Guidelines for clinical management of maternalhyperthyroidism during pregnancy • 5. Consider thyroidectomy if persistently high doses of thionamide (PTU > 600 mg/d or MMI > 40 mg/d) are required,or if the patient cannot tolerate thionamide therapy. • 6. β-Adrenergic blocking agents and low doses of iodine may be used perioperatively to control hyperthyroid state. • 7. Check fetal cord blood at delivery for TSH and T4.

30. 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

31. 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.

32. 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.

33. 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

34. 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

35. Hypothyroidism in pregnancy • elevated serum TSH concentration:2.5% of pregnancies • In iodine-sufficient environment • Hashimoto’s thyroiditis • prior radioactive iodine treatment • surgical ablation of Graves’ disease • less common causes: overtreatment of hyperthyroidism with thionamides, transient hypothyroidism owing to postpartum thyroiditis, medications that alter the absorption or metabolism of levothyroxine, and pituitary/hypothalamic disease)

36. Hypothyroidism in pregnancy • diagnosis • Symptoms masked by the hypermetabolic state of pregnancy. • 20% to 30% overt hypothyroidism develop symptoms • weight gain, lethargy, decrease in exercise capacity, and intolerance to cold,constipation, hoarseness, hair loss, brittle nails, dry skin, goiter, or delay in the relaxation phase of the deep tendon reflexes • Elevated serum TSH concentration • Central hypothyroidism do not manifest an elevated serum TSH level

37. Hypothyroidism in pregnancy • Pregnancy outcome • depends on the severity of disease and adequacy of treatment • Gestational hypertension in overtly hypothyroid women (36%) vs subclinical disease (25%) or the general population (8%) • Overt hypothyroid vs subclinical disease, • increased use of cesarean section because of fetal distress • placental abruption, anemia, andpostpartum hemorrhage increased rates of miscarriage, preeclampsia,placental abruption, growth restriction, prematurity and stillbirths • fetuses are at risk for impaired neurologic development low-birth-weight neonates

38. Hypothyroidism in pregnancy • TSH can be elevated with or without suppressed levels of free T4. • antithyroid autoantibodies (eg, antithyroglobulin, antithyroid • peroxidase) are present • elevated creatine phosphokinase, cholesterol, and liver function tests • 5% to 8% prevalence of hypothyroidism in type I diabetes • mellitus and women who have type I diabetes have a 25% risk of developing postpartum thyroid dysfunction

39. Causes of hypothyroidism • Worldwide, the most common is iodine deficiency. • impaired neurologic development; severe mental retardation, deafness, • muteness, and pyramidal or extrapyramidal syndromes; • Hashimoto’s thyroiditis • Idiopathic hypothyroidism; atrophic thyroid gland • and absent antithyroid antibodies. • 131I treatment for Graves’ disease and thyroidectomy • Drugs interfere with the metabolism of thyroid hormones

40. Subclinical hypothyroidism • normal free T4 level • elevated TSH above the upper limit of reference range (4.5–10.0mIU/L) • thresholds based on gestational age. • TSH in the first half of pregnancy is 3.0 mIU/L • prevalence of subclinical hypothyroidism 2–5% • increased risk of placental abruption and preterm birth • important to monitor TSH and free T4 levels. • 2–5% progress to overt hypothyroidism each year

41. Isolated maternal hypothyroxinemia • normal TSH • free T4 below 0.86 ng/dl. • In the first half of pregnancy, • prevalence 1.3%. • not associated with adverse perinatal outcome

42. Guidelines for clinical management of maternalhypothyroidism during pregnancy • 1. Check serum TSH level as soon as pregnancy is confirmed. • 2. For newly diagnosed hypothyroid women, initial levothyroxine dosage is based on severity of hypothyroidism. For overt hypothyroidism, administer 2 mcg/kg/d. If TSH is < 10 mU/L, initial dose of 0.1 mg/d may be sufficient. • 3. For previously diagnosed hypothyroid women, monitor serum TSH every 3–4 weeks during first half of pregnancy and every 6 weeks thereafter. • 4. Adjust levothyroxine dosage to maintain serum TSH ≤2.5 mU/L. • 5. Monitor serum TSH and total T4 levels 3–4 weeks after every dosage adjustment. When levothyroxine dosage achieves equilibrium, resume monitoring TSH alone Shane O. LeBeau, Endocrinol Metab Clin N Am 35 (2006) 117–136

43. Treatment • 6. Levothyroxine ingestion should be separated from prenatal vitamins containing iron, iron and calcium supplements,and soy products by at least 4 hours to ensure adequate absorption. • 7. After delivery, reduce levothyroxine to prepregnancy dosage, and check serum TSH in 6 weeks • adjusting levothyroxine • 1. TSH < 10 mU/L, increase 0.05 mg/d. • 2. TSH =10–20 mU/L, increase 0.075 mg/d. • 3. TSH > 20 mU/L, increase 0.1 mg/d. • normal range for total T4 concentrations during pregnancy is 1.5 times the nonpregnant • iodine :prenatal vitamin 220 mg/day

44. 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

45. 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)

46. 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

47. 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.

48. 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

49. 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.

50. Thyroid cancer • Thyroid tumors ;most common endocrine neoplasms. • thyroid cancer accounts for 1% of all cancers. ¾ women; 1/2 reproductive years. • biopsy ,Serum TSH and free T4 levels,ultrasonography & Fine needle aspiration • Radionucleotide scanning is contraindicated during pregnancy • malignant or suspicious for papillary cancer, surgery at the earliest safe period • no evidence that pregnancy causes a reactivation of thyroid cancer or that exposure to radioactive iodine poses a risk to future pregnancies • maintained on thyroid replacement therapy with monitoring of TSH and free T4 levels every 8 weeks.