Hyperthyroidism in Pregnancy D. Wang 1.2.15

Learning Objectives Describe the pathophysiology and common causes of hyperthyroidism in pregnancy Describe the evaluation, diagnosis and treatment of hyperthyroidism in pregnancy Identify the complications of untreated hyperthyroidism in pregnancy for mother and fetus Describe the effects of fetal and neonatal hyperthyroidism Prerequisites: THYROID PHYSIOLOGY IN PREGNANCY See also – for closely related topics HYPOTHYROIDISM IN PREGNANCY

Hyperthyroidism in Pregnancy Incidence: occurs in 0.2% of pregnancies Common causes: Graves disease (95% of hyperthyroidism cases) hCG-mediated hyperthyroidism (peaks at 10-12 weeks) “Gestational transient thyrotoxicosis” Associated with hyperemesis, multiple gestation, molar pregnancy Benign and self-limited, treat only for severe or prolonged symptoms Less common causes: Familial gestational hyperthyroidism Thyroiditis Toxic adenoma Toxic nodular goiter Overt hyperthyroidism: suppressed thyrotropin [TSH], elevated free thyroxine [T4] and/ortriiodothyronine [T3]. Overt hyperthyroidism (low TSH, high free T4/T3) is relatively uncommon in pregnancy, occurring in 0.1 to 0.4% of all pregnancies (UpToDate 2014) Graves’ disease: usually becomes less severe as pregnancy progresses hCG-mediated hyperthyroidism: may occur transiently in first half of pregnancy and less severe overall than Graves’ disease

Pathophysiology of Graves Disease Maternal antibodies (TSHR-Ab or TRAb) bind to thyrotropin (TSH) receptors on the thyroid gland causing release of T3 and T4, and reflex suppression of the pituitary Maternal risks of poor control thyroid storm, cardiac failure, severe pre-eclampsia Fetal risks of poor control SAB, preterm delivery, low birth weight Fetal/neonatal risks due to maternal antibodies Immune-mediated hypo- or hyperthyroidism in neonate Fetal thyrotoxicosis  tachycardia, IUGR, hydrops fetalis Risk persists despite h/o maternal thyroid ablation/excision, due to maternal antibodies crossing the placenta Overt hyperthyroidism: suppressed thyrotropin [TSH], elevated free thyroxine [T4] and/ortriiodothyronine [T3] (UpToDate 2014)

Graves Disease in Pregnancy Diagnosis Signs and symptoms: tachycardia, heat intolerance, anxiety, insomnia, weight loss, goiter, palpitations, frequent stools, hypertension, widened pulse pressure, lid lag, hoarseness, fine tremor, dry skin Graves’ specific findings: diffuse goiter, exophthalmos, pretibial myxedema Laboratory evaluation TSH levels are suppressed or undetectable (< 0.01 mU/L) Free T4 is usually elevated Free T3 doesn’t need to be checked unless patient has suppressed TSH with normal free T4 levels (T3 thyrotoxicosis is rare) Thyrotropin receptor antibody (TRAb), thyroid stimulating immunoglobulins (TSI) can be evaluated if diagnosis uncertain If clinical diagnosis is uncertain, consider measuring thyrotropin receptor antibody (TRAb or thyroid stimulating immunoglobulins) using second-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assays. Assays are positive in 95 percent of patients with Graves' disease (Up To Date 2014). Note: Use of radioiodine for diagnosis of thyroid disease (e.g. Graves vs. thyroiditis) is a ABSOLUTELY contraindicated in pregnancy due to risk of ablation of fetal thyroid tissue after 10-12 weeks gestation.

Management of Graves Disease Monitoring: Begin biweekly antepartum testing whenever diagnosed after ≥28 weeks and fetal growth scans q4 weeks Includes (iatrogenic) HYPOthyroid or euthyroid Graves patients Maternal antibodies still present  risk to fetus/neonate If testing suggests fetal thyrotoxicosis: Ultrasound to check for hydrops, fetal goiter If diagnosis uncertain, PUBS for fetal thyroid tests (rare) Check free T4 every 2-4 weeks Goal of therapy: maintain free T4 near or slightly above upper limit of normal throughout pregnancy, using lowest dose of thioamides to minimize fetal exposure Pharm notes Mechanism of action for thioamides: Actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines. Available thionamides: Propylthiouracil (PTU): less teratogenic than MMI, but increased risk of liver failure, justifying the transition to MMI in the second semester Methimazole (MMI): more teratogenic than PTU. Avoid in 1st trimester Carbimazole (CBZ): completely metabolized to MMI β- blockers: usage beyond 2-6 weeks not recommended due to increased risk of fetal growth retardation, hypoglycemia, respiratory depression, and bradycardia. Atenolol 25-50mg Qday or propranolol 20mg Q 6-8 hours. Can taper off once hyperthyroidism is controlled by thionamides (when PTU or MMI kicks in). (Up to Date 2014) Thyroidectomy is a surgical alternative for patients who cannot tolerate thionamides due to allergy or agranulocytosis. Pre-treat with beta blockers x7-10 days and iodine prior to surgery. 1Momotani 1986

Management of Graves Disease I131: Contraindicated in pregnancy can destroy fetal thyroid tissue (case reports of stillbirth1) Surgical therapy: relatively contraindicated thyroid is more vascular  increased risk Medical therapy: thioamides (PTU and MMI) inhibit the thyroid uptake of iodide and T4/T3 synthesis (PTU also inhibits the peripheral conversion of T4 to T3) Pharm notes Mechanism of action for thioamides: Actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines. Available thionamides: Propylthiouracil (PTU): less teratogenic than MMI, but increased risk of liver failure, justifying the transition to MMI in the second semester Methimazole (MMI): more teratogenic than PTU. Avoid in 1st trimester Carbimazole (CBZ): completely metabolized to MMI β- blockers: usage beyond 2-6 weeks not recommended due to increased risk of fetal growth retardation, hypoglycemia, respiratory depression, and bradycardia. Atenolol 25-50mg Qday or propranolol 20mg Q 6-8 hours. Can taper off once hyperthyroidism is controlled by thionamides (when PTU or MMI kicks in). (Up to Date 2014) Thyroidectomy is a surgical alternative for patients who cannot tolerate thionamides due to allergy or agranulocytosis. Pre-treat with beta blockers x7-10 days and iodine prior to surgery. 1Berg 2008

Treatment of Graves Disease Treatment varies by trimester in order to decrease fetal and maternal morbidity from medications Propylthiouracil (PTU) Crosses placenta less freely than Methimazole (MMI) BUT, rare but increased risk of maternal hepatotoxicity, relative to MMI MMI rare embyropathy (esophageal or chloanal atresia, aplasia cutis) Both drugs: Transient leukopenia in 10%, does NOT require therapy cessation Acute agranulocytosis Discontinue drug immediately NOT dose or treatment duration-related and very rare, so no routine lab monitoring; patients advised to stop drug and call for evaluation and CBC if they develop sore throat and/or fever Pharm notes Mechanism of action for thioamides: Actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines. Available thionamides: Propylthiouracil (PTU): less teratogenic than MMI, but increased risk of liver failure, justifying the transition to MMI in the second semester Methimazole (MMI): more teratogenic than PTU. Avoid in 1st trimester Carbimazole (CBZ): completely metabolized to MMI β- blockers: usage beyond 2-6 weeks not recommended due to increased risk of fetal growth retardation, hypoglycemia, respiratory depression, and bradycardia. Atenolol 25-50mg Qday or propranolol 20mg Q 6-8 hours. Can taper off once hyperthyroidism is controlled by thionamides (when PTU or MMI kicks in). (Up to Date 2014) Thyroidectomy is a surgical alternative for patients who cannot tolerate thionamides due to allergy or agranulocytosis. Pre-treat with beta blockers x7-10 days and iodine prior to surgery.

Treatment of Graves Disease Recommendations for empiric therapy: First trimester: Propylthiouracil (PTU) – 100-150mg PO q8h Second trimester: Methimazole (MMI) – 10-20mg PO q12h β- blockers (atenolol, propranolol) for severe tachycardia and tremor. Discontinue when thioamides begin working or after 2-6 weeks of use Pharm notes Mechanism of action for thionamides: Actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines. Available thionamides: Propylthiouracil (PTU): less teratogenic than MMI, but increased risk of liver failure, justifying the transition to MMI in the second semester Methimazole (MMI): more teratogenic than PTU. Avoid in 1st trimester Carbimazole (CBZ): completely metabolized to MMI β- blockers: usage beyond 2-6 weeks not recommended due to increased risk of fetal growth retardation, hypoglycemia, respiratory depression, and bradycardia. Atenolol 25-50mg Qday or propranolol 20mg Q 6-8 hours. Can taper off once hyperthyroidism is controlled by thionamides (when PTU or MMI kicks in). (Up to Date 2014) Radioactive iodine ablation: contraindicated as it can cause ablation of fetal thyroid tissue after 10-12 weeks gestation

Thyroid Storm in Pregnancy Life-threatening exacerbation of thyrotoxicosis precipitated by stress, labor, infection, preeclampsia, or C-section Incidence: 1% of pregnant patients with hyperthyroidism Signs and symptoms: fever, tachycardia, tremor, changes in mental status, nausea, vomiting, diarrhea Complications of untreated thyroid storm: shock, stupor, coma, maternal heart failure Treatment of thyroid storm (ACOG guidelines) *Provide supportive therapy with IV fluids, cooling blankets, and glucose. Treatment of Thyroid Storm in Pregnant Women 1. Propylthiouracil(PTU),600–800mgorally,stat, then 150–200 mg orally every 4–6 hours. If oral administration is not possible, use methimazole rectal suppositories. 2. Starting1–2 hours after PTUadministration, saturated solution of potassium iodide (SSKI), 2–5 drops orally every 8 hours, or sodium iodide, 0.5–1.0 g intravenously every 8 hours, or Lugol’s solution, 8 drops every 6 hours, or lithium carbonate, 300 mg orally every 6 hours. 3. Dexamethasone,2mgintravenouslyorintra- muscularly every 6 hours for four doses. 4. Propranolol, 20–80mgorallyevery4–6hours, or propranolol, 1–2 mg intravenously every 5 minutes for a total of 6 mg, then 1–10 mg intravenously every 4 hours. If the patient has a history of severe bronchospasm: Reserpine, 1–5 mg intramuscularly every 4–6 hours Guanethidine, 1mg/kg orally every 12 hours Diltiazem, 60 mg orally every 6–8 hours 5. Phenobarbital,30–60mgorallyevery6–8hours as needed for extreme restlessness.

Tx of Thyroid Storm in Pregnancy IV Hydration with D5 source, cooling measures, cardiac monitoring, O2 as needed PTU (1,000 mg PO loading dose; then 200 mg PO q6h) Propanolol for tachycardia (if safe given cardiac function) Steroids to inhibit peripheral conversion (Dexamethasone 2mg IV q6h x 4 OR hydrocortisone 100mg IV q8hrs x 3) Iodides 1-2 hours after PTU (SSKI 5 drops PO q8h OR NaI 500mg-1000mg IV q8h) Treatment of thyroid storm (ACOG guidelines) *Provide supportive therapy with IV fluids, cooling blankets, and glucose. Treatment of Thyroid Storm in Pregnant Women 1. Propylthiouracil(PTU),600–800mgorally,stat, then 150–200 mg orally every 4–6 hours. If oral administration is not possible, use methimazole rectal suppositories. 2. Starting1–2 hours after PTUadministration, saturated solution of potassium iodide (SSKI), 2–5 drops orally every 8 hours, or sodium iodide, 0.5–1.0 g intravenously every 8 hours, or Lugol’s solution, 8 drops every 6 hours, or lithium carbonate, 300 mg orally every 6 hours. 3. Dexamethasone,2mgintravenouslyorintra- muscularly every 6 hours for four doses. 4. Propranolol, 20–80mgorallyevery4–6hours, or propranolol, 1–2 mg intravenously every 5 minutes for a total of 6 mg, then 1–10 mg intravenously every 4 hours. If the patient has a history of severe bronchospasm: Reserpine, 1–5 mg intramuscularly every 4–6 hours Guanethidine, 1mg/kg orally every 12 hours Diltiazem, 60 mg orally every 6–8 hours 5. Phenobarbital,30–60mgorallyevery6–8hours as needed for extreme restlessness.

Sources ACOG Practice Bulletin Number 148, April 2015 UpToDate: Overview of thyroid disease in pregnancy UptoDate: Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes Momotani et al NEJM 1986;315:24-8 Berg et al Acta Onc 2008;47(1): 145