1. Hyperthyroidism in Pregnancy
D. Wang

2. 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

3. Hyperthyroidism in Pregnancy
Incidence: occurs in 0.2% of pregnancies
Common causes:
Graves disease (95% of hyperthyroidism cases)
hCG-mediated hyperthyroidism (peaks at 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

4. 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)

5. 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 weeks gestation.

6. 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

7. 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

8. 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.

9. Treatment of Graves Disease
Recommendations for empiric therapy:
First trimester: Propylthiouracil (PTU) – mg 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 weeks gestation

10. 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.

11. 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.

12. 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