Autoimmune Thyroid Disease and Pregnancy

Background: Thyroid disorders are the second most common endocrinopathies found in pregnancy. Thyroid disorders are estimated to affect 0.2% of all pregnancies.

Autoimmune thyroid dysfunctions remain a common cause of both hyperthyroidism and hypothyroidism in pregnant women. Graves disease accounts for more than 85% of hyperthyroid cases, while Hashimoto thyroiditis remains the most common cause of hypothyroidism. In the postpartum period, postpartum thyroiditis (PPT) is reported to affect 4-10% of women. Interestingly, symptoms of autoimmune thyroid diseases tend to improve during pregnancy. A postpartum exacerbation is not uncommon, perhaps because of an alteration in the maternal immune system during pregnancy.

Pathophysiology: The defect that predisposes an individual to autoimmune thyroid disease is still unknown. Proposed mechanisms include a tissue-specific defect in suppressor T-cell activity, a genetically programmed presentation of a thyroid-specific antigen, and an idiotype-antiidiotype reaction. Regardless of the cause, the common outcome is the production of one or more types of autoantibodies.

Adams and Purves described the concept of Graves disease as autoimmune dysfunction of the thyroid gland. These investigators noted that the sera of patients with Graves disease contained a factor that stimulated the mouse thyroid and had a longer duration of action than thyrotropin, namely the long-acting thyroid stimulator. Further studies revealed that these long-acting thyroid stimulators are actually autoantibodies directed against the thyrotropin receptor. The activating version of the thyrotropin receptor is the thyroid-stimulating autoantibodies, which activate adenylate cyclase and stimulate thyroid function. Histologically, the thyroid glands of patients with Graves disease show follicular hypertrophy and hyperplasia.

Hashimoto thyroiditis is also known as goitrous chronic thyroiditis. Almost all of these patients have positive test results for the antithyroid peroxidase (anti-TPO) antibodies, autoantibodies against the thyroid peroxidase enzyme. Of these patients, 50-70% also have positive test results for antithyroglobulin antibodies. Extensive lymphocytic infiltration, follicular rupture, eosinophilia, varying degrees of hyperplasia, and fibrosis are the classic findings upon histologic examination.

Atrophic chronic thyroiditis is a rare autoimmune cause of hypothyroidism and is characterized by the presence of blocking autoantibodies to the thyrotropin receptors.

PPT is a variant of chronic autoimmune thyroiditis (Hashimoto thyroiditis). PTT is characterized by the presence of antimicrosomal antibodies. Histologic examination of thyroid glands affected by PPT shows destructive lymphocytic thyroiditis.

Frequency:

• In the US: Hyperthyroidism affects 2 in 1000 pregnancies. Graves disease accounts for 90-95% of these cases. Hypothyroidism affects 1 in 1600-2000 pregnancies. Hashimoto thyroiditis is the most common cause. Atrophic thyroiditis is less common. PPT affects 1 in 20 women in the postpartum period.

• Internationally: The reported range in frequency for PPT is wide. In Thailand, as few as 2 in 100 postpartum women are affected. On the other hand, some Canadian studies report a frequency of 2 in 10 postpartum women. These differences in frequency may be due to variation in diagnostic criteria, genetic factors, and differences in iodine consumption.

Mortality/Morbidity: Fetal and maternal outcomes are improved with normalization of thyroid function.

• Hyperthyroidism: Uncontrolled hyperthyroidism, especially in the second half of pregnancy, can lead to numerous complications. Maternal complications include miscarriage, infection, preeclampsia, preterm delivery, congestive heart failure (CHF), thyroid storm, and placental abruption. Fetal and neonatal complications include prematurity, size that is small for gestational age, intrauterine fetal death, toxemia, and fetal or neonatal thyrotoxicosis.

• Hypothyroidism: Maternal complications of untreated hypothyroidism include microcytic anemia, preeclampsia, placental abruption, postpartum hemorrhage, cardiac dysfunction, and miscarriage. Fetal or neonatal complications include prematurity, low birth weight, congenital anomalies, stillbirths, and poor neuropsychological development.

• Postpartum thyroiditis: Complications associated with PPT are maternal in nature, and depression is common. Permanent hypothyroidism occurs in as many as 30% of patients. These patients are also at high risk for recurrent PPT with subsequent pregnancies.

Sex:

• Autoimmune thyroid diseases occur more often in females than in males. The female-to-male ratio is 7:1.

Age:

• Autoimmune thyroid dysfunction most often affects women of reproductive age.

Treatment
Medical Care:

• Hyperthyroidism: The goal of treatment is to maintain clinical euthyroidism, with the mother's FT4 level in the high-normal range.

• Thioamide drugs (antithyroid drugs [ATDs]) are the first-line treatment in pregnancy. PTU, methimazole (MMI), and carbimazole (CMI) are the ATDs available in the United States. These drugs inhibit iodination of thyroglobulin and thyroglobulin synthesis by competing with iodine for the enzyme peroxidase. PTU and MMI or CMI are equally effective. PTU has not been associated with fetal scalp defects, aplastic cutis, or choanal atresia. Therefore, PTU tends to be the first choice in this class of drugs. ATDs should be maintained at the lowest dose needed to keep the mother's FT4 level in the high-normal range. Weight gain, pulse rate, FT4, and thyrotropin should be monitored monthly.

• Beta-blockers (eg, atenolol, nadolol, propranolol) are a valuable adjunct to ATDs. These drugs effectively alleviate symptoms of hypermetabolic states. With prolonged use, beta-blockers are associated with fetal morbidity; therefore, these drugs should only be used for a short period (ie, 2 wk), while waiting for the ATDs to take effect.
• Iodide decreases serum T4 and T3 levels by 30-50% in 10 days. Iodide is used in combination with ATDs and beta-blockers during the preoperative treatment of patients with hyperthyroidism. Iodide can also be used in the medical treatment of patients with thyroid storm. Fetal hypothyroidism resulting from placental passage is reported with prolonged use of iodide products; therefore, iodide use should be limited to less than 2 weeks.
• Radioactive iodine is contraindicated in pregnancy.

• Hypothyroidism: The goal of treatment is to normalize maternal thyrotropin levels.

• Thyroid hormone replacement is the treatment for patients with hypothyroidism. A full replacement dose should be instituted at the time of diagnosis.

• Patients with subclinical hypothyroidism should be treated to normalize maternal thyrotropin levels.
• In general, the thyroid hormone requirement increases approximately 50% during pregnancy; therefore, the thyrotropin level should be monitored closely. Serum thyrotropin levels should be measured 4-6 weeks after each change in T4 dosage.

Surgical Care:

• Hyperthyroidism

• Subtotal thyroidectomy, for reasons that remain unclear, induces remission in most patients with Graves disease. Surgery should be used as the second line of treatment in pregnant patients.

• Surgery is reserved for those patients who meet one of the following criteria:
  • High doses of ATDs (PTU >300 mg, MMI >20 mg) required
  • Inability to control clinical hyperthyroidism
  • Fetal hypothyroidism occurring at dose needed for maternal control
  • Inability to tolerate ATDs
  • Noncompliance
  • Suspected malignancy

• When surgery is needed, it should be performed during the second trimester.

• Hypothyroidism: No surgical care is recommended.

Consultations: Consultation with perinatologists and endocrinologists is recommended in difficult cases or in those with potential fetal compromise.

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antithyroid drugs -- Effective reversible treatment of hyperthyroidism. Consensus among experts is that ATDs should be first-line treatment for pregnant patients with hyperthyroidism. ATDs inhibit iodination of thyroid thyroglobulin and thyroglobulin synthesis by competing with iodine for peroxidase. PTU and MMI are available in the United States. PTU and MMI are equally effective. Both PTU and MMI cross the placenta and can cause fetal hypothyroidism and goiter.

Drug Name	Propylthiouracil -- Derivative of thiourea that inhibits organification of iodine by thyroid gland. Blocks oxidation of iodine in thyroid gland, thereby inhibiting thyroid hormone synthesis. Inhibits T4-to-T3 conversion (advantage over other agents). DOC in patients with hyperthyroidism during pregnancy. This is in response to reports of fetal aplasia cutis, a reversible scalp defect associated with MMI or CMI use. Taper gradually to minimum dose required to keep patient clinically euthyroid and to avoid fetal hypothyroidism.
Adult Dose	50-150 mg PO q8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Has anti–vitamin K activity; may potentiate activity of oral anticoagulants
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor PT during therapy; may cause hypoprothrombinemia and bleeding; once symptoms of hyperthyroidism resolve, lower maintenance dose if serum thyrotropin levels are elevated; associated with 1-5% risk of allergic reactions, including minor or major skin changes, arthralgias, metallic taste, lupuslike syndrome, fever, bronchospasm, ulcerations, and hepatitis

Drug Name	Methimazole (Tapazole) -- Inhibits thyroid hormone by blocking oxidation of iodine in thyroid gland; however, not known to inhibit peripheral conversion of thyroid hormone. Taper gradually to minimum dose required to keep patient clinically euthyroid and to avoid fetal hypothyroidism. Cases of fetal aplasia cutis reported.
Adult Dose	20-40 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Has anti–vitamin K activity; may potentiate activity of oral anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor PT during therapy; may cause hypoprothrombinemia and bleeding; once symptoms of hyperthyroidism resolve, presence of elevated serum thyrotropin indicates lower maintenance dose should be used

Drug Category: Iodides -- Inhibit release of stored thyroid hormones. Decrease serum T4 and T3 by 30-50% by the 10th day of treatment. Reserved for treatment of severe thyrotoxicosis or for use preoperatively in combination with ATDs and beta-blockers. Readily cross placenta by 12th week of gestation and are taken up readily by fetal thyroid. Long-term use can lead to fetal hypothyroidism and goiter. Generally recommended for no more than 2 wk in pregnant patients.

Drug Name	Iodide (SSKI, Pima) -- DOC, rapidly inhibits release of thyroid hormones via a direct effect on thyroid gland and inhibits synthesis of thyroid hormones. Also appears to attenuate cAMP-mediated effects of thyrotropin.
Adult Dose	1-5 gtt solution containing 1 g/mL (50-250 mg of iodide) bid for 10-14 d; 3 gtt SSKI q8h or sodium iodide IV 0.5 mg q12h for thyroid storm
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pulmonary edema, bronchitis, tuberculosis, hyperkalemia
Interactions	Increases lithium toxicity by producing additive hypothyroid effects; coadministration with potassium-sparing agents can lead to hyperkalemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Prolonged use may result in hypothyroidism; caution in renal failure and GI obstruction; large doses can lead to iodism (metallic taste, soreness of teeth, coryza, sneezing, eye irritation, headache, pulmonary edema, fatal eruptions); prolonged use in pregnancy can lead to fetal hypothyroidism

Drug Category: Thyroid hormones -- Several forms of thyroid hormones are commercially available, including levothyroxine, liothyronine, and liotrix. Levothyroxine is DOC for treatment of pregnant patients with hypothyroidism.

Drug Name	Levothyroxine (Synthroid) -- Levo isomer of T4. Once absorbed, T4 is deiodinated to T3 in extrathyroidal tissues. First choice in treatment of hypothyroidism during pregnancy because it mimics physiologic state. Measure thyrotropin q4wk and adjust dosage.
Adult Dose	0.1-0.15 mg/d PO or 2 mcg/kg actual weight/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncorrected adrenal insufficiency; acute MI
Interactions	Cholestyramine may decrease absorption; estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; effect of anticoagulants increased when coadministered; activity of some beta-blockers may decrease when hypothyroid patient is converted to a euthyroid state
Pregnancy	A - Safe in pregnancy
Precautions	Caution in angina pectoris or cardiovascular disease; monitor thyroid status periodically; skin reactions reported but are very rare

Drug Category: Beta-adrenergic blocking agents -- Valuable adjunct to ATDs. Effective for alleviating symptoms of hypermetabolic state (eg, palpitation, sweating, nervousness, tremor). Safe during pregnancy for immediate control of symptomatic thyrotoxicosis. Goal is to reduce maternal heart rate to <100>

Drug Name	Propranolol (Inderal) -- DOC in treating cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within minutes.
Adult Dose	20-40 mg PO q6-8h; adjust to keep maternal resting heart rate <100>
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncompensated CHF; bradycardia, Raynaud phenomenon, cardiogenic shock; AV conduction abnormalities
Interactions	Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase; potentiates peripheral vasoconstrictive effect of ergot
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely; caution in renal and hepatic impairment