Hyperthyroidism and Pregnancy
1. What every clinician should know
Overt hyperthyroidism complicates approximately2/1000 of pregnancies. Pregnant women with hyperthyroidism are at increased risk for spontaneous pregnancy loss, congestive heart failure, thyroid storm, preterm birth, preeclampsia, fetal growth restriction, and associated increased perinatal morbidity and mortality.
The most common cause of overt hyperthyroidism is Graves’ disease, an organ-specific autoimmune process whereby thyroid-stimulating autoantibodies attach to and activate thyroid-stimulating hormone (TSH) receptors. In pregnant women with a history of Graves’ disease, thyroid stimulating antibody activity may actually decline, leading to temporary “remission” during pregnancy. Other causes of overt hyperthyroidism include a functioning adenoma or toxic nodular goiter, thyroiditis or excessive thyroid hormone intake/supplementation.
2. Diagnosis and differential diagnosis
Clinical features of hyperthyroidism are often confused with those typical of pregnancy. Suggestive complaints include nervousness, heat intolerance, palpitations, thyromegaly, failure to gain weight or weight loss, and exophthalmos. Although nausea is common during early pregnancy, the occurrence of hyperemesis gravidarum together with weight loss can signify overt hyperthyroidism. Thyroid testing may be beneficial in these circumstances. Otherwise, routine thyroid testing in women with hyperemesis gravidarum is not recommended.
The diagnosis of overt hyperthyroidism can be reliably made by evaluating serum TSH and free-T4. In women with a depressed serum TSH level (less than 0.45 mIU/L), clinical hyperthyroidism is confirmed by an elevation in fT4 (greater than 1.8 ng/dL) concentration. However, one must consider the impact of gestational age on measurement of TSH. For example, the 2.5th percentile for TSH during the first half of pregnancy may fall below 0.1 mU/L (see Figure 1). There is minimal effect of pregnancy on maternal thyroxine levels so use of nonpregnant fT4 thresholds is still recommended (0.7-1.8 ng/dL).
Rarely, symptomatic hyperthyroidism is caused by an abnormally high serum T3 in women with a normal free-T4 . In women with depressed TSH yet normal free-T4, evaluation of free-T3 or the T3 index can help explain the presence of hypermetabolic symptoms. However, definitive serum T3 thresholds for initiating therapy have not been established; therefore, therapy should probably be reserved for women with hypermetabolic symptoms plus significantly elevated serum T3 levels.
Gestational transient thyrotoxicosis
There is a unique form of hyperthyroidism associated with pregnancy called Gestational transient thyrotoxicosis (GTT). It is typically associated with hyperemesis gravidarum and can be due to high levels of hCG resulting from molar pregnancy. These high hCG levels lead to TSH receptor stimulation and temporary hyperthyroidism. Women with GTT are rarely symptomatic and treatment with anti-thyroxine drugs has not been shown to be beneficial. Importantly, gestational transient thyrotoxicosis has not been associated with poor pregnancy outcomes.
Subclinical hyperthyroidism is defined as a serum TSH concentration below the statistically defined lower limit of the reference range when serum free-T4 and free-T3 concentrations are within their reference range. Subclinical hyperthyroidism affects 1.7% of pregnant women and is now more frequently diagnosed with the use of extremely sensitive, third-generation serum TSH assays.
Its prevalence is higher in iodine-insufficient areas and increases with age. In non-pregnant women beyond reproductive age, subclinical hyperthyroidism has been reported to have long-term adverse sequelae that include osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis or thyroid failure. However, during pregnancy the diagnosis of subclinical hyperthyroidism has not been found to be associated with any adverse outcomes. In fact, subclinical hyperthyroidism may even have a protective effect against development of hypertension during pregnancy.
At present there is no convincing evidence that subclinical hyperthyroidism should be treated in nonpregnant individuals. Therefore, treatment during pregnancy seems especially unwarranted since maternal antithyroid drugs cross the placenta.
Treatment of hyperthyroid women to achieve adequate metabolic control has been associated with improved pregnancy outcome. Thyrotoxicosis during pregnancy can nearly always be controlled by thioamide drugs. Some clinicians prefer propylthiouracil (PTU) because it partially inhibits the conversion of T4 to T3 and crosses the placenta less readily than methimazole.
Although not proven, methimazole used in early pregnancy has been associated with esophageal and choanal atresia as well as aplasia cutis in the fetus. Recently, the Food and Drug Administration issued a warning in response to reports of serious liver injury associated with the use of PTU in adult and pediatric patients. This has prompted several endocrinologic organizations to recommend converting women from PTU to methimazole after the first trimester. Importantly, the impact of switching thioamide drugs during pregnancy on outcomes has not been evaluated.
Transient leukopenia occurs in about 10% of pregnant women treated with thioamides but usually does not require cessation of therapy. In approximately 0.2% of women, agranulocytosis develops suddenly and mandates discontinuation of the drug. Agranulocytosis is not dose related, and because of its acute onset, serial leukocyte counts during treatment have not been helpful in prevention. Therefore, women given thioamide drugs should discontinue medication immediately if they develop a fever or sore throat until complete evaluation for agranulocytosis can be performed.
The dose of thioamide is empirical. In nonpregnant women, the American Thyroid Association recommends an initial daily dose of 100-600 mg for PTU or 10-40 mg for methimazole. The goal of treatment during pregnancy is to maintain free-T4 in the upper normal range using the lowest possible dose of thioamide (see Figure 2). Improvement in free-T4 levels are generally seen in 4 weeks and the median time to normalization of the TSH concentration is 6-8 weeks.
Importantly, caution against overtreatment is recommended as it may result in maternal or fetal hypothyroidism. Serial ultrasound assessment of fetal thyroid size to assist in management of pregnant women taking thioamide drugs has been reported. However, routine ultrasonic evaluation of the fetal thyroid is currently not recommended. Evaluation of TSH receptor antibodies also has been shown to be helpful in assessing women with Grave’s disease and has been associated with delivery of an infant with hypothyroidism.
There are other alternatives for treatment of overt hyperthyroidism but they are rarely undertaken during pregnancy. For example, thyroidectomy is typically reserved for treatment outside of pregnancy. However, occasionally women who cannot adhere to medical therapy or in whom therapy is toxic may benefit from surgical management. Ablative radioactive iodine is contraindicated in pregnancy as it can destroy the fetal thyroid. It has been recommended that women avoid pregnancy for a period of 6 months after radioablative therapy.
Thyroid storm/thyrotoxic heart failure
Thyroid storm is an acute, life-threatening exacerbation of thyrotoxicosis. The classic findings are fever, tachycardia, tremor, nausea, vomiting, diarrhea, dehydration, and delirium or coma. Thyroid storm is rare in pregnancy and its diagnosis is based entirely on clinical grounds in women with laboratory tests indicative of overt hyperthyroidism. Heart failure due to cardiomyopathy from excessive thyroxine in women with uncontrolled hyperthyroidism is more common in pregnant women
Treatment of thyroid storm or thyrotoxic heart failure is similar. They both should be treated as medical emergencies in an intensive care setting. Specific treatment consists of 1g of PTU given orally or crushed and placed through a nasogastric tube. This drug is continued in 200-mg doses every 6 hours. An hour after initial PTU dosing, iodide is given to inhibit thyroid release of T3 and T4. It is given every 8 hours as 500-1000 mg of intravenous sodium iodide; or it can be given orally as five drops of supersaturated solution of potassium iodide (SSKI) or as 10 drops of oral Lugol solution every 8 hours. If there is a history of iodine-induced anaphylaxis, lithium carbonate, 300 mg every 6 hours, is given instead.
Most authorities also recommend dexamethasone be given intravenously as 2 mg every 6 hours for four doses to further block peripheral conversion of T4 to T3. Treatment with a β-blocker to control tachycardia is usually reserved for heart rates of 120 beats per minute or higher. Propranolol, labetalol and esmolol have all been used successfully in pregnancy.
5. Prognosis and Outcome
Women with Graves’ disease should be followed closely after delivery because recurrence or aggravation of symptoms is not uncommon in the first few months postpartum. Most asymptomatic women should have a TSH and free-T4 performed approximately 6 weeks postpartum. Both PTU and methimazole are excreted in breast milk but PTU is largely protein bound and does not seem to pose a significant risk to the breastfed infant.
Methimazole has been found in breastfed infants of treated women in amounts sufficient to cause thyroid dysfunction. However, at low doses (10-20 mg/day) it does not appear to pose a major risk to the nursing infant. The American Academy of Pediatricians considers both acceptable in breast feeding mothers.
There are two recognized clinical phases of postpartum thyroiditis. Between 1 and 4 months after delivery, approximately 4% of all women develop transient thyrotoxicosis from excessive release of thyroid hormone from glandular disruption. The onset is abrupt, and a small, painless goiter is commonly found. Fatigue and palpitations are the most common complaints in women with early postpartum thyroiditis. Antithyroid medications such as thioamides are typically ineffective and approximately two thirds of these women return to a euthyroid state.
However, if symptoms are severe a β-blocker may be given. Between 4 and 8 months postpartum, 2-5% of women develop hypothyroidism. Importantly, hypothyroidism can even develop within one month of the onset of thyroiditis. Thyromegaly and other symptoms are common and more prominent than during the thyrotoxic phase. Thyroxine replacement is recommended for at least 6-12 months. Most women identified with postpartum thyroiditis will return to the euthyroid state within 12 months of delivery. Women who experience either type of postpartum thyroiditis have about a 30% risk of developing permanent hypothyroidism.
6. What is the evidence for specific management and treatment recommendations
Casey, BM, Leveno, KJ. “Thyroid disease in pregnancy”. Obstet Gynecol. vol. 108. 2006. pp. 1283-92.
Casey, BM, Dashe, JS, Wells, CE, McIntire, DD, Leveno, KJ. “Subclinical Hyperthyroidism and Pregnancy Outcomes”. Obstet Gynecol. vol. 107. 2006. pp. 337-41.
Brent, GA. “Graves’ disease”. N Engl J Med. vol. 358. 2008. pp. 2594
DeGroot, L, Abalovich, M, Alexander, EK. “Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 97. 2012. pp. 2543
Stagnaro-Green, A. “Approach to the patient with postpartum thyroiditis”. J Clin Endocrinol Metab. vol. 97. 2012. pp. 334
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- Hyperthyroidism and Pregnancy
- 1. What every clinician should know
- 2. Diagnosis and differential diagnosis
- 3. Management
- 5. Prognosis and Outcome
- 6. What is the evidence for specific management and treatment recommendations