Graves Hyperthyroidism and Pregnancy: A Clinical Update

Komal Patil-Sisodia, MD; Jorge H. Mestman, MD


Endocr Pract. 2010;16(1):118-129. 

In This Article

Adverse Effects of Antithyroid Drugs

PTU and methimazole, both US Food and Drug Administration pregnancy category D drugs, are the 2 commercially available forms of thionamides in the United States. Both are equally effective at achieving euthyroidism in a similar time period, and both cross the placenta at comparable rates. Many controversies surround the use of these medications.[32] PTU has a higher incidence of hepatotoxicity,[33,34] whereas methimazole has been associated with aplasia cutis and choanal/esophageal atresia, commonly occurring with a cadre of other congenital defects that are known collectively as methimazole embryopathy.[35] A few isolated case reports and 2 small case series from registries in Europe and Sweden link methimazole use during the first trimester with choanal or esophageal atresia[35,36] and aplasia cutis. These defects have been reported alone, as well as part of an embryopathy that includes hearing loss, dysmorphic facial features, and developmental delay.[35,37] Embryopathies with PTU use have only been reported anecdotally, and there are no known reports of aplasia cutis. One report of choanal atresia in a PTU-exposed fetus has been published in the literature.[38] PTU is known to cause fulminant hepatic failure, with an overall incidence of 0.5% of patients treated with PTU and a higher incidence in women than in men. Assuming there are 3000 to 4000 cases of hyperthyroidism in pregnancy per year, 4 to 8 pregnant hyperthyroid women could be affected if treated with PTU.[39] A 25% mortality rate has been reported in fulminant hepatic failure caused by PTU. The incidence of PTU-induced liver failure cannot be predicted based on the PTU dosage, the age of the patient, or the duration of treatment.[34] Baseline liver function tests are not useful in monitoring patients for this rare, but life-threatening disorder. Until recently, PTU was considered the first-line treatment of hyperthyroidism in pregnancy,[40] although several reports have shown PTU and methimazole to be equally effective in achieving euthyroidism in pregnant women.[41,42] Given the paucity of new information regarding the prevalence of aplasia cutis with methimazole use or the consequences of in utero methimazole exposure in infants vs background Graves hyperthyroidism[43] and the higher rates of PTU-associated hepatic failure, the use of PTU during the first trimester followed by a change to methimazole in the second and third trimesters is now recommended (Fig. 2).[39] This recommendation remains controversial given that no positions have been taken by the medical societies.

Maternal adverse effects from these medications may affect 3% to 5% of patients,[32] most commonly in the form of skin rashes and pruritus (Table 4). Agranulocytosis is the most life-threatening complication associated with both medications with an incidence of 1 in 300 patients. It occurs within the first 12 weeks of treatment and is more frequently associated with higher dosages of both medications. Patients should be advised to discontinue medications and undergo immediate evaluation at the nearest emergency facility if they present with sore throat, fevers, malaise, or gingivitis. Migratory polyarthritis, lupus-like syndromes, and cholestatic jaundice are also rare complications of both medications.