In 2009, the FDA published a warning on the use of propylthiouracil because of 32 reported cases of serious liver injury associated with its use (400,401). The average daily dose associated with liver failure was 300 mg, and liver failure was reported to occur anywhere from 6 days to 450 days after initiation of therapy (402). Traditionally PTU was the drug of choice to treat hyperthyroidism for the duration of pregnancy because it less readily crosses the placenta, and methimazole was associated with an increased risk of choanal atresia and aplasia cutis (403– 406). Because of the case reports of PTU-related liver failure and the increased risk of birth defects associated with methimazole use during embryogenesis, the FDA and the Endocrine Society recommend PTU never be used as first-line medical treatment of hyperthyroidism for nonpregnant patients. It is recommended that its use be limited to pregnant women during the first trimester; situations where surgery or radioactive iodine treatment are contraindicated, and individuals who have developed a toxic reaction to methimazole (400,402). The FDA recommends monitoring patients closely for signs and symptoms of liver injury while taking PTU.If liver injury is suspected, PTU should be promptly discontinued (400). The American Thyroid Association recommends an initial dose of 100 to 600 mg per day in three divided doses with a goal to maintain T4 in the upper limit of normal using the lowest possible dose. Minor reactions such as pruritus affect 3% to 5% of patients treated with thionamide therapy, and antihistamines may eliminate symptoms and allow continued use. Agranulocytosis is a rare and potentially fatal complication of PTU and methimazole therapy, and developing in 0.2% of women treated, and it mandates immediate discontinuation of the drug (403). Agranulocytosis most commonly presents with fever and a sore throat followed by sepsis; the occurrence of fever, sore throat, or a viral-like syndrome should prompt an urgent evaluation.
Methimazole is the first-line drug for the treatment of hyperthyroidism, except in the first trimester of pregnancy, as it has been shown to be more effective than PTU at controlling severe hyperthyroidism and is associated with higher adherence rates and less toxicity (407). The American Thyroid Associated recommends initial daily doses of 10 to 40 mg per day in a single dose. Like treatment with PTU, the goal is to maintain a free T4 level in the upper limits of normal using the lowest possible dose. Free T4 levels show improvement 4 weeks after therapy, and TSH levels take 6 to 8 weeks to normalize (403). Methimazole use in pregnancy is associated with an 18-fold risk of fetal choanal atresia compared with the general population (95% CI, 3–121) (408). Congenital aplasia cutis was associated with maternal use of methimazole during pregnancy; however, it is not known at this time whether the risk (0.03%) is greater than that seen in the general population (409).