Teratogen update: antithyroid drugs-methimazole, carbimazole, and propylthiouracil.

Thyrotoxicosis occurs in about 0.2% of pregnancies and is caused most frequently by Graves disease (Burrow, ’85; Kriplani et al., ’94). Graves disease is an autoimmune disorder characterized by the production of antibodies, immunoglobulins of the IgG class, directed against thyroid stimulating hormone (TSH) receptors (Shoenfeld and Schwartz, ’84). This results in the excess production of thyroid hormones. Because IgG antibodies pass through the human placenta, their transfer can induce stimulation of the fetal thyroid gland causing fetal hyperthyroidism (Hollingsworth, ’83). Thyrotoxic fetuses have a high risk for prematurity, intrauterine growth retardation, craniostenosis, cardiac failure, fetal hydrops, and intrauterine death (Treadwell et al., ’96; Zimmerman, ’99). This is apparently unrelated to the status of maternal thyroid function and effectiveness of treatment (Hollingsworth, ’83; Porreco and Bloch, ’90). Antithyroid drugs, which interfere with the synthesis of thyroid hormones, are the treatment of choice for thyrotoxicosis in pregnancy. Propylthiouracil (PTU), methimazole (MMI) and carbimazole (CMZ) are thioureylenes, which belong to the family of thioamides. The antithyroid compounds currently used in the United States are PTU and MMI. In the United Kingdom and Europe, CMZ, a carboxy derivative of MMI, is available, and its antithyroid action is due to its conversion to MMI after absorption. Although both PTU and MMI cross the placenta, MMI was originally reported to have a three times greater placental transfer than PTU (Marchant et al., ’77). PTU is therefore preferred over MMI because of its lower transplacental passage (Farwell and Braverman, ’96). It was recently suggested, however, that both drugs have similar kinetics of placental transfer (Mortimer et al., ’97). All antithyroid drugs may inhibit fetal thyroid function causing fetal hypothyroidism. This is usually transient with a return to the euthyroid state within several days or weeks after birth. (Kriplani et al., ’94; Wing et al., ’94; Vanderpump et al., ’96;). For that reason, and because of the transplacental passage of maternal antithyroid antibodies, it may be important to assess fetal thyroid function in treated mothers with Graves disease either by Doppler echography or, in selected cases, by fetal blood sampling (Porreco and Bloch, ’90; Lutton et al., ’97). Fetal hyperthyroidism can be treated by administration of PTU to the mother (Wallace et al., ’95; Treadwell et al., ’96). Infants of mothers with Graves disease who had been treated with antithyroid drugs may have hypothyroidism (due to drug transfer) or hyperthyroidism (due to the transfer of antibodies). It is therefore important to assess the thyroid function of each neonate born to a treated hyperthyroid mother, especially if thyroid enlargement is observed by ultrasonography (Brunner and Dellinger, ’97; Momotani et al., ’97; Zimmerman, ’99). This update will review the use of antithyroid drugs during pregnancy addressing the risk of congenital anomalies. Special attention will be given to the possible associations between in utero exposure to MMI and aplasia cutis congenita and a spectrum of congenital anomalies including choanal atresia. The risk of fetal goiter after treatment with all antithyroid drugs, and possible neurodevelopmental toxicity will also be discussed.