ABSTRACT
QUESTION I have a 33-year-old patient with hyperthyroidism who is 6 weeks pregnant. Her thyroid function is well controlled with a 5-mg dose of methimazole 3 times daily. She was initially treated with propylthiouracil but was switched to methimazole owing to urticaria. I have heard about birth defects in infants whose mothers used methimazole during pregnancy. How safe is it?
ANSWER In North America, propylthiouracil has been the drug of choice for hyperthyroidism during pregnancy. Methimazole is widely used in Europe, South America, and Asia, and is an alternative for patients who cannot tolerate propylthiouracil. Some case reports raised concern about fetal toxicity from methimazole, which is reportedly characterized by aplasia cutis, esophageal atresia, choanal atresia, facial abnormalities, and mental retardation. However, causality is unclear and the overall risk of congenital abnormalities in infants exposed to methimazole in utero was not higher than in those exposed to nonteratogenic drugs in cohort studies. It is important for a pregnant woman to continue methimazole, if necessary, because uncontrolled hyperthyroidism increases the risk of complications such as preterm labour and low birth weight.
Hyperthyroidism occurs in 1 to 2 of every 1000 pregnant women.1 The most common cause of hyper-thyroidism (80% to 85%) is Graves disease. Other causes include functioning adenoma, thyroiditis, and excessive thyroid hormone intake. Clinical practice guidelines for the management of hyperthyroidism during pregnancy have been developed by academic societies, including the Endocrine Society, American Association of Clinical Endocrinologists, and American College of Obstetricians and Gynecologists.2–4
Hyperthyroidism caused by Graves disease tends to get worse during the first trimester, improve later in pregnancy, and get worse again after delivery. Placental human chorionic gonadotropin is structurally similar to thyroid-stimulating hormone (TSH), and the increase in human chorionic gonadotropin in the first trimester has been suggested to be the cause of thyroid stimulation. As pregnancy progresses, patients usually require lower doses of antithyroid drugs. Close monitoring of thyroid function needs to be continued after delivery in anticipation of postpartum exacerbation until the patient reaches a stable euthyroid state.
Fetal thyroid function
The fetus is dependent on the small supply of thyroxine (T4) from the mother until 10 to 12 weeks of gestation, when the fetal thyroid gland starts secreting thyroid hormones. By 20 weeks of gestation, the fetal thyroid gland becomes responsive to TSH from its own pituitary gland, but the function of the thyroid gland remains T4 across the relatively low. While transfer of maternal placenta is limited and the serum T4 level in a fetus is about one-third of the maternal level, maternal TSH-receptor antibodies in Graves disease are immunoglobulin G antibodies and readily cross the placenta. As a result, maternal TSH-receptor antibodies can cause fetal hyperthyroidism after 20 weeks of gestation. Antithyroid drugs, such as methimazole and propylthiouracil, also cross the placenta and therefore serve as treatment for both maternal and fetal hyperthyroidism.
Complications
Uncontrolled hyperthyroidism is associated with serious maternal, fetal, and neonatal morbidity, and mortality. Maternal complications include miscarriage, pregnancy-induced hypertension, preterm labour, placental abruption, heart failure, and thyroid storm. Fetal and neonatal complications include stillbirth, low birth weight, goiter, hyperthyroidism, and hypothyroidism.5–7 These risks can be decreased with the appropriate treatment of maternal hyperthyroidism.5
Management
Hyperthyroidism during pregnancy should be treated with an antithyroid drug. The goal of treatment is to maintain maternal free T4 in the upper normal range, using the lowest possible dose of the antithyroid drug. This approach aims at minimizing the risk of fetal hypothyroidism.8 Thyroid hormones are critical for fetal brain development, and caution against overtreatment is warranted. Mild hyperthyroidism is usually monitored closely without therapy as long as both the mother and the fetus are not symptomatic. If thyroidectomy is indicated for treatment failure with a high-dose antithyroid drug or adverse effects from an antithyroid drug, it is optimally performed during the second trimester of pregnancy. Radioactive iodine is contraindicated during pregnancy, as it readily crosses the placenta and is taken up in the fetal thyroid gland. For pregnant women with past or current Graves disease, Doppler examination of the fetal thyroid gland is useful in detecting goiter, which is associated with fetal hyperthyroidism or hypothyroidism.9
Antithyroid drugs during pregnancy
Propylthiouracil is the drug of choice for hyperthyroidism during pregnancy in North America owing to the suspected association of methimazole with congenital abnormalities (sometimes referred to as methimazole embryopathy), characterized by aplasia cutis, esophageal atresia, choanal atresia, facial abnormalities, and developmental delay. Since the association of methimazole with aplasia cutis was first suggested by an epidemiological study,10 cases of aplasia cutis or other associated abnormalities in infants exposed to methimazole in utero have been reported in the literature.11–13 However, in a prospective cohort study in which 241 women used methimazole and 1089 women used non-teratogenic drugs, the overall risk of serious congenital abnormalities in infants in the methimazole group was not higher than in those in the nonteratogenic drug group.14 In addition, 2 retrospective studies did not find an increase in congenital abnormalities in infants exposed to methimazole in utero.15,16 Another reason for the preference of propylthiouracil over methimazole is that a small study reported limited transplacental passage of propylthiouracil compared with methimazole.17 This finding was refuted by a later study.18 The risk of fetal hypothyroidism was not different between women with Graves disease taking propylthiouracil and those taking methimazole.19 Methimazole has been widely used in Europe, South America, and Asia and is an alternative to propylthiouracil in North America for patients with hyperthyroidism who cannot tolerate propylthiouracil.
Antithyroid drugs during lactation
Propylthiouracil is often recommended as the antithyroid drug of choice during lactation because the transfer of propylthiouracil to a nursing infant via breast milk seems to be less than the transfer of methimazole. However, neither propylthiouracil nor methimazole seem to pose a serious risk to nursing infants. A study that included 139 lactating mothers taking methimazole and their nursing infants showed no adverse effects on thyroid function or neurodevelopment of the infants.20 Methimazole doses of up to 20 mg/d did not cause hypothyroidism in nursing infants.21 Until more studies are available, thyroid function of nursing infants should be monitored if the mother receives a high dose of methimazole during lactation.
Conclusion
Propylthiouracil is the drug of choice for hyperthyroidism during pregnancy; however, methimazole is an alternative for patients who cannot tolerate propylthiouracil. Although there are case reports of fetal toxicity from methimazole, the overall risk of congenital abnormalities in infants exposed to methimazole in utero does not seem to be higher than those exposed to non-teratogenic drugs or propylthiouracil. It is important for a pregnant woman to continue methimazole, if necessary, because uncontrolled hyperthyroidism increases the risk of complications such as preterm labour and low birth weight.
MOTHERISK
Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Drs Inoue, Arata, and Ito are members and Dr Koren is Director of the Motherisk Program. Dr Koren is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation. He holds the Ivey Chair in Molecular Toxicology in the Department of Medicine at the University of Western Ontario in London.
Do you have questions about the effects of drugs, chemicals, radiation, or infections in women who are pregnant or breastfeeding? We invite you to submit them to the Motherisk Program by fax at 416 813-7562; they will be addressed in future Motherisk Updates.
Published Motherisk Updates are available on the Canadian Family Physician website (www.cfp.ca) and also on the Motherisk website (www.motherisk.org).
Footnotes
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Competing interests
None declared
- Copyright© the College of Family Physicians of Canada
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