When can methimazole be safely initiated after what week of gestation?

From the Guidelines

Methimazole can be safely initiated after the first trimester, specifically after week 12 of gestation. This recommendation is based on the potential risks associated with methimazole use during early pregnancy, as highlighted in the study published in the American Family Physician 1. Prior to this point, propylthiouracil (PTU) is the preferred antithyroid medication during early pregnancy due to the possible teratogenicity of methimazole in the first trimester.

The key considerations for this timing recommendation include:

• The association of methimazole with rare but serious congenital abnormalities when used during the first trimester, such as aplasia cutis, choanal atresia, and esophageal atresia, collectively known as "methimazole embryopathy" 1.
• The preference for methimazole over PTU after the first trimester due to its better side effect profile, particularly regarding liver toxicity which is more common with PTU 1.
• The importance of regular monitoring of thyroid function tests during pregnancy to ensure proper dosing and maintain maternal free T4 in the upper normal range or slightly elevated.

In terms of dosing, the typical starting dose of methimazole after week 12 ranges from 5-30 mg daily, depending on the severity of hyperthyroidism, often divided into two or three doses. The goal is to achieve euthyroidism before pregnancy and maintain it throughout, as hyperthyroidism can result in significant maternal and neonatal morbidity, with outcomes correlating with disease control 1.

From the FDA Drug Label

Pregnancy Category D See WARNINGS If methimazole is used during the first trimester of pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus In pregnant women with untreated or inadequately treated Graves’ disease, there is an increased risk of adverse events of maternal heart failure, spontaneous abortion, preterm birth, stillbirth and fetal or neonatal hyperthyroidism Because methimazole crosses placental membranes and can induce goiter and cretinism in the developing fetus, hyperthyroidism should be closely monitored in pregnant women and treatment adjusted such that a sufficient, but not excessive, dose be given during pregnancy In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction of dosage may be possible. In some instances, anti-thyroid therapy can be discontinued several weeks or months before delivery Due to the rare occurrence of congenital malformations associated with methimazole use, it may be appropriate to use an alternative anti-thyroid medication in pregnant women requiring treatment for hyperthyroidism particularly in the first trimester of pregnancy during organogenesis. Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters.

Methimazole can be safely initiated after the first trimester of pregnancy, specifically during the second and third trimesters, as the potential maternal adverse effects of propylthiouracil may make methimazole a preferable choice during this time 2.

From the Research

Safety of Methimazole in Pregnancy

• Methimazole is an antithyroid drug used to treat hyperthyroidism, but its safety during pregnancy is a concern due to the potential risk of congenital anomalies 3, 4.
• Studies have shown that propylthiouracil (PTU) may be a safer alternative to methimazole during the first trimester of pregnancy, as it has a lower risk of congenital anomalies 3, 5.
• However, PTU can cause myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which can occur within several weeks after initiation of PTU treatment 5.

Timing of Methimazole Initiation

• There is no clear consensus on when methimazole can be safely initiated after a certain week of gestation.
• One study suggested that substituting potassium iodide for methimazole in the first trimester may reduce the incidence of congenital anomalies 4.
• Another study found that propylthiouracil and methimazole are equally effective and safe in the treatment of hyperthyroidism during pregnancy, but the incidence of major congenital malformations was slightly higher in the methimazole group 6.
• A retrospective study found that the rates of spontaneous miscarriage and major congenital malformations were not higher than in the general population in women treated with methimazole or propylthiouracil during pregnancy 7.

Considerations for Methimazole Use

• The decision to use methimazole during pregnancy should be made on a case-by-case basis, taking into account the individual patient's risk factors and medical history.
• Patients treated with methimazole should be carefully monitored for signs of congenital anomalies and other potential side effects 3, 4.
• Further studies are needed to fully clarify the safety of methimazole during pregnancy and to develop evidence-based guidelines for its use 3, 7.