What are the guidelines for using methimazole (MMI) during pregnancy?

Management of Methimazole During Pregnancy

Propylthiouracil (PTU) should be used instead of methimazole (MMI) during the first trimester of pregnancy due to the risk of congenital malformations associated with MMI, while methimazole is preferred in the second and third trimesters due to propylthiouracil-associated hepatotoxicity. 1, 2

First Trimester Considerations

• Methimazole is contraindicated in the first trimester due to its association with rare but serious congenital malformations:

  • Aplasia cutis (skin defects)
  • Craniofacial malformations
  • Choanal atresia
  • Esophageal atresia with or without tracheoesophageal fistula
  • Omphalocele and abnormalities of the omphalomesenteric duct 2

• The FDA label clearly warns that methimazole crosses placental membranes and can cause fetal harm when administered in the first trimester 2

• Recent meta-analysis confirms that pregnant women treated with MMI have a higher risk of congenital anomalies than those treated with PTU (OR 0.80,95%CI 0.69-0.92) 3

Second and Third Trimester Management

• Switch from PTU to methimazole after the first trimester 1

• This approach balances the risks:

  • Avoids MMI-associated birth defects (first trimester concern)
  • Avoids PTU-associated hepatotoxicity (concern throughout pregnancy) 1, 3

• When using methimazole during pregnancy:

  • Use the lowest possible dose to control maternal disease 2
  • Monitor thyroid function tests every 2-4 weeks initially, then every 4-6 weeks 1
  • Target free T4 or Free T4 Index in the high-normal range 1

Monitoring During Pregnancy

• For women with active hyperthyroidism requiring treatment:

  • Monitor thyroid function at frequent intervals (every 2-4 weeks initially) 2
  • Adjust dose to maintain sufficient but not excessive control 2
  • Be aware that thyroid dysfunction often diminishes as pregnancy progresses, potentially allowing dose reduction 2

• For women with history of treated hyperthyroidism but not currently on therapy:

  • The risk of reactivation is low 4
  • Perform close follow-up with coccidioidal serologic testing at initial visit and every 6-12 weeks throughout pregnancy 4

Special Considerations

• For women who become pregnant while on methimazole:

  • If discovered during first trimester, consider switching to PTU immediately 3, 5
  • Counsel about potential fetal risks 2
  • Consider alternative treatments if appropriate 2

• Breastfeeding:

  • Methimazole is present in breast milk but several studies found no effect on clinical status in nursing infants 2
  • Monitor infant thyroid function at frequent (weekly or biweekly) intervals 2
  • Fluconazole is considered safe during breastfeeding, but other azole antifungals are not recommended 4

Common Pitfalls and Caveats

1. Failing to switch from PTU to MMI after first trimester, exposing mother to unnecessary risk of hepatotoxicity
2. Using excessive doses of antithyroid medication, causing fetal hypothyroidism
3. Inadequate monitoring of thyroid function during pregnancy
4. Not recognizing that hyperthyroidism may improve during pregnancy, requiring dose adjustment
5. Continuing MMI during first trimester when pregnancy is discovered

The evidence strongly supports using PTU in the first trimester followed by MMI for the remainder of pregnancy as the safest approach to manage hyperthyroidism during pregnancy 1, 3, 5. This strategy minimizes both the risk of MMI-associated birth defects and PTU-associated hepatotoxicity.