When do we switch from Propylthiouracil (PTU) to Methimazole in pregnancy?

Timing of Switch from PTU to Methimazole in Pregnancy

Switch from propylthiouracil (PTU) to methimazole at the end of the first trimester, specifically after 12-13 weeks of gestation, to minimize both first-trimester teratogenicity from methimazole and hepatotoxicity risk from prolonged PTU exposure. 1, 2

Rationale for Trimester-Specific Therapy

First Trimester (Conception through 12-13 weeks)

• PTU is the preferred agent during the first trimester because methimazole carries a higher risk of congenital malformations during organogenesis 1, 2, 3, 4
• Methimazole-associated birth defects include choanal atresia and a specific pattern of rare teratogenic effects when exposure occurs during the first trimester 5, 6
• Meta-analysis demonstrates significantly higher odds of birth defects with methimazole versus PTU in the first trimester (OR 1.29,95% CI 1.09-1.53, P=0.003) 6

Second and Third Trimesters (After 12-13 weeks through delivery)

• Methimazole becomes the preferred agent after the first trimester due to PTU's association with severe hepatotoxicity, including hepatic failure requiring liver transplantation or resulting in death 1, 2, 3, 4
• PTU causes significantly more liver function injury (OR 2.40,95% CI 1.16-4.96) and elevated transaminases (OR 3.96,95% CI 2.49-6.28) compared to methimazole 6
• The FDA labels explicitly state that it may be preferable to switch from PTU to methimazole for the second and third trimesters 3, 4

Practical Switching Protocol

Direct Substitution Approach

• PTU and methimazole can be directly substituted without a washout period due to their similar mechanisms of action 2
• Both drugs inhibit thyroid peroxidase to reduce thyroid hormone production 7

Monitoring During Transition

• Check thyroid function tests (free T4 or free thyroxine index) every 2-4 weeks after switching to ensure adequate control 1
• The goal is to maintain free T4 or FTI in the high-normal range using the lowest effective dose 1
• Monitor for side effects of both medications, particularly agranulocytosis (presenting as sore throat and fever) and hepatotoxicity 1

Critical Caveats

Hepatotoxicity Warning

• PTU carries a black box warning from the FDA for severe hepatotoxicity, particularly concerning in pediatric populations but also relevant in adults with prolonged exposure 4, 8
• If patients develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise while on PTU, the drug should be discontinued immediately and liver function tests obtained 4

Teratogenicity Considerations

• While methimazole has clearer teratogenic risks in the first trimester, PTU can also cross the placenta and induce goiter and cretinism in the developing fetus 3, 4
• The rare occurrence of congenital malformations with methimazole makes it inappropriate for first-trimester use, particularly during organogenesis 3

Inadequate Treatment Risks

• Untreated or inadequately treated hyperthyroidism increases risks of maternal heart failure, spontaneous abortion, preterm birth, stillbirth, and fetal/neonatal hyperthyroidism 3, 4
• These serious complications underscore the importance of maintaining adequate treatment throughout pregnancy, making the switch from PTU to methimazole essential rather than optional 1

Special Circumstances

Thyroid Storm

• In the rare emergency of thyroid storm during pregnancy, treatment should not be delayed and may include either PTU or methimazole along with potassium/sodium iodide, dexamethasone, and supportive care 1
• Avoid delivery during thyroid storm unless absolutely necessary 1

Postpartum Considerations

• Inform the newborn's physician about maternal Graves' disease due to risk of neonatal thyroid dysfunction 1
• Both PTU and methimazole are present in breast milk, but studies have found no adverse effects on nursing infants with appropriate monitoring 3, 4