What are the guidelines for using Propylthiouracil (PTU) in the third trimester of pregnancy?

PTU in Third Trimester

Switch from PTU to methimazole for the second and third trimesters of pregnancy to minimize the risk of maternal hepatotoxicity while avoiding the teratogenic risks of methimazole that are specific to first trimester exposure. 1

Rationale for Switching

The FDA drug label explicitly states that "given the potential for maternal hepatotoxicity from propylthiouracil, it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters during pregnancy." 1 This recommendation is based on:

• PTU carries significant hepatotoxicity risk: PTU can cause severe liver injury ranging from asymptomatic transaminase elevation to acute liver failure requiring transplantation or resulting in death, with this risk being particularly concerning during pregnancy when maternal survival is paramount 1, 2, 3

• Methimazole's teratogenic risk is trimester-specific: The birth defects associated with methimazole (choanal atresia, esophageal atresia, aplasia cutis) occur primarily with first trimester exposure, making it safer after organogenesis is complete 4, 5

• PTU has lower but not absent teratogenic risk: While PTU shows less clear evidence of major congenital abnormalities compared to methimazole, it still crosses the placenta and can induce fetal goiter and cretinism if dosed excessively 1

Clinical Management Algorithm

Timing of Switch

• Perform the switch at the beginning of the second trimester (around 12-14 weeks gestation) when organogenesis is complete and methimazole's teratogenic window has passed 6, 4

Dosing Conversion

• Direct substitution is appropriate due to similar mechanisms of action, though methimazole is approximately 10-15 times more potent than PTU on a weight basis 6
• Use the lowest effective dose to maintain maternal euthyroidism while avoiding fetal hypothyroidism 1

Monitoring Requirements During Third Trimester on Methimazole

Thyroid function tests:

• Monitor periodically throughout pregnancy, as thyroid dysfunction often diminishes as pregnancy progresses 1
• An elevated TSH indicates the need for dose reduction 1
• Dosage reduction or discontinuation may be possible several weeks to months before delivery 1

Liver function surveillance:

• While methimazole has lower hepatotoxicity risk than PTU, baseline and periodic monitoring remains prudent 2, 5

Hematologic monitoring:

• Both drugs carry similar risks of agranulocytosis, requiring patient education about reporting fever, sore throat, or signs of infection immediately 1, 5

Important Caveats

PTU continuation may be necessary if:

• The patient has demonstrated methimazole intolerance or allergy (rare scenario where PTU must continue despite hepatotoxicity risk) 1
• Switching occurs very late in pregnancy where the risk-benefit may favor maintaining current therapy

Fetal considerations:

• Both drugs cross the placenta and require careful dosing to prevent fetal goiter and cretinism 1
• The goal is sufficient maternal treatment without excessive fetal thyroid suppression 1

Postpartum management:

• Both PTU and methimazole are present in breast milk in clinically insignificant amounts and are compatible with breastfeeding 1
• Dose adjustments are typically needed postpartum as pregnancy-related changes in drug clearance normalize 1

Evidence Quality Assessment

The recommendation to switch from PTU to methimazole after the first trimester is based on:

• FDA drug labeling (highest authority for drug safety) 1
• Systematic reviews and meta-analyses showing PTU's greater hepatotoxic potential (OR 2.40 for liver injury, OR 3.96 for elevated transaminases) and methimazole's first-trimester-specific teratogenicity (OR 1.29 for birth defects in first trimester only) 5
• Case-control studies identifying specific methimazole-associated defects like choanal atresia that are trimester-dependent 4

Critical limitation: No randomized controlled trials have directly tested the switching strategy, though observational data and pharmacologic rationale strongly support this approach 2, 7

Common Pitfalls to Avoid

• Continuing PTU throughout pregnancy due to inertia or fear of switching medications—this exposes the mother to ongoing hepatotoxicity risk that can be catastrophic 2, 3
• Excessive dosing of either drug leading to fetal hypothyroidism and goiter 1
• Inadequate patient education about warning signs of agranulocytosis (fever, sore throat) or hepatotoxicity (jaundice, right upper quadrant pain, anorexia) that require immediate drug discontinuation 1
• Failing to reduce doses as pregnancy progresses and hyperthyroidism often improves spontaneously 1