Methimazole and Pregnancy
Primary Recommendation
Propylthiouracil (PTU) should be used as first-line therapy during the first trimester of pregnancy, with a switch to methimazole for the second and third trimesters. 1, 2
Treatment Algorithm by Trimester
First Trimester (Weeks 1-13)
- Use PTU exclusively during organogenesis due to methimazole's association with rare but serious congenital malformations 1, 2
- Methimazole exposure in the first trimester has been linked to:
- Meta-analysis confirms pregnant women treated with methimazole have significantly higher risk of congenital anomalies compared to PTU (OR 0.80,95% CI 0.69-0.92, P=0.002) 4
Second and Third Trimesters (Weeks 14-40)
- Switch to methimazole after the first trimester is complete 1, 2
- Methimazole up to 30 mg/day is considered safe in later pregnancy 2
- The rationale for switching: PTU carries risk of severe hepatotoxicity including acute liver failure, which can be catastrophic during pregnancy 2, 5
- This trimester-based approach balances the teratogenic risk of methimazole against the hepatotoxic risk of PTU 6
Treatment Goals and Monitoring
Thyroid Function Targets
- Maintain maternal free T4 (FT4) or free thyroxine index (FTI) in the high-normal range or just above normal using the lowest effective dose 1, 2
- Use the minimum thioamide dosage necessary to achieve this target 1
Monitoring Schedule
- Check FT4 or FTI every 2-4 weeks during active treatment until stable 1, 2
- Once stable, continue monitoring every 4 weeks 2
- Check TSH every trimester 1
- A rising serum TSH indicates the need for dose reduction 1, 2
Critical Safety Monitoring
Agranulocytosis (Life-Threatening)
- Instruct patients to immediately report fever or sore throat 2, 3
- Obtain complete blood count immediately if agranulocytosis is suspected 2
- Discontinue the drug immediately if agranulocytosis is confirmed 3
Hepatotoxicity
- Monitor for symptoms: anorexia, pruritus, right upper quadrant pain 3
- Evaluate liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) if symptoms develop 3
- Discontinue drug promptly if hepatic transaminases exceed 3 times the upper limit of normal 3
- PTU-induced liver disease, though uncommon, can be catastrophic in pregnancy with risk of liver failure 5
Vasculitis
- Patients must promptly report new rash, hematuria, decreased urine output, dyspnea, or hemoptysis 2
- Cases include ANCA-positive vasculitis, acute kidney injury, glomerulonephritis, and pulmonary hemorrhage 3
- Discontinue therapy if vasculitis is suspected 3
Other Monitoring
- Monitor prothrombin time, especially before surgical procedures (risk of hypoprothrombinemia and bleeding) 3
- Monitor for thrombocytopenia and aplastic anemia 3
Symptomatic Management
- Use propranolol for symptomatic relief of tachycardia, tremor, and anxiety while awaiting thyroid hormone normalization 2
- Beta-blockers can be used temporarily until thioamide therapy reduces thyroid hormone levels 1
- Common pitfall: Beta-blocker dose may need reduction when the hyperthyroid patient becomes euthyroid due to decreased clearance 3
Absolute Contraindications
- Radioactive iodine (I-131) is absolutely contraindicated during pregnancy as it causes fetal thyroid ablation 1, 2
- Women must wait 4 months after I-131 treatment before attempting pregnancy or breastfeeding 1
When Surgery is Indicated
- Reserve thyroidectomy for patients who:
- If surgery is necessary, perform during the second trimester when safest 1, 2
Risks of Untreated Hyperthyroidism
Maternal Risks
Fetal/Neonatal Risks
- Low birth weight 1
- Stillbirth 3
- Fetal or neonatal hyperthyroidism 3
- Fetal goiter and cretinism (from excessive antithyroid drug dosing) 3
- Outcomes correlate directly with disease control, making treatment essential despite medication risks 2
Special Considerations
Graves' Disease
- Maternal thyroid-stimulating antibodies can cross the placenta and cause fetal/neonatal thyroid dysfunction 2
- Inform the pediatrician of maternal Graves' disease due to risk of neonatal thyroid dysfunction 1, 2
Hyperemesis Gravidarum
- Biochemical hyperthyroidism associated with hyperemesis gravidarum rarely requires treatment unless other clinical signs of hyperthyroidism are present 1
Thyroid Storm (Medical Emergency)
- Presents with fever, disproportionate tachycardia, altered mental status, vomiting, diarrhea, and cardiac arrhythmia 1
- Treat immediately without waiting for laboratory confirmation 1
- Treatment includes PTU or methimazole, potassium/sodium iodide solutions, dexamethasone, phenobarbital, and supportive care 1
- Avoid delivery during thyroid storm unless absolutely necessary 1
Dose Adjustments During Pregnancy
- In many pregnant women, thyroid dysfunction diminishes as pregnancy progresses 3
- Dose reduction may be possible, and in some cases, antithyroid therapy can be discontinued several weeks or months before delivery 3
Important Caveats
- Switching between PTU and methimazole during pregnancy did not reduce the risk of birth defects compared to PTU alone in meta-analysis (OR 1.18, CI 1.00-1.40, P=0.061), though this remains an area requiring further study 4
- The FDA classifies methimazole as Pregnancy Category D, indicating positive evidence of fetal risk 3
- Both drugs cross the placenta and can cause fetal hypothyroidism if dosed excessively 3
- No statistically significant differences exist between PTU and methimazole for hepatotoxicity or miscarriage rates, though individual case severity differs 4