BACKGROUND AND PURPOSE: 

• Approximately 4,000 women are treated for Graves disease with the following equally effective medications during pregnancy 
  • Propylthiouracil (PTU) 
  • Methimazole (MMI) 
  • Carbimazole
• PTU has been promoted as the preferable antithyroid drug (ATD) due to risk of aplasia cutis and choanal or esophageal atresia with MMI 
• However, PTU has also been associated with fatal hepatotoxicity  
  • FDA has recommended that PTU be used only in the first trimester and then MMI from the second trimester onward 
  • Evidence based on ‘expert opinion’ rather than data  
• Sao and Kim (Annals of Internal Medicine, 2018) examined the association between maternal ATD use and congenital malformations 

METHODS: 

• Cohort study  
• Nationwide registry based on compulsory public medical insurance system  
• Participants: Women who were prescribed ATDs during pregnancy and delivered a liveborn infant  
• Definition of a child exposed to maternal ATD in the first trimester  
  • Mother received at least 1 ATD prescription during first trimester 
• 3 ATD exposure groups  
  • PTU alone (n = 9930) 
  • MMI alone (n = 1120) 
  • Both PTU and MMI (n = 1841) 
• 210 cases of carbimazole use in the MMI groups with equal potency (10 mg of carbimazole was converted to 6 mg of MMI) 
• Risk for overall and organ-specific congenital malformations in offspring was assessed 
• Potential confounders were controlled for using a logistic regression model 

RESULTS: 

• 12,891 pregnancies (0.45%) were exposed to ATDs during the first trimester  
• Prevalence of malformations in exposed offspring was 7.27%, compared with 5.94% in offspring of women who were not prescribed ATDs during pregnancy (P<0.001) 
  • Adjusted odds ratio (OR), 1.19 (95% CI, 1.12 to 1.28) 
• Compared with non-ATD pregnancies, absolute increase in the prevalence of congenital malformations per 1000 live births were as follows 
  •  8.81 cases (95% CI, 3.92 to 13.70 cases) for PTU alone 
    • PTU: adjusted OR 1.16 (95% CI, 1.07 to 1.25) 
    • Musculoskeletal system, face, neck, genitourinary tract systems affected  
  • 17.05 cases (95% CI, 1.94 to 32.15 cases) MMI 
    • MMI: adjusted OR 1.31 (95% CI, 1.06-1.63) 
    • Nervous, circulatory, and digestive systems affected  
  • 16.53 cases (CI, 4.73 to 28.32 cases) both PTU and MMI 
    • Both PTU and MMI: adjusted OR 1.3 (95% CI, 1.10-1.54)  
    • Nervous and circulatory systems, cleft lip, and cleft palate affected 
• In the MMI group, a high cumulative dose (>495 mg) during the first trimester was associated with an increased risk for malformations compared with a low dose (1 to 126 mg)  
  • Adjusted OR, 1.87 (95% CI, 1.06 to 3.30) 
• Switching from PTU to MMI increased the absolute risk (by 47 cases per 1000 live births) compared with continuing to receive PTU alone 

CONCLUSION: 

• This study suggests exposure to ATDs during the first trimester is associated with increased risk for congenital malformations 
• Risks for overall congenital malformations were modestly increased for PTU  
• Risks were particularly increased in pregnancies where women received MMI or both PTU and MMI  
• The authors recommend  
  • Switching from MMI to PTU preconception  
  • Remain on PTU during the first trimester 
  • Counsel patient regarding risk of birth defects and hepatic failure with PTU 

Learn More – Primary Sources: 

Antithyroid Drugs and Congenital Malformations: A Nationwide Korean Cohort Study 

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