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#Grand Rounds

Do Antithryroid Drugs Increase Risk for Congenital Malformations?

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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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Related ObG Topics:

Labeling of Drugs in Pregnancy and Lactation: What Happened to A, B, C, D, and X?
Antiepileptic Drugs: What is the Impact on Risk for Birth Defects
FDA Reviews Fluconazole in Pregnancy
Do ACE Inhibitors early in pregnancy increase risk of birth defects?

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