Grand Rounds

Do Antithryroid Drugs Increase Risk for Congenital Malformations?

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

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

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

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

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