Antithyroid drug use in early pregnancy increased birth defect risk.

The treatment of hyperthyroidism during pregnancy with both methimazole/carbimazole and propylthiouracil was linked to birth defects, but the type of malformations differed, according to recent study findings.

The prevalence of birth defects was greater among children exposed to antithyroid drugsduring early pregnancy (propylthiouracil, 8%; methimazole/carbimazole, 9.1%; methimazole/carbimazole and propylthiouracil, 10.1%; P<.001), according to data. Researchers did not see an increased risk for birth defects in infants born to mothers treated with antithyroid drugs before or after pregnancy (no antithyroid drugs, 5.4%; nonexposed, 5.7%;P<.001).

“It is imperative to treat overt hyperthyroidism in pregnant women, but the use of [antithyroid drugs] in early pregnancy should be limited when possible,” the researchers said. “For the present, it may be optimal to shift women planning pregnancy from [methimazole/carbimazole] to [propylthiouracil] before pregnancy.”

The researchers used the Danish nationwide register-based cohort study, including 817,093 children live-born from 1996 to 2008 to determine how the use of antithyroid drugs used in early pregnancy increased the prevalence of birth defects.

Patients were assigned to the following groups:

  • Propylthiouracil (n=564);
  • Methimazole/carbimazole (n=1,097);
  • Methimazole/carbimazole and propylthiouracil (n=159);
  • No antithyroid drugs during pregnancy, but taken before or after pregnancy (n=3,543); and
  • Nonexposed females (n=811,730).

Data indicate that mothers who were assigned both methimazole/carbimazole (adjusted OR=1.66; 95% CI 1.35-2.04) and propylthiouracil (OR=1.41; 95% CI, 1.03-1.92) with maternal shift between methimazole/carbimazole and propylthiouracil during early pregnancy (OR=1.82; 95% CI, 1.08-3.07) demonstrated an increased prevalence of birth defects, researchers wrote.

In particular, methimazole/carbimazole and propylthiouracil were associated with urinary system malformation, and propylthiouracil with malformations in the face and neck region.

Moreover, choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies and aplasia cutis were common in methimazole/carbimazole-exposed children (combined, adjusted OR=21.8; 95% CI, 13.4-35.4), according to data.

Further studies are warranted to confirm these results, researchers wrote.

  • There is concern over whether carbimazole/methimazole or propylthiouracil is the most appropriate antithyroid drug to use when treating hyperthyroidism in pregnant women. Traditionally, propylthiouracil has been preferred, as it was felt to be associated with a lower risk for congenital abnormalities. However, concerns regarding propylthiouracil use have arisen owing to the rare complication of propylthiouracil-induced hepatitis in pregnancy, which can have catastrophic consequences.

    This study is very important, as it substantially adds to our current knowledge of birth defects associated with antithyroid drug exposure for carbimazole/methimazole and propylthiouracil. This study crucially highlighted that both carbimazole/methimazole and propylthiouracil were associated with an increased risk for birth defects. However the birth defects associated with propylthiouracil may be less common and severe than those associated with carbimazole/methimazole. Of particular note was that, in the small number of women who switched from carbimazole/methimazole to propylthiouracil during the first trimester, there was no obvious amelioration in the risk for birth defects. This implies switching to propylthiouracil during the first trimester may be too late to prevent carbimazole/methimazole-associated abnormalities. This would support the argument that in women considering pregnancy, propylthiouracil should be used instead of carbimazole/methimazole, as swapping in the first trimester may be too late. However, further studies are needed.

    The use of robust national registry data provided the very large population required to identify rare but clinically important outcomes and also protected against differential recall of exposure between carbimazole/methimazole and propylthiouracil-treated pregnancies. This is a particular strength as traditional reporting methods may be biased by clinicians’ preconceptions regarding these antithyroid drugs.

    • Peter N. Taylor, MRCP
    • Welsh clinical academic trainee in diabetes and endocrinology
      Thyroid Research Group
      Institute of Molecular and Experimental Medicine
      Cardiff University School of Medicine

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