Choice of Antithyroid Drugs in Pregnancy

Dear Editor:

I read with interest the Guest Editorial by Boelaert (1) recently published in Thyroid. I believe that some of the comments made about the choice of antithyroid drug in pregnancy require comment.

First, the article by Chattaway and Klepser (2) quoted as supporting the notion that propylthiouracil (PTU) crosses the placenta less than methimazole (MMI) in fact does the opposite. Chattaway and Klepser reviewed a study from our group (3), using the perfused placental lobule, that indicates similar transfer kinetics for the two drugs. They also reviewed a series of clinical studies that show, essentially, no differences in maternal or fetal outcome between PTU and MMI treatment. The authors state in their summary that “The selection of PTU over MMI as the drug of choice to treat Graves' disease in pregnancy should not be based solely on misleading statements in the literature that PTU has less placental transfer than methimazole….”

Second, the article by Cooper and Rivkees (4) is referenced by Boellaert as supporting use of PTU as a “first line drug” in pregnancy. Cooper and Rivkees discuss risks of aplasia cutis and more major teratogenesis from MMI versus risks of severe hepatotoxicity from PTU. The authors estimate that in the United States four pregnant women per year will have severe PTU-related liver damage. They go on to say that “because of our limited understanding of the risk of birth defects associated with Graves' disease and the use of antithyroid drugs, until we have additional information on MMI drug safety for the fetus, it is reasonable to recommend that pregnant hyperthyroid women be treated with PTU during the first trimester rather than with MMI. This is in accord with The Endocrine Society Guideline (5). The risk of PTU for expectant mothers can be reduced by limiting PTU use to the first trimester and then changing to MMI.”

PTU has not, however, been totally absolved from suspicions of teratogenicity. A recent large international case-affected study (6) of antithyroid drug treatment-related birth defects confirmed an association between maternal use of MMI and omphalocele and choanal atresia in offspring. The study also identified three malformations (situs inversus, unilateral renal agenesis/dysgenesis, and cardiac outflow tract lesions) associated with prenatal PTU exposure. The results were, however, of marginal statistical significance and the authors point out that a firm conclusion that PTU is teratogenic will require further studies. Congenital malformations in infants of women with Graves' disease who take antithyroid drugs are fortunately rare. This and uncertainties about the relative roles of antithyroid drugs, maternal and fetal thyroid status, and interactions between drugs and thyroid status, in inducing fetal malformations, mean that a definitive conclusion about PTU-induced teratogenicity is unlikely to be reached quickly. While recommendations that PTU be used in the first trimester but then changed to MMI may, in the light of present knowledge, seem reasonable they do not recognize the reality that many women taking MMI for Graves' disease may be well into the first trimester before pregnancy is diagnosed.