Abstract
I thank Robin Mortimer for his useful comments and critical appraisal of my Guest Editorial. I agree that the conclusions of the review by Chattaway and Klepser (1) have been misinterpreted and that whilst older literature suggested that propylthiouracil crosses the placenta less than methimazole (2,3), this is not supported by more contemporary data indicating similar transplacental transfer kinetics for propylthiouracil and methimazole (4). The selection of propylthiouracil as the drug of choice for treatment of Graves' disease in pregnancy should therefore not be based on the notion of lower placental transfer.
Recent guidelines from the American Thyroid Association and the American Association of Clinical Endocrinologists on the management of hyperthyroidism (5) recommend the use of propylthiouracil during the first trimester of pregnancy, in line with the previous guideline from the Endocrine Society (6). This applies to patients in whom antithyroid drugs are started during pregnancy (recommendation 70) as well as to those already treated with antithyroidals prior to diagnosis of pregnancy. Those becoming pregnant whilst taking methimazole should be swapped to propylthiouracil at the earliest suggestion of pregnancy (recommendation 71). At the beginning of second trimester pregnant women should be switched to treatment with methimazole, and this should also be the drug of choice if treatment is started during the second or third trimester (recommendations 70 and 71) (5). These recommendations are based on concerns regarding rare but potentially fatal hepatotoxicity in pregnant women treated with propylthiuoracil as well as risk of teratogenicity with use of methimazole.
With regard to teratogenecity caused by antithyroid drugs, the large case-affected control analysis including 18,131 cases and quoted by Dr. Mortimer (7), confirmed a significant association between methimazole exposure and omphalocele and choanal atresia, suggesting that these malformations may be part of a specific, albeit rare, embryopathy. The finding in this study of teratogenicity induced by propylthiouracil requires further exhaustive evaluation because of the low number of reported birth defects, the lack of biological plausibility, and the possibility of underdiagnosis, as stated by Clementi et al. (7).
Since it is unclear whether the underlying thyroid status of both mother and fetus contribute to the risk of teratogenicity, a valid concern is that changing back and forth between methimazole and propylthiouracil may result in poorly controlled thyroid function, especially since there are uncertainties regarding dose equivalents. Some therefore suggest that rather than switching to methimazole, propylthiouracil could be continued throughout pregnancy with monitoring of liver function tests coinciding with thyroid function testing. In the absence of prospective data indicating that this type of monitoring is effective in preventing fulminant hepatotoxicity, recommendation of this approach seems unsubstantiated.
The recent guidance recommends the use of the lowest possible dose of antithyroid drugs, aiming to keep the mother's thyroid hormone levels slightly above the trimester-specific reference range with serum thyrotropin concentrations suppressed, in order to avoid fetal hypothyroidism (recommendation 72) (5). This seems appropriate in view of the suggestion that the abnormalities in the underlying fetal thyroid status may be contributing to the observed birth defects (7). Large prospective studies are required in order to answer a number of outstanding questions, including those evaluating the teratogenic effects of propylthiouracil, the risks of propylthiouracil-induced liver damage in pregnancy, and the consequences of swapping antithyroid drugs during pregnancy. I concur with Dr. Mortimer that, based on the currently available evidence, the recommendation to use propylthiouracil during the first trimester of pregnancy seems reasonable.