Therapeutic drug monitoring of antithyroid drugs in pregnancy: The knowledge gaps

In their paper on therapeutic drug monitoring of antithyroid drugs in pregnancy, Koren and Soldin1 underline that there is an unacceptable void in knowledge of fetal safety of propylthiouracil (PTU), despite its wide use in pregnancy. The authors hypothesize that the lack of epidemiologic controlled studies could be the cause of the lack of reports of congenital malformations in children exposed prenatally to PTU in confront with those exposed to methimazole (MMI). However, in 19992 we reported a child affected with multiple malformations and delineated the phenotype of the MMI embryopathy on the basis of our case and 6 cases previously reported in the literature. In 2001 we performed an epidemiologic study3 of 241 prospective cases collected by Teratogen Information Services in Europe and found 2 cases of choanal and esophageal atresia, the major malformations described in the MMI embryopathy. After our papers, to our knowledge, 14 further cases of MMI embryopathy have been described, although there have not been reports of these malformations or other major malformations in children prenatally exposed to PTU. In particular, an epidemiologic study in Sweden4 in the period 1995 to 2000 registered data on 42 women who had taken MMI and 50 who had taken PTU during the first trimester, 2 MMI children presented the MMI embryopathy, although none of the PTU children had congenital anomalies. On the basis of this evidence, Shepard et al5 concluded that the findings observed in the so-called MMI embryopathy are more likely to result from the MMI treatment than from hyperthyroidism itself. MMI has then been included in the recently recognized teratogenic exposures in humans.6 Further studies, however, are needed to substantiate a causal relationship between MMI treatment during the first trimester of pregnancy and the above-described embryopathy. On the other hand, there have not been reports of embryopathy in newborns prenatally exposed to PTU. This lack of case reports does not exclude, of course, a very minor teratogenic risk and it is, therefore, difficult to perform a quantitative risk comparison between the wo drugs. As far as neurocognitive functions and intellectual development are concerned, there is enough data orroborating a lack of evidence of severe defects associated with MMI renatal exposure, although several studies have reported no difference between children prenatally exposed to PTU and controls for several developmental outcomes including ntelligence. These studies, however, do not correlate the developmental outcome with the fetal thyroid function.7 We conclude that, until large prospective and follow-up studies on PTU are available, the evidence of several cases of MMI embryopathy and the lack of case reports on PTU teratogenicity despite its wide use, makes it preferable at present to treat thyrotoxicosis in childbearing women with PTU because it is apparently safe for use in the fertile period.