Reproductive Toxicology 43 (2014) 26–29 Contents lists available at ScienceDirect Reproductive Toxicology jo ur nal home p age: www. elsevier.com/locate/reprotox Short communication Methotrexate embryopathy after exposure to low weekly doses in early pregnancy María Cecilia Martín a , Pablo Barbero a , Boris Groisman a , Miguel Ángel Aguirre a , Gideon Koren b,* a The Argentine Teratogenic Agents Information Service “Fetal Health”, Argentine National Center of Medical Genetics, ANLIS “Malbrán”, Buenos Aires, Argentina b The Motherisk Program, Department of Pediatrics, Hospital for Sick Children and the University of Toronto, ON, Canada a r t i c l e i n f o Article history: Received 21 August 2013 Received in revised form 7 October 2013 Accepted 18 October 2013 Available online 27 October 2013 Keywords: Methotrexate Pregnancy Aminopterin embryopathy Rheumatoid arthritis a b s t r a c t Objective: Methotrexate (MTX) is a potent teratogen when used in high doses for cáncer or termination of tubal pregnancy. In contrast, it has been perceived as safe when used once weekly at low dose for rheumatological conditions. Methods: A prospective observational controlled study of women exposed to low dose MTX. The control group were women exposed to MTX only before conception. Results: Among the 8 MTX-exposed pregnancies, there was a case of typical MTX embryopathy, the first to be described to date at this lower once weekly dose Schedule. Conclusions: This case has important implications for rheumatologists treating women of reproductive age, as the assumption of fetal safety of MTX, implied from small cohorts, is premature. © 2013 Elsevier Inc. All rights reserved. Methotrexate (MTX) is commonly prescribed to women of reproductive age treated for numerous autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, as well as after organ transplant [1]. This anticancer drug has been shown to be a potent teratogen in animal studies [2,3], as well as among women receiving high doses for cancer, or for termination of tubal pregnancies [4,5]. However, the fetal safety of the lower weekly dose used in autoimmune diseases has been only sparsely studied. In general, these studies failed to show increased teratogenic risk, and none of them reported on typical cases of MTX (Aminopterin) embryopathy with doses lower than or equal to 10 mg given once weekly [4]. The objectives of the present study were to describe pregnancy outcomes among women who consulted the Argentine Teratogenic Agents Information Service “Fetal Health” following exposure to MTX during pregnancy or during the 6 months prior to conception, before pregnancy outcome was known. 1. Patients and methods We analyzed the medical records of pregnant women who con- sulted “Fetal Health” to obtain information about the potential * Corresponding author at: Motherisk Program, Department of Pediatrics, Hospi- tal for Sick Children, Toronto, 555 University Ave, Toronto M5G 1X8, ON, Canada. Tel.: +1 416 813 1500x7413; fax: +1 416 813 7562. E-mail address: gkoren@sickkids.ca (G. Koren). risks of drug use during pregnancy between 2005 and 2012. We identified 18 pregnant women who were exposed to MTX during pregnancy or during the 6 months prior to conception; 14 patients participated in a follow-up telephone interview, while 4 patients were lost for follow-up. All women contacted “Fetal Health” before the outcome of their pregnancy was known. We collected information regarding the outcome of the preg- nancy (newborns without birth defects detected in the neonatal period, newborns with birth defects, fetal death or miscarriage). The babies with birth defects were evaluated by medical geneticists and underwent additional studies. Patients were divided into two groups: group 1 included women who were exposed to MTX during the first trimester of pregnancy (n = 8), and group 2 included patients who were exposed to the drug only during the 6 months prior to conception (n = 6). 2. Results In group 1, upon physical examination and additional tests we detected 6 healthy newborns, 1 case of Down syndrome, and 1 case consistent with MTX (Aminopterin) embryopathy (Table 1). The baby with MTX embryopathy was the second daughter of a 29 years old mother with rheumatoid arthritis. She was exposed to MTX 7.5 mg orally weekly until week 10 of gestation. The mother also used fluconazole (150 mg orally weekly) and rofe- coxib (25 mg a day) during the first trimester of pregnancy, and meprednisone (8 mg a day), ranitidine (300 mg daily) and isoniazid 0890-6238/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.reprotox.2013.10.005