Reproductive Toxicology 50 (2014) 117–121 Contents lists available at ScienceDirect Reproductive Toxicology j ourna l h o mepa ge: www.elsevier.com/locate/reprotox Esophageal atresia and prenatal exposure to mycophenolate M.C. Martín a,f , E. Cristiano b,f , M. Villanueva c , M.L. Bonora d,f , N. Berguio d,f , A. Tocci e,f , B. Groisman a,f , M.P. Bidondo a,f , R. Liascovich a,f , P. Barbero a,f,∗ a National Center of Medical Genetics “Dr Eduardo Castilla”, Buenos Aires, Argentina b Neonatology Service, Penna Hospital, Buenos Aires, Argentina c Medical Genetics Service, Elizalde Hospital, Buenos Aires, Argentina d Neonatology Service, Regional Hospital of Río Cuarto, Córdoba, Argentina e Neonatology Service, Argerich Hospital, Buenos Aires, Argentina f National Registry of Congenital Anomalies of Argentina (RENAC), Argentina a r t i c l e i n f o Article history: Received 29 May 2014 Received in revised form 8 October 2014 Accepted 14 October 2014 Available online 25 October 2014 Keywords: Mycophenolate mofetil Drug induced abnormalities Teratogen Esophageal atresia a b s t r a c t Mycophenolate mofetil is a widely prescribed immunosuppressive agent for transplant patients and autoimmune diseases. Potential teratogenic effects after in utero exposure to mycophenolate mofetil has been described in human clinical observations. The complete clinical pattern is still being delineated. We present four newborns with esophageal atresia and other congenital anomalies, prenatally exposed to mycophenolate mofetil during the first trimester. Two of the cases had other defects related to the embryopathy: microtia, eye abnormalities and oral clefts. Two cases did not show major craniofacial anomalies. We propose that esophageal atresia with or without tracheoesophageal fistula is a feature of mycophenolate embryopathy even without the presence of other major craniofacial anomalies. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommenda- tions about its use in fertile women are stressed. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a congenital anomaly observed with a frequency of 1 in 3500 births [1]. The great majority of cases of EA/TEF occur as sporadic events, and together with the low recurrence risk (approximately 1%) and the low twin concordance rate (2.5%), its evidence for a primarily non-genetic etiology [2]. However, to date, few environmental agents have been suggested as risk factors for the development of tracheoesophageal anomalies like mater- nal diabetes, maternal exposure to methimazole, exogenous sex ∗ Corresponding author at: Centro Nacional de Genética Médica “Dr. Eduardo Castilla”, Hospital Rivadavia, Av. Gral. Las Heras 2670, 3 ◦ piso, C1425ASQ, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. Tel.: +54 11 4809 0799. E-mail addresses: maria cecilia martin@yahoo.com.ar (M.C. Martín), ecristiano@speedy.com.ar (E. Cristiano), mervi3178@yahoo.com.ar (M. Villanueva), drabonora@gmail.com (M.L. Bonora), nydiaberguio@yahoo.com.ar (N. Berguio), anatocci 52@live.com.ar (A. Tocci), bgroisman@gmail.com (B. Groisman), mariapazbidondo@gmail.com (M.P. Bidondo), rosaliascovich@hotmail.com (R. Liascovich), pablobarbero63@hotmail.com (P. Barbero). hormones and maternal alcohol and smoking. So far, no specific environmental risk factor has consistently been identified [3]. Mycophenolate mofetil (MMF) or its metabolite mycophenolic acid (MPA) is an immunosuppressive drug that acts as a selective, non-competitive and reversible inhibitor of the enzyme inosine monophosphate dehydrogenase. This drug is widely used for the management of solid organ transplants and autoimmune diseases, among others. MMF showed teratogenic effects in preclinical studies [4] and in vitro studies [5,6]. In 2007, MMF was reclassified from class C to D because the FDA acted proactively in response to postmarketing studies indicating potential increased risk of first trimester mis- carriage and specific birth defects with predominant craniofacial abnormalities [4]. At present, information on the human teratogenic effect of mycophenolate includes at least 19 case reports with malfor- mations observed after exposure in early pregnancy [7] and a prospective study that identified a 26% of malformations incidence and a rate of spontaneous abortion about twice as high than in low-risk pregnancies [8]. The complete clinical pattern is still being delineated. Esophageal atresia has been described only in a few cases, so their inclusion in mycophenolate embryopathy is not clear [8–11]. http://dx.doi.org/10.1016/j.reprotox.2014.10.015 0890-6238/© 2014 Elsevier Inc. All rights reserved.