The impact of thalidomide use in birth defects in Brazil Fernanda Sales Luiz Vianna a, b, c, d, * , Thayne Woycinck Kowalski a, b , Lucas Rosa Fraga a, b , Maria Teresa Vieira Sanseverino a, b, c , Lavinia Schuler-Faccini a, b, c a National Institute of Medical Population Genetics (INAGEMP), Porto Alegre, Brazil b Post-graduate Program in Genetics and Molecular Biology, Rio Grande do Sul Federal University (UFRGS), Porto Alegre, Brazil c Teratogen Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil d Post-Graduate Program in Epidemiology, Rio Grande do Sul Federal University (UFRGS), Porto Alegre, Brazil article info Article history: Received 14 April 2016 Accepted 12 September 2016 Available online 13 September 2016 Keywords: Thalidomide Embryopathy Teratogenesis Pharmacovigilance abstract Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed. © 2016 Elsevier Masson SAS. All rights reserved. 1. History of thalidomide Thalidomide (a-N-phthalimido-glutarimide) was synthesized in 1954 in West Germany by the Chemie Grünenthal company, and was introduced to the German market in 1956 (Lenz, 1988)(Fig. 1). At the time, it was prescribed for the treatment of several condi- tions such as irritability, poor concentration, anxiety, insomnia, nausea, morning sickness, hyperthyroidism, and even infectious diseases (Lenz, 1988; Saldanha, 1994). Considered to be safe, it was available without medical prescription (Lenz, 1988; Saldanha, 1994). It quickly began to be manufactured and sold worldwide, under different trade names. In 1959, an increasing number of newborns began to be re- ported with a phenotype called phocomelia (limb reduction defects of long bones, in which hands and feet varied between normal and rudimentary), frequently associated to malformations of inner or- gans. However, it was only at the end of 1961 that Lenz suggested a possible link between the sudden emergence of these congenital abnormalities and the use of thalidomide during pregnancy (Lenz and Knapp, 1962). At the same time, in Australia, McBride also observed a 20% increase in babies with phocomelia correlated with the use of the drug (McBride, 1961). Although the teratogeniciy of thalidomide had not yet been experimentally proven at that time, thalidomide was quickly withdrawn from the market in Germany and England, and later in several other countries (Saldanha, 1994). By August 1962, a large decline in births with limb malformations was observed (Shardein, 1993), but at least 10,000 affected children were already born worldwide (Oliveira et al., 1999; Matthews and McCoy, 2003). Still in the 1960s, the therapeutic action of thalidomide on er- ythema nodosum leprosum (ENL) - an inflammatory complication of leprosy - was accidently discovered (Sheskin, 1965). Several studies since then have demonstrated its potential in the treatment of several other conditions d especially ENL and multiple myeloma (MM) d due to its anti-inflammatory, immunomodulatory, and anti-angiogenic properties (Sampaio et al., 1991; Rajkumar and Blood, 2006). Currently, thalidomide is used to treat a range of different conditions around the world, and analogues with better * Corresponding author. Fernanda Sales Luiz Vianna, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos 2350, 90035-903, Porto Alegre, RS, Brazil. E-mail address: fslvianna@gmail.com (F. Sales Luiz Vianna). Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg http://dx.doi.org/10.1016/j.ejmg.2016.09.015 1769-7212/© 2016 Elsevier Masson SAS. All rights reserved. European Journal of Medical Genetics 60 (2017) 12e15