A critical review of the reproductive safety of Leflunomide

  • Birgit Pfaller
  • Anna Pupco
  • Tom Leibson
  • Daniel Aletaha
  • Shinya ItoEmail author
Perspectives in Rheumatology


Leflunomide, an inhibitor of pyrimidine synthesis, is used for the treatment of rheumatic diseases, which are prevalent in women of childbearing age. Due to the very long half-life of the active metabolite, its mechanism of action and the teratogenicity observed in animal studies at doses similar to or lower than human therapeutic doses on a weight basis, it is recommended that women stop the treatment before conception and a drug elimination procedure be performed. However, unintended gestational exposures may occur, posing challenges in risk assessment. In order to address the safety of leflunomide in unintended exposures in pregnancy, we performed a critical review of human studies. We located 13 publications in Medline and Embase, which reported on 222 pregnancies with known outcomes exposed to leflunomide preconception and/or during pregnancy. Among the 169 live births, there were eight congenital malformations with no consistent pattern of anomalies. These studies collectively showed no significant difference in the rates of malformations between exposed and unexposed pregnancies. At present, accumulating human data do not point toward leflunomide as a potent human teratogen, which may inform risk assessment of unintended gestational exposure to leflunomide.


Congenital anomalies Leflunomide Pregnancy Rheumatic disease Safety Teratogen 


Compliance with ethical standards


S. Ito received a grant from UCB Pharma GmbH and a consultant fee from AbbVie.

D. Aletaha received speaker and/or consultancy fees from Abbvie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme and grants from AbbVie, Novartis, Roche.


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Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Toronto Pregnancy and Heart Disease Research Program, Mount Sinai Hospital and Toronto General HospitalTorontoCanada
  2. 2.Division of Clinical Pharmacology and Toxicology, Department of PediatricsHospital for Sick ChildrenTorontoCanada
  3. 3.Department of PediatricsMount Sinai HospitalTorontoCanada
  4. 4.Department of RheumatologyMedical University of ViennaViennaAustria

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