Leflunomide - A human teratogen? A still not answered question. An evaluation of the German Embryotox pharmacovigilance database

Reprod Toxicol. 2017 Aug:71:101-107. doi: 10.1016/j.reprotox.2017.04.007. Epub 2017 May 3.

Abstract

The teratogenic potential of leflunomide (LEF) in humans is still a matter of debate. We evaluated exposed pregnancies of our German Embryotox pharmacovigilance database. Inclusion criteria were LEF exposure anytime between 2 years before and 10 weeks after conception and no wash-out therapy before pregnancy. Of 65 prospectively enrolled pregnancies 47 were exposed during the 1st trimester and 18 preconceptional. Wash-out therapy was confirmed in 25 pregnancies. There were 10 spontaneous abortions and 19 elective terminations. Among 39 live-born children (including twins) one major malformation was recorded. A separate analysis of our retrospective adverse drug reaction database revealed one LEF-exposed case having no malformations. Our findings provide further evidence that LEF is not a major human teratogen. However, an embryotoxic potential resulting in an increased miscarriage rate cannot be ruled out. The recommendation of a waiting period of two years and a plasma level below 0.02mg/L seems too cautious.

Keywords: Birth defect; Leflunomide; Malformation; Pregnancy; Spontaneous abortion; Teratogen; Teriflunomide.

MeSH terms

  • Abnormalities, Drug-Induced / epidemiology*
  • Abortion, Spontaneous / epidemiology*
  • Adolescent
  • Adult
  • Adverse Drug Reaction Reporting Systems
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy
  • Esophageal Atresia / epidemiology
  • Female
  • Germany
  • Humans
  • Infant, Newborn
  • Isoxazoles / therapeutic use*
  • Leflunomide
  • Male
  • Maternal-Fetal Exchange
  • Pharmacovigilance
  • Pregnancy
  • Pregnancy Trimester, First
  • Teratogens
  • Tracheoesophageal Fistula / epidemiology
  • Young Adult

Substances

  • Antirheumatic Agents
  • Isoxazoles
  • Teratogens
  • Leflunomide