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Extended report
Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes
  1. Anick Bérard1,2,
  2. Jin-Ping Zhao1,
  3. Irene Shui3,
  4. Susan Colilla4
  1. 1 Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada
  2. 2 Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
  3. 3 Global Pharmacovigilance and Epidemiology, Sanofi Genzyme, Cambridge, Massachusetts, USA
  4. 4 Global Pharmacovigilance and Epidemiology, Sanofi, Bridgewater, New Jersey, USA
  1. Correspondence to Dr Anick Bérard, Research Center, CHU Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, QC H3T 1C5, Canada; anick.berard{at}


Objectives Leflunomide is known to be embryotoxic and teratogenic in rodents. However, there is less evidence in humans. We quantified the risk of major congenital malformation (MCM), prematurity, low birth weight (LBW) and spontaneous abortion associated with leflunomide exposure during pregnancy in humans.

Methods From a cohort of 289 688 pregnancies in Montreal, Quebec, Canada, from 1998 to 2015, first-trimester leflunomide exposure and other antirheumatic drug exposures were studied for their association with MCM and spontaneous abortions. Also second or third-trimester leflunomide exposures were examined for associations with prematurity and LBW. Logistic regression model-based generalised estimating equations were used.

Results 51 pregnancies were exposed to leflunomide during the first trimester, and 21 during the second/third trimesters. Adjusting for potential confounders, use of leflunomide during the first trimester of pregnancy was not associated with the risk of MCM (adjusted OR (aOR) 0.97, 95% CI 0.81 to 1.16; 5 exposed cases). No association was found between second/third-trimester exposure to leflunomide and the risk of prematurity (aOR 4.03, 95% CI 0.91 to 17.85; 7 exposed cases) nor LBW (aOR 1.06, 95%CI 0.90 to 1.25; 8 exposed cases). Pregnancy exposure to leflunomide was also not associated with the risk of spontaneous abortion (aOR 1.09, 95% CI 0.90 to 1.32; 11 exposed cases).

Conclusions Maternal exposure to leflunomide during pregnancy was not associated with statistically significant increased risk of MCMs, prematurity, LBW or spontaneous abortions. However, given that relatively few women were exposed to leflunomide during pregnancy in this cohort, caution remains warranted.

  • Leflunomide
  • pregnancy exposure
  • major congenital malformation
  • low birth weight
  • spontaneous abortion

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  • Handling editor Tore K Kvien

  • Contributors All authors were involved in drafting the article or revising it critically for important intellectual content and approved the final version to be published. AB had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: AB, JPZ, IS, SC. Acquisition of data: AB. Analysis and interpretation of data: AB, JPZ, IS, SC.

  • Funding The study was supported by the Fonds de la Recherche du Québec-Santé (FRQ-S, grant number 30962 to AB), and sponsored and funded by Sanofi, USA.

  • Competing interests AB and JPZ declare no financial interest relating to the subject discussed in the manuscript; IS and SC are employees of Sanofi.

  • Ethics approval The study was approved by the Quebec Data Access Agency and the CHU Sainte-Justine Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data from this study, published and unpublished, were made available to all authors. Further inqury regarding availability of the data can be addressed to AB (