Leflunomide Exposure During Pregnancy Not Associated With Increased Risk for Adverse Outcomes

pregnant woman taking a pill
pregnant woman taking a pill
The safety of leflunomide use for rheumatoid arthritis during pregnancy was examined in a prospective study.

Although caution still remains, leflunomide exposure during pregnancy was not associated with a statistically significant increased risk for major congenital malformations, prematurity, low birth weight, or spontaneous abortions, according to a prospective study published in the Annals of Rheumatic Diseases.1

Used for the treatment of active rheumatoid arthritis in Canada, leflunomide is a disease-modifying antirheumatic drug that is embryotoxic and teratogenic in rodents.2-4 Previously classified as a pregnancy category X drug by the US Food and Drug Administration, there are few data available on its effects on the developing embryo.3

A population-based cohort study was subsequently conducted using data from an ongoing prospective study of 289,688 pregnancies in Quebec from January 1, 1998, to December 31, 2015.1 Of these, 51 pregnancies were exposed to leflunomide during the first trimester and 21 were exposed to leflunomide during the second/third trimesters of pregnancy.

The study researchers found that during the first trimester, use of leflunomide was not associated with an increased risk for major congenital malformation. During the second or third trimesters, there was no increased risk for prematurity or low birth weight. In addition, there was no increased risk for spontaneous abortion from exposure to leflunomide during pregnancy.

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The main limitation of this study was the small number of women exposed to leflunomide during pregnancy; however, it is the largest population-based study of its kind published to date.1 A second limitation of the study was the lack of data on smoking, folic acid intake, and alcohol use, which are potential confounders.

The study authors concluded, “These findings are consistent with other studies in the literature, but more studies are needed to confirm these findings as the number of exposed pregnant women is still relatively uncommon and lack of statistical power could explain part of our findings.”

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  1. Bérard A, Zhao J, Shui I, et al. Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes [published online December 8, 2017]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2017-212078
  2. Prakash A, Jarvis B. Leflunomide: a review of its use in active rheumatoid arthritis. Drugs. 1999;58:1137-1164.
  3. Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology. 2001;63:106-112.
  4. Fukushima R, Kanamori S, Hirashiba M, et al. Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor leflunomide in mice. Reprod Toxicol. 2007;24:310-316.