FROM ANNALS OF THE RHEUMATIC DISEASES
Leflunomide use in pregnancy was not associated with an increased risk of malformations in newborns in a population-based study of 289,688 pregnancies in Canada.
Leflunomide, prescribed in Canada to treat active rheumatoid arthritis, was previously classified as a category X pregnancy medication because it is embryotoxic and teratogenic in rats and rabbits in doses similar to those used in humans, wrote Anick Bérard, MD , of CHU Sainte Justine, Montreal, and her colleagues, in a study published in Annals of the Rheumatic Diseases .
However, data on the impact of leflunomide on a developing human embryo are limited, so the researchers analyzed the Quebec Pregnancy Cohort, an ongoing study of all pregnancies in Quebec, Canada, between Jan. 1, 1998, and Dec. 31, 2015.
Overall, the researchers found 51 pregnancies that were exposed to leflunomide in the first trimester, which included five cases of major congenital malformations, suggesting no significant association (adjusted odds ratio, 0.97; 95% confidence interval, 0.81-1.16). No significant association appeared between leflunomide use in the second or third trimester (n = 21 pregnancies) and an increased risk of prematurity (aOR, 4.03; 95% CI, 0.91-17.85) or low birth weight (aOR, 1.06; 95% CI, 0.90-1.25). In addition, spontaneous abortion was not associated with leflunomide use at any point during pregnancy (aOR, 1.09; 95% CI, 0.90-1.32).
The findings are consistent with those from previous studies and suggest that continued caution is warranted for women of childbearing age who are taking or considering leflunomide, the researchers concluded.
They also examined the potential impact of several categories of other antirheumatic drugs to account for indication bias: other conventional disease-modifying antirheumatic drugs, biologic agents, nonsteroidal anti-inflammatory drugs, oral corticosteroids, and gold salts. Oral corticosteroid use in the first trimester was associated with an increased risk of major congenital malformations (aOR 1.31; 95% CI, 1.06-1.61), and the risk of prematurity also was significant with their use in the second or third trimester (aOR 1.32; 95% CI, 1.09 to 1.60). The risk of major congenital malformations was significantly higher with the use of NSAIDs in the first trimester (aOR 1.15; 95% CI, 1.03-1.29). Any use of disease-modifying antirheumatic drugs overall between the first day of gestation and the index date increased the odds for spontaneous abortion (aOR, 1.54; 95% CI, 1.06-2.22).
Cholestyramine may lower the blood level of the active metabolite of leflunomide to a safe level, the researchers noted, but the study population showed no evidence of cholestyramine or charcoal use for leflunomide washout, and any cholestyramine exposures during pregnancy were not concurrent with leflunomide exposure. “In three first-trimester leflunomide-exposed pregnancies, cholestyramine was introduced in monotherapy in the third trimester,” they wrote.
The results were limited by the small number of women exposed to leflunomide, despite the population-based study being the largest of its kind published to date, the researchers said.
The study was supported in part by the Fonds de la Recherche du Québec-Santé and by Sanofi. Two authors are employees of Sanofi.