The results of a case series looking at the outcome of women exposed to leflunomide either before or during the first trimester of pregnancy have been published early online in Arthritis & Rheumatism.

The authors note that leflunomide has been found to be embryotoxic and teratogenic in animal studies, but that there are limited data on its use in human pregnancy.  The results of a prospective, controlled cohort study conducted by the Organization of Teratology Information Specialists (OTIS) evaluating the outcome of pregnancies exposed to leflunomide have previously been published.  This did not find any increased risk of adverse outcomes; however only a small proportion of women were exposed to full doses of leflunomide beyond conception (as all women stopped treatment when they realised they were pregnant).

The current study looks at the outcomes of an additional 45 women enrolled in OTIS, who did not meet the criteria for inclusion in this previous study, but who were exposed to leflunomide in pregnancy (n=16; all during the first trimester) or only prior to pregnancy (n=29).  Specifically, the reasons that they did not meet the cohort inclusion criteria included enrolment after 20 weeks’ gestation, use for an indication other than rheumatoid arthritis, or discontinuation of the drug less than two years prior to conception, with no confirmation that the drug had been eliminated prior to pregnancy (so there could have possibly been exposure during pregnancy).  These women had all contacted the Teratology Information Services in the US or Canada between 1999 and 2009.   

The authors report that all women in the pregnancy-exposed group stopped leflunomide upon recognition of pregnancy, and most (81.3%) underwent at least one washout procedure with cholestyramine.  In the pre-conception group, the majority (65.5%) discontinued treatment during the last 15 weeks prior to conception, and most (72.4%) underwent the washout procedure.  The proportion of women exposed to systemic steroids and NSAIDs was comparable in the two groups, but women who discontinued leflunomide therapy before conception more commonly reported taking systemic steroids during the first trimester of pregnancy (51.7%). Therapy of three women in the pregnancy-exposed group (18.8%) also included methotrexate.

The main findings reported were as follows:

• All 16 of the pregnancies exposed during pregnancy and 27 (93%) of those exposed only prior to conception resulted in live born infants.

• There were two infants with major malformations among those exposed during pregnancy, with a potential known alternative aetiology for at least some of the defects observed (aplasia cutis congenital in one [possibly the result of a co-twin demise] and multiple anomalies in the other [born to a mother with systemic lupus erythematosus]).

• There were no major congenital malformations reported in the preconception exposure group.

• Women exposed to leflunomide during pregnancy had a higher rate of preterm delivery than those whose last dose was prior to conception; the authors suggest that this is likely to be a consequence of the underlying maternal diseases and/or the concomitant use of oral steroids

• One case with functional anomalies was observed in each of the two groups (sensorineural hearing loss and intrauterine growth restriction and cerebral palsy; the latter was born at the 31st week of gestation to a mother with juvenile rheumatoid arthritis, diabetes, hypertension and asthma).

• Three or more minor anomalies were seen in 50% of infants in the pregnancy-exposed group and 42.9% of infants in the pre-conception group.  Two in the pregnancy-exposed group had the same three defects but the authors comment that this pattern may be due to chance as it was not seen in any of the exposed infants in the previously published cohort study, and was not associated with additional major malformations in this exposure case series.

The authors discuss the limitations of their study, including the lack of an unexposed control group, and the use of a volunteer sample (which may limit generalisability).  They say however that it adds to the previous cohort study by providing data on pregnancies exposed beyond the first 3-4 weeks (40% continued until at least 6.9 weeks post-conception), and on those who stopped treatment prior to conception but who did not have their preconception blood levels documented.  They conclude that their data provide “additional reassurance to women who inadvertently become pregnant while taking leflunomide and who undergo the washout procedure, and women who discontinue the medication prior to conception but have no pre-pregnancy documentation of drug clearance.”  They caution however that women taking leflunomide should be advised to use contraceptive methods and avoid pregnancy, until more conclusive data become available.