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Leflunomide is a pyrimidine synthesis inhibitor with proven teratogenic and fetotoxic effects in animal studies, and its active metabolite is detectable in plasma up to 2 years after discontinuation of the drug.1–3 For this reason the fetus could have in utero exposure to leflunomide up to 2 years after the end of treatment unless an oral cholestyramine regimen, 8 g three times daily for 11 days, is administered to obtain undetectable plasmatic levels.1–3 Leflunomide has been classified as pregnancy category X by the Federal Drug Administration and the manufacturer recommends that for women of childbearing age “treatment with leflunomide must not be started until pregnancy is excluded and it has been confirmed that reliable contraception is being used”.1,4 Label instructions about paternal exposure recommend a washout procedure to minimise any possible risk.1,4 To date, there have been no epidemiological human studies of pregnancies after or during paternal or maternal leflunomide exposure, and current knowledge is restricted to a few cases.2,4
We report on five cases of women who conceived within 2 years after the discontinuation of, or during, leflunomide treatment, and one case of pregnancy during paternal exposure (table 1). They were referred to our teratogen information service between July 2002 and January 2004.
Four women were exposed in the first trimester and one conceived 6½ months after stopping the treatment. Despite our recommendation, none of the women performed the washout procedure, resulting, therefore, in fetal exposure to therapeutic drug levels during organogenesis. In the case of paternal exposure, leflunomide was taken from 6 months before conception and during the whole pregnancy with intercourse without a condom during the gestation.
Three women had voluntary abortions owing to the fear of malformation and three women had live births with healthy babies (two maternal and one paternal exposure). In one of the two cases of maternal exposure the leflunomide treatment was given until 6½ months before the conception, in the other until the 9th week of gestation. They delivered their babies at 39 and 36 weeks, both by caesarean section, weighing 2600 and 2200 g respectively, with normal neonatal outcome. These cases increase the number of previously reported cases, bringing to four the number of live birth normal babies with complete follow up. To date there has been no report of human congenital malformation after prenatal leflunomide exposure. In the case of paternal treatment, a normal baby of 3350 g was delivered by caesarean section at 38 weeks—the first reported case.
Seven cases of babies born with congenital malformations were reported by Ostensen referring to a manufacturer’s safety update to 2003 about 164 pregnancies followed up completely in 310 women exposed. Of these 164 cases, 85 were full term pregnancies, 43 were voluntary abortions, and 36 miscarried.5
Chakravarty et al reported 10 pregnancies in patients taking leflunomide: two cases lost at follow up, two continuing pregnancies, two legal abortions, one spontaneous abortion, two full term healthy babies, and one preterm infant without detailed follow up.4
The scarcity of published data about human pregnancy and neonatal outcome justifies the collection of as many cases as possible because in teratological counselling it is mandatory to consider all known human cases once a drug has been indicated as a potential teratogen in experimental studies. A post-marketing surveillance study has been established by the manufacturer to monitor the outcome of pregnancies, including first trimester exposures.2,6
At present the possible fetal and neonatal side effects of leflunomide exposure are being investigated by a Canadian OTIS (Organisation of Teratology Information Service) in a prospective study.5
We consider it advisable to warn couples that no controlled or adequate study is available and for inadvertent exposure during pregnancy it is necessary to inform them about the theoretical reproductive risk reported in animal studies and to recommend the washout procedure and accurate fetal ultrasound examinations.