READING, UK—Leflunomide (AravaR) has been reported to cause teratogenic effects in animals and is suspected of causing blindness and cerebral palsy in the son of a woman who took the drug through the first 21 weeks of gestation, report Drs. C. E. Neville and J. McNally in a letter in Rheumatology.¹

"Patients on leflunomide and other teratogenic drugs should use contraception and be frequently reminded during clinic visits of the dangers of pregnancy and the potential for teratogenicity of DMARDs," Dr. Neville writes.

Exposure in first 21 weeks of gestation

The mother in this case had active, difficult-to-control rheumatoid arthritis (RA) and was "intermittently compliant with blood tests and clinic visits because of a fear of hospitals." Methotrexate had been discontinued after a chest infection and the patient refused to restart it. She had problems with diarrhea during azathioprine treatment, and she was maintained for 4 years on prednisolone alone but with poor disease control. The woman had three prior pregnancies: the first baby died of a congenital heart defect within 24 hours of birth in 1982; a healthy daughter was born in 1988; and a son, later diagnosed with autism, was born in 1991.

Leflunomide was started in March 2001. The authors write, "Before starting the drug, the patient was counselled specifically about the risks of pregnancy and the need for adequate contraception. Written advice was also given to the patient, who was literate."

Leflunomide brought the RA into remission within 6 months, but the patient failed to use contraception and became pregnant in December, at which time she had been taking leflunomide 20 mg/day for at least 8 months. At 21 weeks of gestation, she was seen urgently by an obstetrician, who stopped leflunomide and began treatment with cholestyramine. The patient refused amniocentesis and termination, and the fetus appeared normal on a scan that day.

"An apparently healthy male was born 9 weeks prematurely, but was subsequently found to be blind in the right eye, and to have cerebral palsy with left-sided spasticity," Dr. Neville reports.

But association is not causality

Monika Østensen, MD, with the department of rheumatology at the University Hospital of Bern, in Switzerland, told CIAOMed that she is not convinced that leflunomide caused these problems.

"Cerebral palsy occurs in 2 of 1000 live births, and in 80% of cases the reason is unknown," she said. "The known reasons are mainly maternal infection. Prematurity, which the child of the case report had, increases the risk of cerebral palsy. Based on these facts I find it difficult to state a causal relationship between intake of leflunomide and the malformations."

Dr. Østensen added, "the results of an ongoing study of the Organization of Teratology Information Specialists (OTIS), which collects prospective data on intrauterine exposures to leflunomide, are thus far not alarming. The preliminary results of 63 RA pregnancies exposed to leflunomide during the first trimester have not shown any increase in miscarriage or congenital malformations compared to 108 RA pregnancies not exposed." Dr. Østensen recently reported that 20% of pregnancies in women with RA are conceived during treatment with a potentially fetotoxic drug.²

After patients are unintentionally exposure to leflunomide, Dr. Østensen always recommends amniocentesis or chorionic villi biopsy. She notes that neither procedure would have detected the problems of the child in the reported case, however.

"Because of limited human experience, we still cannot answer whether leflunomide is a human teratogen. One case does not change that," Dr. Østensen concluded.

References

1. Neville CE and McNally J. Maternal exposure to leflunomide associated with blindness and cerebral palsy.  Neville CE and McNally. Rheumatology. 2007; doi:10.1093/rheumatology/kem170 [Epub ahead of print].

2. Ã˜stensen M, von Esebeck M, Villiger PM. Therapy with immunosuppressive drugs and biological agents and use of contraception in patients with rheumatic disease. J Rheumatol. 2007;34:1266-1269.