Little Risk With Leflunomide in Early Pregnancy?

Janis C. Kelly

February 13, 2012

February 13, 2012 — Women with rheumatoid arthritis (RA) who inadvertently become pregnant while taking leflunomide or who were exposed to leflunomide before conception will likely no longer be routinely advised to terminate the pregnancy, thanks to reassuring data reported by the Organization of Teratology Information Specialists (OTIS) Collaborative Research Group in an article published online February 3 in Arthritis & Rheumatism.

Megan E.B. Clowse, MD, MPH, director of the Duke Autoimmunity in Pregnancy Clinic and Registry at Duke University Medical Center in Durham, North Carolina, who reviewed the article for Medscape Medical News, said, "These data are extraordinarily reassuring. In combination with this group's earlier cohort study of leflunomide (which found a rate of anomalies similar to that in the general population for women who had early leflunomide exposure and underwent the full cholestyramine drug elimination procedure), this paper should be reassuring to patients who become pregnant unexpectedly while taking or after taking leflunomide."

Dr. Clowse added, "Patients who become pregnant while taking leflunomide should be advised to discontinue the drug immediately and undergo full-dose cholestyramine washout. I would then follow them closely with ultrasound throughout the pregnancy."

In an article published in the May 2010 issue of the same journal ( Arth Rheum. 2010;62:1494-1503) senior author Christina Chambers, PhD, MPH, and colleagues had reported a cohort study of pregnancy outcomes in women who became pregnant while receiving leflunomide and who underwent the cholestyramine drug elimination procedure.

The new study, based on 45 women who did not meet the eligibility criteria for inclusion in the cohort study and who had been exposed to leflunomide either during the first trimester of pregnancy or before conception, found no malformations in babies in the preconception group. Two infants exposed during early pregnancy had major malformations, but there were potential known alternative etiologies for at least some of the defects observed.

Leflunomide Not a Major Cause of Birth Defects

Dr. Chambers, who is professor of pediatrics and family and preventive medicine at the University of California, San Diego, told Medscape Medical News, "We think this study adds to our findings from the previously published cohort study in supporting the conclusion that this medication, at least when used in the first weeks of gestation and followed by the washout procedure, is not a major cause of birth defects."

Dr. Chambers added that the important consideration for women now taking leflunomide, but planning conception, is the need to have blood level of the drug checked before attempting to conceive to be sure that levels of the drug are below the recommended limits.

Among the study participants in the extended article, there were 2 infants with major malformations in the 16 pregnancies in women exposed during the first trimester (all of whom discontinued leflunomide on recognition of pregnancy, and 15 of whom underwent at least 1 washout procedure with cholestyramine). There were no major malformations among the 27 pregnancies in women exposed within 2 years before the estimated date of conception.

One of the newborns with major malformations was a live-born female monozygotic twin with aplasia cutis congenita involving both thighs. The authors report that the other twin was spontaneously aborted and that "there are several case reports in the literature of this skin defect found in body areas other than the scalp in the surviving member of a monozygotic twin pair."

The other newborn with a major malformation was a boy with multiple anomalies (Pierre Robin sequence, spina bifida occulta, patent ductus arteriosus, chondrodysplasia punctata, and congenital heart block), who was born to a mother with both RA and systemic lupus erythematosus (SLE). Dr. Clowse, who is familiar with this case, told Medscape Medical News, "In the little-known Pierre Robin anomaly, there appears to be an association between neonatal lupus and the cartilage defects. There are at least a dozen cases in the literature of reporting an association between this anomaly and autoantibodies. In addition, the mother had been on a very low dose of leflunomide. It seems clear the leflunomide was not the sole cause, assuming that it was involved at all."

"Black Box" Warning Explained: Animal vs Human Data on Leflunomide

The "black box warning" about the risk for birth defects associated with leflunomide was in part a result of the work of Robert L. Brent, MD, PhD, head of the Clinical and Environmental Teratology Research Lab at the A.I. duPont Hospital for Children in Wilmington, Delaware. Dr. Brent served as a consultant to sanofi-aventis during preparation of the clinical data for obtaining US Food and Drug Administration (FDA) approval for the drug.

Dr. Brent told Medscape Medical News, "I reviewed all of the preclinical, clinical, and laboratory data for leflunomide, and the rodent and rabbit studies showed a very [high] rate of birth defects at the same blood levels as the therapeutic level in humans. That was the reason for the black box warning.

"But after leflunomide was widely available, something unexpected happened: Within 2 months, I received calls regarding 2 women with RA who had become pregnant while taking leflunomide. Both had suffered from RA for many years, and both were not using birth control because they thought they were infertile. I don't really have a hypothesis about what happened, but within a few months 30 women who took leflunomide and conceived while assuming they were infertile had been referred to me. Given the data we had then, all I could tell them was that the animal data suggest a high risk for major malformations. Twenty-seven of those 30 terminated their pregnancies. The other 3 had normal babies. The calls kept coming in, and finally I suggested that the company work with the OTIS to study these pregnancies."

Ashima Makol, MD, from the Division of Rheumatology at the Mayo Clinic in Rochester, Minnesota, also reviewed the study for Medscape Medical News and is somewhat more cautious.

Dr. Makol said, "Two cases of major malformations were detected in the pregnancy-exposed group, 1 of which had multiple anomalies (Pierre Robin sequence, spina bifida occulta, patent ductus arteriosus, chondrodysplasia punctata, and congenital heart block). Some of these features could potentially be seen with leflunomide exposure as well, and its role here cannot be conclusively determined or ruled out. The authors suggest the possibility of the congenital heart block to be related to overlap with SLE in that patient, but whether the patient had positive Ro and La antibodies that are associated with congenital heart block was not described in the study findings."

"Overall," Dr. Makol added, "I think it is still reassuring and a sigh of relief for some women who inadvertently become pregnant while on leflunomide and undergo the washout procedure, reducing the drug to insignificant levels. But it is hard to ignore the preclinical studies in rats and rabbits that have consistently demonstrated fetal anomalies.

"These findings could be species-specific, as similar types of congenital anomalies have not been observed in humans exposed to the drug, based on observational studies so far, but since the pharmacokinetic level of leflunomide's active metabolite reached clinically in humans is in the range that results in teratogenesis in animals, the teratogenic potential of leflunomide has thus been extrapolated to humans. This metabolite has a long half life of about 96 days, and due to this, the drug could potentially be bioavailable in a woman even 2 years after discontinuing leflunomide."

He concluded, "Fortunately, an 11-day washout with cholestyramine at 8 g 3 times daily prior to conception reduces the active metabolite's half-life to 1 day and drops the level of the active metabolite to less than 0.02 μg/mL, which has been shown to be the 'no-effect' level in humans, reducing any possibility of causing problems with organogenesis during the critical period from third to eighth weeks after conception."

Dr. Brent told Medscape Medical News that subsequent research on leflunomide appears to explain the difference between the rodent/rabbit and human data. "We learned that the issue with leflunomide is not pharmacokinetics. Researchers found that in rodents and rabbits, the drug suppresses an enzyme required for DNA synthesis, but in humans that enzyme is not very sensitive to leflunomide. So I was not surprised at Dr. Chambers' findings."

How Do the Data Affect Women of Reproductive Age?

All of the physicians interviewed for this story emphasized that these data do not mean leflunomide is safe for use during pregnancy.

Dr. Makol said, "All women in the reproductive age group should be counseled about the potential risks of pregnancy while on leflunomide. It continues to be labeled a pregnancy category X drug by the FDA, based on preclinical data, and hence discussing the risk of embryotoxicity and teratogenicity is critical. Women should ideally use 2 different contraceptives while on the medication."

He added, "Leflunomide should be stopped 2 years prior to conception to ensure complete elimination of the drug from the body, or a washout with cholestyramine for 11 days be attempted if this is not feasible. Those with active disease can be switched to safer medications like hydroxychloroquine, sulfasalazine, or azathioprine, which have more human data to back up their safety. Corticosteroids can be used at lowest possible doses or intra-articularly for acute flares. [Nonsteroidal anti-inflammatory drugs] can also be used, but must be avoided in the third trimester to avoid premature closure of the ductus arteriosus."

Dr. Brent concluded, "I never tell a mother what to do [in the situation of becoming pregnant while taking leflunomide]. Tell them what the risks are, but they make the decision. And always tell them that even if they are perfectly healthy, there is a 3% risk of birth defects and a 15% miscarriage rate associated with any pregnancy."

The study was supported by sanofi-aventis. Dr. Brent has served as a consultant for sanofi-aventis. Dr. Chambers, Dr. Clowse, and Dr. Makol have disclosed no relevant financial relationships.

Arthritis Rheum. Published online February 3, 2012. Abstract

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