Women who took Arava had a 5.4 percent rate of major structural defects while a disease-matched comparison group and a healthy comparison group each had rates of 4.2 percent. According to principal investigator Christina D. Chambers, PhD, MPH, of the Department of Pediatrics at the University of California, San Diego School of Medicine, that is not a significant difference from the 3 to 4 percent rate expected in the general population. In addition, there was no specific pattern of minor malformations in the women who used Arava early in pregnancy.
“The recommendation still stands that leflunomide should be avoided in pregnancy and, if a woman becomes pregnant, she should go through the drug washout procedure,” explained Chambers. “And though ours is a small study which cannot definitively rule out increased risks for specific major congenital defects with prenatal leflunomide exposure, the findings can help clinicians to better counsel those patients who have very early pregnancy exposure and have gone through the washout procedure.”
For 10 years, Chambers and colleagues from the Organization of Teratology Information Specialists (OTIS) Collaborative Research Group conducted a pregnancy outcome study of women with first-trimester exposure of any duration to the drug. Participants were recruited from the 70,000 pregnant women who call the OTIS counseling program throughout the U.S. and Canada each year, as well as from contacts with rheumatologists. Sanofi-Aventis, the drug manufacturer, also encouraged referrals.
A total of 250 participants from the U.S. and Canada enrolled in the study – 64 in the leflunomide-exposed group, 108 in the disease-matched comparison group, and 78 in the healthy comparison group. The women in the exposed group had rheumatoid arthritis or juvenile rheumatoid arthritis and had taken at least one dose of the drug after conception.
A unique feature of this study was the specialized physical examination conducted for the majority of live-born infants by one of a team of pediatric dysmorphologists led by co-principal investigator, Kenneth Lyons Jones, MD, chief of the division of dysmorphology and teratology in the UCSD Department of Pediatrics. These blinded physical examinations were conducted in the participant’s location and allowed the investigators to determine that there was no specific pattern of minor anomalies in infants born to mothers exposed to Arava.
This is the first human study on this Category X medication, one of only six medications in the U.S.in this category. A Category X designation indicates that the drug is to be avoided in pregnancy under all circumstances, as it is presumed to cause birth defects, leading to almost universal termination of pregnancy. These study results have already prompted a label change for leflunomide in Europe.
In addition to Chambers and Jones, the research team included Diana L. Johnson, MS; Janina Lopez-Jiminez, MA; Nicole Mirrasoul, BS; Elizabeth Salas, BA; and Yunjun Luo, MS of the Department of Pediatrics, UC San Diego and Rady Children’s Hospital, San Diego; as well as Ronghui Xu, PhD, Department of Family and Preventive Medicine and Department of Mathematics, UC San Diego; Shelia Jin, MD, MPH, Department of Family and Preventive Medicine, UC San Diego; Luther K. Robinson, MD, Department of Pediatrics, University of Buffalo; and Stephen R. Braddock, MD, Department of Pediatrics, University of Virginia.
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