Pregnancy in Autoimmune Disease

Meghan Clowse, M. D.

514: Pregnancy Outcome in Women Exposed to Adalimumab: The OTIS Autoimmune Diseases in Pregnancy Project

513: Pregnancy Outcome in Women Exposed to Leflunomide: The OTIS Autoimmune Diseases in Pregnancy Project

Authors: Christina D. Chambers, Diana L. Johnson, Kenneth Lyons Jones, OTIS Collaborative Research Group. University of California at San Diego, La Jolla, CA

The OTIS Autoimmune Diseases in Pregnancy Project presented abstracts on the use of 2 important rheumatologic medications.  The OTIS registry is a nationwide effort to enroll women with rheumatoid arthritis, psoriatic arthritis, and spondyloarthropathies during pregnancy.  The registry includes all medication exposures during pregnancy, and the baby is examined by the OTIS perinatologist for any congenital abnormalities.  In previous years, this group has presented studies documenting the safety issues of infliximab and etanercept.

The OTIS project enrolls women with inflammatory arthritis whether they are taking medications or not.  Those women not taking the medication of interest serve as a control group in each study.  The project also enrolls women without autoimmune disease to serve as a non-diseased control group.

This study, in addition to providing valuable data on the safety of DMARD’s during pregnancy, is also recording important pregnancy outcomes for women with RA.  In particular, the rate of preterm birth among women with RA seems to be elevated over the non-diseased cohort: ¼ of RA pregnancies are preterm versus less than 1/10 pregnancies to healthy women.  Nationwide, about 13% of pregnancies are delivered prematurely.

Leflunomide (Arava):
63 pregnancies were exposed to leflunomide.  Two women continued the medication into the second trimester, as they did not recognize the presence of the pregnancy earlier.  The remaining women stopped the drug early in the first trimester (an average of 5.5 weeks gestation).

There were no differences seen between the pregnancies exposed to leflunomide and RA pregnancies without exposure.  In particular, there was no increase in pregnancy loss rates or congenital abnormalities.  Importantly, there was neither a specific pattern of abnormalities seen in these babies, nor any changes consistent with those seen in animal models.

Editorial:  Leflunomide’s FDA pregnancy classification is X, meaning that the risk of fetal abnormality far outweighs any potential benefit of the drug.  The manufacturer recommends stopping leflunomide at least several months prior to pregnancy, and the administration of cholestryramine to eliminate any residual drug prior to pregnancy.  It is not clear if any of the women with leflunomide-exposed pregnancy in this study were treated with cholestyramine. 

The rate of fetal abnormalities in this study is not statistically different for women with leflunomide exposure, however it is several fold higher than that seen in healthy pregnancies.  This rate, as well as the rate in the cohort of women with RA but no leflunomide exposure, is higher than seen in other OTIS DMARD studies. 

This study demonstrated that the dire consequences feared from leflunomide therapy during pregnancy may be overblown.  I would still recommend avoiding leflunomide during pregnancy, and would follow the guideline to stop the drug several months prior to pregnancy, if possible.  However, if a pregnancy inadvertently occurs while on the drug, pregnancy termination for fear of anomalies, in the absence of a clearly identified fetal abnormality, would not be recommended.  The medication should also be stopped as early as possible in pregnancy.

Adalimumab (Humira)
This cohort includes 23 prospectively followed pregnancies exposed to adalimumab, as well as an additional 8 pregnancies that reported retrospectively.  Of the prospectively followed pregnancies, 2 resulted in a spontaneous abortion (9%) and one baby had congenital hip dysplasia.  Of the 8 retrospective pregnancies, 4 ended as a spontaneous abortion; fetal abnormalities are not reported for these pregnancies.  The rate of pregnancy loss and fetal abnormalities was not higher than seen in other RA pregnancies without adalimumab exposure, nor in healthy pregnancies.

Editorial:  Based on the small size of this study, it is difficult to draw a clear conclusion on the safety of adalimumab in pregnancy.  However, the results are reassuring, and fall in line with other studies of TNF inhibitors in pregnancy.  The majority of women in this study stopped their adalimumab in the first trimester, but a significant minority (data not reported, but personal communication from the authors) continued it throughout pregnancy.

TNF-inhibitors carry an FDA pregnancy classification of B, meaning that there is no animal data suggesting teratogenicity.  As the number of pregnancies grow that have had exposure, and as data continues to reassure, I move closer to feeling comfortable with their use during pregnancy.  Continuing these drugs up until the time of a positive pregnancy test, at least, may be safe.

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