Pregnant women taking tumor necrosis factor inhibitors at conception experienced a higher rate of spontaneous abortion than did patients who did not.

The data were culled from the British Society for Rheumatology Biologics Register.

Despite its relatively large size, the study was unable to control for the looming possibility that disease severity itself plays a role in adverse pregnancy outcomes, the authors said.

“[W]ithout further evidence, guidelines that suggest these drugs should be avoided at the time of conception must remain” in place, recommended Dr. Suzanne M.M. Verstappen of the University of Manchester's Arthritis Research UK Epidemiology Unit, and her associates.

The investigators looked at women in the register who received adalimumab, etanercept, or infliximab either at conception or at any time prior to conception.

A subset was also exposed to methotrexate and/or leflunomide at time of conception in addition to the anti-TNFs, two drugs with a “known risk of adverse pregnancy outcomes,” according to the authors.

A fourth cohort with active rheumatoid arthritis had no history of anti-TNF use but rather received nonbiologic disease-modifying antirheumatic drugs, excluding methotrexate and leflunomide (Ann. Rheum. Dis. 2011 [doi:10.1136/ard.2010.140822]).

Among cohort Ia, which included 20 women (21 pregnancies) who took anti-TNFs plus either methotrexate and/or leflunomide at conception, there were 10 live births, 4 terminations, and 7 (33%) spontaneous abortions (miscarriages occurring prior to 20 weeks or to viability outside the womb).

Among cohort Ib, which included 44 women who took anti-TNFs at conception, but not methotrexate or leflunomide, there were 50 pregnancies.

They included 32 live births among this cohort, 4 terminations, 12 spontaneous abortions (24%), and 2 intrauterine deaths (occurring post-20 weeks).

There was also one neonatal death registered.

The women who had taken anti-TNFs in the past, but not at the time of conception (cohort II), did have seemingly better outcomes: The 59 pregnancies (54 women) resulted in live births in 46 cases (including one of two twins), terminations in 2, and spontaneous abortions in 10 (17%).

There were two intrauterine deaths, including the twin death.

Finally, among the 10 pregnancies in 10 women who had no history of anti-TNF use (cohort III), there were 0 terminations and 1 spontaneous abortion (10%).

The baseline disease activity score–28 (DAS28) was significantly higher in the anti-TNF cohorts, vs. cohort III: 6.5, 6.1, and 6.0 in cohorts Ia, Ib, and II, respectively, vs. 5.1 in cohort III.

Dr. H. Michael Belmont, medical director of New York University's Hospital for Joint Diseases, as well as the director of the lupus clinic at Bellevue Hospital, New York, commented that, until more data are available, “The default choice would be to avoid these drugs during pregnancy. Starting their use in a women contemplating conception should be delayed based on the data on hand.”

The study investigators disclosed that the British Society for Rheumatology receives restricted income from Abbott Laboratories, Biovitrum, Roche, Shering-Plough, and Wyeth Pharmaceuticals.

They added that they had no personal competing interests in relation to this study.

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What I Tell My Pregnant Patients

The only way to definitively address the question of risk associated with anti-TNFs and pregnancy would be to conduct a randomized controlled trial, according to Dr. Deborah P.M. Symmons.

There are, however, a few problems with that strategy. “Clearly, this would be very difficult to design, would need to be very large, and is never going to happen!” she joked.

“Beyond that, we have to wait for anecdotal evidence to accumulate.”

In the meantime, she said, “We advise all patients with rheumatoid arthritis to discuss a planned pregnancy with their rheumatologist prior to conception in order to make prospective plans about what to do about treatment. There are a number of other antirheumatic drugs, for example methotrexate and leflunomide, which carry a substantially higher risk than has been seen with anti-TNF therapy so far. However, many patients on anti-TNFs take them with another anti-rheumatic drug.”

According to Dr. Symmons, when treating a female patient of child-bearing age, “I would share what is currently known about the risks and benefits of continuing anti-TNF therapy with the woman with RA and let her ask further questions and make up her own mind about what to do.

“This study is reassuring for us to continue our current practice.”

DR. SYMMONS is one of the authors of the current study as well as a professor of rheumatology and musculoskeletal epidemiology at the University of Manchester, England. She had no financial interests to disclose.

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Anti-TNFs Use in Pregnancy Still Requires Caution