Are we coming to terms with tumor necrosis factor inhibition in pregnancy

Rheumatic diseases commonly affect women of childbearing age, who often receive immunosuppressive treatments that pose risks to the mother and/or fetus during pregnancy. Due to the benefits of early and aggressive treatment of inflammatory arthritis, rheumatologists prescribe tumor necrosis factor (TNF ) inhibitors early in disease and to a large number of patients. According to a recent survey, 44.2% of practicing US rheumatologists prescribe TNF inhibitors for at least half of their patients with rheumatoid arthritis (RA) (1). All commercially available TNF inhibitors are classified by the Food and Drug Administration as pregnancy risk category B: no adverse pregnancy effects have been observed in animal studies, but there have been insufficient controlled human studies. Given the lack of data in humans, it remains unclear how the practicing rheumatologist should manage TNF inhibitor therapy in women of childbearing age. Underscoring this uncertainty, 38–47% of practicing US rheumatologists recently surveyed believe that the TNF inhibitors etanercept and infliximab are contraindicated during pregnancy (2). However, many women taking TNF inhibitors become pregnant. According to an online survey of 1,023 practicing US rheumatologists, 454 patients with RA became pregnant while receiving anti-TNF therapy. Surprisingly, 31.3% of these patients continued taking TNF inhibitors throughout pregnancy (1). Despite the fact that disease severity tends to decrease in roughly three-fourths of pregnant patients with RA (3), rheumatologists may be reluctant to discontinue a medication that has proven effective. The published experience with TNF inhibition during pregnancy consists of a limited number of case reports, series, and ongoing registry data. Most reported exposures to TNF inhibitor therapy occurred prior to or at the time of conception or during the first trimester of pregnancy. In a retrospective study from the Infliximab Safety Database of 96 pregnancies in women (85% with Crohn’s disease) exposed to infliximab prior to or early in pregnancy, 67% resulted in a live birth, 15% in a miscarriage, and 19% in an elective termination (4). This finding is comparable with historical pregnancy outcomes in the general white population of the US reported by the National Center for Health Statistics (5). An interim data analysis by the Organization of Teratology Information Services compared pregnancy outcomes in 32 patients with RA exposed to etanercept or infliximab with outcomes in 74 patients with RA not exposed to anti-TNF therapy, and with 49 nondisease controls. Rates of miscarriage and fetal malformation did not differ significantly among these 3 groups, but there was a significant increase in the rates of preterm delivery and low-birth-weight infants in all patients with RA compared with controls (6), suggesting that the RA disease state rather than TNF inhibitor therapy predisposes patients to these adverse fetal outcomes. Whereas additional studies have also shown increased rates of adverse pregnancy outcomes among women with RA (7,8), including an increased incidence of low-birthweight infants (9), other investigators have failed to confirm these findings (3). In this issue of Arthritis & Rheumatism, Hyrich et al report data from the British Society for Rheumatology Biologics Register on pregnancy outcomes in a series of 32 women with rheumatic diseases (91% with RA) exposed to anti-TNF therapy (10). Of these women, 23 were exposed to TNF inhibitor therapy (74% to etanercept) at the time of conception, and 11 were also receiving either methotrexate or leflunomide. Overall, 69% of these 32 pregnancies resulted in a live birth, 22% in a miscarriage, and 9% in an elective termination, outcomes comparable with previously reJane E. Salmon, MD, Deborah Alpert, MD, PhD: Hospital for Special Surgery–Weill Medical College, Cornell University, New York, New York. Dr. Salmon has received consulting fees (less than $10,000 each) from Amgen and Genentech and owns stock in Amgen, Johnson and Johnson, and Biogen/Idec. Address correspondence and reprint requests to Jane E. Salmon, MD, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail: salmonj@hss.edu. Submitted for publication March 21, 2006; accepted in revised form May 8, 2006.