Pregnancy outcome in women who were exposed to anti–tumor necrosis factor agents: Results from a national population register

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Drugs that block the action of tumor necrosis factor α (TNFα) have significantly improved outcomes among patients with rheumatoid arthritis (RA) and related rheumatic diseases. These conditions occur more frequently in women, who may also be in their childbearing years. Thus, it is inevitable that there will be a few patients who are exposed to these drugs during pregnancy, typically during the early stages of an unplanned pregnancy. Prior to the marketing and the widespread use of such drugs, data on any potential harmful effects in a human pregnancy are very limited. These agents are listed as pregnancy category B drugs (i.e., animal studies have failed to demonstrate a risk to the fetus but there are no adequate and well-controlled studies of the effect of the drugs on pregnant women) (1–3). Early case series of the use of anti-TNFα agents in both RA and Crohn's disease (4–6) did not suggest a strong association with adverse pregnancy outcomes, although the majority of these studies included <10 RA patients. We now present the outcome in 32 patients with rheumatic diseases directly exposed to anti-TNFα therapies during or immediately prior to pregnancy.

The British Society for Rheumatology Biologics Register (BSRBR) is systematically collecting information on patients receiving anti-TNFα therapies for rheumatic diseases. This database was searched for all reports of pregnancy. Details, including demographic characteristics, diagnoses, exposure to disease-modifying antirheumatic drugs (DMARDs) and biologic drugs, and maternal and fetal outcomes, were collected using standardized forms. As of August 1, 2005, a total of 11,473 patients taking anti-TNFα agents were registered with the BSRBR. Thirty-five pregnancies had been reported, of which the outcomes were known in 32 (2 lost to followup, 1 not yet delivered). The majority of these women had RA (91%). The mean age of the women with RA was 31 years (range 16–40). One patient had psoriatic arthritis, 1 had juvenile idiopathic arthritis, and 1 had a seronegative spondylarthropathy.

Of these patients, 23 were directly exposed to anti-TNFα therapy at the time of conception (etanercept in 17, infliximab in 3, and adalimumab in 3). Nine were also receiving methotrexate (MTX), and 2 leflunomide. All but 2 patients discontinued their antirheumatic therapies during the first trimester of pregnancy. One patient discontinued etanercept treatment after pregnancy was confirmed at 20 weeks, and 1 patient chose to continue taking etanercept throughout her pregnancy. Among these patients, there were 6 first-trimester miscarriages (4 in patients taking etanercept, 1 in a patient taking infliximab, and 1 in a patient taking adalimumab; 3 of these patients were also receiving MTX), 3 elective first-trimester terminations (all in patients receiving etanercept; 2 also receiving MTX), and 14 live births. There were no major fetal abnormalities. One patient with RA, who was receiving both etanercept and leflunomide at the time of conception, delivered a healthy infant 4 weeks prematurely. A second patient with RA, who was also receiving etanercept at the time of conception, delivered an infant with low birth weight (2,180 grams). A third RA patient receiving adalimumab and MTX at conception reported recurrent cystitis during the pregnancy, but delivered a healthy infant. In the patient who continued etanercept into the second trimester, an emergency cesarean section was performed at term for fetal distress. The single patient who continued ETA throughout the pregnancy delivered at term by cesarean section complicated by a postpartum hemorrhage. Both of these mothers and infants were alive and well postpartum.

The other 9 patients electively discontinued their anti-TNFα therapy (etanercept in 4, infliximab in 5) prior to conceiving. The mean length of time between anti-TNFα drug discontinuation and conception was 5 months (range 1–10 months). None of these patients were receiving standard DMARDs at the time of conception, although 3 patients had discontinued MTX 4–6 months prior to conception and 1 patient had discontinued the combination of MTX and sulfasalazine 1 month prior to conception. Among these patients, there were 8 live births and 1 first-trimester miscarriage (etanercept treatment discontinued 10 months prior to conception). One patient with RA who had discontinued infliximab and MTX 4 months prior to conception had a twin pregnancy. One fetus died in utero, and the other remained healthy and was delivered at term. Another RA patient who had discontinued etanercept and MTX 4 months prior to conception developed preeclampsia at term. There were no reports of congenital malformations.

In this series of 32 women with rheumatic diseases exposed to anti-TNFα therapies at the time of conception or in the 10 months preceding, 91% elected to continue their pregnancy. Of these, 76% delivered healthy infants, and 24% had first-trimester miscarriages. In considering these findings, it should be noted that there is some evidence to suggest an increased rate of adverse pregnancy outcomes among women with RA (7, 8), including an increased risk of low birth weight in those with active disease (9). The absence of major congenital malformations or evidence of maternal harm is reassuring. The rate of miscarriages is consistent with the expected background population rate, estimated to approach 30% (10, 11). However, because the latter figure also includes early pregnancy losses in clinically unrecognized pregnancies, it is possible that the rate in the present study is somewhat increased. There is some evidence, though, to suggest that women with RA may already have a higher rate of spontaneous abortion (12). There is also the added risk caused by other antirheumatic therapies, including MTX, which 3 of the 7 women who miscarried in this series were receiving at the time of conception. MTX has been linked to an increased rate of miscarriage (13) and has been used as an agent for medical abortion (14). However, since anti-TNFα therapy is increasingly being coprescribed with MTX, it is appropriate to examine the effects on pregnancy in this situation.

Although it is difficult to prove absolute safety, these data suggest that women who inadvertently become pregnant while taking anti-TNFα agents can be reassured that, based on our experience, continuation of pregnancy does not appear to hold any increased risk to either themselves or their baby. However, in the absence of formalized studies, the regular use of anti-TNFα therapies during pregnancy cannot be advocated.

Acknowledgements

Dr. Hyrich is a former Fellow of the Canadian Arthritis Society. Drs. Symmons and Silman's work was supported by the Arthritis Research Campaign. The British Society for Rheumatology Biologics Register (BSRBR) is supported by a research grant from the British Society for Rheumatology (BSR) to the University of Manchester, which is indirectly funded by Schering Plough, Wyeth Laboratories, Abbott Laboratories, and Amgen. Under the terms of the contract between the BSR and the sponsoring pharmaceutical companies, all publications from the BSRBR are sent in advance to the companies prior to submission for purposes of information. The companies can if they wish point out factual errors but they have no role in the content or interpretation of the material presented. All publications are also reviewed by the BSR, but the material presented and the views expressed in all publications from the BSRBR are those of the authors and do not necessarily represent the views of the BSR. The authors acknowledge the enthusiastic collaboration of all consultant rheumatologists and their specialist nurses in the UK in providing the data used in this report. The substantial contribution of Andy Tracey, Katie McGrother, and Mark Lunt in database design and manipulation is acknowledged. We also acknowledge Dr. Ian Griffiths (Chairman of the BSRBR Management Committee) and Professors Gabriel Panayi, David G. I. Scott, and David Isenberg (Presidents of the BSR during the period of data collection) for their active role in developing and supporting the Register, and Samantha Peters and Mervyn Hogg (BSR staff) for considerable administrative support.

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