MANCHESTER, UK—Data from the British Society of Rheumatology Biologics Register (BSRBR) provide some reassurance for women who become pregnant while taking TNF inhibitors but should not be taken to mean that TNF inhibitor use throughout pregnancy is safe, Kimme L. Hyrich, MD, PhD, FRCPC, and colleagues in the British Society for Rheumatology Biologics Register group report in Arthritis & Rheumatism.¹ 

"Although it is difficult to prove absolute safety, these data suggest that women who inadvertently become pregnant while taking anti-TNF-α 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-TNF-α therapies during pregnancy cannot be advocated," writes Dr. Hyrich, who is at the University of Manchester, UK.

Exposure to TNF inhibitors in early pregnancy increasing with more widespread use

In an accompanying editorial, Drs. Jane E. Salmon and Deborah Alpert note that the move toward earlier, more aggressive treatment for inflammatory arthritis has meant that increasing numbers of pregnant women are exposed to TNF inhibitors. Although current data suggest that such treatment does not harm and might even help during the first trimester, more research is needed.²

"I recommend discontinuing TNF inhibitors prior to planned pregnancy," Dr. Salmon, who holds the Collete Kean Research Chair at the Hospital for Special Surgery, New York, NY,  told CIAOMed. "However, patients must recognize that underlying disease activity may itself compromise pregnancy outcome. Fortunately, the majority of patients with RA have remissions during pregnancy."

BSRBR has been systematically collecting information on patients receiving TNF inhibitors since those drugs were approved for use in the National Health Service. Dr. Hyrich and colleagues analyzed all reports of pregnancy among the 11,473 patients in the registry and found 35 pregnancies, of which outcomes were known in 32 (2 were lost to follow-up, and 1 has not yet been delivered). Most of these women have RA (91%).

No increase in miscarriage, birth defects seen with first-trimester exposure

"In this series of 32 women with rheumatic diseases exposed to anti-TNF-α 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," Dr. Hyrich reports.

The researchers also point out that there is some evidence linking RA itself to adverse pregnancy outcomes and that the rate of miscarriage in this series is similar to that expected in the general population, about 30%. They note that the absence of major congenital malformations or evidence of harm to the mother in this group of patients is reassuring.

Dr. Hyrich reports that 23 of 35 were taking TNF inhibitors at the time of conception (74% etanercept), nine were also taking methotrexate (MTX), and two were taking leflunomide. Nearly all patients discontinued antirheumatic therapies during the first trimester. One patient continued etanercept throughout her pregnancy, and one discontinued etanercept after her pregnancy was confirmed at 20 weeks.

The patient who continued etanercept throughout pregnancy had a baby delivered at term by cesarean section complicated by a postpartum hemorrhage. The patient who had continued etanercept into the second trimester had an emergency cesarean section for fetal distress. The investigators report that both mothers and infants are alive and well.

One patient taking etanercept and leflunomide at the time of conception had a healthy infant 4 weeks prematurely, one patient taking etanercept at conception had a low birth-weight baby, and a third RA patient taking adalimumab and MTX at conception reported recurrent cystitis but delivered a healthy infant.

Among the nine patients who stopped TNF inhibitor therapy 1 to 10 months before conceiving, there were eight live births and one first-trimester miscarriage (in a patient who had discontinued etanercept 10 months before conceiving).

The British data also raise more questions about MTX. Three of the seven women who miscarried were taking MTX at the time of conception, and the authors point out that because TNF inhibitors are increasingly being prescribed with MTX, more research is needed on effects of these combinations in pregnancy. 

Drs. Salmon and Alpert raise the intriguing possibility that TNF inhibitors might actually prevent miscarriage in some settings, as in their murine model of antiphospholipid syndrome. "TNF-α plays a role in both inflammatory and hormonally mediated pregnancy loss. Consequently, a scientific rationale for exploring further therapeutic applications of TNF-α inhibition does exist. A precise definition of the ‘window of opportunity' for TNF-α inhibition, the time period when therapy would be safe for the developing fetus, is an important consideration," they write.

This question assumes greater importance in the US context, where TNF inhibitor use is less tightly restricted than in the UK.

Drs. Salmon and Alpert cite a study of 1023 US rheumatologists, who reported that 454 patients became pregnant while taking TNF inhibitors and that 31.3% of those women continued taking the drugs throughout pregnancy. They speculate that "rheumatologists may be reluctant to discontinue a medication that has proven effective" despite the fact that about three-fourths of pregnant patients with RA have significant decreases in disease activity during pregnancy.

None of the available data provide much insight into the effect of TNF inhibitors in the second and third trimesters of pregnancy, and Drs. Salmon and Alpert believe that a major collaborative study is needed. "Given the ethical considerations implicit in randomized controlled trials of these agents in pregnant patients, an international collaborative effort to prospectively collect information about pregnancy outcomes in patients treated with TNF-α inhibitors, as well as other biologic agents, is needed," they conclude.

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