NICE, France—Three recent case reports add to an accumulating body of evidence that TNF-blockers are safe during pregnancy, but one new report that appears in the April issue of Rheumatology¹ is far from the final word on the issue. TNF-blockers are currently considered category B drugs by the federal Food and Drug Administration (FDA).

"Human experience of anti-TNF is still extremely limited, particularly in patients with rheumatic diseases, among whom there are several alarming reports," conclude researchers led by Christian H. Roux, MD, at Hospital l'Archet, in Nice, France. "The potential risk of their use should be balanced against the known risks associated with disease modifying antirheumatic drugs (DMARDs) and steroid therapy."

Of 442 patients treated with TNF-blockers since 1999, three women with rheumatoid arthritis (RA) unexpectedly became pregnant. One patient who was treated with etanercept (Enbrel®) terminated her pregnancy at 2½ months, despite any ultrasound abnormalities and satisfactory fetal growth; the other two patients, one who was treated with adalimumab (Humira®) and one with etanercept, delivered healthy babies. Perinatal complications included prematurity, neonatal jaundice, neonatal urinary Escherichia coli infection, and adrenal congenital hyperplasia of probable hereditary origin.

Literature review uncovers some "alarming" cases

Dr. Roux et al also conducted a literature review and uncovered several reassuring reports on the use of TNF-inhibitors among patients with RA and Crohn's disease. They also came across an alarming report concerning a psoriatic arthritis patient who was treated with high doses of etanercept during pregnancy and gave birth to a child with VATER association, a pattern of related birth defects involving three or more of the following: vertebrae, anus and rectum, heart, trachea, esophagus, radius, and kidneys.

"The rate of major fetal complications in anti-TNF-α treated patients whether with Crohn's disease or RA, is similar to that expected in untreated populations," the authors conclude. "The VATER association in child born to a woman with psoriatic arthritis and treated with etanercept throughout her pregnancy is alarming and may be attributable to TNF-α inhibition."

Rat studies have shown that nonselective COX-1, selective COX-2, and specific COX-2 inhibitors interfere with normal blastocyst implantation, so in theory TNF-α blockers could affect implantation or ovulation. There is, however, no direct evidence of such a link. There is also no evidence of embryotoxicity or teratogeneicity in animal studies of TNF blockade.

CIAOMed recently reported on data from the British Society of Rheumatology Biologics Register² that included 32 women with rheumatic diseases and who were exposed to anti-TNF-α therapies at the time of conception or in the preceding 10 months. Of the 91% who elected to continue their pregnancy, 76% delivered healthy infants and 24% had first-trimester miscarriages, that study showed.

Dr. Roux and colleagues point out that there is some evidence linking RA itself to adverse pregnancy outcomes and that the rate of miscarriage in their study patients is similar to that in the general population. They also note that the absence of major congenital malformations or evidence of harm to the mother in this group of patients is reassuring.

"Large registries will be necessary before firm conclusions can be drawn," Dr. Roux and colleagues write.

Jury still deliberating

"I think that the jury is still out about the use of anti-TNF medications during pregnancy," Megan E. B. Clowse, MD, MPH, assistant professor of rheumatology at Duke University Medical Center, in Durham, North Carolina, told CIAOMed. "The data demonstrating their safety, however, is slowly increasing."

Fortunately, Dr. Clowse said, RA in many women will improve during pregnancy. "Those [whose RA does not improve] can use moderate doses of prednisone, hydroxychloroquine, and sulfasalazine to control their disease," she said. "If necessary, however, the decision to continue an anti-TNF medication during pregnancy must be made acknowledging our inability to guarantee safety. For some women, the benefit from the medication may outweigh the potential and unproven risk to the baby."

A leading high-risk obstetrician weighs in