Data from a Food and Drug Administration registry suggesting an increase in birth defects among women treated with etanercept and infliximab have rekindled controversy over the use of tumor necrosis factor blockers in pregnancy.
Authors of a new review of FDA data advise clinicians against prescribing anti-TNF agents to pregnant women based on their findings that etanercept and infliximab may be responsible for a “seemingly high number” of congenital anomalies. “Clinicians should not prescribe TNF antagonists to women during pregnancy,” wrote the authors of the review.
However, conflicting preliminary data from an ongoing study by the Organization of Teratology Information Specialists (OTIS) argue that anti-tumor necrosis factor agents are safe for this population. Dr. Christina Chambers, a coinvestigator on the OTIS study, said it was alarmist to recommend avoiding anti-TNF agents in pregnancy, and said that reviews of the FDA adverse events database are “inherently biased.” Based on her group's results, she said, “We're not able to draw any conclusions that suggest that we are seeing any specific pattern of defects, whether major or minor, based on the children that have been evaluated so far.”
Dr. John J. Cush, who is not involved with either of these studies but who has conducted his own surveys on the issue, said in an interview that “the FDA database serves an important role in providing insight into what may be a potential hazard to those receiving these drugs.”
However, he added, “There are biases regarding underreporting, sources of reports, the lack of a denominator, and a grossly underestimated numerator.” Of course, all databases—including the OTIS database—have inherent biases, he cautioned.
“Nonetheless, there is no reason or convincing data to emphatically deny effective anti-TNF therapy to patients who need it to control their disease, either before or during pregnancy,” said Dr. Cush, director of the clinical rheumatology program at Baylor Research Institute in Dallas.
The review of the FDA adverse events database, led by Dr. John D. Carter, involved more than 120,000 adverse events for all entries between 1999 and 2005 found with the keywords “congenital anomaly,” “congenital anomalies,” “birth defect,” and “birth defects.” A total of 41 children with 61 congenital anomalies born to 40 different mothers who were taking a TNF antagonist during pregnancy were recorded (J. Rheumatol. 2008 Dec. 15 [doi:10.3899/jrheum.080545
Overall, 22 of these mothers had been taking etanercept at some point during their pregnancy; 19 had been taking infliximab. “In all 41 cases, the TNF-α antagonist was considered the 'primary suspect' as the cause of the birth defect,” wrote Dr. Carter of the division of rheumatology at the University of South Florida, Tampa.
A total of 34 different types of birth defects were seen, 19 of which were part of the VACTERL spectrum.
In an interview, Dr. Chambers took issue with the VACTERL findings, noting that to include children's defects as part of the VACTERL spectrum means that they must exhibit at least three of the seven defects in the spectrum—not just one. And though the authors emphasize that 24 of 41 children (59%) “had one or more congenital anomalies that are part of VACTERL,” only one was diagnosed with the pattern of associated birth defects within the original study period, according to Dr. Chambers.
Dr. Carter said that he thinks women of child-bearing age taking anti-TNFs should be strongly encouraged to use contraception, as they are with known teratogenic drugs such as Accutane.
Dr. Carter did not declare any conflicts of interest with regard to his study. Dr. Chambers said she did not have any personal conflicts, but that OTIS receives grant funding from nine different pharmaceutical companies, two of which are manufacturers of anti-TNFs. Dr. Cush has served as a consultant or advisor to, or received grant money from, multiple pharmaceutical companies, including the makers of the three anti-TNFs looked at in these studies.