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 use of tumor necrosis factor blockers in pregnancy.
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, said in an interview that “the FDA database serves an important role.” However, he agreed that the database has incomplete and biased data.
“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,” he said.
Neither the American College of Rheumatology nor the European League Against Rheumatism have any guidelines concerning treatment during pregnancy, added 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. 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 took etanercept at some point in pregnancy; 19 took 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 (vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limb abnormalities). “Since congenital anomalies are present in 3%-5% of all live births, and VACTERL occurs in 1.6/10,000 live births, you would expect to see [about] 1.6 cases of VACTERL association in every 300–500 children born with congenital anomalies,” wrote the authors. “We have now seen 2/42 (4.8%) cases of VACTERL” (including 1 case outside of the study period).
In an interview, Dr. Chambers took issue with the VACTERL findings, noting that to include a case as part of the VACTERL spectrum 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 1 was diagnosed with the pattern of associated birth defects within the original study period, said Dr. Chambers.
Dr. Cush pointed out that there are currently no studies that address the potential effects of stopping anti-TNF therapy before pregnancy, though it could be hazardous. Furthermore, the lack of alternative therapies that approximate the effect of anti-TNFs on disease means that clinicians may have to lean on palliative agents such as prednisone and NSAIDs, “both of which also pose potential harms to mother and child.”
Dr. Carter did not declare any conflicts of interest. Dr. Chambers said she did not have any personal conflicts, but OTIS receives grant funding from nine drug companies, two of which make anti-TNFs. Dr. Cush has served as a consultant or adviser to, or received grant money from, multiple drug companies, including the makers of anti-TNFs.