From the AGA Journals

Anti-TNF agents vary in ability to cross placenta

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'Substantial transplacental transfer'

These two studies firm up our knowledge regarding anti-TNF therapy during pregnancy. They confirm that the IgG1 monoclonal antibodies infliximab and adalimumab have substantial transplacental transfer that increases during the third trimester. Infants born to women who continue these medications during the third trimester will have detectable drug concentrations that persist for 2-7 months.

No serious infectious events occurred in these studies. However, there is a previous report of an infant whose mother took infliximab during the third trimester who was vaccinated with the live organism BCG [Bacille Calmette Guerin] and developed disseminated BCG, which ultimately led to death (J. Am. Acad. Dermatol. 2011;65:870). This case report demonstrates that infants who are born with detectable infliximab or adalimumab levels are at risk for opportunistic infections. In contrast, certolizumab pegol does not cross the placenta.

The studies also show that interruption of infliximab or adalimumab at the end of the second trimester substantially reduces the amount of antibody transferred to the infant and shortens the time required for the infant to clear the antibody. Finally, discontinuation of infliximab and adalimumab during the third trimester appears to be associated with a low risk of relapse.

Altogether, these findings would appear to support the discontinuation of infliximab and adalimumab during the third trimester. Discontinuation of certolizumab pegol is not necessary.

William J. Sandborn, M.D., AGAF, is chief of the division of gastroenterology and director of the UCSD IBD Center in the University of California San Diego Health System. He has consulted for and received research grants from Janssen and consulted for AbbVie (previously Abbott Laboratories) and UCB Pharma.



Two small studies now add to the very sparse clinical experience with the use of anti-TNF-alpha agents in women who have inflammatory bowel disease and become pregnant, according to separate groups of researchers writing in the March issue of Clinical Gastroenterology and Hepatology.

Both studies confirm that two TNF antagonists do cross the placenta to the fetus at high levels and persist in the infant for months after birth. Discontinuing the drugs during the second trimester lessens but does not eliminate this exposure.

"At this time, we do not know what a safe or harmful level of drug in the newborn is, and what the full consequences of neonatal anti-TNF-alpha exposure to newborn development will be. The risks and benefits of therapy should be individualized, and pediatricians should be cautioned to monitor for potential infections and other abnormalities," said Dr. Uma Mahadevan of the University of California, San Francisco, and her associates (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.11.011]).

In their study, Dr. Mahadevan and her colleagues identified 31 pregnant women in their practice or in the Crohn’s Colitis Foundation of America’s Pregnancy IBD and Neonatal Outcomes registry who had Crohn’s disease and were taking infliximab (11 women), adalimumab (10 women), or certolizumab (10 women).

Dr. Uma Mahadevan

The first two of these anti-TNF-alpha agents are both of the IgG1 subclass and thus should, in theory, cross the placenta at high rates during the third trimester. Certolizumab, a pegylated fragment of an anti-TNF-alpha monoclonal antibody, in theory should not be transported across the placenta. To test these theories, the researchers determined the concentrations of each medication in samples of cord blood, infant serum, and the mother’s plasma taken on the day of birth. None of the infants had birth defects or required neonatal ICU care.

In the infliximab group, the median interval between the last dose of the agent and delivery was 35 days (range, 2-91 days). In every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 160:100. The drug persisted in the infants’ circulation for 2-7 months postpartum.

In the adalimumab group, the median interval between the last dose of the agent and delivery was 5.5 weeks. Again, in every case, cord blood and infant serum samples showed much higher levels of the TNF-alpha antagonist than did maternal plasma samples, at a median ratio of 179:100. The drug persisted in the infants’ circulation for at least 11 weeks.

In contrast, no certolizumab was detected in any of the infant samples.

"Based on the results of this study and available safety data, infliximab, adalimumab, and certolizumab can be used through conception and the first and second trimester of pregnancy on schedule. However, the significant placental transfer and subsequent slow postpartum clearance of infliximab and adalimumab raise concerns about their use during the third trimester," Dr. Mahadevan and her associates said.

Such concerns must be balanced against the risk of a flare of IBD, "which has far more consequences to neonatal development," impairing nutritional status of mother and fetus; raising the risk of preterm delivery; and possibly requiring harmful diagnostic testing, medication, and even surgery on the pregnant patient.

Physicians may consider switching patients to certolizumab during pregnancy because of its lack of transfer to the fetus, but "if a pregnant patient is doing well on infliximab or adalimumab, there is no indication, and even a potential risk, of switching ... as the primary goal remains to maintain a quiescent disease state that is critical for a successful pregnancy," they noted.

In the other study, Dr. Zuzana Zelinkova of Erasmus Medical Center, Rotterdam, the Netherlands, and her associates assessed 28 pregnant women who had Crohn’s disease or ulcerative colitis for which they were taking TNF-alpha antagonists.

Of the 17 taking infliximab, 12 had IBD in remission and discontinued the drug at a mean of 23 weeks’ gestation. Three others had perianal fistulas but discontinued early in the second trimester, while two had perianal fistulas and active luminal disease and didn’t discontinue the drug until weeks 30 and 34. None developed IBD relapses.

All 11 study subjects who were taking adalimumab had quiescent disease in the second trimester and discontinued the drug at a mean gestation of 22 weeks (range, 21-27 weeks). Two of them (18%) developed relapses of IBD.

There were three spontaneous miscarriages during the first trimester, and one child was born with polydactyly.

Levels of TNF-alpha antagonists in cord blood samples were significantly lower in the group who discontinued the drugs early, compared with the group who continued taking them until 10 or fewer weeks before delivery. "We recommend considering the discontinuation of anti-TNF-alpha treatment in patients who have quiescent disease at the beginning of the second trimester," to decrease but not completely eliminate the child’s exposure to these agents, Dr. Zelinkova and her associates said.


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