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Anti-TNF drugs detected up to 12 months in infants whose mothers received agents
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Recent findings published in Gastroenterology showed that the anti-tumor necrosis factor drugs infliximab and adalimumab can be detected for up to 12 months in infants born to mothers who had received these agents during pregnancy.
“This prospective observational study shows that infant clearance of infliximab after exposure during pregnancy is slower than previously reported,” Mette Julsgaard, MD, PhD, of the department of gastroenterology and hepatology at Aarhus University Hospital in Denmark, and colleagues wrote. “More rapid clearance was seen with adalimumab.”
Mette Julsgaard
The anti-tumor necrosis factor alpha antibodies (anti-TNF) adalimumab (Humira, AbbVie) and infliximab (Remicade, Centocor) are used to treat patients with inflammatory bowel disease, with more than $20 billion of global sales in 2013, the researchers wrote. Pregnant women with IBD often use these agents to reduce premature birth and low birth weight. Although previous studies found anti-TNF drugs were not be associated with adverse outcomes for newborns, there are little data for how they affect older infants.
The researchers performed a prospective study of 80 pregnant women with IBD at tertiary hospitals in Denmark, Australia and New Zealand between 2012 and 2014. Thirty-six of these women received adalimumab and 44 received infliximab. In addition, 39 received concomitant thiopurines. The researchers measured the concentration of anti-TNF agents in the blood sample during delivery, in the umbilical cord and then in the infant for every 3 months until the drug was no longer detected.
The researchers found that the median ratio of infant-to-mother drug concentration at birth was 1.21 for adalimumab (95% CI, 0.94-1.49) and 1.97 for infliximab (95% CI, 1.5-2.43). The mean time to drug clearance was 4 months for adalimumab (95% CI, 2.9-5) and 7.33 months for infliximab (95% CI, 6.2-8.3), while both were no longer detected after 12 months of age. Bacterial infections developed in 5% of infants and viral infections developed in 20%, all with benign courses. Infants whose mothers received a combination of anti-TNF and thiopurine were more likely to develop infection compared with those who received anti-TNF alone (RR = 2.7; 95% CI, 1.09-6.78).
In addition, the umbilical cord blood’s drug concentration was not associated with the risk for infant infection in the first year of life, the researchers wrote.
“Based on these results, we suggest that no live virus vaccine should be given during the first year of life in offspring of women treated with anti-TNF during pregnancy,” the researchers wrote. “Pregnant women treated with combination therapy should receive counselling regarding potential risk of postnatal infections in their infant, which should be promptly assessed.” – by Will Offit
Disclosure: Two researchers report receiving consultation fees from AbbVie. Please see the full study for all other researchers’ relevant financial disclosures.
Perspective
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Edward V. Loftus, MD, FACG, AGAF, FACP
The paper by Julsgaard and colleagues from Denmark, Australia, and New Zealand is packed with potentially clinically useful information about how to manage anti-TNF therapy in women with inflammatory bowel disease who are pregnant.
Among the 80 women studied, 18 of 44 women on infliximab and 7 of 36 women on adalimumab had held anti-TNF therapy prior to gestational week 30. Interestingly, those who held anti-TNF therapy before week 30 did not have an increased risk for relapse during the third trimester. However, we are not told if there were differences in the risk for post-partum flares in these two groups.
Median umbilical cord blood levels of adalimumab were 2 µg/mL, on average, 20% higher than the maternal blood level at delivery, whereas median cord blood concentrations of infliximab were 5.9 µg/mL, on average, twice as high as that in maternal blood. There were significant correlations between cord blood levels and the timing of the last dose of anti-TNF (r values, –0.77 for infliximab and –0.64 for adalimumab).
Figures 1a and 1b suggest that for the anti-TNF concentration to be under 1 µg/mL, on average, the last dose of anti-TNF would need to be given at approximately gestational week 20 for infliximab and week 30 for adalimumab. Average time to clearance of infliximab from the children’s blood was 7.3 months for infliximab and 4 months for adalimumab. Approximately 20% of offspring had viral infections in the first year of life, but none were deemed serious, and there were no sequelae.
Perhaps the most important statement in the paper is in the last paragraph of the Results — continuing anti-TNF therapy in the mother beyond gestational week 30 was not associated with increased risk for infection in the offspring in the first year of life. However, combination therapy with an immunomodulator increased the risk for infection in the offspring by a factor of 2. In my own practice, I have generally been recommending continuation of anti-TNF therapy during pregnancy, and will continue to do so unless we see more compelling evidence of adverse events in either mothers or offspring.
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