Background & objective: In North America, infections are the leading cause of mortality in children ages younger than 5 years old, accounting for over 30% of deaths. Tumor necrosis factor inhibitors (TNFi’s) are important drugs in the treatment of rheumatoid arthritis (RA), being used in one-third of patients. Because animal studies did not show fetal risk, TNFi’s have been commonly—and increasingly used—during pregnancy, now prescribed in 20% of RA pregnancies, representing a threefold increase over the past 10 years.
Despite existing concerns that these potent drugs may cause immunosuppression, data on the risk of serious infection in exposed offspring are limited. During pregnancy, active transplacental transport of maternal circulating immunoglobulins (IgG) through their Fc portion takes place. TNFi’s are all monoclonal IgG with an Fc part, except for etanercept and certolizumab, and most TNFi’s are actively transported across the placenta, with some reaching higher fetal than maternal blood levels.
Vinet et al. set out to evaluate the risk of serious infections in children of women with RA exposed to TNFi’s in the gestational period compared with unexposed offspring of women with RA, as well as to children from the general population.
Methods: These researchers used U.S. claim data (2011–2015) to identify 2,989 offspring born to women who have RA and a randomly selected group of 14,596 control children, matched ≥4:1 for maternal age, year of delivery and state of residence. The researchers defined TNFi exposure based on one or more filled prescriptions during pregnancy. They ascertained serious infections based on one or more hospitalizations, with infection as a primary diagnosis, at 12 months or younger. They performed multivariable analyses, adjusting for maternal demographics, comorbidities, pregnancy complications and drugs.
Results: Among RA offspring, 380 (12.7%) were exposed to TNFi’s during pregnancy. At 2%, the rate of serious infections in RA offspring with no TNFi exposure was similar to non-RA offspring (1.9%); the percentage of serious infections in RA offspring with TNFi exposure was 3.2%. In multivariable analyses, the researchers could not establish an increased risk of serious infections in RA offspring exposed to TNFi’s compared with unexposed offspring of women with RA or RA offspring unexposed to TNFi.
Conclusion: These researchers did not demonstrate a marked excess risk for serious infections in RA offspring exposed to TNFi’s during pregnancy when compared with unexposed offspring of women with RA or general population controls. However, they could not exclude a differential risk according to specific TNFi, with infliximab potentially resulting in a threefold increase in the risk of serious infections compared with other TNFi’s. More studies are needed to further evaluate if the risk of serious infections in exposed offspring is influenced by individual TNFi characteristics.