Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection

Mette Julsgaard, Lisbet A. Christensen, Peter R. Gibson, Richard B. Gearry, Jan Fallingborg, Christian L. Hvas, Bo M. Bibby, Niels Uldbjerg, William R. Connell, Ourania Rosella, Anne Grosen, Steven J. Brown, Jens Kjeldsen, Signe Wildt, Lise Svenningsen, Miles P. Sparrow, Alissa Walsh, Susan J. Connor, Graham Radford-Smith, Ian C. Lawrance, Jane M. Andrews, Kathrine Ellard, Sally J. Bell

Little is known about in utero exposure to and postnatal clearance of anti- tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, or New Zealand from March 2012 through November, 2014; 36 received adalimumab and 44 infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants every 3 months until the drug was no longer detected. The time from last exposure to anti-TNF agent during pregnancy correlated inversely with concentration of the drugs in umbilical cord (r= -0.64 for adalimumab, P=.0003 and r= -0.77 for infliximab, P<.0001) and in mothers at time of birth (r= -0.80 for adalimumab and r= -0.80 for infliximab, P<.0001 for each). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval [CI], 0.94-1.49) and 1.97 for infliximab (95% CI, 1.50-2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9-5.0) and 7.3 months for infliximab (95% CI, 6.2-8.3; P<.0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09-6.78; P=.02). In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold, compared with anti-TNF monotherapy. Live vaccines should therefore be avoided for up to 1 year, unless drug clearance is documented, and pregnant women should be educated on risks of anti-TNF use.