Mette Julsgaard1, Lisbet A Christensen2, Peter R Gibson3, Richard B Gearry4, Jan Fallingborg5, Christian L Hvas2, Bo M Bibby6, Niels Uldbjerg7, William R Connell8, Ourania Rosella3, Anne Grosen2, Steven J Brown8, Jens Kjeldsen9, Signe Wildt10, Lise Svenningsen11, Miles P Sparrow3, Alissa Walsh12, Susan J Connor13, Graham Radford-Smith14, Ian C Lawrance15, Jane M Andrews16, Kathrine Ellard17, Sally J Bell8. 1. Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark; Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: mjn@clin.au.dk. 2. Department of Hepatology and Gastroenterology, University of Aarhus, Aarhus, Denmark. 3. Department of Gastroenterology, Alfred Hospital, Monash University, Melbourne, Victoria, Australia. 4. Department of Medicine, Christchurch Hospital, University of Otago, Christchurch, New Zealand. 5. Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark. 6. Department of Biostatistics, University of Aarhus, Aarhus, Denmark. 7. Department of Obstetrics and Gynaecology, Aarhus University Hospital, University of Aarhus, Aarhus, Denmark. 8. Department of Gastroenterology, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia. 9. Department of Gastroenterology, Odense University Hospital, University of Odense, Odense, Denmark. 10. Department of Medicine, Køge Hospital, University of Copenhagen, Køge, Denmark. 11. Department of Medicine, Herning Hospital, Herning, Denmark. 12. Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia. 13. Department of Gastroenterology, Liverpool Hospital, Sydney, New South Wales, Australia. 14. Inflammatory Bowel Diseases Unit, Royal Brisbane and Women's Hospital, University of Queensland School of Medicine, Brisbane, Queensland, Australia. 15. School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, Western Australia, Australia; Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Western Australia, Australia. 16. Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia. 17. Department of Gastroenterology, Royal North Shore Hospital, Sydney, Australia.
Abstract
BACKGROUND & AIMS: 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. METHODS: We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received 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 for every 3 months until the drug was no longer detected. RESULTS: The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). 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). CONCLUSIONS: 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 the 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 therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.
BACKGROUND & AIMS: Little is known about in utero exposure to and postnatal clearance of anti-tumornecrosis 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. METHODS: We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received 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 for every 3 months until the drug was no longer detected. RESULTS: The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). 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). CONCLUSIONS: 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 the 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 therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.
Authors: Christopher Andrew Lamb; Nicholas A Kennedy; Tim Raine; Philip Anthony Hendy; Philip J Smith; Jimmy K Limdi; Bu'Hussain Hayee; Miranda C E Lomer; Gareth C Parkes; Christian Selinger; Kevin J Barrett; R Justin Davies; Cathy Bennett; Stuart Gittens; Malcolm G Dunlop; Omar Faiz; Aileen Fraser; Vikki Garrick; Paul D Johnston; Miles Parkes; Jeremy Sanderson; Helen Terry; Daniel R Gaya; Tariq H Iqbal; Stuart A Taylor; Melissa Smith; Matthew Brookes; Richard Hansen; A Barney Hawthorne Journal: Gut Date: 2019-09-27 Impact factor: 23.059
Authors: Dawn B Beaulieu; Ashwin N Ananthakrishnan; Christopher Martin; Russell D Cohen; Sunanda V Kane; Uma Mahadevan Journal: Clin Gastroenterol Hepatol Date: 2017-09-01 Impact factor: 11.382