Timing of Live Attenuated Vaccination in Infants Exposed to Infliximab or Adalimumab in Utero: A Prospective Cohort Study in 107 Children

Author:

Liu Zheng123,Julsgaard Mette456ORCID,Zhu Xiao78ORCID,Martin Jennifer1,Barclay Murray L9,Cranswick Noel2,Gibson Peter R10,Gearry Richard B11,van der Giessen Janine12,Connor Susan J131415ORCID,Rosella Ourania10,Grosen Anne4,Toong Catherine1416,Flanagan Emma6ORCID,Wieringa Jantien W1718,Janneke van der Woude C12,Bell Sally J619,Kanis Shannon12,Fallingborg Jan20,Hvas Christian L21,Christensen Lisbet A21,Connell William R22,Brown Steven J22,Kjeldsen Jens23,Wildt Signe24,Svenningsen Lise25,Sparrow Miles P26,Walsh Alissa27,Radford-Smith Graham28,Lawrance Ian C2930,Andrews Jane M31,Ellard Kathrine32,

Affiliation:

1. Clinical Pharmacology, School of Medicine and Public Health, University of Newcastle, Hunter Medical Research Institute , Kookaburra Circuit , Australia

2. Clinical Pharmacology, Department of Medicine, The Royal Children’s Hospital Melbourne , Australia

3. Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University , Parkville, Victoria , Australia

4. Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus , Denmark

5. Institute of Clinical Medicine, Aarhus University , Aarhus , Denmark

6. Department of Gastroenterology, St Vincent’s Hospital, and University of Melbourne , Melbourne , Australia

7. Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University , China

8. School of Pharmacy, University of Otago , Dunedin , New Zealand

9. Departments of Gastroenterology & Clinical Pharmacology, Christchurch Hospital , Christchurch , New Zealand

10. Department of Gastroenterology, Alfred Hospital, and Monash University , Melbourne, VIC , Australia

11. Department of Medicine, University of Otago, Christchurch , New Zealand

12. Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam , Rotterdam , The Netherlands

13. Department of Gastroenterology, Liverpool Hospital , Sydney

14. South Western Sydney Clinical, University of NSW Sydney

15. Ingham Institute of Applied Medical Research , Sydney , Australia

16. Sydney South West Pathology Service, Liverpool Hospital, University of NSW , Sydney , Australia

17. Department of Pediatrics, Haaglanden Medical Center , the Hague , The Netherlands

18. Department of Pediatrics, Division of Paediatric Infectious Diseases and Immunology, Erasmus MC University Medical Centre-Sophia Children’s Hospital , Rotterdam , The Netherlands

19. Department of Gastroenterology, Monash Health, and School of Clinical Sciences Monash University , Melbourne, VIC , Australia

20. Aalborg University Hospital, Department of Gastroenterology , Aalborg , Denmark

21. Aarhus University Hospital, Department of Hepatology and Gastroenterology , Aarhus , Denmark

22. St Vincent’s Hospital, Department of Gastroenterology, University of Melbourne , Melbourne, VIC , Australia

23. Odense University Hospital, Department of Gastroenterology, University of Odense , Odense , Denmark

24. Køge Hospital, Department of Medicine, University of Copenhagen , Køge , Denmark

25. Horsens Hospital, Department of Medicine , Horsens , Denmark

26. Alfred Hospital, Department of Gastroenterology, Monash University , Melbourne, VIC , Australia

27. St. Vincent’s Hospital, Department of Gastroenterology , Sydney, NSW , Australia

28. Royal Brisbane & Women’s Hospital, Inflammatory Bowel Diseases Unit, University of Queensland School of Medicine , Brisbane, QLD , Australia

29. School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research , Murdoch, WA , Australia

30. Centre for inflammatory Bowel Diseases, Saint John of God Hospital , Subiaco, WA , Australia

31. Royal Adelaide Hospital, Department of Gastroenterology & Hepatology, University of Adelaide , Adelaide, SA , Australia

32. Royal North Shore Hospital, Department of Gastroenterology , Sydney , Australia

Abstract

Abstract Background and Aims For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy. Methods We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included. Results Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/. Conclusions Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children.

Funder

Health Research Fund of Central Denmark Region

Colitis-Crohn Organization Denmark

A.P. Moeller Foundation

Monash University

Alfred Hospital

Publisher

Oxford University Press (OUP)

Subject

Gastroenterology,General Medicine

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