Original Contribution

Inflammatory Bowel Disease

Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study

  • The American Journal of Gastroenterology volume 113, pages 396403 (2018)
  • doi:10.1038/ajg.2017.501
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Subjects

Abstract

Objectives:

The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs.

Methods:

Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan–Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring.

Results:

The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8–1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5–4.3)).

Conclusions:

In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

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Acknowledgements

We thank the Clinical Committee (ClinCom) of the European Crohn and Colitis Organisation (ECCO) and the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) for their support in the study. In addition, we thank M. Ramas and A.G. McNicholl for programming the e-CRF in AEG-REDCap and T O’Boyle for the final English language revision funded by MSD.

Author information

Affiliations

  1. Gastroenterology Units Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain

    • M Chaparro
    • , M J Casanova
    • , A Garre
    • , M G Donday
    •  & J P Gisbert
  2. Department of Gastroenterology and Department of Pediatric Gastroenterology, University Hospitals Leuven, KU Leuven, Leuven, Belgium

    • A Verreth
  3. Hospital Universitari Germans Trias i Pujol and CIBEREHD, Badalona, Spain

    • T Lobaton
    •  & P Torres
  4. Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

    • E Gravito-Soares
    •  & M Gravito-Soares
  5. Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    • M Julsgaard
    •  & D Rudbeck-Resdal
  6. University of Padua, Padua, Italy

    • E Savarino
    •  & O Bartolo
  7. Centro Hospitalar São João, Porto, Portugal

    • F Magro
    •  & A Peixoto
  8. Gastroenterology Devision, Rabin Medical Center, Petach Tikva, Israel

    • I Avni Biron
    •  & G Martin
  9. Hospital Universitario Fundación Alcorcón, Alcorcón, Spain

    • P Lopez-Serrano
  10. Hospital Clinic and CIBEREHD, Barcelona, Spain

    • M Gompertz
  11. Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Lisboa, Portugal

    • S Vitor
  12. Hospital Clinico Universitario Lozano Blesa, IIS Aragon, CIBEREHD, Zaragoza, Spain

    • M Arroyo
  13. IBD Unit, Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Roma, Italy

    • D Pugliese
    •  & A Armuzzi
  14. Hospital Universitari Mutua de Terrassa and CIBEREHD, Terrassa, Spain

    • Y Zabana
  15. Hospital Universitario Miguel Servet, Zaragoza, Spain

    • R Vicente
  16. Hospital Universitario La Fe and CIBEREHD, Valencia, Spain

    • M Aguas
  17. Shaare Zedek Medical Center, Jerusalem, Israel

    • A Bar-Gil Shitrit
  18. Hospital General Universitario de Alicante and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Alicante, Spain

    • A Gutierrez
  19. St. Vincents University Hospital, Dublin, Ireland

    • G A Doherty
  20. Hospital Clinico Universitario de Valladolid, Valladolid, Spain

    • L Fernandez-Salazar
  21. Hospital Universitario Alvaro Cunqueiro, Vigo, Spain

    • J Martínez Cadilla
  22. Hospital General Universitario de Valencia, Valencia, Spain

    • J M Huguet
  23. Beaumont Hospital, Dublin, Ireland

    • A O'Toole
  24. IRCCS Saverio de Bellis, Castellana Grotte, Italy

    • E Stasi
  25. Hospital Universitario Infanta Sofia, Madrid, Spain

    • N Manceñido Marcos
  26. Hospital Universitari Parc Taulí.Institut d’Investigació i Innovació Parc Taulí. Departament de Medicina, Universitat Autònoma de Barcelona.CIBERehd, Instituto de Salud Carlos III, Sabadell, Spain

    • A Villoria
  27. Venizeleio General Hospital, Heraklion, Greece

    • K Karmiris
  28. CHU UCL Namur, Yvoir, Belgium

    • J F Rahier
  29. Complejo Universitario de Navarra, Pamplona, Spain

    • C Rodriguez
  30. Hospital Universitario A Coruña, Coruña, Spain

    • M Diz-Lois Palomares
  31. IBD Center, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy and Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy

    • G Fiorino
  32. Hospital Universitario Reina Sofia and IMIBIC, Córdoba, Spain

    • J M Benitez
  33. Azienda Policlinico Ospedaliero-Universitaria di Bari, Bari, Italy

    • M Principi
  34. Meir Hospital Kfar saba Tel Aviv University, Tel Aviv, Israel

    • T Naftali
  35. Hospital Clínico San Carlos and IdISSC, Madrid, Spain

    • C Taxonera
  36. Evangelismos, Ophthalmiatreion Athinon and Polyclinic Hospitals, Athens, Greece

    • G Mantzaris
  37. Azienda Ospedaliera “Pugliese-Ciaccio”, Catanzaro, Italy

    • L Sebkova
  38. Hospital de Clinicas, Montevideo, Uruguay

    • B Iade
  39. Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

    • D Lissner
  40. Hospital de Manises, Manises, Spain

    • I Ferrer Bradley
  41. Hospital Ramón y Cajal, Madrid, Spain

    • A Lopez-San Roman
  42. Hospital General Universitario Gregorio Marañón and IiSGM, Madrid, Spain

    • I Marin-Jimenez
  43. Hospital Universitario de Cruces, Baracaldo, Spain

    • O Merino
  44. Complejo Universitario de León, León, Spain

    • M Sierra
  45. Hospital de Torrejón, Torrejón de Ardoz, Spain

    • M Van Domselaar
  46. Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano AND Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

    • F Caprioli
  47. Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain

    • I Guerra
  48. Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal

    • P Peixe
  49. Consorci Sanitari de Terrasa, Terrasa, Spain

    • M Piqueras
  50. Hospital de Galdakao, Vizcaya, Spain

    • I Rodriguez-Lago
  51. Hospital San Jorge, Huesca, Spain

    • Y Ber
  52. Department of Paediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium

    • K van Hoeve
  53. Hospital Sant Joan de Deu, Barcelona, Spain

    • F J Martín de Carpi

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Competing interests

Guarantors of the article: M. Chaparro, MD, PhD, and J.P. Gisbert.

Specific author contributions: M.Chaparro and J.P. Gisbert: study design, data collection, data analysis, data interpretation, writing the manuscript. Rest of authors: patient inclusion and data collection. All authors approved the final version of the manuscript.

Financial support: This research has been funded by grant from the Instituto de Salud Carlos III (PI13/00041).

Potential competing interests: M. Chaparro has served as a speaker, or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, and Tillotts Pharma. M. Julsgaard has served as a speaker, compensated by MSD, Ferring, UCB, and Takeda, and has been on the advisory board for Janssen. J. Rahier: speaker fee—Abbvie, MSD, Takeda, Pfizer, Ferring, and Falk; consultancy—Abbvie, Takeda, Hospira, Mundipharma, MSD, Pfizer, and GlaxoSK; research grant—Takeda and Abbvie. C. Taxonera has served as a speaker, a consultant, and an advisory member for MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, and Gebro Pharma. G. Mantzaris has served as advisory board member for AbbVie, Astellas, Celgene, Danone, Ferring, Genesis, Hospira, Janssen, Millennium Pharmaceuticals, MSD, Otsuka, Pharmacosmos, Pfizer, Sandoz, Takeda, and UCB; speaker for AbbVie, Angelini, Astellas, Danone, Falk Pharma, Ferring, Galenica, Hospira, Janssen, MSD, Omega Pharma, and Takeda; consultant for MSD and Takeda, and has received research support AbbVie, Galenica, Genesis, Menarini Group, MSD, and Pharmathen. F. Caprioli served as consultant to Mundipharma, Abbvie, MSD, Takeda, Janssen, Roche, and Celgene. He received lecture fees from Abbvie, Ferring, Takeda, Allergy Therapeutics, and Janssen, and unrestricted research grants from Giuliani, Sofar, MS&D, Takeda, and Abbvie. I. Guerra has served as speaker for Pfizer, and consultant and advisory member for Kern Pharma. F.J. Martín de Carpi has received travel grants and lecture’s honorarium, and has served as consultant for Abbvie, MSD, Kern, and Celltrion. J.P. Gisbert has served as a speaker, a consultant, and an advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma. A. Armuzzi has received consulting and/or advisory board fees from AbbVie, Allergan, Biogen, Celgene, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Pfizer, Samsung, Sofar, Takeda; lecture and/or speaker bureau fees from AbbVie, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Pfizer, Otsuka, Samsung, Takeda, Tigenix, Zambon; research grant from MSD. G Fiorino served as a consultant and Advisory Board Member for MSD, AbbVie, Takeda, Janssen, Mundipharma, Sandoz, Pfizer. Donata Lissner received a research grant from Pfizer and lecture fees from Abbvie and Falk. A Verreth served as speaker for Takeda. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to M Chaparro.