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

Chaparro, M MD, PhD1; Verreth, A MD2; Lobaton, T MD, PhD3; Gravito-Soares, E MD4; Julsgaard, M MD, PhD5; Savarino, E MD, PhD6; Magro, F MD, PhD7; Biron, Avni I MD8; Lopez-Serrano, P MD, PhD9; Casanova, M J MD, PhD1; Gompertz, M MD10; Vitor, S MD11; Arroyo, M MD12; Pugliese, D MD13; Zabana, Y MD, PhD14; Vicente, R MD15; Aguas, M MD, PhD16; Shitrit, Bar-Gil A MD17; Gutierrez, A MD, PhD18; Doherty, G A MB, PhD, FRCP19; Fernandez-Salazar, L MD20; Cadilla, Martínez J MD21; Huguet, J M MD, PhD22; O'Toole, A MD23; Stasi, E MD24; Marcos, Manceñido N MD, PhD25; Villoria, A MD, PhD26; Karmiris, K MD, PhD, FEBGH27; Rahier, J F MD, PhD28; Rodriguez, C MD29; Palomares, Diz-Lois M MD, PhD30; Fiorino, G MD, PhD31; Benitez, J M MD32; Principi, M MD33; Naftali, T MD34; Taxonera, C MD, PhD35; Mantzaris, G MD, PhD36; Sebkova, L MD37; Iade, B MD38; Lissner, D MD39; Bradley, Ferrer I MD40; Roman, Lopez-San A MD, PhD41; Marin-Jimenez, I MD, PhD42; Merino, O MD43; Sierra, M MD44; Van Domselaar, M MD45; Caprioli, F MD, PhD46; Guerra, I MD47; Peixe, P MD48; Piqueras, M MD49; Rodriguez-Lago, I MD50; Ber, Y MD51; van Hoeve, K MD52; Torres, P MD3; Gravito-Soares, M MD4; Rudbeck-Resdal, D MD5; Bartolo, O MD6; Peixoto, A MD7; Martin, G MD8; Armuzzi, A MD, PhD13; Garre, A MSc1; Donday, M G MSc1; de Carpi, Martín F J MD53; Gisbert, J P MD, PhD, Professor1

American Journal of Gastroenterology: March 2018 - Volume 113 - Issue 3 - p 396–403
doi: 10.1038/ajg.2017.501

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 drugsin uterowith 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 uteroexposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

1Gastroenterology 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

2Department of Gastroenterology and Department of Pediatric Gastroenterology, University Hospitals Leuven, KU Leuven, Leuven, Belgium

3Hospital Universitari Germans Trias i Pujol and CIBEREHD, Badalona, Spain

4Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

5Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

6University of Padua, Padua, Italy

7Centro Hospitalar São João, Porto, Portugal

8Gastroenterology Devision, Rabin Medical Center, Petach Tikva, Israel

9Hospital Universitario Fundación Alcorcón, Alcorcón, Spain

10Hospital Clinic and CIBEREHD, Barcelona, Spain

11Hospital de Santa Maria - Centro Hospitalar Lisboa Norte, Lisboa, Portugal

12Hospital Clinico Universitario Lozano Blesa, IIS Aragon, CIBEREHD, Zaragoza, Spain

13IBD Unit, Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Roma, Italy

14Hospital Universitari Mutua de Terrassa and CIBEREHD, Terrassa, Spain

15Hospital Universitario Miguel Servet, Zaragoza, Spain

16Hospital Universitario La Fe and CIBEREHD, Valencia, Spain

17Shaare Zedek Medical Center, Jerusalem, Israel

18Hospital General Universitario de Alicante and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Alicante, Spain

19St. Vincents University Hospital, Dublin, Ireland

20Hospital Clinico Universitario de Valladolid, Valladolid, Spain

21Hospital Universitario Alvaro Cunqueiro, Vigo, Spain

22Hospital General Universitario de Valencia, Valencia, Spain

23Beaumont Hospital, Dublin, Ireland

24IRCCS Saverio de Bellis, Castellana Grotte, Italy

25Hospital Universitario Infanta Sofia, Madrid, Spain

26Hospital 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

27Venizeleio General Hospital, Heraklion, Greece

28CHU UCL Namur, Yvoir, Belgium

29Complejo Universitario de Navarra, Pamplona, Spain

30Hospital Universitario A Coruña, Coruña, Spain

31IBD Center, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy and Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy

32Hospital Universitario Reina Sofia and IMIBIC, Córdoba, Spain

33Azienda Policlinico Ospedaliero-Universitaria di Bari, Bari, Italy

34Meir Hospital Kfar saba Tel Aviv University, Tel Aviv, Israel

35Hospital Clínico San Carlos and IdISSC, Madrid, Spain

36Evangelismos, Ophthalmiatreion Athinon and Polyclinic Hospitals, Athens, Greece

37Azienda Ospedaliera “Pugliese-Ciaccio”, Catanzaro, Italy

38Hospital de Clinicas, Montevideo, Uruguay

39Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

40Hospital de Manises, Manises, Spain

41Hospital Ramón y Cajal, Madrid, Spain

42Hospital General Universitario Gregorio Marañón and IiSGM, Madrid, Spain

43Hospital Universitario de Cruces, Baracaldo, Spain

44Complejo Universitario de León, León, Spain

45Hospital de Torrejón, Torrejón de Ardoz, Spain

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

47Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain

48Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal

49Consorci Sanitari de Terrasa, Terrasa, Spain

50Hospital de Galdakao, Vizcaya, Spain

51Hospital San Jorge, Huesca, Spain

52Department of Paediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium

53Hospital Sant Joan de Deu, Barcelona, Spain

Correspondence: M. Chaparro, MD, PhD, Inflammatory Bowel Disease Unit, Department of Gastroenterology, University Hospital La Princesa, Diego de León, 62, Madrid 28006, Spain. E-mail:

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published online 20 February 2018

Received 28 May 2017; accepted 26 November 2017

© The American College of Gastroenterology 2018. All Rights Reserved.
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