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DOP016 Long-term safety of in utero exposure to anti-tumor necrosis factor for the treatment of inflammatory bowel diseases: results from the multicenter European TEDDY study

Chaparro M.*1, Verreth A.2, Lobaton T.3, Gravito-Soares E.4, Julsgaard M.5, Savarino E.6, Magro F.7, Avni Biron I.8, Lόpez-Serrano P.9, Casanova M.1, Gompertz M.10, Vitor S.11, Arroyo M.12, Pugliese D.13, Zabana Y.14, Vicente R.15, Aguas M.16, Bar-Gil Shitrit A.17, Gutierrez A.18, Doherty G.19, Fernández-Salazar L.20, Martinez Cadilla J.21, Huguet J.22, O'Toole A.23, Stasi E.24, Manceñido Marcos N.25, Villoria A.26, Karmiris K.27, Rahier J.28, Rodriguez C.29, Diz-Lois Palomares M.30, Fiorino G.31, Benítez J.32, Principi M.33, Naftali T.34, Taxonera C.35, Mantzaris G.36, Sebkova L.37, Iade B.38, Lissner D.39, Ferrer Bradley I.40, Lόpez-San Román A.41, Marín-Jiménez I.42, Merino O.43, Sierra M.44, Van Domselaar M.45, Caprioli F.46, Guerra I.47, Peixe P.48, Piqueras M.49, Rodríguez-Lago I.50, Ber Y.51, Van Hoeve K.2, Torres P.3, Gravito-Soares E.4, Rudbeck-Thomsen D.5, Bartolo O.6, Peixoto A.7, Martín G.8, Pérez J.1, Garre A.1, Donday M.G.1, Martín de Carpi J.52, Gisbert J.P.1 Gastroenterology Units, on behalf of the TEDDY Study Group Investigators

1Hospital Universitario de La Princesa, IIS-IP and CIBERehd, Madrid, Spain 2University Hospitals Leuven, Leuven, Belgium 3Hospital Universitari Germans Trias i Pujol, Badalona, Spain 4Centro Hopitalar e Universitario de Coimbra, Coimbra, Portugal 5Aarhus University Hospital, Aarhus, Denmark 6University of Padua, Padua, Italy 7Centro Hospitalar Sao Joao, Porto, Portugal 8Rabin Medical Center, Petaj Tikva, Israel 9Hospital Universitario Fundaciόn Alcorcόn, Alcorcόn, Spain 10Hospital Clinic Barcelona, Barcelona, Spain 11Hospital de Santa Maria de Lisboa, Lisboa, Portugal 12Hospital Clínico de Zaragoza, Zaragoza, Spain 13Complesso Integrato Columbus Catholic University, Roma, Italy 14Hospital Universitari Mútua de Terrassa, Terrassa, Spain 15Hospital Universitario Miguel Servet, Zaragoza, Spain 16Hospital Universitario La Fe, Valencia, Spain 17Shaare Zedek Medical Center Jerusalem, Jerusalem, Israel 18Hospital General Universitario de Alicante, Alicante, Spain 19St. Vincents University Hospital, Dublin, Ireland 20Hospital Clínico Universitario de Valladolid, Spain, 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 Infanta Sofía, Madrid, Spain 26Hospital Parc Taulí, Sabadell, Spain 27Venizeleio General Hospital, Heraklion, Greece 28CHU Dinant Godinne, Dinant, Belgium 29Complejo Universitario de Navarra, Pamplona, Spain 30Hospital Universitario A Coruña, Coruña, Spain 31Humanitas Research Hospital, Milan, Italy 32Hospital Reina Sofia, Cόrdoba, Spain 33Azienda Ospedaliera Policlinico de Bari, Bari, Italy 34Meir Hospital Kfar saba Tel Aviv University, Tel Aviv, Israel 35Hospital Clínico San Carlos, Madrid, Spain 36Evangelismos, Ophthalmiatreion Athinon and Polyclinic Hospitals, Athens, Greece 37Azienda Ospedaliera “Pugliese-Ciaccio”, Catanzaro, Italy 38Hospital de Clínicas, Montevideo, Uruguay 39Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany 40Hospital de Manises, Manises, Spain 41Hospital Ramόn y Cajal, Madrid, Spain 42Hospital General Universitario Gregorio Marañon, Madrid, Spain 43Hospital Universitario de Cruces, Baracaldo, Spain 44Hospital de Leόn, Leόn, Spain 45Hospital de Torrejόn, Torrejόn de Ardoz, Spain 46IRCCS Ospedale Ca Granda Policlinico di Milano, Milano, 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 52Hospital Sant Joan de Déu, Barcelona, Spain

Background

Long-term safety of anti-tumor necrosis factor therapy (anti-TNF) during pregnancy has hardly been studied.

Aims: To estimate the relative risk of severe infections in offspring of mothers with inflammatory bowel disease (IBD) exposed in utero to anti-TNF

Methods

For this retrospective multicenter cohort study we identified: offspring of mothers with IBD under anti-TNF (with or without thiopurines) at any time during pregnancy or 3 months before conception (Exposed group, EG). The non-exposed group (NEG) consisted of offspring of mothers with IBD treated neither with anti-TNFα nor with thiopurines during this time period. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared by the log-rank test. Cox-regression analysis was performed to identify independent predictive factors for severe infections. AEG-REDCap provided the study e-CRF

Results

In total, 841 children were included, 388 (46%) of them exposed in utero to anti-TNF drugs; 38% of the mothers maintained anti-TNF throughout the whole pregnancy. From children exposed to anti-TNF, 99 (25%) were also exposed to thiopurines. Median (IQR) follow-up after delivery was 54 (9–202) months in the EG and 72 (13–216) months in the NEG (p<0.01). The proportions of CD diagnosis and previous surgery were higher in the EG than in the NEG (75 vs. 42%, p<0.001, and 35 vs. 18%, p<0.01, respectively). Other relevant characteristics were similar between both groups. The proportion of pregnancy complications was similar among both groups. Delivery complications were more frequent in the EG (57 vs. 43%, p<0.01), with a higher rate of caesarean sections in the EG (44 vs. 32%, p<0.01). The proportion of newborn complications was higher in the EG (25 vs. 16%, p<0.01), with a higher rate of low-birth weight in this group (11 vs. 7%, p=0.05) and more frequent need of intensive care unit admission in the EG (7 vs. 3%, p<0.01). The proportion of breastfed babies was higher in the NEG in comparison with the EG (79 vs. 57%, p<0.001). A total of 90 children (11%) developed severe infections during follow-up. The incidence rate of severe infections was similar between NEG and EG (1.6 vs. 2.8% person-years, p=0.2). In multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (HR=2.5; 95% CI: 1.5–4.3). anti-TNF exposure during pregnancy was not associated with a higher risk of severe infections (HR: 1.2; 95% CI: 0.8–1.8)

Conclusion

The exposition to anti-TNFα in utero seems not to be associated with a higher risk of infections in children, neither in the short, nor in the long-term