Do in vitro fertilization, intrauterine insemination or female infertility impact the risk of congenital anomalies in singletons? A longitudinal national French study Patricia Fauque 1, *, Jacques De Mouzon 2 , Aviva Devaux 3 , Sylvie Epelboin 4 , Marie-Jose ´ Gervoise-Boyer 5 , Rachel Levy 6 , Morgane Valentin 7 , Ge ´ raldine Viot 8 , Marianne Berge `re 9 , Claire De Vienne 9 , Philippe Jonveaux 9 , and Fabienne Pessione 9 1 Universite ´ Bourgogne Franche-Comte ´ - INSERM UMR 1231, CHU Dijon Bourgogne, Laboratoire de Biologie de la Reproduction - CECOS, Dijon, France 2 Unilabs, direction me ´dicale, Clichy-La-Garenne, France 3 Centre d’assistance me ´dicale a ` la procre ´ation, biologie de la reproduction, CHU Amiens, Amiens, France 4 Centre d’assistance me ´dicale a ` la procre ´ation, gyne ´cologie obste ´trique, me ´decine de la reproduction, universite ´ Paris 7 Diderot, groupe hospitalier Bichat Claude-Bernard, Paris, France 5 Service de me ´decine et biologie de la reproduction, ho ˆ pital Saint-Joseph, Marseille, France 6 Inserm, e ´quipe lipodystrophies ge ´ne ´tiques et acquises, service de biologie de la reproduction-CECOS, Saint-Antoine Research center, Sorbonne universite ´, ho ˆpital Tenon, Paris, France 7 Diagnostic ante ´natal, gyne ´cologie obste ´trique, universite ´ Paris 7 Diderot, groupe hospitalier Bichat Claude-Bernard, Paris, France 8 Unite ´ de Ge ´ne ´tique Clinique de La Muette, Paris, France 9 Agence de la biome ´decine, La Plaine Saint Denis, France *Correspondence address. Universite ´ Bourgogne Franche-Comte ´ - INSERM UMR1231, 2 rue Ange ´lique Ducoudray, Dijon F-21000, France; CHU Dijon Bourgogne, Laboratoire de Biologie de la Reproduction - CECOS, 14 rue Gaffarel, Dijon F-21000, France. E-mail: patricia.fau- que@chu-dijon.fr Submitted on July 6, 2020; resubmitted on October 22, 2020; editorial decision on October 29, 2020 STUDY QUESTION: Do IVF, IUI or female infertility (i.e. endometriosis, polycystic ovary syndrome [PCOS] and primary ovarian insufficiency [POI]) lead to an increased risk of congenital anomalies in singletons? SUMMARY ANSWER: After multivariable adjustments, the increased risks of congenital defects associated with IUI were no longer significant, but the underlying maternal infertility presented a potential emental risk, in addition to the risk associated with IVF. WHAT IS KNOWN ALREADY: Most epidemiological studies suggest that singletons born from ART have a higher risk of birth defects, specifically musculoskeletal, cardiovascular and urogenital disorders. However, most of these studies were established on data obtained at birth or in the neonatal period and from relatively small populations or several registries. Moreover, to our knowledge, female infertility, which is a potential confounder, has never been included in the risk assessment. STUDY DESIGN, SIZE, DURATION: Using data from the French National Health System database, we conducted a comparative analysis of all singleton births (deliveries 22 weeks of gestation and/or >500 g of birthweight) in France over a 5-year period (2013–2017) resulting from fresh embryo or frozen embryo transfer (fresh-ET or FET from IVF/ICSI cycles), IUI and natural conception (NC). Data were available for this cohort of children at least up to early childhood (2.5 years old). PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 3 501 495 singleton births were included (3 417 089 from NC, 20 218 from IUI, 45 303 from fresh-ET and 18 885 from FET). Data were extracted from national health databases and used to identify major birth defects. Malformations were classified according to the 10th revision of the International Classification of Disease. To analyse the effect of mode of conception, multivariable analyses were performed with multiple logistic regression models adjusted for maternal age, primiparity, obesity, smoking, history of high blood pressure or diabetes and female infertility. MAIN RESULTS AND THE ROLE OF CHANCE: In our cohort of children, the overall prevalence of congenital malformations was 3.78% after NC, 4.53% after fresh-ET, 4.39% after FET and 3.91% after IUI (132 646 children with major malformations). Compared with infants conceived naturally, children born after fresh-ET and after FET had a significantly higher prevalence of malformations, with an V C The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com Human Reproduction, Vol.36, No.3, pp. 808–816, 2021 Advance Access Publication on December 30, 2020 doi:10.1093/humrep/deaa323 ORIGINAL ARTICLE Reproductive epidemiology Downloaded from https://academic.oup.com/humrep/article/36/3/808/6055895 by guest on 12 October 2023