Patricia Fauque1, Jacques De Mouzon2, Aviva Devaux3, Sylvie Epelboin4, Marie-José Gervoise-Boyer5, Rachel Levy6, Morgane Valentin7, Géraldine Viot8, Arianne Bergère9, Claire De Vienne9, Philippe Jonveaux9, Fabienne Pessione9. 1. CHU Dijon Bourgogne, Laboratoire de Biologie de la Reproduction - CECOS - Université Bourgogne Franche-Comté - INSERM UMR1231, Dijon, France. patricia.fauque@chu-dijon.fr. 2. Unilabs, direction médicale, Clichy-La-Garenne, France. 3. Centre d'assistance medicale à la procreation, biologie de la reproduction, CHU Amiens, Amiens, France. 4. Centre d'assistance medicale à la procreation, gynécologie obstétrique, médecine de la reproduction, Université Paris 7 Diderot, groupe hospitalier Bichat Claude-Bernard, AP-HP, Paris, France. 5. Service de medecine et biologie de la reproduction, Hôpital Saint-Joseph, Marseille 8, France. 6. Sorbonne Université, Saint Antoine Research Center, INSERM équipe Lipodystrophies genetiques et acquises, Service de biologie de la reproduction-CECOS, Hôpital Tenon, AP-HP, 75012, Paris, France. 7. Diagnostic antenatal, gynécologie obstétrique, Université Paris 7 Diderot, groupe hospitalier Bichat Claude-Bernard, AP-HP, Paris, France. 8. Unité de Génétique Clinique de La Muette, 50 rue Nicolo, 75116, Paris, France. 9. Agence de la Biomédecine, 1 avenue du stade de France, 93212, La Plaine Saint Denis, France.
Abstract
BACKGROUND: Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility. From the French national health database, a cohort of 3,501,495 singletons born over a 5-year period (2013-2017) following fresh embryo or frozen embryo transfers (fresh-ET or FET from in vitro fertilization), intrauterine insemination, or natural conception was followed up to early childhood. Based on clinical features, several syndromes/diseases involving imprinted genes were monitored. The effects of ART conception and the underlying cause of female infertility were assessed. RESULTS: Compared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprinting-related diseases, with an aOR of 1.43 [95% CI 1.13-1.81, p = 0.003]. Namely, we observed an increased risk of neonatal diabetes mellitus (1.96 aOR [95% CI 1.43-2.70], p < 0.001). There was an overall independent increase in risk of imprinting diseases for children with mothers diagnosed with endometriosis (1.38 aOR [95% CI 1.06-1.80], p = 0.02). Young and advanced maternal age, primiparity, obesity, smoking, and history of high blood pressure or diabetes were also associated with high global risk. CONCLUSIONS: This prospective epidemiological study showed that the risk of clinically diagnosed imprinting-related diseases is increased in children conceived after fresh embryo transfers or from mothers with endometriosis. The increased perturbations in genomic imprinting could be caused by controlled ovarian hyperstimulation and potentially endometriosis through the impairment of endometrial receptivity and placentation, leading to epigenetic feto-placental changes. Further studies are now needed to improve understanding of the underlying molecular mechanisms (i.e. genetic or epigenetic causes).
BACKGROUND: Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility. From the French national health database, a cohort of 3,501,495 singletons born over a 5-year period (2013-2017) following fresh embryo or frozen embryo transfers (fresh-ET or FET from in vitro fertilization), intrauterine insemination, or natural conception was followed up to early childhood. Based on clinical features, several syndromes/diseases involving imprinted genes were monitored. The effects of ART conception and the underlying cause of female infertility were assessed. RESULTS: Compared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprinting-related diseases, with an aOR of 1.43 [95% CI 1.13-1.81, p = 0.003]. Namely, we observed an increased risk of neonatal diabetes mellitus (1.96 aOR [95% CI 1.43-2.70], p < 0.001). There was an overall independent increase in risk of imprinting diseases for children with mothers diagnosed with endometriosis (1.38 aOR [95% CI 1.06-1.80], p = 0.02). Young and advanced maternal age, primiparity, obesity, smoking, and history of high blood pressure or diabetes were also associated with high global risk. CONCLUSIONS: This prospective epidemiological study showed that the risk of clinically diagnosed imprinting-related diseases is increased in children conceived after fresh embryo transfers or from mothers with endometriosis. The increased perturbations in genomic imprinting could be caused by controlled ovarian hyperstimulation and potentially endometriosis through the impairment of endometrial receptivity and placentation, leading to epigenetic feto-placental changes. Further studies are now needed to improve understanding of the underlying molecular mechanisms (i.e. genetic or epigenetic causes).
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