Fauque Patricia, De Mouzon Jacques, Devaux Aviva, Epelboin Sylvie, Gervoise-Boyer Marie-José, Levy Rachel, Valentin Morgane, Viot Géraldine, Bergère Arianne, De Vienne Claire, Jonveaux Philippe, Pessione Fabienne
CHU Dijon Bourgogne, Laboratoire de Biologie de la Reproduction - CECOS - Université Bourgogne Franche-Comté - INSERM UMR1231, Dijon, France.
Unilabs, direction médicale, Clichy-La-Garenne, France.
Clin Epigenetics. 2020 Dec 11;12(1):191. doi: 10.1186/s13148-020-00986-3.
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.
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.
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).
流行病学研究表明，通过辅助生殖技术（ART）出生的单胎婴儿发生围产期不良结局的风险较高，尤其是印记紊乱方面。由于ART过程发生在表观遗传重编程/印记发生之时，人们担心ART会影响基因组印记。然而，目前对于根据ART类型或潜在女性不孕症类型导致的印记缺陷风险知之甚少。从法国国家健康数据库中，选取了一组在5年期间（2013 - 2017年）通过新鲜胚胎或冷冻胚胎移植（体外受精的新鲜胚胎移植或冷冻胚胎移植）、宫内人工授精或自然受孕出生的3,501,495名单胎婴儿，并随访至幼儿期。基于临床特征，监测了几种涉及印记基因的综合征/疾病。评估了ART受孕的影响以及女性不孕症的潜在原因。
与自然受孕的婴儿相比，新鲜胚胎移植后出生的儿童患印记相关疾病的患病率更高，调整后比值比（aOR）为1.43 [95%置信区间（CI）1.13 - 1.81，p = 0.003]。具体而言，我们观察到新生儿糖尿病的风险增加（aOR为1.96 [95% CI 1.43 - 2.70]，p < 0.001）。被诊断患有子宫内膜异位症的母亲所生儿童的印记疾病总体风险独立增加（aOR为1.38 [95% CI 1.06 - 1.80]，p = 0.02）。年轻和高龄产妇、初产、肥胖、吸烟以及高血压或糖尿病病史也与较高的总体风险相关。
这项前瞻性流行病学研究表明，在新鲜胚胎移植后受孕的儿童或患有子宫内膜异位症的母亲所生儿童中，临床诊断的印记相关疾病风险增加。基因组印记中增加的扰动可能是由控制性卵巢过度刺激以及潜在的子宫内膜异位症通过损害子宫内膜容受性和胎盘形成导致的，从而引起表观遗传的胎儿 - 胎盘变化。现在需要进一步研究以更好地理解潜在的分子机制（即遗传或表观遗传原因）。
