Abstract
BackgroundEpidemiological 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.ResultsCompared 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.ConclusionsThis 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).
Highlights
Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, for imprinting disorders
Compared with infants conceived naturally, children born after fresh-ET had a higher prevalence of imprint‐ ing-related diseases, with an Adjusted odds ratios (aOR) of 1.43 [95% confidence intervals (CI) 1.13–1.81, p = 0.003]
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)
Summary
Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, for imprinting disorders. Epidemiological studies suggest that singletons born following the use of ART have an increased risk of adverse perinatal outcomes (e.g. low birth weight after fresh embryo transfers and abnormal placentation) [3, 4]. ART-conceived offspring have an increased risk of rare imprinting disorders, such as Beckwith–Wiedemann (BWS), Russell–Silver (SRS), Angelman (AS) and Prader–Willi (PWS) syndromes [5,6,7,8,9,10]. In a recent meta-analysis, a positive association was still found between conception after ART and four imprinting conditions (BWS, SRS, AS, PWS), among which BWS had a summary odds ratio of 5.8 [95% CI 3.1–11.1] [13]. Fertility problems could be involved in these two last syndromes in ART children [11], but the results of any meta-analysis must be interpreted in light of the limitations of the contributing studies
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