Assisted Reproductive Technologies and imprinting disorders: Results of a study from a French congenital malformations registry

Introduction: Assisted Reproductive Technologies (ART) is increasingly used to help infertile couples to have children around the world. A number of studies have been published reporting an increased risk of major malformations in children born following ART, especially an increased incidence of epigenetic diseases (ED). This study aimed to assess the incidence of epigenetic diseases with affected imprinting genes in infants or children from pregnancies obtained through IVF/ICSI compared to infants or children from pregnancies obtained spontaneously. Patient data: This is a monocentric retrospective epidemiological study based on data from a French congenital malformations registry called REMERA (Registre des Malformations en Rhone-Alpes) which exhaustively monitors all pregnancies in Rhone-Alpes region, whatever their nature of onset (spontaneous pregnancies or pregnancies from ART). This registry collects all malformations, except minor malformations (EUROCAT), and all polymalformative syndromes concerning all fetuses and children born alive or not, from 20 weeks of pregnancy (or 22 weeks of amenorrhea) and all medical termination of pregnancy whatever the term. Inclusion criteria are all diagnoses of epigenetic diseases (ED) related to parental imprinting recorded in the period January 2006 to December 2015. Methods: For each year, the total number of births (including stillbirths) was collected from the annual activity reports of the registry. The exhaustive number of cases of epigenetic diseases was known in the registry. Were collected the number of births resulting from ART pregnancies in the study population. This incidence of ED was compared between births from spontaneous pregnancies and those obtained through ART (IVF/ICSI) with a generalized linear model (GLM: binomial regression). Results: In total, 46 cases of epigenetic diseases were analyzed on the REMERA registry files from 2006 to 2015. 4 cases from the 46 analyzed cases were from pregnancies induced by ART. ART was a risk factor for epigenetic disease (OR = 2.9 [1.06-8.22] (p = .039)). In ART-pregnancies there were 2 diagnoses: Beckwith-Wiedemann syndrome (BWS) (3 cases out of 4) and Silver-Russell syndrome (SRS) (1 out of 4). Discussion: Infants and children obtained through IVF/ICSI appear to be related to a higher risk of epigenetic diseases compared to naturally conceived children. The perspectives of this study are to raise awareness about the creation of registries of congenital malformations and genetic and epigenetic syndromes with systematic and strict reports of all the cases on all the French territory and thus to widen this study with a bigger cohort.