Background: More than 10 million individuals have now been conceived by Assisted Reproductive Technologies (ART) worldwide. ART conception is associated with an increased risk of preterm birth, low birth weight, being small or large for gestational age, congenital anomalies and perinatal mortality. Given the periconception period is associated with widespread epigenetic remodeling, it is feasible that epigenetics may play a role ART associated perinatal, and potentially longer term, health outcomes.
Objective: To summarise and extend current evidence in humans related to DNA methylation variation in those conceived via ART, including an examination of tissue specificity, stability over time and component processes leading to ART-associated epigenetic effects.
Methods: We carried out a combined analysis of published human DNA methylation datasets generated using either Illumina Infinium HumanMethylation 450 or EPIC datasets for which ART-conception status was available, and supplemented these with additional novel analyses in local cohorts.
Results: We show evidence for specific ART-associated variation in DNA methylation around birth, much of which occurs independently of embryo culturing [1]. Multiple genomic loci were replicated in independent ART epigenome-wide association studies (EWAS) [2], including imprinted regions and environmentally sensitive metastable epialleles. Global ‘average’ DNA methylation in blood at birth may also be altered in association with ART conception. Importantly, ART-associated epigenetic variation at birth largely resolves by adulthood with little evidence to date that it impacts development and health [1,3].
Conclusions: Compelling evidence now exists linking ART conception to specific variation in DNA methylation in newborns, primarily in blood. In addition to potential ‘shifts’ in global methylation, numerous instances of gene-specific variation are also apparent, some of which vary according to tissue, age and ART processes. The relationship to previously described ART associated adverse perinatal outcomes and significance to later health remains unclear and requires careful further investigation.