A Systematic Review of Genome Wide Analyses of Methylation Changes Associated with Assisted Reproductive Technologies in Various Tissues

As analytic technologies improve, increasing amounts of data on methylation differences between assisted reproductive technology (ART) and unassisted conceptions are available. However, various studies utilize different tissue types and different populations in their analyses, making comparing and integrating the data difficult. The objective of this systematic review is to compare and integrate data of genome wide analyses of methylation differences due to ART, allowing for exposure of overarching themes. All studies undertaking genome wide analysis of human methylation differences due to ART or infertility in any tissue type across the lifespan were assessed for inclusion. Seventeen studies were identified that met inclusion criteria. One study assessed trophectoderm biopsies, two first trimester placenta, one first trimester fetal tissue, two term placenta, seven cord blood, three newborn dried blood spots, one childhood buccal smears, one childhood peripheral blood, and two adult peripheral blood. Eleven studies compared tissues from in vitro fertilization (IVF) conceptions to unassisted conceptions, four compared ICSI (intracytoplasmic sperm injection) to unassisted, four non-IVF fertility treatment (NIFT) to unassisted, four NIFT to IVF, and five compared an infertile population (conceiving via various methods) to an unassisted presumably fertile population. In studies assessing placental tissue, one gene with potential methylation changes due to IVF when compared to unassisted was identified by two studies. In blood, eleven potential genes with methylation changes in IVF compared to unassisted were identified by two studies, one of which was identified by three studies. Three potentially affected genes were identified by two studies in blood between ICSI and unassisted populations. There were no overlapping genes identified in any tissue type between NIFT and unassisted populations, between NIFT and IVF, or the infertility combined population when compared to the unassisted fertile population. Comparing studies is challenging due to differing variables between analyses. However, even in similar tissue types and populations, overlapping methylation changes are limited, suggesting differences due to ART are minimal. Information from this systematic review is significant for providers and patients who provide and utilize ART to understand methylation risks that may be associated with the technology.