Stability of Genomic Imprinting and Gestational-Age Dynamic Methylation in Complicated Pregnancies Conceived Following Assisted Reproductive Technologies1

Abstract

For the past three decades, assisted reproductive technologies (ART) have revolutionized infertility treatments. The use of ART is thought to be safe. However, early investigations suggested that children born as a result of ART had higher risk of diseases with epigenetic etiologies, including imprinting disorders caused by a lack of maternal methylation at imprinting control elements. In addition, large epidemiology studies have highlighted an increased risk of obstetric complications, including severe intrauterine growth restriction (IUGR) in babies conceived using ART. It is plausible that the increased frequency of IUGR may be due to abnormal imprinting because these transcripts are key for normal fetal growth and development. To address this, we have collected a large cohort of placenta and cord blood samples from ART conceptions and compared the imprinting status with appropriate non-ART population. Using a custom DNA methylation array that simultaneously quantifies 25 imprinted differentially methylated regions, we observed similar epigenetic profiles between groups. A multiplex Sequenom iPLEX allelic expression assay revealed monoallelic expression for 11 imprinted transcripts in our placenta cohort. We also observe appropriate gestational age-dependent methylation dynamics at retrotransposable elements and promoters associated with growth genes in ART placental biopsies. This study confirms that children conceived by ART do not show variability in imprinted regulation and that loss-of-imprinting is not commonly associated with nonsyndromic IUGR or prematurity.