DNA Methylation in Offspring Conceived after Assisted Reproductive Techniques: A Systematic Review and Meta-Analysis

Background: In the last 40 years, assisted reproductive techniques (ARTs) have emerged as potentially resolving procedures for couple infertility. This study aims to evaluate whether ART is associated with epigenetic dysregulation in the offspring. Methods. To accomplish this, we collected all available data on methylation patterns in offspring conceived after ART and in spontaneously conceived (SC) offspring. Results. We extracted 949 records. Of these, 50 were considered eligible; 12 were included in the quantitative synthesis. Methylation levels of H19 CCCTC-binding factor 3 (CTCF3) were significantly lower in the ART group compared to controls (SMD -0.81 (-1.53; -0.09), I-2 = 89%, p = 0.03). In contrast, H19 CCCTC-binding factor 6 (CTCF6), Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1OT1), Paternally-expressed gene 3 (PEG3), and Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) were not differently methylated in ART vs. SC offspring. Conclusion: The methylation pattern of the offspring conceived after ART may be different compared to spontaneous conception. Due to the lack of studies and the heterogeneity of the data, further prospective and well-sized population studies are needed to evaluate the impact of ART on the epigenome of the offspring.