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Children conceived by Assisted Reproductive Technologies (ART) are at moderately increased risk for a number of undesirable outcomes, including low birth weight. Whether the additional risk is associated with specific procedures used in ART or biological factors that are intrinsic to infertility has been the subject of much debate, as has the mechanism by which ART or infertility might influence this risk. The potential effect of ART clinical and laboratory procedures on the gamete and embryo epigenomes heads the list of mechanistic candidates that might explain the association between ART and undesirable clinical outcomes. The reason for this focus is that the developmental time points at which ART clinical and laboratory procedures are implemented are precisely the time points at which large-scale reorganization of the epigenome takes place during normal development. In this manuscript, we review the many human studies comparing the epigenomes of ART children with children conceived in vivo, as well as assess the potential of individual ART clinical and laboratory procedures to alter the epigenome.

Assisted reproductive technologies (ARTs) lead to an increased risk for pregnancy complications, congenital abnormalities, and specific imprinting disorders. Epigenetic dysfunction is thought to be one common mechanism which may be affecting these outcomes. The timing of multiple ART interventions overlaps with developmental time periods that are particularly vulnerable to epigenetic change. In vitro embryo culture is known to impact blastocyst development, in vitro fertilization (IVF) success rates, as well as neonatal outcomes. Embryo culture, in contrast to other procedures involved in ART, is obligatory, and has the highest potential for causing alterations in epigenetic reprograming. In this review, we summarize progress that has been made in exploring the effects of embryo culture, culture media, and oxygen tension on epigenetic regulation in the developing embryo. In humans, it is difficult to isolate the role of embryo culture on epigenetic perturbations. Therefore, additional well-controlled animal studies isolating individual exposures are necessary to minimize the epigenetic effects of modifiable factors utilized during ART. Findings from these studies will likely not only improve IVF success rates but also reduce the risk of adverse perinatal outcomes., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: We analyzed placental DNA methylation levels at repeated sequences ( LINE1 elements) and all CCGG sites (the LUMA assay) to study the effect of modifiable clinical or laboratory procedures involved in in vitro fertilization. We included four potential modifiable factors: oxygen tension during embryo culture, fresh embryo transfer vs frozen embryo transfer, intracytoplasmic sperm injection (ICSI) vs conventional insemination or day 3 embryo transfer vs day 5 embryo transfer., Results: Global methylation levels differed between placentas from natural conceptions compared to placentas conceived by IVF. Placentas from embryos cultured at 20% oxygen showed significant differences in LINE1 methylation compared to in vivo conceptions, while those from embryos cultured at 5% oxygen, did not have significant differences. In addition, placentas from fresh embryo transfer had significantly different LINE1 methylation compared to placentas from in vivo conceptions, while embryos resulting from frozen embryos were not significantly different from controls. On sex-stratified analysis, only males had significant methylation differences at LINE1 elements stratified for the modifiable factors. As expected, LINE1 methylation was significantly different between males and females in the control population. However, we did not observe sex-specific differences in the IVF group. We validated this sex-specific observation in an additional cohort and in opposite sex IVF twins., Conclusion: We show that two clinically modifiable factors (embryo culture in 5 vs 20% oxygen tension and fresh vs frozen embryo transfer) are associated with global placental methylation differences. Interestingly, males appear more vulnerable to such treatment-related global changes in DNA methylation than do females.

Computer-automated time-lapse analysis has been shown to improve embryo selection by providing quantitative and objective information to supplement traditional morphology. In this multi-centre study, the relationship between such computer-derived outputs (High, Medium, Low scores), embryo implantation and clinical pregnancy were examined. Data were collected from six clinics, including 205 patients whose embryos were imaged by the Eeva(TM) System. The Eeva scores were blinded and not considered during embryo selection. Embryos with High and Medium scores had significantly higher implantation rates than those with Low scores (37% and 35% versus 15%; P < 0.0001; P = 0.0004). Similar trends in implantation rates were observed in different IVF centres each using their own protocols. Further analysis revealed that patients with at least one High embryo transferred had significantly higher clinical pregnancy rates than those with only Low embryos transferred (51% versus 34%; P = 0.02), although patients' clinical characteristics across groups were comparable. These data, together with previous research and clinical studies, confirm that computer-automated Eeva scores provide valuable information, which may improve the clinical outcome of IVF procedures and ultimately facilitate the trend of single embryo selection., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)