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ART COMPLICATIONS

The epigenetic signature of ART fades away in adulthood

Despite conflicting evidence from some studies, a new large-scale study has found no significant correlation between moderate levels of air pollution and outcomes from IVF.

Published 23 September 2019

A longitudinal cohort study has found that the majority of epigenetic changes found in neonates and attributed to ART seem to be resolved later in life.

A new longitudinal cohort study led by Australian investigators has questioned the assumptions of several earlier studies which found that ART alters the DNA of offspring. This latest work, published in Nature Communications in September, assessed DNA methylation in the blood of 131 ART-conceived and 55 non-ART conceived individuals, who were sampled as newborns and as adults, and found that the majority of ART-associated changes in neonates resolved later in life.(1)

ART has been occasionally associated with various pregnancy and neonatal complications, such as premature birth, pre-eclampsia, low birth weight and congenital anomalies. Such findings lay behind the theory that ART procedures intrinsically modulate the genetics of embryonic cells, not in the traditional mutation-introducing manner but by means of unwanted epigenetic modifications, which may persist until birth and beyond. For example, ART may mis-apply methylation, an epigenetic modification used by cells to temporarily silence genes, and thereby affect the health of the offspring. Describing this ART-associated variation in methylation has been the objective of many studies, which have, however, produced largely inconsistent findings because of design heterogeneity (for example, sampling blood via different routes and at diverse time points).

This new study, however, was the first to take a follow-up approach for a more definitive conclusion. The investigators used matching blood samples from ART and non-ART individuals at birth (neonatal spot) and between 22-35 years of age. Their epigenome-wide association study (EWAS) identified 18 DNA regions that were differentially methylated in neonates conceived with ART when compared to neonates from natural pregnancy. To their surprise, they found that only three out of the 18 differentially methylated regions were conserved into adulthood, suggesting that ageing and environmental factors possibly served to attenuate the minimal, but existent, impact of ART.

They also found that one of the three regions with a continuing ART-associated epigenetic variation was in close proximity to the gene Acetylcholine Receptor subunit Epsilon (CHRNE), a mutation of which can lead to congenital myasthenic syndrome. However, in contrast to the developing notion that ART contributes to the risk of acquiring imprinting disorders, this study did not detect ART-associated epigenetic variations in the known imprinted genes of neonates or adults.

Finally, a subgroup analysis assessing different ART protocols and conditions did not identify a specific technique to account for the observed epigenetic variation in neonates, although the authors did argue that ovarian stimulation and infertility per se are the most plausible candidates. The epigenetic signature of ART observed at birth was shown to fade away over time but, add the authors, this finding must now be validated in larger studies before any assumption that ART is safe.

1. Novakovic B, Lewis S, Halliday J, et al. Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolve by adulthood. Nat Commun 2019; doi: 10.1038/s41467-019-11929-9.