Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood

Boris Novakovic; Sharon Lewis; Jane Halliday; Joanne Kennedy; David P Burgner; Anna Czajko; Bowon Kim; Alexandra Sexton-Oates; Markus Juonala; Karin Hammarberg; David J Amor; Lex W Doyle; Sarath Ranganathan; Liam Welsh; Michael Cheung; John McBain; Robert McLachlan; Richard Saffery

doi:10.1038/s41467-019-11929-9

Assisted Reproduction · Safety and Risks

Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood

Novakovic B, Lewis S, Halliday J, Kennedy J, Burgner DP, Czajko A, Kim B, Sexton-Oates A, Juonala M, Hammarberg K, Amor DJ, Doyle LW, Ranganathan S, Welsh L, Cheung M, McBain J, McLachlan R, Saffery R

Published September 2, 2019 Nature communications

DOI 10.1038/s41467-019-11929-9 PMID 31477727 PMC PMC6718382

RRM Academy Synopsis

ART-linked methylation differences at birth mostly fade by adulthood

ART-associated DNA methylation differences at birth mostly faded by adulthood, a longitudinal cohort study found. Researchers compared blood from 149 ART-conceived and 58 non-ART newborns, and from 158 ART-conceived and 75 non-ART adults. After correction for multiple testing, 2340 sites differed at birth and none differed in adults.

Key Findings

Newborn blood showed 2340 differentially methylated probes between the ART and non-ART groups after correction for multiple testing. Adult blood showed none.
At birth, 136 probes differed by 5% or more: 116 (85%) had higher and 20 (15%) lower methylation in the ART group. Six differed by 5% or more in adults, less strongly.
Region analysis found 18 differentially methylated regions at birth and 4 in adulthood. Three regions appeared at both ages, near the genes CHRNE, PRSS16 and TMEM18.
In an independent set of 94 ART and 43 non-ART newborns, the CHRNE and PRSS16 regions replicated in direction and size. Little supporting data appeared for TMEM18.
Only 2 imprinting-associated probes differed at birth after correction. At a relaxed threshold (unadjusted p-value below 0.05), 4% of them qualified, against approximately 9% of all probes.

Interpretation

The study measured DNA methylation, a chemical mark on DNA, in blood taken at birth and in adulthood. ART and non-ART groups were compared in a longitudinal cohort, so the findings describe associations. Limits the authors list include no test of whether the differences change gene activity and no direct assessment of ovarian stimulation. Adult participants may also have been a comparatively healthy, self-selected group. The authors call the sample the largest of its type but small for epigenome-wide work. They caution against over-interpreting the health implications.

RRM Context

Earlier studies the authors cite link ART conception to an approximately two-fold increased risk of outcomes such as preterm birth and low birth weight. The CHRNE difference appeared after IVF, GIFT and IUI. GIFT and IUI involve no embryo culturing. The authors suggest ovarian stimulation or infertility itself as possible contributors. ART bypasses the cause of infertility without resolving it. Restorative reproductive medicine begins by identifying that cause.

Our editorial summary of this paper, not the article's abstract.

Abstract

More than 7 million individuals have been conceived by Assisted Reproductive Technologies (ART) and there is clear evidence that ART is associated with a range of adverse early life outcomes, including rare imprinting disorders. The periconception period and early embryogenesis are associated with widespread epigenetic remodeling, which can be influenced by ART, with effects on the developmental trajectory in utero, and potentially on health throughout life. Here we profile genome-wide DNA methylation in blood collected in the newborn period and in adulthood (age 22-35 years) from a unique longitudinal cohort of ART-conceived individuals, previously shown to have no differences in health outcomes in early adulthood compared with non-ART-conceived individuals. We show evidence for specific ART-associated variation in methylation around birth, most of which occurred independently of embryo culturing. Importantly, ART-associated epigenetic variation at birth largely resolves by adulthood with no direct evidence that it impacts on development and health.

Topics

Assisted Reproduction Safety and Risks Long Term Child Outcomes

Assisted Reproduction › Safety and Risks › Long Term Child Outcomes

Boris Novakovic, Sharon Lewis, Jane Halliday, Joanne Kennedy, David P Burgner, Anna Czajko, Bowon Kim, Alexandra Sexton-Oates, Markus Juonala, Karin Hammarberg, David J Amor, Lex W Doyle, Sarath Ranganathan, Liam Welsh, Michael Cheung, John McBain, Robert McLachlan, Richard Saffery

B Novakovic, S Lewis, J Halliday, J Kennedy, Dave Burgner, D Burgner, A Czajko, B Kim, Alex Sexton-Oates, A Sexton-Oates, M Juonala, K Hammarberg, Dave Amor, D Amor, L Doyle, S Ranganathan, L Welsh, Mike Cheung, M Cheung, Jack McBain, J McBain, Bob McLachlan, Rob McLachlan, Bobby McLachlan, R McLachlan, Rick Saffery, Dick Saffery, Rich Saffery, R Saffery

PMID 31477727 31477727 DOI 10.1038/s41467-019-11929-9 10.1038/s41467-019-11929-9 Novakovic et al. 2019, Novakovic 2019

Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood

ART-linked methylation differences at birth mostly fade by adulthood

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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