DNA methylation in newborns conceived by assisted reproductive technology

Siri E Håberg; Christian M Page; Yunsung Lee; Haakon E Nustad; Maria C Magnus; Kristine L Haftorn; Ellen Ø Carlsen; William R P Denault; Jon Bohlin; Astanand Jugessur; Per Magnus; Håkon K Gjessing; Robert Lyle

doi:10.1038/s41467-022-29540-w

Assisted Reproduction · Safety and Risks

DNA methylation in newborns conceived by assisted reproductive technology

Håberg SE, Page CM, Lee Y, Nustad HE, Magnus MC, Haftorn KL, Carlsen EØ, Denault WRP, Bohlin J, Jugessur A, Magnus P, Gjessing HK, Lyle R

Published April 7, 2022 Nature communications

DOI 10.1038/s41467-022-29540-w PMID 35393427 PMC PMC8989983

RRM Academy Synopsis

ART-conceived newborns show widespread DNA methylation differences

Newborns conceived by ART showed widespread differences in cord blood DNA methylation at birth. A Norwegian cohort study compared 962 ART-conceived singletons with 983 naturally conceived singletons. It found 607 CpG sites (DNA positions that carry methyl tags) that differed, even after accounting for the parents' own methylation.

Key Findings

Researchers identified 607 CpGs with genome-wide significance (false discovery rate under 0.01), annotated to 176 known genes, comparing 962 ART-conceived with 983 naturally conceived newborns.
Overall, 74% of CpGs had lower methylation in ART-conceived newborns, yet 65% of the 607 significant CpGs had higher methylation.
Of the 607 sites, 597 (98%) stayed significant after adjusting for gestational age, and 520 (86%) after further adjusting for birthweight, maternal education, paternal age and cell composition.
Against naturally conceived newborns, fresh transfer (n = 764) showed 800 significant CpGs and frozen transfer (n = 126) showed three. IVF with and without ICSI did not differ significantly.
Adjusting for parental methylation kept the differences (Pearson correlation of effect sizes 0.95). Among naturally conceived newborns, time to pregnancy over 12 months versus under 3 months gave no significant CpGs.

Interpretation

Researchers compared newborns conceived by ART with newborns conceived naturally in a sample from the Norwegian MoBa cohort. Newborn methylation was measured once, in cord blood at birth. The health meaning of the differences is unknown, and the authors call for replication, gene expression studies and follow-up over time. Some confounder data came from questionnaires and may be misclassified. The frozen transfer group was the smaller group (n = 126), and the clinics' culture media and incubation times could not be examined.

RRM Context

Restorative reproductive medicine looks for why conception has not occurred and treats that cause in both partners. ART bypasses the question, and the couple remains infertile afterward. The cohort measured newborn biology after ART. Genes involved in growth and brain development carried methylation differences, and these remained after accounting for the parents' own methylation.

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

Abstract

Assisted reproductive technology (ART) may affect fetal development through epigenetic mechanisms as the timing of ART procedures coincides with the extensive epigenetic remodeling occurring between fertilization and embryo implantation. However, it is unknown to what extent ART procedures alter the fetal epigenome. Underlying parental characteristics and subfertility may also play a role. Here we identify differences in cord blood DNA methylation, measured using the Illumina EPIC platform, between 962 ART conceived and 983 naturally conceived singleton newborns. We show that ART conceived newborns display widespread differences in DNA methylation, and overall less methylation across the genome. There were 607 genome-wide differentially methylated CpGs. We find differences in 176 known genes, including genes related to growth, neurodevelopment, and other health outcomes that have been associated with ART. Both fresh and frozen embryo transfer show DNA methylation differences. Associations persist after controlling for parents' DNA methylation, and are not explained by parental subfertility.

Topics

Assisted Reproduction Safety and Risks Procedure-Attributable Risk

Assisted Reproduction › Safety and Risks › Procedure-Attributable Risk

Siri E Håberg, Christian M Page, Yunsung Lee, Haakon E Nustad, Maria C Magnus, Kristine L Haftorn, Ellen Ø Carlsen, William R P Denault, Jon Bohlin, Astanand Jugessur, Per Magnus, Håkon K Gjessing, Robert Lyle

S Håberg, C Page, Y Lee, H Nustad, M Magnus, K Haftorn, E Carlsen, Bill Denault, Will Denault, Billy Denault, W Denault, Jonathan Bohlin, J Bohlin, A Jugessur, P Magnus, H Gjessing, Bob Lyle, Rob Lyle, Bobby Lyle, R Lyle

PMID 35393427 35393427 DOI 10.1038/s41467-022-29540-w 10.1038/s41467-022-29540-w Håberg et al. 2022, Håberg 2022

DNA methylation in newborns conceived by assisted reproductive technology

ART-conceived newborns show widespread DNA methylation differences

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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