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. 2024 Jan;121(1):80-94.
doi: 10.1016/j.fertnstert.2023.10.007. Epub 2023 Oct 10.

A systematic review of genome-wide analyses of methylation changes associated with assisted reproductive technologies in various tissues

Amelia M Schaub  1 , Tania L Gonzalez  1 , Anna E Dorfman  1 , Allynson G Novoa  1 , Rimsha A Hussaini  1 , Paige M Harakuni  1 , Mayaal H Khan  1 , Brandon J Shabani  1 , Akhila Swarna  1 , Erica T Wang  1 , Jessica L Chan  1 , John Williams 3rd  2 , Margareta D Pisarska  3
Affiliations

A systematic review of genome-wide analyses of methylation changes associated with assisted reproductive technologies in various tissues

Amelia M Schaub et al. Fertil Steril. 2024 Jan.

Abstract

Importance: Because analytic technologies improve, increasing amounts of data on methylation differences between assisted reproductive technology (ART) and unassisted conceptions are available. However, various studies use different tissue types and different populations in their analyses, making data comparison and integration difficult.

Objective: To compare and integrate data on genome-wide analyses of methylation differences due to ART, allowing exposure of overarching themes.

Evidence review: All studies undertaking genome-wide analysis of human methylation differences due to ART or infertility in any tissue type across the lifespan were assessed for inclusion.

Findings: Seventeen studies were identified that met the inclusion criteria. One study assessed trophectoderm biopsies, 2 first-trimester placenta, 1 first-trimester fetal tissue, 2 term placenta, 7 cord blood, 3 newborn dried blood spots, 1 childhood buccal smears, 1 childhood peripheral blood, and 2 adult peripheral blood. Eleven studies compared tissues from in vitro fertilization (IVF) conceptions with those of unassisted conceptions, 4 compared intracytoplasmic sperm injection with unassisted conceptions, 4 compared non-IVF fertility treatment (NIFT) with unassisted conceptions, 4 compared NIFT with IVF, and 5 compared an infertile population (conceiving via various methods) with an unassisted presumably fertile population. In studies assessing placental tissue, 1 gene with potential methylation changes due to IVF when compared with unassisted conceptions was identified by 2 studies. In blood, 11 potential genes with methylation changes due to IVF compared with unassisted conceptions were identified by 2 studies, 1 of which was identified by 3 studies. Three potentially affected genes were identified by 2 studies involving blood between intracytoplasmic sperm injection and unassisted populations. There were no overlapping genes identified in any tissue type between NIFT and unassisted populations, between NIFT and IVF, or the infertility combined population when compared with the unassisted fertile population.

Conclusions: Comparing studies is challenging due to differing variables between analyses. However, even in similar tissue types and populations, overlapping methylation changes are limited, suggesting that differences due to ART are minimal.

Relevance: Information from this systematic review is significant for providers and patients who provide and use ART to understand methylation risks that may be associated with the technology.

Keywords: DNA methylation; epigenetics; infertility; in vitro fertilization.

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Conflict of interest statement

Declaration of interests A.M.S. has nothing to disclose. T.L.G. has nothing to disclose. A.E.D. has nothing to disclose. R.A.H. has nothing to disclose. P.M.H. has nothing to disclose. M.H.K. has nothing to disclose. B.J.S. has nothing to disclose. A.S. has nothing to disclose. E.T.W. has nothing to disclose. J. L. C. is a scientific advisor for BINTO. J. W. III is a member of The Advisory Board for Natera. M. D. P. is a Ferring Pharmaceuticals consultant, serves at the Society for the Study of Reproduction Development Committee, previously served as a Team Lead on the Endocrine Society Annual Meeting Steering Committee, and previously received a speaker honorarium from Natera.

Figures

Fig 1.
Fig 1.. Tissue Timeline Table.
The table displaying the 17 included studies, stratified by tissue type (horizontally) and populations compared (vertically). Studies that compared the same tissue type and the same populations fall into the same cell of the table. *NIFT cohort contained those with history of infertility conceiving unassisted ** IVF cohort Also contained GIFT
Fig 2–4.
Fig 2–4.. Tile Charts of Identified Genes in IVF vs Unassisted Populations.
The tile charts display genes identified as being significantly altered in a study comparing IVF conceptions to unassisted conceptions. If a CpG site reported as significant did not correlate with a specific gene, the CpG site itself is listed. Those genes/CpG sites reported as significant by more than 1 study are boldened. The genes are organized by chromosome. Figure 1 contains genes on chromosomes 1–5. Figure 2 contains genes on chromosomes 6–13. Figure 3 contains genes located on chromosomes 14– 22 and chromosome X. The study reference number is listed on the top of each column, and the studies are grouped by tissue type. A green tile indicates higher methylation in the unassisted population. A pink tile indicates higher methylation in the IVF population. A yellow tile indicates the direction of methylation was mixed in the CpG sites associated with that gene (for example, one methylation site more methylation in unassisted and another more methylated in IVF). A grey tile indicates no significant alteration.
Fig 2–4.
Fig 2–4.. Tile Charts of Identified Genes in IVF vs Unassisted Populations.
The tile charts display genes identified as being significantly altered in a study comparing IVF conceptions to unassisted conceptions. If a CpG site reported as significant did not correlate with a specific gene, the CpG site itself is listed. Those genes/CpG sites reported as significant by more than 1 study are boldened. The genes are organized by chromosome. Figure 1 contains genes on chromosomes 1–5. Figure 2 contains genes on chromosomes 6–13. Figure 3 contains genes located on chromosomes 14– 22 and chromosome X. The study reference number is listed on the top of each column, and the studies are grouped by tissue type. A green tile indicates higher methylation in the unassisted population. A pink tile indicates higher methylation in the IVF population. A yellow tile indicates the direction of methylation was mixed in the CpG sites associated with that gene (for example, one methylation site more methylation in unassisted and another more methylated in IVF). A grey tile indicates no significant alteration.
Fig 2–4.
Fig 2–4.. Tile Charts of Identified Genes in IVF vs Unassisted Populations.
The tile charts display genes identified as being significantly altered in a study comparing IVF conceptions to unassisted conceptions. If a CpG site reported as significant did not correlate with a specific gene, the CpG site itself is listed. Those genes/CpG sites reported as significant by more than 1 study are boldened. The genes are organized by chromosome. Figure 1 contains genes on chromosomes 1–5. Figure 2 contains genes on chromosomes 6–13. Figure 3 contains genes located on chromosomes 14– 22 and chromosome X. The study reference number is listed on the top of each column, and the studies are grouped by tissue type. A green tile indicates higher methylation in the unassisted population. A pink tile indicates higher methylation in the IVF population. A yellow tile indicates the direction of methylation was mixed in the CpG sites associated with that gene (for example, one methylation site more methylation in unassisted and another more methylated in IVF). A grey tile indicates no significant alteration.
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