DNA methylation differences between in vitro- and in vivo-conceived children are associated with ART procedures rather than infertility

Sisi Song; Jayashri Ghosh; Monica Mainigi; Nahid Turan; Rachel Weinerman; May Truongcao; Christos Coutifaris; Carmen Sapienza

doi:10.1186/s13148-015-0071-7

Assisted Reproduction Safety and Risks

DNA methylation differences between in vitro- and in vivo-conceived children are associated with ART procedures rather than infertility

Song S, Ghosh J, Mainigi M, Turan N, Weinerman R, Truongcao M, Coutifaris C, Sapienza C

Clinical epigenetics, 2015

DOI 10.1186/s13148-015-0071-7 PMID 25901188 PMC PMC4404660

RRM Academy Synopsis

IVF placentas differ at some methylation sites, donor eggs included

Placental DNA methylation differed at some sites after IVF, including with donor eggs from fertile women. The cohort study looked at placentas from 66 IVF births to infertile couples, 22 donor-egg IVF births and 49 births with no medical help. Researchers checked 37 DNA sites.

Key Findings

Across 37 CpG sites in 16 genes, 11 sites (29.73 %) differed among the three groups by ANOVA.
Of those 11 sites, 7 differed between the donor-egg IVF group and the unassisted-conception group, and 2 differed between the infertile-couple IVF group and that group. Two sites differed in both comparisons.
Of 20 sites flagged in an earlier study, 9 differed again between infertile-couple IVF and unassisted conception (a 45% validation rate). Nine more sites differed, for 18 of 37 sites (48.65%).
Of those 18 sites, 12 (in seven genes) also differed between the donor-egg IVF group and the unassisted-conception group.

Interpretation

The authors report an association in placentas from one IVF center. Egg donors were fertile women, and recipients had no male factor infertility. Recipients in the donor-egg group were older (mean age 41.5 years, against 34.5 years for unassisted conception). The team tested candidate sites chosen from earlier work. It applied no correction for multiple testing, sampled one spot per placenta and could not split results by infant sex. Methylation differences were small, and the study did not link them to health outcomes in the children. Fresh versus frozen embryo transfer could not be ruled out as a contributor.

RRM Context

The study asks whether differences after IVF trace to the couple's infertility or to the procedures. Donor-egg pregnancies, with no infertility diagnosis in the egg source, showed similar differences. That points toward the procedures. The authors cite earlier work associating IVF with low birth weight, preterm delivery and imprinting disorders. Restorative reproductive medicine aims to find and treat the cause of infertility.

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

Abstract

We, and others, have demonstrated previously that there are differences in DNA methylation and transcript levels of a number of genes in cord blood and placenta between children conceived using assisted reproductive technologies (ART) and children conceived in vivo. The source of these differences (the effect of ART versus the underlying infertility) has never been determined in humans. In this study, we have attempted to resolve this issue by comparing placental DNA methylation levels at 37 CpG sites in 16 previously identified candidate genes in independent populations of children conceived in vivo ('fertile control' group) with ART children conceived from two groups: either autologous oocytes with infertility in one or both parents ('infertile ART' group) or donor oocytes (obtained from young fertile donors) without male infertility ('donor oocyte ART' group). Of the 37 CpG sites analyzed, significant differences between the three groups were found in 11 CpGs (29.73 %), using ANOVA. Tukey's post hoc test on the significant results indicated that seven (63.63 %) of these differences were significant between the donor oocyte ART and fertile control groups. In addition, 20 of the 37 CpGs analyzed had been identified as differentially methylated between ART and fertile control groups in an independent population in a prior study. Of these 20 CpG sites, 9 also showed significant differences in the present population. An additional 9 CpGs were found to be significantly different between the two groups. Of these 18 candidate CpGs, 12 CpGs (in seven candidate genes) also showed significant differences in placental DNA methylation levels between the donor oocyte ART and fertile control groups. These data suggest strongly that the DNA methylation differences observed between ART and in vivo conceptions are associated with some aspect of ART protocols, not simply the underlying infertility.

Topics

Assisted Reproduction

Safety and Risks Procedure-Attributable Risk

Assisted Reproduction › Safety and Risks › Procedure-Attributable Risk

Sisi Song, Jayashri Ghosh, Monica Mainigi, Nahid Turan, Rachel Weinerman, May Truongcao, Christos Coutifaris, Carmen Sapienza

S Song, J Ghosh, M Mainigi, N Turan, R Weinerman, M Truongcao, C Coutifaris, C Sapienza

PMID 25901188 25901188 DOI 10.1186/s13148-015-0071-7 10.1186/s13148-015-0071-7 Song et al. 2015, Song 2015

DNA methylation differences between in vitro- and in vivo-conceived children are associated with ART procedures rather than infertility

IVF placentas differ at some methylation sites, donor eggs included

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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