Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants

Both infertility and intracytoplasmic sperm injection alter DNA methylation at specific genomic loci, including metastable epialleles. In some cases this effect seems to be somewhat mitigated by frozen embryo transfer.

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Volume 106, Issue 3, Pages 629-639


Molly S. Estill, M.S., Jay M. Bolnick, M.D., Robert A. Waterland, Ph.D., Alan D. Bolnick, M.D., Michael P. Diamond, M.D., Stephen A. Krawetz, Ph.D.



To evaluate the effect of infertility and intracytoplasmic sperm injection (ICSI) on DNA methylation of offspring.


Microarray analysis of DNA methylation in archived neonatal bloodspots of in vitro fertilization (IVF)/ICSI-conceived children compared with controls born to fertile and infertile parents.


Academic research laboratory.


: Neonatal blood spots of 137 newborns conceived spontaneously, through intrauterine insemination (IUI), or through ICSI using fresh or cryopreserved (frozen) embryo transfer.



Main Outcome Measure(s)

The Illumina Infinium HumanMethylation450k BeadChip assay determined genome-wide DNA methylation. Methylation differences between conception groups were detected using a Bioconductor package, ChAMP, in conjunction with Adjacent Site Clustering (A-clustering).


The methylation profiles of assisted reproductive technology and IUI newborns were dramatically different from those of naturally (in vivo) conceived newborns. Interestingly, the profiles of ICSI-frozen (FET) and IUI infants were strikingly similar, suggesting that cryopreservation may temper some of the epigenetic aberrations induced by IVF or ICSI. The DNA methylation changes associated with IVF/ICSI culture conditions and/or parental infertility were detected at metastable epialleles, suggesting a lasting impact on a child's epigenome.


Both infertility and ICSI alter DNA methylation at specific genomic loci, an effect that is mitigated to some extent by FET. The impact of assisted reproductive technology and/or fertility status on metastable epialleles in humans was uncovered. This study provi

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility┬« is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.