Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study

Abstract

BackgroundWhile a possible link between assisted reproductive technology (ART) and rare imprinting disorders has been found, it is not clear if this is indicative of subtler disruptions of epigenetic mechanisms. Results from previous studies have been mixed, but some methylation differences have been observed.MethodsChildren conceived through ART and children conceived spontaneously were recruited for this cross-sectional study. Information about reproductive history, demographic factors, birth characteristics, and infertility treatment was obtained from maternal interview and medical records. Peripheral blood lymphocytes and buccal cell samples were collected from participating children. Methylation analysis was performed on five loci using pyrosequencing. Statistical analysis of methylation differences was performed using linear regression with generalized estimating equations. Results are reported as differences with 95% confidence intervals (CI).ResultsA total of 67 ART children and 31 spontaneously conceived (SC) children participated. No significant difference in methylation in lymphocyte samples was observed between groups for any loci. Possible differences were found in buccal cell samples for IGF2 DMR0 (Difference: 2.07; 95% confidence interval (CI): -0.28, 4.42; p = 0.08) and IGF2R (Difference: -2.79; 95% CI: -5.74, 0.16; p = 0.06). Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility.ConclusionsObserved differences in methylation between the ART and SC groups were small for all loci in the two sample types examined and no statistical differences were observed. It is still unclear whether or not small differences observed in several studies represent a real difference between groups and if this difference is biologically meaningful. Larger studies with long term follow-up are needed to fully answer these questions.

Long-term follow-up of children conceived through assisted reproductive technology

“…Nevertheless, several recent studies (Tierling et al, 2010;Li et al, 2011a;2011c;Puumala et al, 2012b;Rancourt et al, 2012) have shown no significant epigenetic differences between ART-conceived and NC offspring. Using bisulfite-based technologies, Tierling et al (2010) analyzed 10 DMRs of maternal peripheral blood, umbilical cord blood, and amnion/ chorion tissue of 185 phenotypically normal children.…”

Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection?

“…No meaningful differences were found. Puumala et al (31) compared imprinting in lymphocytes and buccal smears in 67 ART and 31 spontaneously conceived children and found no meaningful differences. If we assume that in the group of children born after IVF/ICSI the prevalence of BWS is 1:2,700 and that the prevalence in the normal population is 1:13,700, study groups of >45,000 would be necessary to demonstrate a statistically significant difference with an a of 5% and b of 20% (see: www.biomath.info/power/chsq.htm).…”

Preimplantation Stress and Development

“…Although imprinted genes encompass 0.1 to 0.5% of the genome, they play a pivotal role in early development by controlling processes such as nutrient consumption and the cell cycle (Fowden et al, ). Inappropriate regulation of imprinted genes—inherited, sporadic, or environmentally induced—has been associated by some with diseases of growth and development (Miozzo and Simoni, ), but not by others (Rancourt et al, ; Puumala et al, ). While rare, the increased observation of BWS and AS may reflect more widespread, as‐of‐yet unidentified epigenetic alterations occurring after preimplantation stress.…”