A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously

Abstract

Background: Increasing numbers of children are being conceived by assisted reproductive technology (ART). A number of studies have highlighted an altered epigenetic status in gametes from infertile couples and the possibility of an increased risk of imprinting defects and somatic epigenetic changes in ART conceived children, but the results have been heterogeneous.We performed a systematic review of existing studies to compare the incidence of imprinting disorders and levels of DNA methylation in key imprinted genes in children conceived through in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with those in children conceived spontaneously. methods: A detailed search strategy was used to conduct electronic literature searches (spanning 1978 to 2013) on Medline, EMBASE, the Cochrane Library and Web of Science. Abstracts of relevant conference papers were identified. As randomized trials are not feasible in this context,weincludedobservational (cohort andcase-control) studies comparingoutcomes inchildrenconceivedthroughARTwiththoseconceived spontaneously, irrespective of the language of publication.The outcomemeasureswereDNAmethylation and the incidence of imprinting disorders. results: A total of 351 publications were identified by the initial search.Of these, 26 were excluded as duplicates and 241 were excluded after reviewing the abstracts, then of those remaining 66were excluded after reviewof the full text.Atotal of 18 paperswere included in the review.Apart fromone case-control study, allwere cohort studies. Therewas a degree of clinical heterogeneity in terms of the study population, type of infertility treatment, and samples obtained fromexposed and unexposed children.DNAmethylation levelswere either presented as categorical data (hypo-, hyper- or normallymethylatedDNA) or continuous data (i.e. percentage ofmethylatedDNA). The combined odds ratio (95%confidence intervals) of any imprinting disorder in children conceived through ART was 3.67 (1.39, 9.74) in comparison with spontaneously conceived children. Metaanalysis of data from relevant studies revealed that the weighted mean difference (95% confidence intervals) in methylation percent between IVF/ICSI versus spontaneously conceived children were as follows: H19: 20.46(21.41, 0.49), PEG1-MEST: 0.47 (22.07, 3.01), GRB10: 20.05 (20.43, 0.33), IGF2: 20.15 (21.09, 0.79), SNRPN: 20.55 (21.55, 0.46), KvDMR/KCNQ10T1: 20.16 (20.34, 0.02) and PEG3: 20.24 (21.72, 1.24). conclusions: There was an increase in imprinting disorders in children conceived though IVF and ICSI but insufficient evidence for an association between ART and methylation in other imprinted genes.Heterogeneity in the types of fertility treatment, the imprinted regions studied, the tissues usedandthemethods ofmeasurement, reduceour ability to assess thefulleffectofARTonDNAmethylationandimprinting.More controlled studies, using standardized methodologies, in larger, better clinically defined populations are needed.