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, we included observational (cohort and case-control) studies comparing outcomes in children conceived through ART with those conceived spontaneously, irrespective of the language of publication. The outcome measures were DNA methylation 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 66 were excluded after review of the full text. A total of 18 papers were included in the review. Apart from one case-control study, all were cohort studies. There was a degree of clinical heterogeneity in terms of the study population, type of infertility treatment, and samples obtained from exposed and unexposed children. DNA methylation levels were either presented as categorical data (hypo-, hyper- or normally methylated DNA) or continuous data (i.e. percentage of methylated DNA). 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. Meta-analysis 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: -0.46(-1.41, 0.49), PEG1-MEST: 0.47 (-2.07, 3.01), GRB10: -0.05 (-0.43, 0.33), IGF2: -0.15 (-1.09, 0.79), SNRPN: -0.55 (-1.55, 0.46), KvDMR/KCNQ10T1: -0.16 (-0.34, 0.02) and PEG3: -0.24 (-1.72, 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 used and the methods of measurement, reduce our ability to assess the full effect of ART on DNA methylation and imprinting. More controlled studies, using standardized methodologies, in larger, better clinically defined populations are needed.

中文翻译：

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对IVF / ICSI设想的儿童与自然发生的儿童进行DNA甲基化水平和印迹障碍的系统评价和荟萃分析。

背景技术辅助生殖技术（ART）正在孕育越来越多的儿童。大量研究强调了不育夫妇配子表观遗传状态的改变，以及在ART设想的儿童中印记缺陷和体细胞表观遗传变化的风险增加的可能性，但结果却是异质的。我们对现有研究进行了系统的综述，以比较通过体外受精（IVF）和胞浆内精子注射（ICSI）受孕的儿童与自发受孕的儿童的印记障碍的发生率和关键印记基因的DNA甲基化水平。方法采用详细的搜索策略在Medline，EMBASE，Cochrane图书馆和Web of Science上进行电子文献搜索（跨度为1978年至2013年）。确定了相关会议论文的摘要。由于在这种情况下随机试验不可行，因此我们纳入了观察性研究（队列研究和病例对照研究），比较了通过ART接受的儿童和自发接受的儿童的结局，而与发表的语言无关。结果指标是DNA甲基化和印迹障碍的发生率。结果初步搜索共找到351种出版物。在这些摘要中，有26篇作为重复本被排除在外，而241篇在通过摘要阅读后被排除在外，然后其余66篇在通过全文阅读后被排除在外。该评价共纳入18篇论文。除一项病例对照研究外，所有研究均为队列研究。在研究人群，不孕治疗类型，以及从接触过和未接触过的孩子那里获得的样本。DNA甲基化水平以分类数据（低，高或正常甲基化DNA）或连续数据（即甲基化DNA的百分比）表示。与自然受孕儿童相比，通过ART接受妊娠的儿童任何印迹障碍的综合优势比（95％置信区间）为3.67（1.39，9.74）。对相关研究数据的荟萃分析显示，IVF / ICSI与自然受孕儿童之间甲基化百分比的加权平均差异（95％置信区间）如下：H19：-0.46（-1.41，0.49），PEG1-MEST： 0.47（-2.07，3.01），GRB10：-0.05（-0.43，0.33），IGF2：-0.15（-1.09，0.79），SNRPN：-0.55（-1.55，0.46），KvDMR / KCNQ10T1：-0.16（-0.34） （0.02）和PEG3：-0.24（-1.72，1.24）。结论试管婴儿通过IVF和ICSI引起的印记障碍有所增加，但没有足够的证据证明其他印记基因的ART和甲基化之间存在关联。生育治疗类型，研究的印迹区域，使用的组织和测量方法的异质性降低了我们评估ART对DNA甲基化和印迹的全部作用的能力。需要使用标准化方法对更大，临床定义更好的人群进行更严格的研究。降低了我们评估ART对DNA甲基化和印迹影响的全部能力。需要使用标准化方法对更大，临床定义更好的人群进行更严格的研究。降低了我们评估ART对DNA甲基化和印迹影响的全部能力。需要使用标准化方法对更大，临床定义更好的人群进行更严格的研究。