在一些生育诊所中使用延时系统(TLS),目的是预测IVF期间的胚胎活力和活产机会。已经假设非整倍体胚胎由于其异常的染色体补体而显示出改变的形态动力学。由于非整倍体是IVF失败和流产的根本原因之一,注意力集中在利用形态动力学来开发模型,对胚胎的倍性状态进行非侵入性风险分层.这可以避免或减少与非整倍性植入前遗传测试(PGT-A)相关的成本。此外,TLS提供了对其他畸形的真实患病率的理解。假设,将形态特征结合到模型中可以协同作用,提高模型预测倍性状态的判别能力。
本系统综述和荟萃分析的目的是研究倍性状态与TLS上通常表示的形态动力学或形态特征之间的关联。这将确定整倍性预测模型的可行性,并总结模型开发中包含的最有用的预后标志物。
在Medline进行了五次单独的搜索,Embase,PubMed和Cinahl从成立到2021年7月1日。包括搜索词和单词变体,其中,PGT-A,倍性,形态动力学和时间流逝,后者被依次替换为以下形态参数:碎片化,多核化,异常的卵裂和收缩。研究仅限于人体研究。
总的来说,58项研究纳入了超过40.000个胚胎。当通过预后研究工具的质量评估时,除一项研究外,所有研究在至少一个领域都具有中等偏倚风险。在非整倍体胚胎中,十个形态动力学变量显着延迟。当排除使用不太可靠的遗传技术的研究时,最值得注意的变量是:8个细胞的时间(t8,1.13h,95%CI:0.21-2.05;三项研究;n=742;I2=0%),t9(2.27小时,95%CI:0.5-4.03;两项研究;n=671;I2=33%),形成完整胚泡的时间(tB,1.99h,95%CI0.15-3.81;四项研究;n=1640;I2=76%)和扩大胚泡的时间(tEB,2.35h,95%CI:0.06-4.63;四项研究;n=1640;I2=83%)。碎片化程度可能有一定的预后潜力,多核形成持续到四细胞阶段和胚胎收缩的频率。在这项荟萃分析中,反向切割与整倍体相关;然而,这篇文章认为,这些可能是虚假的结果,需要进一步调查。在进展为胚泡的胚胎中,与直接不平等的卵裂没有关联,或在第2天或双细胞阶段评估的多核化。然而,由于结果不均匀和证据质量差,在可靠地得出结论之前,需要进一步研究这些形态成分之间的关联。
对形态和形态动力学与倍性状态关联的第一个系统综述和荟萃分析证明了最有用的形态动力学变量,即t8、t9和tEB将包括在未来的模型开发中。非整倍体和整倍体胚胎内存在相当大的变异性,因此不可能对它们进行明确的分类;然而,将胚胎优先用于活检是可行的.此外,这些结果支持了活产算法可能具有预测能力的机制,提示非整倍性会导致胞质分裂延迟。我们在结果中强调了显著的异质性,其次是当地条件和不同的患者人群,因此,呼吁未来的模型在内部得到强有力的开发和测试。如果成功,当访问PGT-A不适合夫妻时,这样的模型将构成有意义的突破。
A time lapse system (TLS) is utilized in some fertility clinics with the aim of predicting embryo viability and chance of live birth during IVF. It has been hypothesized that aneuploid embryos display altered morphokinetics as a consequence of their abnormal chromosome complement. Since aneuploidy is one of the fundamental reasons for IVF failure and miscarriage, attention has focused on utilizing morphokinetics to develop models to non-invasively risk stratify embryos for ploidy status. This could avoid or reduce the costs associated with pre-implantation genetic testing for aneuploidy (PGT-A). Furthermore, TLS have provided an understanding of the true prevalence of other dysmorphisms. Hypothetically, the incorporation of morphological features into a model could act synergistically, improving a model\'s discriminative ability to predict ploidy status.
The aim of this systematic
review and meta-analysis was to investigate associations between ploidy status and morphokinetic or morphological features commonly denoted on a TLS. This will determine the feasibility of a prediction model for euploidy and summarize the most useful prognostic markers to be included in model development.
Five separate searches were conducted in Medline, Embase, PubMed and Cinahl from inception to 1 July 2021. Search terms and word variants included, among others, PGT-A, ploidy, morphokinetics and time lapse, and the latter were successively substituted for the following morphological parameters: fragmentation, multinucleation, abnormal cleavage and contraction. Studies were limited to human studies.
Overall, 58 studies were included incorporating over 40 000 embryos. All except one study had a moderate risk of bias in at least one domain when assessed by the quality in prognostic studies tool. Ten morphokinetic variables were significantly delayed in aneuploid embryos. When excluding studies using less reliable genetic technologies, the most notable variables were: time to eight cells (t8, 1.13 h, 95% CI: 0.21-2.05; three studies; n = 742; I2 = 0%), t9 (2.27 h, 95% CI: 0.5-4.03; two studies; n = 671; I2 = 33%), time to formation of a full blastocyst (tB, 1.99 h, 95% CI 0.15-3.81; four studies; n = 1640; I2 = 76%) and time to expanded blastocyst (tEB, 2.35 h, 95% CI: 0.06-4.63; four studies; n = 1640; I2 = 83%). There is potentially some prognostic potential in the degree of fragmentation, multinucleation persisting to the four-cell stage and frequency of embryo contractions. Reverse cleavage was associated with euploidy in this meta-analysis; however, this article argues that these are likely spurious results requiring further investigation. There was no association with direct unequal cleavage in an embryo that progressed to a blastocyst, or with multinucleation assessed on Day 2 or at the two-cell stage. However, owing to heterogeneous results and poor-quality evidence, associations between these morphological components needs to be investigated further before conclusions can be reliably drawn.
This first systematic
review and meta-analysis of morphological and morphokinetic associations with ploidy status demonstrates the most useful morphokinetic variables, namely t8, t9 and tEB to be included in future model development. There is considerable variability within aneuploid and euploid embryos making definitively classifying them impossible; however, it is feasible that embryos could be prioritized for biopsy. Furthermore, these results support the mechanism by which algorithms for live birth may have predictive ability, suggesting aneuploidy causes delayed cytokinesis. We highlight significant heterogeneity in our results secondary to local conditions and diverse patient populations, therefore calling for future models to be robustly developed and tested in-house. If successful, such a model would constitute a meaningful breakthrough when accessing PGT-A is unsuitable for couples.