Noninvasive Biomarkers of Human Embryo Developmental Potential

There are two types of noninvasive biomarkers of human embryo developmental potential: those based on a direct assessment of embryo morphology over time and those using spent media after embryo in vitro culture as source of information. Both are derived from previously acquired knowledge on different aspects of pre-implantation embryo development. These aspects include embryo morphology and kinetics, chromosomal ploidy status, metabolism, and embryonic gene transcription, translation, and expression. As to the direct assessment of morphology and kinetics, pertinent data can be obtained by analyzing sequential microscopic images of in vitro cultured embryos. Spent media can serve a source of genomic, metabolomic, transcriptomic and proteomic markers. Methods used in the early pioneering studies, such as microscopy, fluorescence in situ hybridization, autoradiography, electrophoresis and immunoblotting, or enzyme-linked immunosorbent assay, are too subjective, invasive, and/or time-consuming. As such, they are unsuitable for the current in vitro fertilization (IVF) practice, which needs objective, rapid, and noninvasive selection of the best embryo for uterine transfer or cryopreservation. This has been made possible by the use of high-throughput techniques such as time-lapse (for direct embryo evaluation), next-generation sequencing, quantitative real-time polymerase chain reaction, high-performance liquid chromatography, nanoparticle tracking analysis, flow cytometry, mass spectroscopy, Raman spectroscopy, near-infrared spectroscopy, and nuclear magnetic resonance spectroscopy (for spent culture media analysis). In this review, individual markers are presented systematically, with each marker's history and current status, including available methodologies, strengths, and limitations, so as to make the essential information accessible to all health professionals, even those whose expertise in the matter is limited.