Human embryos created for in vitro fertilization, or IVF, can be subjected to a new form of analysis and classified as chromosomally normal or abnormal within 30 hours of their creation. Such speedy evaluation could help clinicians and embryologists select only the healthiest embryos for implantation and improve IVF success rates. Currently, as many as four out of five embryos created for IVF have a chromosomal abnormality that precludes pregnancy and leads, instead, to miscarriage.
The new form of analysis combines advances in noninvasive cell imaging and single-cell genetic profiling—more specifically, the techniques of time-lapse complete chromosomal assessment and single-cell RT-qPCR. These techniques were deployed in tandem by scientists at Oregon Health & Science University, Stanford University, the University of Valencia, and Igenomix, to collect information from human embryos, starting immediately after fertilization and continuing up to the eight-cell stage.
In the period leading up to the eight-cell stage, embryonic fate can be predicted by a 12-gene transcriptomic signature. [Shawn L. Chavez, Ph.D.]
The scientists determined that by looking at the duration of the first mitotic phase—a short period in the cell cycle—one can identify chromosomally normal versus abnormal embryos. They also found that single-cell profiling makes it possible to correlate the chromosomal make-up of an embryo to a subset of 12 genes that are activated prior to the first cell division.
These findings appeared July 7 in the journal Nature Communications, in an article entitled, “Prediction model for aneuploidy in early human embryo development revealed by single-cell analysis.” The article proposed that the chromosomal fate of an embryo could be determined as early as the pronuclear stage. Most important, however, was the authors’ assertion that their model could “largely predict embryo ploidy status using a 12-gene transcriptomic signature.”
The article described how researchers began with 117 frozen human zygotes, which originated from 19 couples. Ultimately, after thawing, 85 embryos survived and were available for culture.
“In addition to normal cell cycle divisions, we also were able to detect abnormal division events in certain embryos, including divisions from one to three cells or from one to four cells instead of the typical one to two cells,” the authors wrote. “These atypical events were observed in 23.6% (n=20) of embryos with the majority dividing from one to three blastomeres (n=17) and a much smaller subset dividing from one to four cells (n=3). Notably, 85% (n=17) of all abnormal divisions occurred during the first mitosis, whereas only 15% (n=3) occurred in either the second or third mitosis, stressing the importance of the first mitotic division.”
Complete ploidy results were obtained for 89 cells from a total of 57 embryos. “Our data,” the authors continued, “indicate that the chromosomal status of aneuploid embryos (n=26), including those that are mosaic (n=3), correlates with significant differences in the duration of the first mitotic phase when compared with euploid embryos (n=28).”
These findings, an Oregon Health & Science University press notice explained, could expedite identification of the healthiest embryo for implantation and reduce the amount of time an embryo is cultured in the laboratory prior to transfer. Embryos typically need to be implanted within three to five days of creation, the notice pointed out, which has created a challenge for the IVF field because chromosomal abnormalities may not be identified until day five or six.
The notice also cited comments by one of the study’s authors, Shawn L. Chavez, assistant scientist in the division of reproductive and developmental sciences at the Oregon National Primate Research Center at OHSU, and assistant professor of obstetrics and gynecology, and physiology and pharmacology, in the OHSU School of Medicine: “A failed IVF attempt takes an emotional toll on a woman who is anticipating a pregnancy as well as a financial toll on families, with a single IVF treatment costing thousands and thousands of dollars per cycle. Our findings also bring hope to couples who are struggling to start a family and wish to avoid the selection and transfer of embryos with unknown or poor potential for implantation.”
The study’s authors noted that their predictive model is not currently intended for clinical use, and that it needs to be further substantiated in larger studies. Indeed, the main goal of their prediction model, the authors emphasized, is not to predict aneuploidy by itself, but to “identify cellular pathways and related molecules indicative of the embryo ploidy status in culture medium or via other methods.” The authors concluded that they consider their study “a keystone in the knowledge of early human embryogenesis that may lead to the development of new noninvasive diagnostic tools that can reliably predict aneuploidy generation for IVF clinical routine.”