Understanding Embryo Development
In 2010 a Stanford University research team of biologists, engineers and clinical embryologists took a multidisciplinary approach to address a very specific goal: finding non-invasive markers that would enable IVF clinicians to identify viable embryos early1. The team combined time-lapse microscope imaging and molecular biology techniques to study an expansive number of human embryos cultured from the Day 1 pronucleus stage to the Day 5 blastocyst stage - The blastocyst stage is a key indicator of a viable embryo2.
Examining a wide range of potential non-invasive markers - and using gene expression data to assess embryo viability - it became clear that the markers with the greatest predictive power were the measures of time it took each embryo to achieve specific cell development milestones during the first 2 days after fertilization in vitro.
Normal embryos followed precise patterns of cell division timing in: (1) the duration of first cytokinesis (i.e., the time from when the 1st cell division starts, to when it completes), (2) the time interval between cytokinesis 1 and cytokinesis 2 (i.e., the time from the 2-cell to 3-cell stage), and (3) the time interval between cytokinesis 2 and cytokinesis 3 (i.e., the time from the 3-cell to 4-cell stage). Overall, the remarkable discovery signified that these precise cell division timing parameters could non-invasively predict by Day 2 which embryos were likely to become viable blastocysts.
Embryonic Gene Expression
An essential and unique component of the research was the correlation of imaged embryo cell division timings with their patterns of gene expression. Genes are collections of DNA that carry instructions for making proteins and other functional molecules of a cell. The transition of a fertilized egg to an embryo is controlled by specific maternal gene expression patterns from the mother, and specific embryonic gene expression patterns from the embryo. Gene patterns thus indicate the “molecular health” of the embryo, including how well an embryo is producing the gene products it needs to properly develop and thrive.
Importantly, the gene expression patterns of embryos that followed precise cell division timing parameters were discovered to be distinctly different from the gene expression patterns of embryos that followed abnormal cell division times. Further, gene expression for normal embryos was consistent with the expected levels and timing of maternal and embryonic gene expression of in vitro fertilized embryos.
These results, together with additional findings described in the Stanford research (Wong et al), provided the first link between embryo developmental outcome, cell division events, and the molecular health of the embryos.
- Wong et al. Nature Biotechnology (2010)
- Diamond et al. Journal of Assisted Reproduction & Genetics (2012)
Computer Automation Innovation
The research developed an assay leveraging uniquely intelligent software to automatically analyze embryo development against the scientifically derived cell division time periods. The software not only provided novel quantitative information, but ensured consistent and reliable measurements to assess embryo development versus the manual methods used today in IVF clinical practice2.
- Conaghan et al. Fertility & Sterility (2013)
- Loewke et al. Fertility & Sterility/ASRM Annual Meeting (2012)
To ensure the reproducibility and reliability of the Eeva™ Test, Auxogyn applied rigorous standards for clinical validation. In a multi-center, prospective clinical trial of 54 patients with approximately 758 embryos, adjunctive use of Eeva was found to be:
- Safe and effective.
- Highly informative in identifying embryos that will develop to the blastocyst stage.
- The overall odds ratio* for the adjunctive use of Eeva with traditional morphology was 2.57 and highly statistically significant (p<0.0001).
- The overall odds ratio for traditional morphology alone was 1.68 and was also statistically significant (p<0.0001). 1
- The specificity for the adjunctive use of the Eeva Test with traditional morphology was 76%, compared to the specificity of traditional morphology alone, which was 39%1.
- Highly consistent among diverse embryologists
- Operator performance variability was reduced with adjunctive use of the Eeva Test compared to traditional morphology grading.1,2
- Every embryologist benefitted from adjunct use of Eeva
- Improved consistency of embryo selection
Additional scientific and clinical research studies are underway to further the advancement of non-invasive assays that will provide IVF clinicians and their patients with quantifiable information about the health of their embryos. The continuing goal of Auxogyn’s research is to improve fundamental understanding of early in vitro human development and provide sound scientific and clinical evidence to positively impact clinical care in reproductive health.
Odds ratio is a measure of association between an exposure and an outcome. The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure.
OR=1 Exposure does not affect odds of outcome
OR>1 Exposure associated with higher odds of outcome
OR<1 Exposure associated with lower odds of outcome
- Data on file at Auxogyn.
- Conaghan et al. Fertility & Sterility (2013)