When women who suffered a subsequent miscarriage were compared to women who had a live birth, following the endometrial biopsy, the number of significantly differentially expressed genes was 421, mapping to processes relevant to embryo implantation and early stages of pregnancy such as biosynthetic process, signal transduction, response to stress, immune system process, cell differentiation, catabolism, cell death, cell proliferation, homeostatic process, cytoskeleton organization, cell adhesion and reproduction.
From the same research group, J Chu (O-204) demonstrated abnormal endometrial metabolomic profiles may also build on the evidence to support nonchromosomal causes for higher-order miscarriages.
Again, there were distinct metabolomic profiles between the endometrial samples obtained from women with higher-order miscarriages, and changes were also identified in the metabolomic profiles of women who suffered a subsequent miscarriage compared to those who had a live birth following the endometrial biopsy.
Validation of the findings from these studies may aid the development of a predictive test for use in clinical practice.
P Ruane (O-032) described how receptive endometrial epithelium induces trophectoderm differentiation to invasive syncytiotrophoblast, which initiates invasive implantation. Further research and understanding may lead to embryo assessment for syncytiotrophoblast differentiation propensity pre-implantation or assessment of endometrial epithelium for propensity to induce syncytiotrophoblast differentiation.
There are conflicting studies regarding the suitability of mtDNA as a biomarker of embryo implantation potential. M Galain (O-314) observed a significant difference in mtDNA in terms of ploidy and maternal age but not in terms of implantation rates, pregnancy rates, miscarriage rates or live birth rates, suggesting it does not appear to be a clinically useful biomarker.
J Mertens (O-138) found significant differences in the mitochondrial genome of children born after ART, which relates to a background of maternal infertility and birth weight. These results suggest a link between maternal infertility and mtDNA variant composition, which is transmitted to the offspring.
C Lin (O-064) determined that H3.3 Chaperone Hira complex (present in the oocyte) is essential for male pronucleus formation. In the loss-of-function mouse models abnormal fertilization occurred and formation of a single pronucleus (1PN).
In human 1PNs it was observed that Hira chaperone molecules failed to incorporate into male chromatin. This suggested possible development of “1PN rescue” using overexpression, or nuclear transfer approaches for patients with repeated 1PN abnormal fertilization.
K Ezoe (O-063) identified prolactin (PRL) as a potential therapeutic target and developed supplemented media. PRL is thought to influence preimplantation development and implantation. Human embryos do not appear to express the prolactin receptor (PRLR) before the morula stage – PRLR signaling stimulates blastocyst adhesion.
The supplementation of the embryo culture medium with PRL did not improve the rate of embryonic development to the blastocyst stage or their morphological grade but significantly increased blastocyst outgrowth. PRL treatment during embryo culture could be advantageous for improving pregnancy outcomes following blastocyst transfer.
Automation, AI and novel technology
In the pre-congress courses, D Sakkas (PC-16) reflected that PGT-A and morphokinetics do not tell us everything about embryo viability and pointed to a lab of the future where non-invasive techniques will eventually replace invasive techniques for assessing embryo viability, including genetic “normality”.
Fluorescence-lifetime imaging microscopy (FLIM) can provide information on the auto-fluorescence of NADH and FAD, important intermediaries in the electron transport chain, and reveals dramatic differences in FAD within the ICM and TE. Hyperspectral microscopy similarly can investigate auto-fluorescent metabolites.
Raman micro-spectroscopy, along with FLIM, has been applied to differentiate euploid and aneuploid embryos. In the future, these non-invasive platforms may be coupled with microfluidics for live-time imaging of individual embryo metabolomics, which could enable a fluid, dynamic system of embryo culture, analysis, and control of development.
A Adjuk (O-310) demonstrated that in addition to visualizing nuclei within morulae, optical coherence microscopy can allow assessment of chromatin conformation in germinal vesicles (GVs) and the number of cells in morulae, and that these correlate with developmental potential.
Following studies showing the ability of convolutional neural networks to identify morphologically normal sperm, J Dickinson (O-163) demonstrated their ability to accurately identify the correct ICSI injection site on the oocyte, possibly moving us one step closer to automation of the procedure.
A Mokhtare (O-165) brought us another step closer, reintroducing Sakkas’s microfluidics vision. They developed a semi-automated oocyte denudation microfluidic chip and using murine cumulus-oocytecomplexes demonstrated less shear stress imposed on the oocyte with comparable denudation efficiency, postICSI survival, fertilization, and blastocyst formation rates.