BONUS 309: Optimal Method of Embryo Selection

June 25, 2021

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Today’s bonus episode guest is Dr. Carol Curchoe, the founder of ART Compass, a senior clinical embryologist at a fertility clinic and a board-certified technical supervisor in embryology

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Dr. Curchoe and Heather discuss the optimal method of embryo selection in an IVF cycle as part of our ongoing research priorities series:

LISTENER QUESTIONS

  • I am 27, and my husband is 29. We are currently undergoing our first IVF cycle of IVF. We had 32 eggs and ended up with 4 normal embryos. We are about to do a frozen embryo transfer, and I’m worried about whether my frozen embryos will survive the thaw. What percentage of embryos survive thawing, and what are the factors affecting the survival?
  • My husband and I are both 38. We have recurrent pregnancy loss, with 3 miscarriages confirmed as genetically normal. We just finished our fourth retrieval. We used ICSI the first 2 retrievals and conventional IVF with the zymot chip for the last 2. With ICSI, we achieved about 80-90% fertilization with 25-33% blast rate. Our third retrieval, we had 100% fertilization with a 33% blast rate. Our fourth retrieval, we had 92% fertilization with a 25% blast rate. However, of our 12 fertilized eggs, 6 fertilized as 1PN. Of the 6 that fertilized normally, only 1 made it to blast and it’s a day 7. The other 2 blasts are day 6 and day 7 from 1PN fertilization. They’re all untested. What could have caused this change in fertilization? What are the chances of success?
  • I am 32, and my husband is 34. I received a photo of my embryo with each of my 2 transfers. However, they don’t look at all alike. One of them looks like a weird 3D blob, which they said was a great 6AA. My other looks just like the textbook photos, and it was a 5AA. Why did they look so different? I personally think my second embryo looks much more perfect than the first, but I have a feeling it’s the technology they used to take the photo. What is the technology difference, and why would they switch it?

TOP RESEARCH PRIORITIES

  • An article was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. Today we will be discussing research priority #4: What is the optimal method of embryo selection in IVF cycles?
  • Why is this a research priority?
    • The primary goal of embryo selection is to produce a live birth from a single embryo transfer and to minimize detrimental outcomes, like implantation failure, miscarriage, or birth defects.
  • Noninvasive imaging (microscopy) systems for gametes and embryos is the primary grading and selection method
    • Common: Hoffman modulation contrast
    • Rare:
      • Polscope. Visualize meiotic spindle placement and formation with polarized light. Now we predict the position of the spindle by positioning the 1st polar body at 12 on the clock when we do our ICSI injections. But the spindle is not always there, and we can damage the chromosome apparatus during the injection causing the second polar body to not be able to extrude from the egg, and failed fertilization. If the spindle has not formed when we inject the egg usually dies. So the method we have now works for 90% of eggs. We don’t usually have access to this specialized microscope.
      • MSOME and IMSI. Expensive experimental systems that require extended handling of the sperm, potential to cause more oxidative damage, lack of agreement on what marker of any indicates sperm DNA damage (vacuoles, cytoplasmic droplet)
      • Time lapse monitoring. Expensive and most labs do not have it. Incubation system where the embryos are placed and grown continuously and monitored. Right now, we take embryos from their little culture chamber and inspect them at set time points. Usually at fertilization, day 3, and then 5/6/7. Time lapse can record things we miss in between those checks. Positive selection criteria include the positioning of the pronuclei and a small organelle called the nucleoli inside them, number of blastomeres, the absence of multinucleation, early cleavage to the two-cell stage, and a low percentage of cell fragments in embryos.
  • Genetic screening selection techniques like PGT-A are peaking in several countries
  • New controversy: polygenic trait selection of embryos
    • There have been and continue to be many many controversies in genetic testing of embryos: namely, mosaic embryos and “segmental aneuploidy” embryos can self correct and make healthy pregnancies 30% of the time.
  • Algorithmic and artificial intelligence scoring generated by computers is gradually enhancing our selection process, but these are not widely used
    • Lack of video imaging systems for continuous monitoring and single step embryo culture systems, as well as lack of data handling methodologies, are holding back these from widespread deployment
  • The race has been on to find metabolomic markers for embryo selection
    • What is the embryo using for energy and growth, and what are its waste products?
    • The metabolomic profiling of embryo culture media has been performed through proton nuclear magnetic resonance (1H NMR). Researchers have discovered that the metabolomics profile is correlated with embryo reproductive potential. From the proton NMR spectrum, alanine, pyruvate, and glucose levels were reduced in the culture media of embryos that resulted in pregnancy. Glutamate levels were found to be higher compared to embryos that failed to implant, possibly due to its generation from α-ketoglutarate and ammonium, thereby lowering the potentially toxic ammonium to developing embryos. A sensitivity ― the ability to identify true implantations/pregnancies ― of 88.2 percent and a specificity ― the ability to correctly predict no implantations/pregnancies ― of 88.2 percent was achieved through 1H NMR
  • Protein markers from the embryo culture medium
    • Not too many have been discovered, but surely there are more. Healthy embryos will be producing characteristic proteins as they go about their work growing.
    • In one study by Noci et al., soluble human leukocyte antigen-G (sHLA-G) was isolated and considered as a possible protein marker of embryo reproductive potential. The presence of sHLA-G shows no correlation with embryo morphology, and the lack of sHLA-G in culture media has a negative predictive value. In another study in which sHLA-G-positive embryos were transferred, implantation and pregnancy rates were 44 percent and 75 percent, respectively, compared to 14 percent and 23 percent of transferred sHLA-G-negative embryos.
    • A protein biomarker that has been found to be upregulated and increased during embryo maturation into the blastocyst stage is a Day 5 secretome ― a set of proteins secreted from the cell ― resembling ubiquitin. Ubiquitin has been implicated in the turnover of key signaling molecules during implantation
  • Other non-embryonic genomic markers (cumulus cells) have potential
    • The cumulus cells (CCs) that surround the oocyte from fertilization until implantation have been analyzed and gene-profiled to gauge embryo potential: the likelihood of an embryo to implant and lead to a successful pregnancy. Several genes expressed in CCs have been correlated with predicting pregnancy, including cyclooxygenase 2 (COX2), steroidogenic acute regulatory protein (STAR), and pentraxin 3 (PTX3). Two upregulated biomarkers have been identified in the CCs of successful pregnancies, BCL2L11 and PCK1, which are involved in apoptosis of abnormal cells and gluconeogenesis.
  • Is there anything else you’d like to add?

WRAPPING UP

  • What words of hope would you offer to infertility warriors with very few embryos or poor embryo quality?

References:

Thanks for listening!

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