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Event Review: International IVF Initiative – My mosaic embryo

25 January 2021
Appeared in BioNews 1080

Session 46 of the International IVF initiative, 'My Mosaic Embryo', was held online to discuss and share the best practice for understanding and communicating mosaicism. The session incorporated evidence to guide the selection of the best mosaic embryo for transfer in an IVF treatment cycle with preimplantation embryo screening. The session was attended by over 500 international delegates from 78 countries, the chat greetings from across the globe set a welcoming atmosphere for an exciting 90 minutes.

Preimplantation diagnosis for aneuploidy (PGT-A), previously called preimplantation genetic screening (PGS), is offered during an IVF treatment cycle to select embryos with the correct or balanced number of chromosomes (euploid) and deselect embryos with an imbalance or incorrect chromosome number (aneuploid),  the concept being that a euploid embryo is more likely to result in a healthy birth than an aneuploid embryo.

In practice, there has been much debate around the efficacy of PGT-A (see BioNews 962). Guidance from the HFEA states that currently there is no clear evidence of an improvement in live birth rates. The controversy has been fuelled by the embryos diagnosed to be mosaic, meaning there are different proportions of both aneuploid and euploid cells identified in the samples of five to seven cells collected in the embryo biopsy.  

Dr Jacques Cohen and Dr Mina Popovic moderated the session. Dr Cohen opened by acknowledging 'PGT-A fatigue', a concept he had coined to describe the anxiety of professionals working in the field around the decision to offer PGT-A. Dr Popovic highlighted that an increase in test sensitivity has led to a rise in the diagnosis of mosaicism. This can lead to uncertainty around the classification of embryos, alongside not knowing if the biopsied cells are representative of the whole embryo. Mosaic embryos are now routinely transferred in IVF treatment across the world; the importance of follow up and discussion is crucial (see BioNews 1056).

The first speaker Professor Semra Kahraman, director of Istanbul Memorial Hospital, ART and Reproductive Genetics Centre in Turkey, shared her experience in transferring embryos with segmental variation and mosaicism. She explained that the incidence of mosaicism varies between 4-24 percent in different studies. She said that it is essential to consider the level of mosaicism (percentage of cells with chromosome imbalance) and the type of mosaicism (which chromosome is involved and whether there is a complete or segmental loss or gain) when prioritising embryos for transfer. She described how mosaicism has been attributed to the degradation of the cells tested, perhaps due to the cells' exposure to laser pulses during the biopsy, or temperature control of the embryos during culture. Also, more sensitive next-generation sequencing technologies can detect imbalances at lower levels, resulting in a higher rate of mosaicism identified. Interestingly, her laboratory and others have found that mosaicism occurs most frequently for larger chromosomes.

In March 2020, Professor Kahraman authored a report on the first fetal mosaicism identified in a healthy baby (2 percent mosaic monosomy 2) following transfer of a known mosaic embryo (35 percent mosaicism of monosomy 2). Worldwide, prenatal diagnosis has shown the depletion of mosaicism in embryos reported as mosaics at transfer; this case demonstrates the need for close prenatal monitoring and diagnosis by early amniocentesis.

The second speaker Dr Manuel Viotti, senior scientist at the Zouves Foundation for Reproductive Medicine, California, spoke about selecting the best mosaic embryo for transfer. Dr Viotti shared the findings of a soon-to-be-published multicentre study of more than 1000 mosaic embryo transfers. All embryos had been tested using the same technology and framework, and were matched with control euploid embryo transfers at the same centres. When normalised for the quality of the embryo cells, the findings showed outcomes could be grouped according to the nature of the mosaicism reported in the embryo. Low-level mosaics with segmental aneuploidies were found to have the highest live birth rate. No embryos where all the cells biopsied were aneuploid resulted in a live birth. Dr Viotti's team has designed an application tool to assist with mosaic embryo ranking for transfer that considers the degree of mosaicism and morphology of the embryo, which will be freely available when released. Dr Viotti advocated for a shift in the way of thinking from a binary report, normal (euploid) or abnormal (aneuploid), to more fluid categories that allow the snapshot of the embryo at biopsy to predict trends of how each embryo may develop after transfer.

The final speaker, Dr Gary Harton, a member of the board of directors for PGD-IS, spoke about communicating mosaicism. Dr Harton supported moving away from a binary embryo diagnosis, explaining that the thresholds applied to place embryos into categories are a critical consideration that should be communicated to the IVF laboratories. In doing so, how labels are given to embryos can then be communicated to patients. He described how the testing laboratory could interpret NGS signals, automatically or manually, and that variation around how interpretations are grouped for reporting can vary. Dr Horton highlighted that patients are looking to each other for support as clinics' advice is not consistent. The Facebook group, 'My Perfect Mosaic Embryo', has over 3800 members, where questions and re-assurance on the transfer of mosaic and aneuploid embryos can be posted. Joining the group gives an interesting and somewhat disquieting insight into the international and local variations in policy and types of reporting. The need for patient support and personalised genetic counselling to discuss risk is evident. Dr Harton noted that as the concepts are difficult for embryologists and clinicians, patients' anxiety is tremendous.

The session was concluded by panellist Jenna Miller, a board-certified genetic counsellor. Miller emphasised the need for real information in the form of a shared database registry. Practically, Miller advised that patients should know that mosaicism is a possibility before consenting to PGT-A but advised against information overload. If a patient does have a mosaic embryo, although it is challenging to interpret technically and clinically, the general message is that mosaic embryos implant less often, miscarry more and are less likely to lead to a live birth. Miller described a traffic light analogy she uses, that complemented the message from earlier speakers, on non-binary PGT-A descriptors where an aneuploid embryo is red (stop), a mosaic embryo is amber (consider), and a euploid embryo is green (continue).

The Q&A had recurring themes, including on whether clinics should opt not to report mosaicism. Generally, it was felt that this would mean someone would lose out, either by a lost chance of a pregnancy or an increased risk of miscarriage. The clear consensus was mosaicism is a grey area, both technically and ethically. Mosaicism in a person does not seem to be the same as in an embryo, continued data and follow up to figure out what mosaicism means for IVF patients is vital, as mosaic live births for every chromosome have been reported with a clinically defined phenotype and adverse outcome. This does not mean that we should shy away from the use of mosaic embryos, but instead the surrounding issues should be tackled through enhancing our understanding the best we can to advantage patients, despite its complexity.

SOURCES & REFERENCES
Session 46: my mosaic embryo
International IVF Initiative |  12 January 2021
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