With around 10,000 delegates and more than 1,000 oral and poster presentations, it is obviously difficult to cover the impact of an entire conference like the European Society of Human Reproduction and Embryology (ESHRE) in one post, so I have decided to focus on those presentations that are likely to have the most practical impact.
Behind all the giveaways and the carpeted booths, there is a more serious intent to the commercial side of this conference: glimpses into how industry is helping drive progress in assisted reproduction. Critics point to a lack of significant progress, often measured in success rates, in the last decade. The danger is that focusing only on national statistics may overlook those clinics utilizing best practices, new technologies, or a combination of both. A lack of standardization across IVF centres worldwide and the natural consequence of this—widely variable success rates—is concerning and represents a huge challenge for the field. For example, nationally reported success rates in Canada in 2012 ranged from single digits up to 40%. This is not a Canadian problem exclusively; it is simply a published example of the gulf between centres in some countries. We hope that initiatives like the Global Fertility Alliance (mentioned in my last blog post) will address this disparity. Industry commitment to making new technologies accessible and easy to use must be a priority for this alliance to succeed.
My only regret this year at the ESHRE was that I had too little time to spend visiting all the booths and assessing their new developments. With that said, and apologies to those booths I didn't manage to visit, I share the following. The last time I cryopreserved an embryo was some time ago but I recognize the immense value in having an automated method for vitrifying precious embryos and thereby saving time and avoiding the potential for operator and device variability. That is what makes GeneaBiomedX’s GAVI, the automated vitrification instrument, so appealing. Research Instruments moved laser technology forward once again with their improved Saturn 5 Laser's Biopsy Mode. With new target shapes making zona drilling and trophectoderm biopsies quicker and simpler, this should improve biopsy success once available. Another innovation developed in collaboration with preimplantation genetic diagnosis (PGD) experts Reprogenetics UK, RI Witness’ new PGD function tracks the history of individual PGD embryos and their corresponding cell samples from the IVF lab to the genetics lab and back again.
In the main scientific programme, Elias Dahdouh's presentation gave a nice summary of published randomized controlled trials of preimplantation genetic screening (PGS) to date. Notably, the study suggests that additional trials are needed, particularly to address advanced maternal age and poorer prognosis patients, as the trials published and meta-analysed so far have focused on good prognosis patients. In my opinion, given the high levels of aneuploidy reported in blastocysts from younger patients and even from egg donors, it seems justifiable to aim to reduce time to pregnancy, reduce miscarriage, and possibly even costs of unnecessary embryo transfers by performing PGS in so-called good prognosis patients. If we can move from a 40% ongoing pregnancy rate in such patients to over 60%, why would we not? Despite challenges in recruitment, a number of registered randomized controlled trials are nearing completion. Among these are IVI's existing trials investigating the benefits of PGS for couples with either advanced maternal age (average 39 years) or male factor infertility (<2 million sperm/ml), and RMA New Jersey's trial for poor prognosis patients. Other ongoing trials using array CGH to test for all 24 chromosomes include the ESHRE-sponsored ESTEEM study examining the possible benefits of testing the first and second polar bodies of oocytes and the IVF Sweden study looking at blastocyst biopsy and single embryo transfer. Finally, two large clinical trials using Illumina's latest next-generation sequencing technology to identify aneuploidy have begun; one in China (BEACON) and the multicentric STAR trial currently recruiting patients at centers in the US, UK, Australia.
It would be remiss not to mention the relationship between mitochondria and IVF, given its recent prominence, particularly in the UK. First, I will make a clear distinction between the different approaches and technologies as there appears to be some confusion and blurring of the lines between. The UK law recently changed to allow pronuclear or spindle transfer into enucleated 'healthy' donor oocytes to avoid transmission of serious mitochondrial disease. Meanwhile, a number of different investigators are currently assessing the relationship between the numbers of mitochondria in embryonic cells taken for genetic analysis of chromosome constitution (PGS) with some controversy as to whether normal or euploid embryos have lower mitochondrial levels than aneuploid embryos. The beauty of such an assay is that the sequencing approach to obtain nuclear chromosomal information (PGS) can also deliver mitochondrial information. Biologically, it may be most likely that there exists an optimal range of mitochondria present in healthy euploid embryos rather than an absolute high or low quota, but ongoing work should answer this question. Finally, to complete the trinity of mitochondrial investigations, we come to the exciting but somewhat controversial practice of introducing additional autologous mitochondria into oocytes from women of advanced maternal age. With little clinical evidence and no publications at present, it is difficult to fairly assess this bleeding edge idea. However, the multiplicity of hurdles including true age of the mitochondria, the dose and precise delivery method required as well as incontrovertible residual aneuploidy may cast doubt on its rush into the clinic.
Nominated for best assisted reproductive technology (ART) laboratory oral presentation, Robert Anderson's presentation on grading blastocyst inner cell mass and trophectoderm and predicting euploidy described comparing blastocyst grades and corresponding the aneuploidy rates and resulting implantation. In line with recent embryo morphokinetic findings, he found that static morphologic grading of embryos was not highly predictive of implantation potential, and that even top quality blastocysts were aneuploid as often as 40% of the time. The group also concluded that trophectoderm grade was more important than inner cell mass grade for predicting implantation potential. Furthermore, sharing this information with patients was integral to the counseling process prior to starting a cycle. Dr. Anderson and his clinic is testament to the fact that good research with important practical implications does not have to come from large academic institutions.
On the subject of prize-winners, I was fortunate to attend Dr. Krivega’s presentation describing a newly discovered undifferentiated human embryonic cell type residing in a state between pluripotency and totipotency - the existence of which could help explain how embryos can recover from cell loss. This work has obvious implications for embryo viability and implantation potential following either biopsy, cryopreservation or both. Similarly, the Basic Science award winner, Zuzana Holubcova, presented astonishing live imaging videos, demonstrating that spindle formation in human oocytes is completely different to mouse and seems to be prone to all sorts of abnormalities– a finding which promises to change the way we think about meiosis in women.
On the combined themes of embryo biopsy safety and laboratory standardization, one talk really struck an important chord for me. When performing embryo biopsy at the blastocyst stage, there is currently no consensus on the number of cells to remove for diagnosis. We know that as a general rule, more cells leads to clearer results with an increased signal-to-noise ratio. However, beyond three cells, the benefits may be less significant. To be clear it is not straightforward identifying a specific number of cells from the trophectodermal sheet of cells and without image analysis this may always prove tricky for embryologists. However, we now learn that taking more than 10 cells at this stage has a significant negative impact on implantation potential. Without any additional benefit accruing, this finding underlines the importance of possibly aiming for 5 cells with the expectation of securing at least 3 intact cells to provide enough genetic material for a successful result. With reference laboratories reporting a range of no result calls from their customer IVF clinics of between 0.1% and 20%, this finding has immediate practical implications.
Other topics of intense interest to those laboratories offering PGS in the clinic relate to chromosomal mosaicism which according to Fragouli and colleagues is approximately half as common in blastocysts versus cleavage stage embryos. Using Veriseq PGS to retest array CGH samples from 150 apparently euploid blastocysts, they found that 44 had low level mosaicism which occasionally resulted in a normal live birth and was more likely to be successful the smaller the abnormality. However, the take home message is that such embryos should be given lower priority for transfer and prenatal testing recommended if pregnancy is achieved.
When I reflect on ESHRE 2015, between the sperm-shaped pens, stress eggs, novelty thumb-drives and the exercise gained walking between the overwhelming range of scientific sessions, I remember that we are all doing our various jobs to help people overcome, or come to terms with, their fertility problems. It was this simple fact that stopped me in my tracks when I saw Fertility Europe's 'Wall of Hope'. This beautiful and touching postcard montage represents a multitude of different fertility journeys from prospective parents all over Europe situated by the main registration area. I think I speak for all my past and present colleagues in the field when I say that this is the reason why we do what we do.
And finally, something to literally brighten up your day wherever you are. Not only does sunshine aid positivity and relaxation (we knew that already), researchers at Ghent University in Belgium report that sunshine a month prior to conception could improve success in IVF patients by up to one-third, possibly by helping egg maturation. News such as this, if confirmed in larger studies, is most welcome but should be seen as neither a passport to unsafe sun exposure nor a substitute for more sophisticated IVF interventions and technologies where they are needed.
See you in Helsinki 2016!
Image: Fertility Europe Wall of Hope taken at ESHRE 2015. Visit http://specialfamilies.eu/