A fluid-filled pod for extremely premature babies to grow inside, robot-assisted ICSI performed from anywhere in the world, and PGT-A analysis that uses AI were among cutting-edge advances outlined at this campus on improving reproductive health and fertility.
Demand for IVF means growing need for innovative techniques to optimise procedures. A recurrent theme of the workshop was how can clinicians balance the benefits of science and technology breakthroughs with ethical considerations. In addition, discussions revolved around the need to keep patients safe while accepting that many will seek out unproven approaches in the quest to become parents.
Organised by SIGs global and socio-cultural aspects of infertility and stem cells, the event incorporated cultural and psychosocial perspectives on fertility, and was essentially a campus of two very distinct halves. Day one was dedicated to traditional and complementary medicine such as acupuncture, herbal remedies and dietary supplements; and the second – to emerging technologies such as AI and CRISPR. An update was also provided on womb transplants and the implications of the procedure becoming established globally.
The first speaker was Alys Einion, from the University of Dundee in Scotland, who talked about the impact of complementary and alternative medicine (CAM) such as acupuncture, homeopathy and reflexology on fertility outcomes. Overall, evidence on the benefits of CAM in ART is inconclusive. However, data presented by Dr Einion show that between 29% and 96% of women globally resort to CAM to aid conception, often for cultural reasons. The fact that patients seek out-treatments without a sound evidence base demonstrates that more research is needed on safety and guidance from trained CAM practitioners; and clinicians need to know if patients are using CAM in case of any adverse interaction with other mainstream medicine. Some types of CAM have been linked with miscarriage and on this basis, Dr Einion called for a standardised reporting system to monitor the effects of CAM: The personal vision she outlined for future ART practice is for the integration of (CAM) with cutting-edge approaches, not for CAM to be seen as a ‘fringe’ science.
The socio-cultural aspects of uterine transplants were debated by Sharmila Rudrappa who is carrying out research into this topic works on this topic in collaboration with Monash University in Australia. Nearly a decade since the first live birth, uterine transplants are no longer experimental and the technology is now standardised, representing a major advance in the treatment of uterine factor infertility. What has yet to be addressed is the different cultural attitudes and ethical values of countries offering these procedures, said Dr Rudrappa from the University of Texas at Austin, USA. Cost to the patient, the recipient’s BMI status and the risk of donors being exploited in countries without robust human rights laws are among many issues faced by doctors. This underlines the case for consensus on worldwide clinical and ethical norms t which Dr Rudrappa said cannot be achieved without a global network of doctors being established.
The debate on day two of the campus switched to automation and AI in fertility clinics; and progress around stem-cell based embryo models and the application of human gonadal reconstituted tissue to advance reproductive and regenerative medicine.
Consistency, convenience and cost-saving are among the benefits of technology that reduces the need for human input in the embryology lab as outlined by Santiago Munne, scientific director of Progenesis. The goal of automation is not to eliminate embryologists, he said, but to eliminate them doing ‘boring tasks’ such as dish preparation, to do more with the same effort, and allow embryologists to become scientists again instead of ‘mere technicians’. By way of illustration, Dr Munne provided details of robot automated ICSI which can be controlled from anywhere in the world using high speed internet (1) and an ex-utero artificial placenta – or artificial womb – that uses lab-made amniotic fluid to fill the lungs of extremely premature infants and improve their odds of survival.
Standardisation and consistency are also benefits of AI-assisted PGT-A. Tony Gordon, senior director of CooperSurgical, said teams of people are required to select euploid embryos but ‘some are better than others’ at this and may not be able to detect whether the changes are genuine. In contrast, AI has the potential to identify copy number variation events in hundreds of embryo biopsy PGT-A results a day and interpretation is not subjective, unlike manual testing. A single centre study based on more than 24,000 embryos concluded that PGT-A using AI platforms significantly increases euploidy classification rates and ongoing pregnancy/live birth rates, and decreases biochemical pregnancy rate when compared to standard next-generation sequencing (2). Looking to the future, Dr Gordon predicted that clinics will be sequencing more embryos in five years with AI but whether this will benefit IVF outcomes is unclear. What is needed is AI that can clinically interpret genetic variants identified through testing but whose significance to the function or health of an embryo is unknown.
AI tools in time lapse image analysis to predict embryo potential are also showing promise. Marcos Meseguer Escriva presented evidence from a retrospective study he co-authored on the efficacy of VIOLET, an AI system that assesses images of mature denuded oocytes. Findings showed the AI software was 75% accurate in predicting the probability of a live birth per oocyte cohort (3). Other AI-based embryo systems outlined by Dr Escriva, from IVI Valencia in Spain, included Life Whisperer, a digital camera mounted on a microscope that can score blastocysts using single images. An advantage of AI tools in image analysis is that they allow clinicians to provide personalised advice for patients, especially those seeking fertility preservation.
In her talk on stem-cell based embryo models, Mina Popovic said the science represents a paradigm shift with a ‘flurry’ of studies which have mainly focused on pluripotent embryonic stem cells. Models are getting more sophisticated with technologies such as microfluidics added into platforms, and the extended culture of mouse embryos from day 5 to day 11 outside the uterus. Dr Popovic said more work is still needed to improve these models: only certain stages of embryonic development can currently be recreated. And lab-grown stem-cell based human embryos may raise the hopes of infertile patients in the future, but this raises ethical questions over whether the models are mimicking in vivo embryos. While developments in the field are exciting, Dr Popovic who is the scientific director of the Eugin Group said findings must not be sensationalised and it is vital to determine when the line from a model to an embryo has been crossed.
Her sentiments about not overstating advances in the field were echoed by Joao Pedro Alves Lopes who presented the latest evidence on modelling human gonadal development in vitro. The science has been advancing over the past decade with mouse pluripotent stem cells used to produce offspring via reconstituting follicle structures; and testicular organoids generated from human gonadal cell suspensions. Future applications include fertility preservation and restoration such as sperm obtained from human pluripotent stem cells. However, Dr Lopes who is an assistant professor at the Karolinska Institutet emphasised that regulatory approaches must be put in place now as scientists move towards clinical applications, not afterwards.
The campus ended on the controversial topic of CRISPR, and presenter Bieke Bekaert attempted to answer the question ‘are we there yet?’. Her conclusion was that germline repairs in a clinical setting are not a reality but germline repair in research is happening. Technical hurdles exist, such as limitations in gene editing assessments caused by allelic dropouts, which calls for solutions either from new techniques, a combination of different techniques or set-up adaptations such as new CRISPR/Cas9 variants (4). Then there are the major ethical issues such as unexpected alterations to the genome. The science has the potential to help people to have babies, said Dr Bekaert from the University of Antwerp in Belgium, but only if it is safe.
References:
1 Costa-Borges Nuno et al. First babies conceived with Automated Intracytoplasmic Sperm Injection. Reproductive BioMedicine Online vol 47 (3) 2023; https://doi.org/10.1016/j.rbmo.2023.05.009
2 Buldo-Licciardi J et al. Utilization of standardized preimplantation genetic testing for aneuploidy (PGT-A) via artificial intelligence (AI) technology is correlated with improved pregnancy outcomes in single thawed euploid embryo transfer (STEET) cycles. J Assist Reprod Genet 40, 289–299 (2023); https://doi.org/10.1007/s10815-022-02695-7
3 Murria L et al. Artificial intelligence oocyte image analysis predicts fertilization, blastocyst development, and live birth outcomes per cohort. Fert and Steril October 2023 (4). DOI:https://doi.org/10.1016/j.fertnstert.2023.08.151
4 Liang D, Mikhalchenko A., Ma H et al. Limitations of gene editing assessments in human preimplantation embryos. Nat Commun 14, 1219 (2023); https://doi.org/10.1038/s41467-023-36820-6
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