The quest to improve the effectiveness and efficiency of ART coupled with concerns around the risks of unproven add-on treatments makes personalised medicine in reproduction a hot topic.
In a first for ESHRE, this three-day workshop was coordinated by all special interest groups, which ensured a multi-disciplinary approach with talks from a variety of specialists ranging from sociologists to andrologists.
Featuring several head-to-head debates as well as analysis of the latest data, the campus explored where the promise of personalised care for patients and the perils of unproven add-ons. The implications of private equity firms increasingly investing in clinics were also addressed.
The meeting was underpinned by an acknowledgement that a one-size-fits-all approach is ineffective but scientists still do not know what works and why in fertility treatment. This makes tailoring care to the needs of individual patients or specific groups an ongoing challenge.
Luca Gianaroli opened the course with a provocative presentation with the title ‘promoting personalised medicine or ‘recovering add-ons’. The long-standing specialist and former chair of ESHRE challenged the audience to consider that add-ons only have a negative connotation in reproductive medicine, not in cardiology or other areas of health.
The ESHRE good practice recommendations on add-ons in reproductive medicine found no evidence to support the use of adjuvant therapies in many cases (1). However, Dr Gianaroli challenged this position by stating that age, BMI and many other factors increase the risk of failure if add-ons are not used. He warned of going backwards to a time when just IVF and ICSI existed.
Add-ons can be described as any technology that is a variation to a normal IVF cycle which Dr Gianaroli said raises the question of what is normal. For example, should PGT-A be considered an add-on despite being introduced more than two decades ago or ICI for azoospermia?
His talk also cast doubt on randomised controlled trials (RCTs) as a gold standard, arguing that few groups have sufficient resources to do RCTs, results may be obsolete by the time of publication, and hedge funds and private equity will be driving study results. Advocating for new options in patient care, Dr Gianaroli reminded the audience that standard is not always the best for everyone. When dealing with a multifactorial disease such as infertility, he said personalising treatments based on specific characteristics and needs is important.
How do fertility medical directors view IVF add-ons and personalised medicine? In a wide variety of ways, according to a presentation by Lucy van de Wiel based on data she and colleagues have collected from UK clinics. A recurring theme identified by this research is the impact of private equity firms who are increasingly investing in fertility care.
Dr van de Wiel, from King’s College London, said participants expressed concerns about the commercialisation and financialisation of the sector and the drive to make money out of fertility treatment. In this changing landscape, the potential exists to make delivery of care more efficient but some medical directors were worried about patient care and physician autonomy such as the pressure to offer add-ons.
Dr van de Wiel also presented evidence from her study to suggest doubts about the quality of RCTs with some participants making a plea for more studies that were multi-centre, by credible people, and from a place where there is research governance.
On the topic of gamete collection and embryo selection, Michel De Vos made a compelling case for preserving the fertility of cancer patients, describing it as a ‘no brainer’. The ESHRE guideline on female fertility preservation says combining different approaches may be possible and Professor De Vos’s talk explored which are feasible.
Ovarian tissue cryopreservation with oocyte freezing increases reproductive options but whether this increases birth rates is unclear. In vitro maturation (IVM) can also be considered but only a handful of births have been reported to date and research suggests IVM is less efficient than oocyte maturation in vivo. Biphasic IVM (CAPA-IVM) is a new approach aimed at improving the developmental competence of oocytes but this has yet to be explored in cancer patients.
In conclusion, Professor De Vos acknowledged that return rates for cancer patients are low which demonstrates the need for large longitudinal follow-up studies to identify the best candidates for combined approaches.
Rossella Cannarella, associate editor of Reproductive Biomedicine Online, emphasised the need for more focus in ART on male health. The clinical andrologist explored how the molecular profile of sperm affects embryo development including insulin-like growth factor 2 (IGF2), a protein expressed in human sperm.
Data from studies on which Dr Cannarella has collaborated show sperm IGF2 mRNA levels are inversely correlated with embryo growth velocity in the early stages of development (2). This suggests that IGF2 in sperm might play a role in how quickly an embryo grows in the very beginning. Her message was that molecular profiling of sperm may enhance ART outcomes in future and that clinics should personalise male fertility by assessing their health such as BMI in the workup.
In her talk, Siobhan Quenby MBE highlighted the value of RCTs and real-world evidence in personalising care om recurrent miscarriage. The consultant obstetrician, from the University of Warwick, reviewed results from two RCTs into the impact of progesterone in early pregnancy on live birth rate (LBR) (3,4). Compared to placebo, progesterone did not significantly increase LBR according to findings from the PROMISE trial (3).
However, results were more encouraging from PRISM which investigated the use of steroid hormones for bleeding in early pregnancy (4). No significantly higher incidence of live births was found but a sub-group of women with a history of recurrent miscarriage and treated with progesterone had a better chance of carrying a pregnancy to term.
Professor Quenby’s own research into miscarriage has provided the basis for a support tool developed by charity Tommy’s. The online calculator, which determines the chance of a successful next pregnancy, was used by over 100,000 people in a year. Professor Quenby says this demonstrates how desperate women are for personalised information and should not have to endure repeat miscarriages before they receive help.
The campus ended as it had begun with the theme of promoting personalised medicine or recovering add-ons. In her comprehensive overview of the ESHRE good practice recommendations, Anja Pinborg provided a counter argument to Dr Gianaroli’s talk by providing insights into the reasons behind the working group’s decisions. In doing so, she rebutted his assertion that the group had said ‘no’ to every add-on.
However, Professor Pinborg from the University of Copenhagen, underlined the importance of explaining to patients what is and isn’t evidence based, and that principle of ‘do no harm’ remains paramount.
With cost a major issue, many patients who spend money on add-ons in the first cycle of fertility treatment cannot then afford to return for a repeat cycle which could have increased their chance of pregnancy. ICSI is a case in point – clinics to continue to offer this for non-male factor infertility despite the lack of evidence highlighted in the ESHRE good practice recommendations.
The course reasserted the need to care for patients in all their complexities including older women, those with endometriosis and other issues that undermine their odds of having a healthy baby. Revision of the ESHRE recommendations on add-ons will also be crucial in ensuring evidence is up to date and patients can make informed choices.
References:
1 ESHRE Add-ons working group, K Lundin, J G Bentzen, G Bozdag, T Ebner, J Harper et al. Good practice recommendations on add-ons in reproductive medicine. Hum Reprod November 2023; volume 38 (11); 2062–2104; https://doi.org/10.1093/humrep/dead184
2 Cannarella R, Rando OJ, Condorelli RA, Chamayou S, Romano S et al. Sperm-carried IGF2: towards the discovery of a spark contributing to embryo growth and development. Molecular Human Reproduction September 2024; vol 30 (9); https://doi.org/10.1093/molehr/gaae034
3 Coomarasamy A, Williams H, Truchanowicz E, Seed Paul T, Small R, Quenby S et al. A Randomized Trial of Progesterone in Women with Recurrent Miscarriages; N Engl J Med 2015 Vol 373 (22); 2141-2148; DOI: 10.1056/NEJMoa1504927
4 Coomarasamy A, Devall AJ, Cheed V, Harb H, Middleton Lee J at al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy; N Engl J Med May 2019 Vol 380 (1); 1815-1824; DOI: 10.1056/NEJMoa1813730
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