Factoring genetics in the management of implantation and early pregnancy


A campus about the applications of knowledge from the pre-conceptional to gestational period and long-term implications of genetic testing. This course addressed the challenges in identifying disease-causing genes and molecular diagnostics in reproductive medicine.

Genetic engineering, GMO and gene manipulation concept

The identification of new disease-causing genes, the molecular diagnosis and the implications for health are a major challenge in reproductive medicine. This course which took place in Florence in November 2023 was organised jointly by SIGs Implantation & Early Pregnancy and Reproductive Genetics. Speakers aimed to deliver basic knowledge and education on genetics relevant to implantation and early pregnancy, with a practical goal: to provide patients with updated, balanced knowledge and support informed consent regarding reproductive genetics to guide them throughout their journey.

As highlighted by Professor Alan Handyside from the University of Kent, UK, the concept of P4 medicine – predictive, personalized, preventive, and participatory – is revolutionising pre-conceptional genetics in the rapidly evolving field of reproductive medicine. This innovative approach, integrating omics sciences, offers profound insights into how our genetic makeup influences our health and paves the way for personalized treatments. Such a paradigm shift promises to transform reproductive healthcare by providing solutions tailored to individual genetic profiles.

However, this advancement is not without its challenges, particularly in preconception screening. In her presentation, Dr Lidewij Henneman from Amsterdam UMC, Netherlands, said significant hurdles remain including identifying target populations and overcoming infrastructural limitations distinct from screening during pregnancy.

Also, the speakers emphasized the crucial distinction between screening and diagnosis while highlighting the evolution of carrier screening methods, especially with the introduction of next generation sequencing (NGS). The practicality and impact of these advanced screening methods are under constant evaluation, considering factors such as cost and their limited scope in addressing specific pathologies.

Furthermore, Dr. Andrea Busnelli, from Humanitas University, Milan, Italy, presented research to demonstrate the cost-effectiveness of expanded carrier screening (1). While comprehensive studies are limited, preliminary findings indicate a potential decrease in the prevalence of affected births, suggesting a substantial influence on reducing healthcare costs. This complex interplay of innovative genetic approaches and pragmatic challenges underscores the dynamic and evolving nature of reproductive health science.

In the realm of reproductive medicine, the journey continues to understand and treat male infertility. Traditional diagnostic methods like karyotype analysis, Y chromosome- azoospermia factor (AZF) deletion, and cystic fibrosis transmembrane conductance regulator (CFTR) mutation screening have been instrumental, yet they leave a substantial number of cases with unclear aetiology (2). As mentioned by Dr Csilla Krausz from the University of Florence, Italy, the advent of NGS has introduced more targeted screening for specific phenotypes, but it is whole exome sequencing that emerges as a particularly promising tool. This advanced technique holds the potential to uncover new genetic factors contributing to infertility, marking a significant stride in the field.

Parallel to these developments, preimplantation genetic testing (PGT) has evolved over the past three decades. Initially designed to detect single gene disorders and chromosomal abnormalities, PGT has expanded its capabilities thanks to technologies like NGS. As highlighted by Dr Antonio Capalbo from JUNO Genetics, Italy, PGT’s role has transcended the mere identification of genetic disorders; it now plays a crucial part in enhancing IVF success rates through strategic embryo selection.

Dr Heidi Mertes from Ghent University, Belgium, shed light on the broader psychological, social, and ethical dimensions of PGT, particularly in early pregnancy management. This technology, while groundbreaking, has complex emotional ramifications for prospective parents and adds to ongoing ethical debates regarding the extent and implications of genetic screening. These insights underscore the multifaceted nature of reproductive genetics, blending cutting-edge science with profound human and ethical considerations.

In the field of reproductive medicine, unravelling the genetic intricacies of implantation failure and pregnancy loss remains challenging. In their presentations, Dr Signe Altmäe from the University of Granada, Spain, and Dr Henriette Svarre Nielsen from the University of Copenhagen, Denmark, showed the complexity of the genetics involved in implantation (3). Aneuploidy stands out as the predominant cause of implantation and pregnancy loss, necessitating a deeper understanding of the others non-genetic factors influencing pregnancy loss by accounting for embryonic or foetal aneuploidy.

The key to successful embryo implantation and development lies in the dialogue established between the embryo and the endometrium. Recent advancements in evaluating embryo morphology and quality have significantly enhanced understanding of the molecular interactions between the embryo and the endometrium (4). So has more profound comprehension of the molecular aspects of endometrial receptivity, However, despite these advancements, the genetic underpinnings of the human implantation process remain largely enigmatic, often described as a ‘black-box’.

The keynote lecture of the campus by Professor Eva Hoffmann from the University of Copenhagen, Denmark, addressed reproductive ageing and embryo developmental arrest, along with discussions on prenatal genetic testing. By using genetics, more information about the natural variation in ageing processes as well as the identification of molecular mechanisms that contribute to aneuploidy could be elucidated.

In the prenatal period, targeted exome sequencing should be chosen if specific disorder is suspected. However, whole exome sequencing should be offered based on certain indication to increase the diagnostic power and enhance the clinical utility. Nonetheless, as Dr Joris Vermessch from KU Leuven, Belgium, and Efthymia Constantinou from the Cyprus Institute of Neurology and Genetics, Cyprus, pointed out that there is insufficient data to support the routine use of these techniques.

The campus concluded with insights into the association of reproductive genetics and the evolution of the human species by Dr. Hans Ivar Hanevik from Telemark Hospital of Oslo, Norway. IVF sets the evolutionary stage for a human species that is increasingly reliant on, and adapted to, technical means of reproduction.

This workshop not only highlighted the current advancements in reproductive genetics but also set the stage for future explorations, promising a new era in personalized reproductive medicine and genetic counselling.

1 Busnelli, A., Ciani, O., Caroselli, S., Figliuzzi, M., Poli, M., Levi-Setti, P. E., Tarricone, R., & Capalbo, A. (2023). Implementing preconception expanded carrier screening in a universal health care system: A model-based cost-effectiveness analysis. Genetics in Medicine, 25(11). https://doi.org/10.1016/j.gim.2023.100943
2 Krausz, C., & Cioppi, F. (2021). Genetic Factors of Non-Obstructive Azoospermia: Consequences on Patients’ and Offspring Health. Journal of Clinical Medicine 2021, Vol. 10, Page 4009, 10(17), 4009. https://doi.org/10.3390/JCM10174009
3 Oddsson, A., Sulem, P., Sveinbjornsson, G., Arnadottir, G. A., Steinthorsdottir, V., Halldorsson, G. H., Atlason, B. A., Oskarsson, G. R., Helgason, H., Nielsen, H. S., Westergaard, D., Karjalainen, J. M., Katrinardottir, H., Fridriksdottir, R., Jensson, B. O., Tragante, V., Ferkingstad, E., Jonsson, H., Gudjonsson, S. A., … Gudbjartsson, D. F. (2023). Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Nature Communications 2023 14:1, 14(1), 1–15. https://doi.org/10.1038/s41467-023-38951-2
4 Koel, M., Krjutškov, K., Saare, M., Samuel, K., Lubenets, D., Katayama, S., Einarsdottir, E., Vargas, E., Sola-Leyva, A., Lalitkumar, P. G., Gemzell-Danielsson, K., Blesa, D., Simon, C., Lanner, F., Kere, J., Salumets, A., & Altmäe, S. (2022). Human endometrial cell-type-specific RNA sequencing provides new insights into the embryo–endometrium interplay. Human Reproduction Open, 2022(4), 1–15. https://doi.org/10.1093/HROPEN/HOAC043

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