Balkan Journal of Medical Genetics

PREIMPLANTATION GENETIC TESTING WITHIN THE PUBLIC HEALTHCARE SYSTEM IN SLOVENIA
Volk M, Writzl K, Veble A, Jaklič H, Teran N, Prosenc B, Štimpfel M, Virant Klun I, Vrtačnik Bokal E, Ban Frangež H, Peterlin B
*Corresponding Author: Prof. Borut Peterlin, MD, PhD, Clinical institute of genomic medicine UMC Ljublja na, Šlajmerjeva 004, 1000 Ljubljana, Slovenia, Telephone: +3861 5226103, Fax: +3861 5401137, borut.peterlin@kclj.si
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DISCUSSION

Our results of 15 years of experience show that PGT has become an established practice in addition to tradi- tional prenatal diagnosis in Slovenia. PGT is performed for requests associated with a high risk for a severe medical condition in offspring, either of chromosomal or monogenic origin. The most com- mon referrals for PGT-SR were reciprocal translocation in female partners and Robertsonian translocation in male partners. By contrast, PGT-M was mainly requested for Huntington’s disease, Duchenne muscular dystrophy, Hae- mophilia A, Myotonic dystrophy, Spinal muscular atrophy, and Charcot Marie Tooth disease. Furthermore, couples at high risk for adult-onset disorders or familial cancer predisposition presented 20% of all PGT-M referrals. Our results are consistent with the published ESHRE PGT Consortium data collection (9, 10). Trophectoderm biopsy and genome-wide analysis increased the accuracy and reliability of the preimplantation genetic testing. When comparing the dataset from 2004-2016 to 2017-19, the delivery rates per embryo transfer significantly increased. The increase may be due to the substantial amount of starting material, whole genome amplification and genome-wide screening. We observed that in 2004-2016, there were, on aver- age, four embryos suitable for biopsy per cycle, while in 2017-2019, up to three embryos. This lower number was expected because, in 2004-2016, embryos were biopsied on day three at the cleavage stage and in 2017-2019 at the blastocyst stage, and not all cleavage stage embryos reached the blastocyst stage. Hormone stimulation may be associated with hyperstimulation syndrome, a life- threatening condition in the most severe form. Therefore, each patient’s hormonal stimulation protocol in our clinic is adjusted to optimize follicle growth and avoid complica- tions associated with hyperstimulation syndrome. Since 2017, only the freeze-all approach has been performed in PGT cycles, which is more convenient to prevent hy- perstimulation than before, when fresh embryo transfers were performed. Putting the patients and their safety first is our priority as well as a critical indicator of the quality of a healthcare system, including IVF-PGT procedures. Most PGT cycles in Slovenia were requested for PGT- M and PGT-SR (375 cycles, 91%). In addition, PGT-A cycles (33 cycles, 9%) were performed because of genetic indications, i.e., parental sex chromosome mosaicism, X- linked monogenic disorder or repeated aneuploid concep- tion. In many IVF centres, PGT-A cycles predominate and are used to shorten the time to pregnancy in the treatment of infertile couples without genetic indication. In the recent ESHRE data collection (9), PGT-A comprised more than 60% of all reported procedures. PGT-A, as an extension of IVF, is not performed in our country nor in Denmark, France, Germany, Hungary, Lithuania, Norway, and the Netherlands (10, 11). However, embryo sex selection by PGT-A is allowed in some European countries to screen for X-linked diseases. The monogenic referrals account for more than 50% of cycles and are increasing yearly. An increase in PGT-M is mainly due to improved genetic diagnostics by next-gen- eration sequencing and preconception carrier screening. The availability of PGT for couples with severe ge- netic indications represents a considerable reproductive option in Slovenia. The costs of PGT cycles are covered by the National Health Insurance, which allows equal access to health care services for eligible couples. Our national public healthcare system provides PGT services in accordance with the needs of the patients to ensure fair and accessible patient-centred medicine. Furthermore, following genetic counselling, about a third of couples at high risk of transmitting a genetic disease to their offspring would opt for the PGT procedure. The practices of PGT vary across different jurisdic- tions and policy approaches, ranging from restrictive to permissive policy models (4). Countries may regulate PGT through state funding (Austria, Belgium, Germany, France, Italy, the Netherlands, Switzerland, United Kingdom, Swe- den, Denmark, Finland, Canada), private (Australia, Israel, United States, Singapore, Brazil, Japan), or a mixture of the two models (Denmark, Finland, United Kingdom) (4). However, PGT practices change with time, according to technological development, diagnostic improvements, ethical considerations, and patient needs and demands. There are certain limitations of our retrospective register-based study. First, we know that a small sample size (n=163 ET in 2004-2016 and n=100 ET in 2017-2019) represents a study limitation. Nevertheless, the clinical outcomes are comparable to larger centres and reflect the actual needs of our patients. It was expected that blas- tocyst biopsies would result in increased implantation and live-birth rates compared to blastomere biopsy (12); however, a large retrospective cohort study showed that a freeze-all strategy is beneficial in high responders but not in intermediate or low responders, thus refuting the idea that freeze-all cycles are preferable for all patients (13). Lastly, we neither addressed the clinical characteristics of the patients in terms of hormone levels, stimulation protocol, endometrium preparation, or the number of re- trieved and matured oocytes nor whether socioeconomic status influences the decision regarding PGT. The study was focused on the development and provision of PGT services in our country rather than assessing the routine protocol for IVF-PGT procedure. In conclusion, we report on our 15 years of experi- ence in PGT, provided by the Slovenian healthcare sys- tem, where about a third of couples at risk for transmit- ting a severe genetic disorder to their offspring would opt for PGT. The results of our study show that the clinical outcomes of PGT cycles are comparable to other larger centres. Furthermore, our study demonstrates that PGT, when provided by the public healthcare system offering accessibility and equity, has become a considerable option in addition to traditional prenatal diagnosis.

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