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Towards elective single embryo transfer: investigating approaches forimproving accessibility and efficacy of in vitro fertilisation treatment andtheir implications for patients

Student thesis: Doctoral Thesis

This study investigates different modalities for achieving elective single embryo transfer in assisted reproductive technologies (ART) and developing protocols and policies that both permit maximum access to care as well as improving safety of ART by limiting the number of embryos that are transferred.
The study includes 16 peer-reviewed journal articles and 1 book chapter published since 2001 and covering my career to date while working in two university affiliated IVF centres: McGill University and the University of Montreal, Canada. It includes research on:

• Improving the clinical application of modified natural cycle IVF

A total of 134 MNCIVF cycles were compared with 370 IVF cycles using COS; in patients under the age of 35 years old the clinical pregnancy rate was 27% versus 47% however in patients older than 35 years old the benefits of MNCIVF did not support the poorer prognostic with a clinical pregnancy rate of only 8%.
The addition of a NSAID, Indomethacin, further optimized the MNCIVF protocol by decreasing the premature ovulation rate from 16% to 6%, this in turn increased the potential of obtaining the oocyte at retrieval from 64% to 76%.
The combination of MNCIVF and surgical sperm retrieval was demonstrated as a viable option in a case report describing a couple who did not want any risk of multiple pregnancy and the least invasive treatment possible to obtain their pregnancies. This treatment was confirmed with a study comparing 81 MNCIVF using ejaculated spermatozoa with 44 MNCIVF using surgically retrieved spermatozoa. There were no differences in the clinical pregnancy rate (31.0% versus 35.1%), however the chance of having an embryo transfer increased in the surgical group (65.9% versus 45.7%). The age of the male partner in the surgical group was older (41.5 versus 36.5) perhaps associated with second relationships; a group for whom MNCIVF can be an interesting treatment option.
The use of MNCIVF in young poor responders is suggested as well as an option for egg donation where the donor wants to avoid gonadotrophins. An analysis of over 1500 MNCIVF was carried out demonstrating a clinical pregnancy rate per embryo transfer of 32.5%. Patient cycles were stratified according to ovarian reserve and in younger patients this had little influence on outcome, however in the patients over 35 years of age, the clinical pregnancy rate dropped significantly with a poor ovarian reserve (26.3% versus 6.3%)

• Investigating the application of the protocol for in vitro maturation of oocytes

One hundred and seven IVM cycles in patients with polycystic ovarian syndrome were case matched with 107 IVF and COS cycles. There was no significant difference in the clinical pregnancy rate (28% versus 41%) although it came close to significance, however there were less oocytes (10.3 versus 14.9), less mature oocytes (7.8 versus 12.0) and less embryos available (5.8 versus 8.6). Importantly there were no cases of OHSS in the IVM group compared to 11% in the IVF with COS group.
A case study describes the use of IVM in combination with PESA and the possibility to successfully obtain and mature oocytes in a PCOS patient and then fertilize those oocytes using spermatozoa retrieved using a simple procedure in an azoospermic partner. Additional more specialized uses of IVM are described including a case report of a young patient with FSH receptor mutation and falling ovarian reserve for whom IVM was used to obtain and mature ten oocytes for fertility preservation following a failed attempt to stimulate her ovaries.

• Studying the implementation of legislation and funding related to ART and the impact on treatment
in Quebec, Canada

An initial study after the introduction of funding demonstrated a reduction from 25.6% to 3.7% in the multiple pregnancy rate following IVF, with an increase in the use of eSET from 1.6% to 50% of performed embryo transfers. This was followed by studies showing that although the pregnancy rate in IVF dropped under funding, the cumulative pregnancy rate would correct for this drop using a predictive calculation (29.7% versus 31.9%). This was confirmed with data analysis after the first complete year of funding in one clinic, indicating that the transfer of one fresh embryo followed by one frozen-thawed embryo gave equivalent pregnancy rates to DET (47.1% versus 47.1%).
A financial analysis furthermore supported the fiscal benefits of funding showing that although funding in absolute terms costs the government more, the cost per baby is lower under funding than with a tax rebate system (49,517$ versus 43,362$) considering the costs of high order multiple pregnancies that are significantly reduced under funding with an eSET policy in place.
A final complete analysis of the totality of the funding program after it was shut down, comparing with the year prior to and the year post funding, clearly indicates that the design of funding can influence not only the fiscal burden but also clinical decision making and that this reflects in the results. The cancellation rate increased dramatically (17.0% versus 34.4%) and the live birth rate dropped in all treatment modalities (33.9% versus 23.7%). However, the multiple pregnancy rate dropped from over 25% to under 5% throughout the course of funding and remained under 5% even once funding was withdrawn.

These publications form a tiny part of the enormous journey that ART has taken over the course of the last 40 years and continues to take on a daily basis. Additional research is required in all these and other areas related to IVF and embryology in order to further improve all aspects of ovarian stimulation, embryo culture and selection and implantation knowledge and application.
Original languageEnglish
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    Award date2019

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