Early embryo developmental kinetics following IVF versus ICSI in patients without severe male factor infertility: a secondary analysis of a multicentre, randomized controlled trial (INVICSI)

Abstract STUDY QUESTION Are there any differences in embryo development and morphokinetics between ICSI and conventional IVF (c-IVF) in first cycle patients without severe male factor infertility? SUMMARY ANSWER ICSI resulted in fewer usable and high-quality blastocysts on Day 5 compared to c-IVF, with no observed differences in morphokinetics or cleavage patterns among patients without severe male factor infertility. WHAT IS KNOWN ALREADY Recent randomized controlled trials (RCTs) comparing ICSI and c-IVF have found that ICSI does not improve live birth rates compared to c-IVF when there is no severe male factor. Data on embryo development and morphokinetics between ICSI and c-IVF are lacking. STUDY DESIGN, SIZE, DURATION This was a secondary analysis of an open-label, multicentre, RCT comparing ICSI and c-IVF in 824 patients without severe male factor infertility, with participants recruited between 29 November 2019 and 14 December 2022. In this secondary study, we aimed to explore potential differences in embryo development between ICSI and c-IVF by using registered data on embryo quality and destiny, along with time-lapse data on embryo morphokinetics and cleavage patterns. All analyses were carried out comparing per protocol results between the ICSI group and the c-IVF group. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible participants were women with a male partner who did not have severe male factor infertility, defined as a minimum of 2 million progressively motile spermatozoa, and women/couples using donor sperm. Data were collected on all retrieved oocytes from the study cycles, along with information on embryo development and utilization. Additionally, time-lapse data were extracted and analysed from three trial sites, allowing for the evaluation of morphokinetic parameters and cleavage patterns. MAIN RESULTS AND THE ROLE OF CHANCE The analysis included 388 participants in the ICSI group and 378 in the c-IVF group. There was no significant difference in the number of retrieved oocytes between the two groups. Compared to c-IVF, ICSI resulted in fewer 1PN and >2PN embryos. However, ICSI was also associated with fewer cleaved embryos on Day 2, lower total number of blastocysts, fewer blastocysts utilized for transfer or vitrification, and fewer high-quality blastocysts on Day 5 (based on Gardner’s criteria) (P < 0.05 for all). No significant differences were observed in the number of high-quality embryos on Day 2, high-quality blastocysts on Day 6 or vitrified Day 6 blastocysts. Blastocyst quality in the first embryo transfer did not differ between groups. The time-lapse imaging subgroup analysis included 482 participants (247 in the ICSI group and 235 in the c-IVF group), and assessment of 1846 ICSI-treated and 1900 c-IVF-treated oocytes. When accounting for an expected c-IVF delay, there were no differences in timing of embryo development between ICSI and c-IVF. No significant differences were found in the incidence of multinucleation at the two-cell or four-cell stage, direct cleavage, rolling or reverse cleavage. LIMITATIONS, REASONS FOR CAUTION Traditional sperm parameters, including sperm count and motility, were used in this study. We did not assess sperm DNA fragmentation or other advanced sperm characteristics, which have been suggested to influence early embryonic development. WIDER IMPLICATIONS OF THE FINDINGS This is the first study based on data from a randomized trial in which patients were assigned to either ICSI or c-IVF to examine the effect of fertilization method on embryo morphokinetics, cleavage patterns and blastocyst formation. ICSI resulted in fewer available blastocysts and high-quality blastocysts on Day 5 compared to c-IVF, while most other outcomes were comparable between groups. These findings are clinically relevant and add to the growing body of evidence that ICSI should not be preferred over c-IVF in the absence of severe male factor infertility. STUDY FUNDING/COMPETING INTEREST(S) The INVICSI study was supported by an unrestricted grant from Gedeon Richter (to S.B.) and funded by the Capital Region of Denmark (A6606), Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Legat (4101466; to S.B.) and Amager/Hvidovre Hospital. The funders had no involvement in the study design, data collection, analysis, interpretation of results, manuscript preparation or the decision to submit the manuscript for publication. S.B. has received a grant from Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Fond outside the current work. A.P. has received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Cryos, all paid to her institution; consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Merck A/S and Cryos; honoraria from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Organon; and travel support from Gedeon Richter (paid directly to institution). M.L.G. has received grants from Gedeon Richter (via her institution) and Merck, and consulting fees from Cooper Surgical. B.N. has received grants from Gedeon Richter, Merck, and Ferring, all paid to his institution, and has received support for attending meetings and/or travel from Gedeon Richter and Merck. N.L.C.F. has received grants from Gedeon Richter, Merck and Cryos (all paid to her institution); consulting fees from Merck; and support for attending meetings from Gedeon Richter, Merck, Ferring Pharmaceuticals and IBSA. E.L. has received honoraria from Pfizer (lecture), hospital compensation from Radiometer (equipment validation) and support for attending meetings and/or travel from Gedeon Richter and Merck. She also serves on the advisory board for Astellas Pharma Nordic. H.S.N. has received grants from Freya Biosciences, Ferring Pharmaceuticals, BioInnovation Institute, Ministry of Education, Novo Nordisk Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Independent Research Fund Denmark and Ole Kirks Fond; and honoraria from Ferring Pharmaceuticals, Merck, AstraZeneca, Cook Medical, Gedeon Richter, Novo Nordisk and IBSA. A.L.E., L.P., A.Z., M.R.P., A.V.G., D.F.S. and D.W. declare no competing interests. TRIAL REGISTRATION NUMBER NCT04128904.