2025/06/01 by Y Misyura, B Aydin, U Dorofeyeva +6
Medicine · #Reproductive Biology and Fertility
paper · pdf · doi:10.1093/humrep/deaf097.068
openalex publication_date 2025/06/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
Abstract Study question Can pronuclear and spindle transfer rescue embryo development and pregnancy outcomes in patients with diminished ovarian reserve (DOR) who consistently yield no euploid blastocysts? Summary answer Mitochondrial replacement therapy led to high fertilization, euploid blastocyst development, pregnancy and live birth rates, allowing DOR patients to maintain genetic similarity with their offspring. What is known already Women with DOR and advanced maternal age must often turn to oocyte donation due to the significantly reduced quality and quantity of autologous oocytes. As mitochondrial dysfunction leads to oocyte aneuploidy and failed IVF outcomes, mitochondrial replacement techniques (MRT) are being explored to prevent transmission of mutations in maternally inherited mitochondrial DNA (mtDNA). Maternal spindle transfer into young donor oocytes improves morphokinetic development and reduced aneuploidy rates while pronuclear transfer at the zygote stage enhances blastocyst development. Due to ethical restrictions, there are few clinical studies on MRT and none that investigated pregnancy outcomes in AMA patients. Study design, size, duration In this prospective cohort study, pronuclear transfer was performed on 323 mature oocytes retrieved following short antagonist controlled ovarian stimulation between June 2022 and January 2024.Main outcomes were the clinical pregnancy, ongoing pregnancy and live birth rates following frozen embryo transfer (FET). Secondary outcomes included the fertilization rate, embryo development and euploidy status determined by preimplantation genetic testing for aneuploidy (PGT-A). Additionally maternity test used for DNA matching. Participants/materials, setting, methods Oocytes were derived from 66 DOR patients (≤46 years of age) who had ≥5 IVF attempts without yielding blastocysts. Karyoplast-containing meiotic spindles from the patients‘ oocytes were transferred into enucleated donor oocytes before fertilization. For pronuclear transfer, the pronuclei of patient and donor zygotes were fused into the HVJ-E virus while the cytoplasmic fragments were neutralized. Embryos were cultured in single-step culture. Statistical differences were evaluated using the Shapiro-Wilk test followed by the Student’s t-test. Main results and the role of chance Participants had a mean age of 39 years and produced, on average, 9.6 mature oocytes . Following spindle or pronuclear transfer, 88.4% of oocytes were successfully fertilized. 97.2% of the embryos reached the 8-cell stage on day 3 on pronuclear transfer and 94.2% for meiotic spindle transfer, 55.7% reached the blastocyst stage (AA, AB, BA, BB quality on day 5/6) for pronuclear transfer and 52.5% reached blastocyst stage as following morphological qualities for meiotic spindle transfer.(p < 0.05 in all cases). PGT-A revealed a 60.3% euploidy rate for meiotic spindle transfer and 56.9% for pro nuclear transfer. Remarkably, 59.6% of these patients achieved clinical pregnancy from pro nuclear transfer and 52.2% of patients achieved clinical pregnancy from meiotic spindle transfer for following FET, 60% had an ongoing pregnancy for pro nuclear transfer and 55% for meiotic spindle transfer. 44% achieved a live birth after 37 weeks’ gestation for pro nuclear transfer and 40% achieved a live birth after 37 weeks‘ gestation for meiotic spindle transfer. All cases confirmed with matched nuclear DNA with source of nuclear DNA from recipiend and mitochondrial DNA match rate found avarage 89,51% with donor-recipient match. Heteroplasmy rate was avarage 9,21% for all cases. Limitations, reasons for caution While pronuclear transfer has minimal risks of micromanipulation compared to spindle transfer, neonatal testing is recommended to screen for any potential genetic and morphologic abnormalities. Larger prospective studies are needed to validate these findings, explore epigenetic alterations, and confirm long-term safety. Wider implications of the findings This study underscores the potential of spindle and pronuclear transfer to achieve competent euploid embryos and live births in DOR patients who exploited conventional IVF options. DOR patients will be able to maintain genetic bonds and physical characteristics with their children, avoiding social stigmas and potential legal issues. Trial registration number Yes