Return rates for the use of ovarian tissue cryopreserved prior to gonadotoxic treatment as fertility preservation: a systematic review.

study questionWhat is the return rate for the use of ovarian tissue cryopreserved for fertility preservation prior to gonadotoxic treatment? SUMMARY ANSWER: The return rate for the use of ovarian tissue cryopreserved for fertility preservation prior to gonadotoxic treatment is modest, with most studies reporting rates of ≤5%. WHAT IS KNOWN ALREADY: A considerable number of years have passed since ovarian tissue cryopreservation (OTC) was first implemented for fertility preservation, and many studies now provide long-term follow-up data, including return rates. This allows for a more comprehensive evaluation of OTC as a fertility preservation option and of the characteristics of the population to whom it is offered. STUDY DESIGN SIZE DURATION: We searched PubMed, EMBASE, and the Cochrane Library for MeSH words, Emtree terms, and text words related to return rates for the use of ovarian tissue cryopreserved prior to gonadotoxic treatment up to March 2025, in the English language. There were no limitations regarding the year of publication. PARTICIPANTS/MATERIALS SETTING

methodsEach study was screened independently by two reviewers who were blinded to each other's choices. We included studies reporting the proportion of women who returned for autologous ovarian tissue transplantation (AOTT) among those who had undergone OTC. We excluded studies in languages other than English, abstracts without full text, letters to the editor, and case series involving fewer than 25 females undergoing OTC. Risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Cohort Studies. The overall certainty of evidence was assessed using GRADE (grading of recommendations, assessment, development, and evaluation). MAIN RESULTS AND THE ROLE OF CHANCE: Out of 2748 studies, 25 were included in the review. All studies were cohort studies that included from 26 to 2475 participants. Of the 25 studies, 18 reported a return rate of ≤5%, 6 reported a return rate of >5 to ≤10% while only 1 study reported a return rate of 14%. The overall quality of the studies in reporting the return rate for the use of cryopreserved ovarian tissue, as assessed using GRADE, was moderate. LIMITATIONS REASONS FOR CAUTION: In most studies, follow-up occurred within the overall study period, and only one study reported a minimum follow-up duration. Since AOTT may occur several years after OTC, limited follow-up time may bias the results. Most studies included both pediatric patients and adults undergoing OTC, without accounting for participants who had not yet reached reproductive age or desired pregnancy when calculating return rates at the end of follow-up. WIDER IMPLICATIONS OF THE

findingsThe modest utilization rates found in this study emphasize the need for careful consideration to avoid subjecting women to potentially unnecessary and costly treatment. This highlights the need for future studies with longer follow-up time to assess patterns of tissue utilization in relation to diagnosis, treatment protocol, and age, thereby setting criteria in the selection of patients who would actually benefit from OTC. STUDY FUNDING/COMPETING INTERESTS: The study is funded by the independent research fund Denmark (Grant ID 10.46540/4308-00130B). A.P. has received grants (payment to institution) and consultancy fees from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, Cryos; honoraria from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, and Organon; and support for attending meetings and/or travel (payment to institution) from Gedeon Richter. These companies had no role in the study. The remaining authors have no conflicts or interests to declare. REGISTRATION NUMBER: The study is registered in PROSPERO, ID number CRD42024537107.