Donor side effects experienced under minimal controlled ovarian stimulation (COS) with in vitro maturation (IVM) versus conventional COS for in vitro fertilization (IVF) treatment

Objective: To evaluate how minimal controlled ovarian stimulation (COS) for in vitro maturation (IVM) affects subjects' oocyte retrieval experiences compared to conventional COS, considering side effects Design: Retrospective Survey Study Setting: Clinical in vitro fertilization (IVF) treatment centers in Spain and the United States. Subjects: Data were collected from subjects undergoing minimal COS (n=110; 600-800 IU FSH) for IVM and conventional COS for egg donation (n=48; 2000-3000 IU FSH) from April 2022 to November 2023. In the same period, a pairwise comparison of subjects (n=13) undergoing both minimal COS for IVM and conventional COS for oocyte cryopreservation was conducted. Intervention/Exposure: Minimal and conventional controlled ovarian stimulation. Main Outcome Measures: The most common side effects suffered during ovarian stimulation and after OPU, satisfaction level, and the likelihood of recommending or repeating minimal or conventional COS. Statistical analysis included Mann Whitney, Wilcoxon, Chi-square, and McNemar tests, with a significance level set at p<0.05. Results: During minimal COS, most subjects did not experience breast swelling (86%), pelvic or abdominal pain (76%), nausea or vomiting (96%), and bleeding (96%). After oocyte pick-up, the majority (75%) reported no pelvic or abdominal pain. The most common side effect was abdominal swelling (52%). Compared to conventional COS cycles, minimal COS subjects reported significantly less post-retrieval pain, with 33% experiencing no pain (vs. 6%; p=0.0011) and with a reduced severe level of pain (5% vs.19%; p=0.0097), leading to fewer subjects requiring pain medication (25% vs. 54%; p=0.0003). Additionally, 85% of women were very satisfied with minimal stimulation and would recommend or repeat the treatment. In the comparison in which each donor underwent both minimal and conventional COS treatments, women indicated more side effects with the conventional stimulation, presenting a significantly overall higher level of pain (p=0.0078). Conclusion: Reducing the hormonal dose for ovarian stimulation has a beneficial effect on subjects, suggesting the combination of minimal COS with IVM techniques is a well-tolerated alternative for women who cannot or do not wish to undergo conventional controlled ovarian hyperstimulation. ### Competing Interest Statement Disclosure Statement: A.G., B.P., T.S., C.C.K., F.B., M.M., S.P., and M.-J.F.-G. are shareholders in the for-profit biotechnology company Gameto Inc. C.C.K., S.P., M.M., A.G., B.P., are listed on a patent covering the use of OSCs for IVM: U.S. Provisional Patent Application No. 63/492,210. Additionally, C.C.K. is listed on three patents covering the use of OSCs for IVM: U.S. Patent Application No. 17/846,725, U.S Patent Application No. 17/846,845, and International Patent Application No.: PCT/ US2023/026012. C.C.K., is additionally listed on three patents for the transcription factor-directed production of granulosa-like cells from stem cells: International Patent Application No.: PCT/US2023/065140, U.S. Provisional Application No. 63/ 326,640, and U.S. Provisional Application No. 63/444,108. The remaining authors have no conflicts of interest to declare. ### Funding Statement Funding Statement: This work was funded by the for-profit entity Gameto Inc. and no other grant or funding agency. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data was retrospectively collected from research subjects who underwent minimal COS or conventional COS between April 2022 and November 2023 at Ruber Juan Bravo University Hospital, Eugin Group (Madrid, Spain), Spring Fertility (New York, USA), and Extend Fertility (New York, USA) with informed consent and ethical approval from CNRHA 47/428973.9/22 (Spain) and Western IRB No. 20225832 (USA), respectively. This research adhered to the ethical principles outlined in the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Sharing Statement: All data needed to evaluate the conclusions in the paper are present in the paper and supplementary tables and figures.