IVM: What are the RCTs Telling Us So Far?

Abstract

Background: In Vitro Maturation (IVM) is a Assisted Reproduction Technology (ART) widely applied in livestock breeding, first attempted in human in the early nineties. While very successful in animals, the IVM technology has so-far not been widely adopted in human ART. The variation in IVM applications are mainly based on the use of gonadotrophins (FSH and/or HCG-trigger before oocyte collection) by the patient. The choice of the laboratory IVM protocols is dictated by the clinical preparation of the patient for oocyte pick-up. In this lecture the use of GV oocytes from fully stimulated cycles (“rescue IVM”) will not be considered. Aim: Summarize the learning from published clinical IVM studies in human from recent years, with a focus on the few randomized control trials (RCT). Method: Review by Pubmed search. Results: So far, the use of HCG administration before oocyte retrieval has been used by most ART centers, which adopted IVM (often in combination with few days of FSH, which makes it a ‘truncated IVF’). The largest series of latter kind (in 921 PCOS patients was reported by Ho et al. 2018) and yielded a 33.4% cumulative live birth rate over 12 months after 1 cycle. However available Cochrane review found no conclusive evidence for a positive role of HCG on number of retrieved or matured oocytes, nor on clinical outcome results. The role of FSH priming is proven in animal IVM studies, but clinically yet unproven in human IVM. The latest studies from Vuong L et al. (2020) applied as low as 150 IU HP-HMG for 2 days to aspirate a sufficient number of cumulus oocyte complexes (COC; 42 hours after the last FSH dose) to vitrify sufficient embryos of excellent quality for deferred transfer. A next RCTs in 351 PCOS patients was announced to evaluate the clinical requirement of FSH (Zheng X et al., 2020), however those results are still not published. Recent clinical data focused on the use of biphasic IVM culture systems in order to be capable of maturing COC from follicles smaller than 6 mm. After minimal FSH (300 IU total dose) and omission of HCG the large majority (>80%) of compacted COC are aspirated from smaller than 6 mm follicles (Sanchez et al., 2019). Using the biphasic IVM culture principle (called ‘capacitation IVM’) several RCTs have been conducted to prove its superiority over ‘standard IVM’ in PCOS and ovarian tissue COC onco-fertility practice (Vuong L et al., 2020; Kirilova A et al., 2021). The CAPA-IVM culture method showed its potential compared to classical IVF standard of care in PCOM patients in a large non-inferiority RCT (546 patients): live birth rate after the first deferred transfer after Capa-IVM was 35% and conventional IVF 43%. After having observed low clinical pregnancies after non-HCG IVM (DeVos et al., 2011; Walls et al., 2015), additional small RCTs have confirmed the advantage of frozen vs fresh embryo transfer after CAPA-IVM (Vuong et al., 2021). Conclusion: Recent developments of IVM have been validated in few RCTs and IVM has been recently declared non-experimental after an extensive analysis of currently available data (ASRM Opinion paper published in 2021). The development of adequate culture media improves developmental capacity prior to meiotic maturation and brings the clinical results very close to the level of conventional IVF. The improved safety, the hugely simplified clinical approach and reduced cost structure could enhance access to ART across the globe for economically defavorised infertile couples.