**7. Clinical application and safety of IVM**

At present, the in vitro maturation rate of immature human oocytes can reach 70%, but the developmental potential of mature oocytes obtained in vitro is still lower than that of mature oocytes obtained in vivo. In addition, the rate of blastocyst development and the rate of implantation are relatively low after the fertilization of IVM oocytes. The main reason of such discrepancy may be related to non-synchronized nuclear and cytoplasmic maturation during IVM. With the further development in the basic and clinical research of IVM, the in-depth study on the mechanisms of oocyte maturation and mastery of key factors involved in oocyte maturation will contribute to the improvement and optimization of clinical IVM technology.

The results of current research showed that human oocytes matured in vivo or in vitro display no significant differences in terms of their spindle morphology, organelle distribution, cortical particle distribution, and mitochondrial morphology [38, 39]. By observing embryos dynamically using time-lapse videos, it was confirmed that oocytes matured in vivo or in vitro showed no significant differences in terms of the morphological dynamics observed during the early development of embryos derived from these oocytes [40]. Another study has also shown that the oocytes matured in vitro and in vivo are different in terms of their organelle function, distribution, and gene expression [41]. The different experimental conclusions mentioned above may be caused by different sources and quality of oocytes used in these studies. Therefore, attention should be paid to clarify the IVM efficiency of oocytes retrieved from different sources, so as to reasonably evaluate the safety of IVM. In terms of epigenetics, a study has reported that IVM exerts no significant effect on the methylation level of maternal imprinted genes, such as

LIT1, SNRPN, PEG3, and GTL2, in human oocytes [42]. After an imprinted gene examination was carried out for infant chorionic cells and cord blood obtained from IVM and a standard stimulation protocol, no significant difference was observed between the two methods [43, 44]. Currently, the follow-up of IVM-aided pregnancies shows that the IVM technique does not increase the risk of pregnancy, the rate of maternal complications, and the rate of neonatal abnormalities [45, 46]. However, due to a small sample size and the lack of in-depth study on epigenetics, the clinical application and safety of IVM still require investigations of large sample sizes to reach a definitive conclusion regarding the safety of IVM in terms of epigenetics.

At present, more than 5000 IVM babies have been born worldwide, and the rate of clinical pregnancy among PCOS patients undergoing IVM treatment can reach about 35–40% [47]. IVM has been extended from the basic research to the treatment of patients with PCOS, ovarian hyperresponsiveness and hyporesponsiveness, as well as cancer patients to preserve the fertility. Therefore, IVM has a prospect of broad applications.
