Xiaoying Zheng1,2,3,4,5, Wei Guo1,2,3,4, Lin Zeng6, Danni Zheng1,2,3,4, Shuo Yang1,2,3,4, Yalan Xu1,2,3,4, Lina Wang1,2,3,4, Rui Wang7, Ben Willem Mol7,8, Rong Li1,2,3,4, Jie Qiao1,2,3,4,5. 1. Department of Obstetrics and Gynecology, Centre for Reproductive Medicine, Peking University Third Hospital, Beijing, China. 2. National Clinical Research Centre for Obstetrics and Gynecology, Beijing, China. 3. Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China. 4. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. 5. Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China. 6. Research Centre of Clinical Epidemiology, Peking University Third Hospital, Beijing, China. 7. Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia. 8. Aberdeen Centre for Women's Health Research, School of Medicine, University of Aberdeen, Aberdeen, UK.
Abstract
STUDY QUESTION: Does in vitro maturation (IVM) result in non-inferior cumulative live birth rates compared to those after standard in vitro fertilization (IVF) in infertile women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: One cycle of IVM, without any stimulation, was inferior to one cycle of standard IVF in women with PCOS in terms of 6-month cumulative live birth rates, when choosing single vitrified-warmed blastocyst transfer. WHAT IS KNOWN ALREADY: IVM is an emerging alternative treatment for women with PCOS who need assisted reproductive technology. Since a minimal or even zero dose of gonadotropins are required in the IVM procedure, the occurrence of ovarian hyperstimulation syndrome (OHSS) is eliminated. Only one clinical trial comparing the pregnancy outcome between IVM with FSH priming and IVF has been reported. However, it is still unknown whether IVM treatment without any stimulation can offer a similar live birth outcome in women with PCOS as compared to that in women receiving the standard IVF procedure with ovarian stimulation. STUDY DESIGN, SIZE, DURATION: This single-centre, open-label randomized controlled non-inferiority trial in an academic infertility centre in China was performed between March 2018 and July 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 20-38 years with PCOS and infertility scheduled for their first IVF attempt were eligible. In total, 351 women were randomly allocated to receive one cycle of unstimulated IVM (n = 175) or one cycle of standard IVF with a flexible GnRH antagonist protocol and hCG as ovulatory trigger (n = 176). A freeze-all and single blastocyst transfer strategy was used in both groups. The primary outcome was ongoing pregnancy (leading to live birth) within 6 months after randomization. A non-inferiority margin of 15% was considered. MAIN RESULTS AND THE ROLE OF CHANCE: The IVM procedure without additional gonadotropin resulted in a lower ongoing pregnancy (leading to live birth) within 6 months after randomization compared to standard IVF treatment (22.3% vs. 50.6%; rate difference -28.3%; 95% confidence interval [CI]: -37.9% to -18.7%). Moderate-severe OHSS did not occur in the IVM group, while in the IVF group, ten women (5.7%) had moderate OHSS and one woman (0.6%) had severe OHSS. There was no statistically significant difference in the occurrence of obstetric and perinatal complications. LIMITATIONS, REASONS FOR CAUTION: The trial was conducted using an IVM protocol without additional stimulation in a single centre, which may limit its generalizability. In addition, a GnRH agonist trigger rather than hCG for IVF stimulation in women with PCOS would be more consistent with current clinical practice. WIDER IMPLICATIONS OF THE FINDINGS: Although IVM is considered to be a convenient, inexpensive and safe alternative to IVF for women with PCOS, our results indicated that one cycle of IVM without any stimulation was inferior to one cycle of standard IVF in terms of the cumulative live birth rate. The inferiority of IVM without ovarian stimulation could be mainly due to the limitations in the developmental potential of embryos. Further IVM development should be tested and validated in a freeze-only and blastocyst transfer setting. Further RCTs are needed to evaluate the effectiveness and safety of other IVM protocols or multiple cycles of IVM compared to IVF. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2016YFC1000201 and 2018YFC1002104) and the National Science Foundation of China (81730038). B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). All other authors declare no competing interests. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT03463772. TRIAL REGISTRATION DATE: 29 January 2018. DATE OF FIRST PATIENT’S ENROLMENT: 16 March 2018.
STUDY QUESTION: Does in vitro maturation (IVM) result in non-inferior cumulative live birth rates compared to those after standard in vitro fertilization (IVF) in infertile women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: One cycle of IVM, without any stimulation, was inferior to one cycle of standard IVF in women with PCOS in terms of 6-month cumulative live birth rates, when choosing single vitrified-warmed blastocyst transfer. WHAT IS KNOWN ALREADY: IVM is an emerging alternative treatment for women with PCOS who need assisted reproductive technology. Since a minimal or even zero dose of gonadotropins are required in the IVM procedure, the occurrence of ovarian hyperstimulation syndrome (OHSS) is eliminated. Only one clinical trial comparing the pregnancy outcome between IVM with FSH priming and IVF has been reported. However, it is still unknown whether IVM treatment without any stimulation can offer a similar live birth outcome in women with PCOS as compared to that in women receiving the standard IVF procedure with ovarian stimulation. STUDY DESIGN, SIZE, DURATION: This single-centre, open-label randomized controlled non-inferiority trial in an academic infertility centre in China was performed between March 2018 and July 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 20-38 years with PCOS and infertility scheduled for their first IVF attempt were eligible. In total, 351 women were randomly allocated to receive one cycle of unstimulated IVM (n = 175) or one cycle of standard IVF with a flexible GnRH antagonist protocol and hCG as ovulatory trigger (n = 176). A freeze-all and single blastocyst transfer strategy was used in both groups. The primary outcome was ongoing pregnancy (leading to live birth) within 6 months after randomization. A non-inferiority margin of 15% was considered. MAIN RESULTS AND THE ROLE OF CHANCE: The IVM procedure without additional gonadotropin resulted in a lower ongoing pregnancy (leading to live birth) within 6 months after randomization compared to standard IVF treatment (22.3% vs. 50.6%; rate difference -28.3%; 95% confidence interval [CI]: -37.9% to -18.7%). Moderate-severe OHSS did not occur in the IVM group, while in the IVF group, ten women (5.7%) had moderate OHSS and one woman (0.6%) had severe OHSS. There was no statistically significant difference in the occurrence of obstetric and perinatal complications. LIMITATIONS, REASONS FOR CAUTION: The trial was conducted using an IVM protocol without additional stimulation in a single centre, which may limit its generalizability. In addition, a GnRH agonist trigger rather than hCG for IVF stimulation in women with PCOS would be more consistent with current clinical practice. WIDER IMPLICATIONS OF THE FINDINGS: Although IVM is considered to be a convenient, inexpensive and safe alternative to IVF for women with PCOS, our results indicated that one cycle of IVM without any stimulation was inferior to one cycle of standard IVF in terms of the cumulative live birth rate. The inferiority of IVM without ovarian stimulation could be mainly due to the limitations in the developmental potential of embryos. Further IVM development should be tested and validated in a freeze-only and blastocyst transfer setting. Further RCTs are needed to evaluate the effectiveness and safety of other IVM protocols or multiple cycles of IVM compared to IVF. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2016YFC1000201 and 2018YFC1002104) and the National Science Foundation of China (81730038). B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). All other authors declare no competing interests. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT03463772. TRIAL REGISTRATION DATE: 29 January 2018. DATE OF FIRST PATIENT’S ENROLMENT: 16 March 2018.
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