In vitro maturation without gonadotropins versus in vitro fertilization with hyperstimulation in women with polycystic ovary syndrome: a non-inferiority randomized controlled trial

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.

Is early-follicular long-acting GnRH agonist protocol an alternative for patients with polycystic ovary syndrome undergoing in vitro fertilization?

“…A previous study found that in fresh transplantation cycles of patients with PCOS, the number of oocytes retrieved (17.49 ± 7.17 vs. 12.85 ± 7.26) and the clinical pregnancy rate (53.92% vs. 40.00%) were significantly increased in EFLL compared with the GnRH antagonist protocol, and there was no significant difference in the incidence of OHSS [ 10 ]. The incidence of moderate to severe OHSS was not statistically different between two groups in our study, but it was significantly lower than that in previously published studies [ 11 – 14 ]. These results suggest that PCOS patients who undergo EFLL have more chances to transfer a fresh embryo and a higher pregnancy rate without increasing the occurrence of OHSS, and the time to reach pregnancy is shortened.…”

Rescue in vitro maturation may increase the pregnancy outcomes among women undergoing intracytoplasmic sperm injection

“…Our study showed that women undergoing ICSI with R-IVM had an increased chance of clinical pregnancy and cumulative live birth. Inconsistent with our results, a few observational studies found that cumulative rates of clinical pregnancy and live birth were significantly lower in the IVM group compared with the standard ICSI group ( 19 , 20 , 37 ). The inconsistency may be related to the differences in the study population.…”

False allegations cannot go unchallenged: an appeal to shield researchers from dubious methods and ambiguous motives

“…Rebuttal: Our two trials (9,10) reported the mean, not the median (Figure 1). The two trials enrolled comparable women for age (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) and BMI (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), expecting to result in similar means and standard deviations (SD). The two trials reported the midpoint confidence interval (CI), not SD (11,12).…”

“…Meanwhile, I urge Professor Mol to practice what he preaches and make the data sets I have raised concerns about available for examination by the independent expert who investigated my research. I would also urge him to make the data sets about which others have voiced concerns on PubPeer available for public assessment (27)(28)(29)(30)(31)(32)(33). Lastly, I have urged our team and other relevant individuals to reserve our rights against any defamatory reporting regarding our team.…”