Livebirth rate after one frozen embryo transfer in ovulatory women starting with natural, modified natural, or artificial endometrial preparation in Viet Nam: an open-label randomised controlled trial.

BACKGROUND: Use of frozen embryo transfer (FET) in in-vitro fertilisation (IVF) has increased. However, the best endometrial preparation protocol for FET cycles is unclear. We compared natural and modified natural cycle strategies with an artificial cycle strategy for endometrial preparation before FET. METHODS: In this randomised, open-label study, we recruited ovulatory women aged 18-45 years at a hospital in Ho Chi Minh City, Viet Nam, who were randomly allocated (1:1:1) to natural, modified natural, or artificial cycle endometrial preparation using a computer-generated random list and block randomisation. The trial was not masked due to the nature of the study interventions. In natural cycles, no oestrogen, progesterone, or human chorionic gonadotropin (hCG) was used. In modified natural cycles, hCG was used to trigger ovulation. In artificial cycles, oral oestradiol valerate (8 mg/day from day 2-4 of menstruation) and vaginal progesterone (800 mg/day starting when endometrial thickness was ≥7 mm) were used. Embryos were vitrified, and then one or two day-3 embryos or one day-5 embryo were warmed and transferred under ultrasound guidance. If the first FET cycle was cancelled, subsequent cycles were performed with artificial endometrial preparation. The primary endpoint was livebirth after one FET. This trial is registered at ClinicalTrials.gov, NCT04804020. FINDINGS: Between March 22, 2021, and March 14, 2023, 4779 women were screened and 1428 were randomly assigned (476 to each group). 99 first FET cycles were cancelled in each of the natural and modified cycle groups, versus none in the artificial cycle group. The livebirth rate after one FET was 174 (37%) of 476 in the natural cycle strategy group, 159 (33%) of 476 in the modified natural cycle strategy group, and 162 (34%) of 476 in the artificial cycle strategy group (relative risk 1·07 [95% CI 0·87-1·33] for natural vs artificial cycle strategy, and 0·98 [0·79-1·22] for modified natural vs artificial cycle strategy). Maternal and neonatal outcomes did not differ significantly between groups, as the power to detect small differences was low. INTERPRETATION: Although the livebirth rate was similar after natural, modified natural, and artificial cycle endometrial preparation strategies in ovulatory women undergoing FET IVF, no definitive conclusions can be made regarding the comparative safety of the three approaches. FUNDING: None.

Developmental outcomes of children born through ICSI versus conventional IVF (cIVF) in couples with non-male factor infertility.

STUDY QUESTION: In non-male factor infertile couples, are there any differences in the developmental outcomes between children born through ICSI and conventional IVF (cIVF)? SUMMARY ANSWER: In this preliminary study, ICSI and cIVF seem to have a comparable effect on developmental outcomes after 12 months in children born to non-male factor infertile couples. WHAT IS KNOWN ALREADY: ICSI, an invasive technique, has raised concerns about potential developmental abnormalities in children. Limited data are available regarding the developmental outcomes of ICSI-conceived infants born to non-male factor infertile couples. STUDY DESIGN, SIZE, DURATION: This prospective cohort study involved a follow-up of all children aged 12 months or older who were born from pregnancies resulting from either ICSI or cIVF as part of a previous randomized controlled trial (RCT) (NCT03428919). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the original RCT, 1064 women were randomly assigned to the ICSI or cIVF groups (532 women for each group). Follow-up was conducted with 155 couples (195 children) in the ICSI group and 141 couples (185 children) in the cIVF group. The Vietnamese version of the Ages & Stages Third Edition Questionnaires (ASQ-3) and the Development Red Flags questionnaires were completed by the participants. A total of 141 (90.1%) women (177 children) in the ICSI group and 113 (80.1%) women (145 children) in the cIVF group returned fully completed questionnaires. The primary outcomes were the developmental outcomes based on responses to the ASQ-3 and the Red Flags questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age of children at follow-up was 19.5 ± 5.0 months in the ICSI group and 19.3 ± 5.5 months in the cIVF group. The mean height and weight of children in both groups were similar. The overall proportion of children with any abnormal ASQ-3 score did not differ significantly between the ICSI and cIVF groups (16.9% vs 13.1%, P = 0.34). The proportion of children with Red Flag signs was also comparable between the two groups (6.2% vs 9.2%, P = 0.36, ICSI vs cIVF, respectively). LIMITATIONS, REASONS FOR CAUTION: Despite a reasonably high follow-up response rate, there is a potential risk of sampling bias, and overall, the number of children with developmental abnormalities was very small. The study relied solely on questionnaires as screening tools, rather than incorporating additional behavioral observations or physical developmental tests; this may have affected the statistical power and the significance of between-group comparisons. WIDER IMPLICATIONS OF THE FINDINGS: The current findings contribute to the existing evidence and support the comparative safety of ICSI and cIVF regarding early childhood development. However, more extensive and prolonged follow-up data for these children are needed to draw definitive conclusions. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study, and no authors reported conflicting interests. TRIAL REGISTRATION NUMBER: NCT04866524 (clinicaltrials.gov).

Clinical factors associated with unexpected poor or suboptimal response in Poseidon criteria patients.

RESEARCH QUESTION: What clinical factors are associated with 'unexpected' poor or suboptimal responses to IVF ovarian stimulation per POSEIDON's criteria, and which AMH and AFC threshold values distinguish this population? DESIGN: Tri-centre retrospective cohort study (2015-2017) involving first-time IVF and ICSI cycles with conventional ovarian stimulation (≥150 IU/day of FSH). Eligibility criteria included sufficient ovarian reserve markers according to POSEIDON's classification (AMH ≥1.2 ng/ml; AFC ≥5). Ovarian response categories were poor (<4 oocytes), suboptimal (4-9 oocytes) and normal (≥9 oocytes). Primary outcomes included clinical factors associated with an unexpected poor or suboptimal response to conventional ovarian stimulation using logistic regression analyses, and the threshold values of AMH and AFC predicting increased risk of such responses using ROC curves. RESULTS: A total of 7625 patients met the inclusion criteria: 204 (9.3%) were poor and 1998 (90.7%) were suboptimal responders. Logistic regression identified significant clinical predictors for a poor or suboptimal response, including AFC, AMH, total gonadotrophin dose, gonadotrophin type and trigger type (P ≤ 0.02). The ROC curves indicated that AMH 2.87 ng/ml (AUC 0.740) and AFC 12 (AUC 0.826) were the threshold values predicting a poor or suboptimal response; AMH 2.17 ng/ml (AUC 0.741) and AFC 9 (AUC 0.835) predicted a poor response; and AMH 2.97 ng/ml (AUC 0.722) and AFC 12 (AUC 0.801) predicted a suboptimal response. CONCLUSIONS: The threshold values of AMH and AFC predicting 'unexpected' poor or suboptimal response were higher than expected. These findings have critical implications for tailoring IVF stimulation regimens and dosages.

An update on the current indications for in vitro maturation.

PURPOSE OF REVIEW: In vitro maturation has become a significant component of modern assisted reproductive techniques. Published data have been supported for the safety and effectiveness of in vitro maturation treatment. In recent years, potential indications for in vitro maturation (IVM) have been a topic of interest and investigation. RECENT FINDINGS: Significant improvements in technique enhancement and data publication for evaluating the efficacy of IVM have been achieved. Recent studies have shown that IVM could offer several advantages over in vitro fertilization. Currently, there are growing indications for IVM beyond the commonly mentioned indication of infertile women with polycystic ovary syndrome. Additionally, some potential candidates might have significant advantages for IVM, such as women diagnosed with gonadotropin resistance ovary syndrome or those seeking fertility preservation. With a better understanding of IVM, from basic science to clinical practice, it can be applied safely, effectively, and affordably to a broader range of patients, making it a more accessible and patient-friendly option. SUMMARY: Despite the possibly acknowledged limitations, the potential of in vitro maturation cannot be denied. As this technique becomes increasingly accessible to patients and more continuous efforts are dedicated to advancing this technique, the impact of in vitro maturation is expected.

Significance of serum AMH and antral follicle count discrepancy for the prediction of ovarian stimulation response in Poseidon criteria patients.

PURPOSE: To determine the risk of not being a poor responder in ovarian stimulation (OS) for in vitro fertilization (IVF) when ovarian reserve markers are discordant-one falling within Poseidon's criteria normal range (e.g., anti-Müllerian hormone (AMH) ≥ 1.2 ng/mL or antral follicle count (AFC) ≥ 5), and the other in the poor ovarian reserve range. METHODS: A tri-center retrospective cohort study (2015-2017) involving women with discordant AMH and AFC values undergoing their first IVF/ICSI cycle using conventional OS (cOS, ≥ 150 IU/day of follicle-stimulating hormone). Discordant serum AMH and AFC values were defined according to Poseidon's criteria (AMH < 1.2 ng/mL and AFC ≥ 5 or AMH ≥ 1.2 ng/mL and AFC < 5). Poor ovarian response (POR) was < 4 retrieved oocytes. Receiver operating characteristic (ROC) curves were used to determine AMH and AFC cut-offs for non-POR. Logistic regression analysis evaluated factors associated with non-POR. RESULTS: Out of 8797 patients who underwent assessment with both AMH and AFC, 1172 (13.3%) exhibited discordant values. Of these, 854 (72.9%) had ≥ 4 oocytes retrieved. Within this group, 726 (85.0%) had "low" AMH values, whereas 128 (15.0%) had "low" AFCs. An AFC of 6 had 77% sensitivity and 52% specificity (AUC = 0.700), while AMH of 1.19 ng/mL had 31% sensitivity and 85% specificity (AUC = 0.492) for non-POR. AFC and the use of recombinant gonadotropins were positive predictors of non-POR. CONCLUSIONS: When serum AMH is < 1.19 ng/mL, but AFC is ≥ 6, there is a moderate likelihood of a non-POR during stimulation. Conversely, if AFC is < 5 but serum AMH is ≥ 1.19 ng/mL, the chances of non-POR are low. Among patients with discordant markers, AFC emerges as the primary predictor of oocyte yield.

Effect of single versus grouped culture of human cumulus-oocyte complexes in PCOS women treated with biphasic in vitro maturation: A sibling oocyte pilot study.

Purpose: This study investigated the differences in the maturation rate of single versus grouped cumulus-oocyte complexes (COCs) culture methods for capacitation in vitro maturation (CAPA-IVM) in women with polycystic ovary syndrome (PCOS). Methods: This study was performed at My Duc Phu Nhuan Hospital, Vietnam from October 1, 2020 to October 24, 2021. Women aged 18-37 years with a diagnosis of PCOS were recruited. COCs from each woman were randomly divided into two groups: single or grouped culture during CAPA-IVM culture. The primary outcome was the maturation rate. Results: A total of 322 COCs from 15 eligible women included were randomly assigned to the two study groups. The maturation rate was comparable between the single and grouped culture groups (61.3% vs. 64.8%; p = 0.56). There were no significant differences in the number of 2-pronuclei fertilized oocytes, number of day-3 embryos, and number of good-quality embryos in the two culture method groups. In the single culture group, COCs morphology was associated with the day-3 embryo formation rate but not the maturation rate. Conclusions: Comparable oocyte maturation and embryology outcomes between single and grouped COCs culture utilizing sibling COCs derived from women with PCOS suggest the feasibility of both methods for CAPA-IVM culture.

Development of children born to women with twin pregnancies treated with cervical pessary or vaginal progesterone: Follow-up of a randomized controlled trial.

INTRODUCTION: Preterm birth is the most common cause of neonatal morbidity and mortality. Women with twin pregnancies and a short cervical length are at high risk for preterm birth. Vaginal progesterone and cervical pessary have been proposed as potential strategies to reduce preterm birth in this high-risk population. Therefore, we aimed to compare the effectiveness of cervical pessary and vaginal progesterone in improving developmental outcomes of children born to women with twin pregnancies and mid-trimester short cervical length. MATERIAL AND METHODS: This was a follow-up study (NCT04295187) of all children at 24 months of age, born from women treated with cervical pessary or progesterone to prevent preterm birth in a randomized controlled trial (NCT02623881). We used a validated Vietnamese version of Ages & Stages Third Edition Questionnaires (ASQ-3) and a red flag questionnaire. In surviving children, we compared the mean ASQ-3 scores, abnormal ASQ-3 scores, the number of children with any abnormal ASQ-3 scores and red flag signs between the two groups. We reported the composite outcome of perinatal death or survival with any abnormal ASQ-3 score in offspring. These outcomes were also calculated in a subgroup of women with a cervical length ≤28 mm (<25th percentile). RESULTS: In the original randomized controlled trial, we randomized 300 women to pessary or progesterone. After counting the number of perinatal deaths and lost to follow-up, 82.8% parents in the pessary group and 82.5% parents in progesterone group returned the questionnaire. The mean ASQ-3 scores of the five skills and red flag signs did not differ significantly between the two groups. However, the percentage of children having abnormal ASQ-3 scores in fine motor skills was significantly lower in the progesterone group (6.1% vs 1.3%, P = 0.01). There were no significant differences in the composite outcome of perinatal death or survival with any abnormal ASQ-3 score in unselected women and in those with cervical length ≤28 mm. CONCLUSIONS: Cervical pessary and vaginal progesterone may have comparable effects on developmental outcomes in children at ≥24 months of age, born to women with twin pregnancies and short cervical length. However, this finding could be likely due to a lack of study power.

Cumulative live birth rate after oocyte in vitro maturation with a pre-maturation step in women with polycystic ovary syndrome or high antral follicle count.

PURPOSE: This study evaluated the 24-month cumulative live birth rate (CLBR) for women with polycystic ovary syndrome (PCOS) or high antral follicle count (AFC) who underwent oocyte in vitro maturation (IVM) with pre-maturation step (CAPA-IVM). METHODS: This multicenter, retrospective study was performed at IVFMD, My Duc Hospital, and IVFMD Phu Nhuan, My Duc Phu Nhuan Hospital from 1 January 2017 to 31 December 2019. All women with PCOS or high AFC treated with a CAPA-IVM cycle were included. Cumulative live birth was defined as at least one live birth resulting from the initiated CAPA-IVM cycle. Where a woman did not return for embryo transfer, outcomes were followed up until 24 months from the day of oocyte aspiration. Logistic regression was performed to identify factors predicting the CLBR. RESULTS: Data from 374 women were analyzed, 368 of whom had embryos for transfer (98.4%), and six had no embryos for transfer (1.6%). The oocyte maturation rate was 63.2%. The median number of frozen embryos was 4 [quartile 1, 2; quartile 3, 6]. Cumulative clinical pregnancy and ongoing pregnancy rates were 60.4% and 43.6%, respectively. At 24 months after starting CAPA-IVM treatment, the CLBR was 38.5%. Multivariate analysis showed that patient age and number of frozen embryos were significant predictors of cumulative live birth after CAPA-IVM. CONCLUSIONS: CAPA-IVM could be considered as an alternative to in vitro fertilization for the management of infertility in women with PCOS or a high AFC who require assisted reproductive technology.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation in couples with infertility in whom the male partner has normal total sperm count and motility: an open-label, randomised controlled trial.

BACKGROUND: The use of intracytoplasmic sperm injection has increased substantially worldwide, primarily in couples with non-male factor infertility. However, there is a paucity of evidence from randomised trials supporting this approach compared with conventional in-vitro fertilisation (IVF). We aimed to investigate whether intracytoplasmic sperm injection would result in a higher livebirth rate compared with conventional IVF. METHODS: This open-label, multicentre, randomised trial was done at two IVF centres in Ho Chi Minh City, Vietnam (IVFMD, My Duc Hospital and IVFAS, An Sinh Hospital). Eligible couples were aged at least 18 years and the male partner's sperm count and motility (progressive motility) were normal based on WHO 2010 criteria. Couples had to have undergone two or fewer previous conventional IVF or intracytoplasmic sperm injection attempts, have used an antagonist protocol for ovarian stimulation, and agree to have two or fewer embryos transferred. Couples were randomly assigned (1:1) to undergo either intracytoplasmic sperm injection or conventional IVF, using block randomisation with variable block size of 2, 4, or 8 and a telephone-based central randomisation method. The computer-generated randomisation list was prepared by an independent statistician who had no other involvement in the study. Embryologists and couples were not masked to study groups because of the type of interventions and differences in hospital fees, but clinicians performing embryo transfer were unaware of study group allocation. The primary outcome was livebirth after the first embryo transfer from the initiated cycle. Analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03428919. FINDINGS: Between March 16, 2018, and Aug 12, 2019, we randomly assigned 1064 couples to intracytoplasmic sperm injection (n=532) or conventional IVF (n=532). Livebirth after the first embryo transfer from the initiated cycle occurred in 184 (35%) of 532 couples randomly assigned to intracytoplasmic sperm injection and in 166 (31%) of 532 couples randomly assigned to conventional IVF (absolute difference 3·4%, 95% CI -2·4 to 9·2; risk ratio [RR] 1·11, 95% CI 0·93 to 1·32; p=0·27). 29 (5%) couples in the intracytoplasmic sperm injection group and 34 (6%) couples in the conventional IVF group had fertilisation failure (absolute difference -0·9%, -4·0 to 2·1, RR 0·85, 95% CI 0·53 to 1·38; p=0·60). INTERPRETATION: In couples with infertility in whom the male partner has a normal total sperm count and motility, intracytoplasmic sperm injection did not improve the livebirth rate compared with conventional IVF. Our results challenge the value of the routine use of intracytoplasmic sperm injection in assisted reproduction techniques for this population. FUNDING: My Duc Hospital and Merck Sharp and Dohme.

Con: freeze-all for all? One size does not fit all.

IVF has traditionally involved transfer of fresh embryos. However, a 'freeze-all' strategy where all embryos are cryopreserved for transfer in subsequent, unstimulated cycles has emerged as an alternative approach. This is thought to eliminate the negative effects of controlled ovarian stimulation on the endometrium and reduce the risk of ovarian hyperstimulation syndrome (OHSS). There are a growing number of studies evaluating live birth rates after use of a freeze-all versus fresh embryo transfer (ET) strategy. However, results to date are inconsistent. Certainly, the benefits of a freeze-all strategy appear to be less clear cut in ovulatory women with infertility, while those with a good ovarian response (more than 10 or 15 oocytes retrieved) may be suitable candidates. Variable responses to a freeze-all strategy compared with fresh ET have also been reported depending on whether cleavage stage embryos or blastocysts were transferred. In terms of safety, the risk of OHSS appears to be lower with a freeze-all strategy. For other safety endpoints, some appear to be better when a freeze-all approach is used (e.g. rates of pregnancy loss/miscarriage, preterm delivery, low birthweight and small for gestational age) while other complications are more common (e.g. hypertensive disorders of pregnancy/pre-eclampsia, large for gestational age and high birthweight). Preliminary longer-term data suggest that a freeze-all strategy does not have a negative impact on childhood development. Other factors to consider include time to pregnancy (longer after freeze-all) and the relative cost-effectiveness of the two approaches. Available data are too inconsistent to allow a freeze-all approach to be recommended for all patients. Instead, a personalized, balanced approach should be taken based on individual patient characteristics (especially steroid hormone levels on the day of trigger) and incorporating patient preference. While a freeze-all strategy might be the right choice for some patients, freeze-all is definitely not good for all.

Development of children born from IVM versus IVF: 2-year follow-up of a randomized controlled trial.

STUDY QUESTION: Is there any difference in developmental outcomes in children born after capacitation IVM (CAPA IVM) compared with conventional IVF? SUMMARY ANSWER: Overall development up to 24 months of age was comparable in children born after CAPA IVM compared with IVF. WHAT IS KNOWN ALREADY: IVM has been shown to be a feasible alternative to conventional IVF in women with a high antral follicle count (AFC). In addition to live birth rate, childhood development is also a relevant metric to compare between the two approaches to ART and there are currently no data on this. STUDY DESIGN, SIZE, DURATION: This study was a follow-up of babies born to women who participated in a randomized controlled trial comparing IVM with a pre-maturation step (CAPA IVM) and IVF. Developmental assessments were performed on 231 children over 24 months of follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants in the randomized controlled trial had an indication for ART and a high AFC (≥24 follicles in both ovaries). They were randomized to undergo one cycle of either IVM (n = 273) or IVF (n = 273). Of these, 96 women and 118 women, respectively, had live births. Seventy-six women (94 children, 79.2%) and 104 women (137 children, 88.1%), respectively, completed Ages & Stages Third Edition Questionnaire assessment (ASQ-3), and underwent evaluation of Developmental Red Flags at 6, 12 and 24 months of age. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics of participants in the follow-up study between the IVM and IVF groups were comparable. Overall, there were no significant differences in ASQ-3 scores at 6, 12 and 24 months between children born after IVM or IVF. The proportion of children with developmental red flags was low and did not differ between the two groups. Slightly, but significantly, lower ASQ-3 problem solving and personal-social scores in twins from the IVM versus IVF group at 6 months were still within the normal range and had caught up to the IVF group in the 12- and 24-month assessments. The number of children confirmed to have abnormal mental and/or motor development after specialist assessment was four in the IVM group and two in the IVF group (relative risk 2.91, 95% CI 0.54-15.6; P = 0.23). LIMITATIONS, REASONS FOR CAUTION: This study is an open-label follow-up of participants in a randomized controlled trial, and not all original trial subjects took part in the follow-up. The self-selected nature of the follow-up population could have introduced bias, and the sample size may have been insufficient to detect significant between-group differences in developmental outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the current findings at 2 years of follow-up, there does not appear to be any significant concern about the effects of IVM on childhood development. These data add to the evidence available to physicians when considering different approaches to fertility treatment, but require validation in larger studies. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number FWO.106-YS.2017.02. L.N.V. has received speaker and conference fees from Merck, grant, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring; T.M.H. has received speaker fees from Merck, Merck Sharp and Dohme, and Ferring; R.J.N. has receives grant funding from the National Health and Medical Research Council (NHMRC) of Australia; B.W.M. has acted as a paid consultant to Merck, ObsEva and Guerbet and is the recipient of grant money from an NHMRC Investigator Grant; J.E.J.S. reports lecture fees from Ferring Pharmaceuticals, Biomérieux and Besins Female Healthcare, grants from Fund for Research Flanders (FWO) and is co-inventor on granted patents on CAPA-IVM methodology in the USA (US10392601B2) and Europe (EP3234112B1); T.D.P., M.H.N.N., N.A.N., T.T.L., V.T.T.T., N.T.N., H.L.T.H. and X.T.H.L. have no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: NCT04296357 (www.clinicaltrials.gov). TRIAL REGISTRATION DATE: 5 March 2020. DATE OF FIRST PATIENT'S ENROLMENT: 7 March 2020.

Development of children born after in vitro maturation with a prematuration step versus natural conception: a prospective cohort study.

PURPOSE: IVM preceded by a prematuration step (capacitation [CAPA]-IVM) improves the acquisition of oocyte developmental competence and can enhance embryo quality. There is currently no follow-up data on babies born from CAPA-IVM. This study investigated developmental outcomes in children born after CAPA-IVM versus natural conception. METHODS: This prospective cohort study was conducted at a fertility clinic in Vietnam in August/September 2019. Children born after CAPA-IVM were propensity score-matched with those born after natural conception. All parents were asked to complete the Developmental Red Flags and Ages & Stages Third Edition (ASQ-3) questionnaires. RESULTS: A total of 46 parents (23 in each group) of 55 babies (31 CAPA-IVM and 24 natural conception) were included in the study. Baseline characteristics, including mother's age and body mass index, gestational age at delivery, and birth weight, were comparable. The mean age of children at the end of follow-up was 15 months. The overall proportion of children with any abnormal ASQ-3 score was 6.5% in the CAPA-IVM group and 20.8% in the natural conception group (p = 0.24). The proportion of children with a developmental red flag did not differ significantly between the CAPA-IVM and natural conception groups (9.7% vs. 4.2%; p = 0.80). CONCLUSIONS: The use of CAPA-IVM did not have any significant impact on childhood physical and mental development compared with children born as a result of natural conception.

Effect of post-warming culture time on the live birth rate after frozen embryo transfer.

Purpose: This study evaluated the influence of post-warming culture time on the live birth rate in day-3 and day-5 frozen embryo transfer (FET) cycles. Methods: This multicenter, retrospective cohort study was performed at IVFMD, My Duc Hospital and IVFMD Phu Nhuan, My Duc Phu Nhuan Hospital in Vietnam between October 2019 and October 2020. Women who underwent FET cycles with the transfer of ≤2 day-3 or day-5 embryos were included in the study. FET cycles were divided into four groups based on the quartiles for the time between embryo warming and embryo transfer. The primary outcome was live birth after FET. Results: Of 2548 FET cycles, 885 and 1663 cycles, respectively, had transfer of day-3 or day-5 embryos. Post-warming culture time ranged from 0.07 to 6.1 h. There were no significant differences between the post-warming culture time quartiles with respect to the number of embryos thawed, the number of embryos transferred, and the number of top-quality embryos transferred. Post-warming culture time was not significantly associated with the live birth rate in FET cycles using either day-3 or day-5 embryos. Conclusions: Post-warming culture time did not affect live birth rate in FET cycles. Therefore, IVF centers should consider scheduling workflows to best suit the patient.

IVF Transfer of Fresh or Frozen Embryos in Women without Polycystic Ovaries.

BACKGROUND: Among women who are undergoing in vitro fertilization (IVF), the transfer of frozen embryos has been shown to result in a higher rate of live birth than the transfer of fresh embryos in those with infertility associated with the polycystic ovary syndrome. It is not known whether frozen-embryo transfer results in similar benefit in women with infertility that is not associated with the polycystic ovary syndrome. METHODS: We randomly assigned 782 infertile women without the polycystic ovary syndrome who were undergoing a first or second IVF cycle to receive either a frozen embryo or a fresh embryo on day 3. In the frozen-embryo group, all grade 1 and 2 embryos had been cryopreserved, and a maximum of two embryos were thawed on the day of transfer in the following cycle. In the fresh-embryo group, a maximum of two fresh embryos were transferred in the stimulated cycle. The primary outcome was ongoing pregnancy after the first embryo transfer. RESULTS: After the first completed cycle, ongoing pregnancy occurred in 142 of 391 women (36.3%) in the frozen-embryo group and in 135 of 391 (34.5%) in the fresh-embryo group (risk ratio in the frozen-embryo group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P=0.65). Rates of live birth after the first transfer were 33.8% and 31.5%, respectively (risk ratio, 1.07; 95% CI, 0.88 to 1.31). CONCLUSIONS: Among infertile women without the polycystic ovary syndrome who were undergoing IVF, the transfer of frozen embryos did not result in significantly higher rates of ongoing pregnancy or live birth than the transfer of fresh embryos. (Funded by My Duc Hospital; ClinicalTrials.gov number, NCT02471573 .).

Positive effects of amphiregulin on human oocyte maturation and its molecular drivers in patients with polycystic ovary syndrome.

STUDY QUESTION: Does use of medium containing amphiregulin improve meiotic maturation efficiency in oocytes of women with polycystic ovary syndrome (PCOS) undergoing in vitro maturation (IVM) preceded by a capacitation culture step capacitation IVM (CAPA-IVM)? SUMMARY ANSWER: Use of medium containing amphiregulin significantly increased the maturation rate from oocytes retrieved from follicles with diameters <6 or ≥6 mm pre-cultured in capacitation medium. WHAT IS KNOWN ALREADY: Amphiregulin concentration in follicular fluid is correlated with human oocyte developmental competence. Amphiregulin added to the meiotic trigger has been shown to improve outcomes of IVM in a range of mammalian species. STUDY DESIGN, SIZE, DURATION: This prospective, randomized cohort study included 30 patients and was conducted at an academic infertility centre in Vietnam from April to December 2019. Patients with PCOS were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the first stage, sibling oocytes from each patient (671 in total) were allocated in equal numbers to maturation in medium with (CAPA-AREG) or without (CAPA-Control) amphiregulin 100 ng/ml. After a maturation check and fertilization using intracytoplasmic sperm injection (ICSI), all good quality Day 3 embryos were vitrified. Cumulus cells (CCs) from both groups were collected at the moment of ICSI denudation and underwent a molecular analysis to quantify key transcripts of oocyte maturation and to relate these to early embryo development. On return for frozen embryo transfer (second stage), patients were randomized to have either CAPA-AREG or CAPA-Control embryo(s) implanted. Where no embryo(s) from the randomized group were available, embryo(s) from the other group were transferred. The primary endpoint of the study was meiotic maturation efficiency (proportion of metaphase II [MII] oocytes; maturation rate). MAIN RESULTS AND THE ROLE OF CHANCE: In the per-patient analysis, the number of MII oocytes was significantly higher in the CAPA-AREG group versus the CAPA-Control group (median [interquartile range] 7.0 [5.3, 8.0] versus 6.0 [4.0, 7.0]; P = 0.01). When each oocyte was evaluated, the maturation rate was also significantly higher in the CAPA-AREG group versus the CAPA-Control group (67.6% versus 55.2%; relative risk [RR] 1.22 [95% confidence interval (CI) 1.08-1.38]; P = 0.001). No other IVM or embryology outcomes differed significantly between the two groups. Rates of clinical pregnancy (66.7% versus 42.9%; RR 1.56 [95% CI 0.77-3.14]), ongoing pregnancy (53.3% versus 28.6%; RR 1.87 [95% CI 0.72-4.85]) and live birth (46.7% versus 28.6%; RR 1.63 [95% CI 0.61-4.39]) were numerically higher in the patients who had CAPA-AREG versus CAPA-Control embryos implanted, but each fertility and obstetric outcome did not differ significantly between the groups. In the CAPA-AREG group, there were significant shifts in CC expression of genes involved in steroidogenesis (STAR, 3BHSD), the ovulatory cascade (DUSP16, EGFR, HAS2, PTGR2, PTGS2, RPS6KA2), redox and glucose metabolism (CAT, GPX1, SOD2, SLC2A1, LDHA) and transcription (NRF2). The expression of three genes (TRPM7, VCAN and JUN) in CCs showed a significant correlation with embryo quality. LIMITATIONS, REASONS FOR CAUTION: This study included only Vietnamese women with PCOS, limiting the generalizability. Although 100 ng/ml amphiregulin addition to the maturation culture step significantly improved the MII rate, the sample size in this study was small, meaning that these findings should be considered as exploratory. Therefore, a larger patient cohort is needed to confirm whether the positive effects of amphiregulin translate into improved fertility outcomes in patients undergoing IVM. WIDER IMPLICATIONS OF THE FINDINGS: Data from this study confirm the beneficial effects of amphiregulin during IVM with respect to the trigger of oocyte maturation. The gene expression findings in cumulus indicate that multiple pathways might contribute to these beneficial effects and confirm the key role of the epidermal growth factor system in the stepwise acquisition of human oocyte competence. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED; grant number FWO.106-YS.2017.02) and by the Fund for Research Flanders (FWO; grant number G.OD97.18N). L.N.V. has received speaker and conference fees from Merck, grants, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring. T.M.H. has received speaker fees from Merck, Merck Sharp and Dohme and Ferring. J.S. reports speaker fees from Ferring Pharmaceuticals and Biomérieux Diagnostics and grants from FWO Flanders, is co-inventor on granted patents on CAPA-IVM methodologies in USA (US10392601B2), Europe (EP3234112B1) and Japan (JP 6806683 registered 08-12-2020) and is a co-shareholder of Lavima Fertility Inc., a spin-off company of the Vrije Universiteit Brussel (VUB, Brussels, Belgium). NA, TDP, AHL, MNHN, SR, FS, EA and UDTH report no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: NCT03915054.

Antral follicle count and anti-Müllerian hormone to classify low-prognosis women under the POSEIDON criteria: a classification agreement study of over 9000 patients.

STUDY QUESTION: What is the agreement between antral follicle count (AFC) and anti-Müllerian hormone (AMH) levels when used to patient classification according to the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria? SUMMARY ANSWER: Our study indicates a strong agreement between the AFC and the AMH levels in classifying POSEIDON patients; thus, either can be used for this purpose, although one in four women will have discordant values when both biomarkers are used. WHAT IS KNOWN ALREADY: According to the POSEIDON criteria, both AFC and AMH may be used to classify low-prognosis patients. Proposed AFC and AMH thresholds of 5 and 1.2 ng/ml, respectively, have their basis in published literature; however, no study has yet determined the reproducibility of patient classification in comparing one biomarker with the other, nor have their thresholds ever been validated within this patient population. STUDY DESIGN, SIZE, DURATION: A population-based cohort study involving 9484 consecutive patients treated in three fertility clinics in Brazil, Turkey and Vietnam between 2015 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were infertile women between 22 and 46 years old in their first in vitro fertilization/intracytoplasmic sperm injection cycle of standard ovarian stimulation with exogenous gonadotropins whose baseline ovarian reserves had been assessed by both AFC and AMH. Details of pre- and post-treatment findings were input into a coded research file. Two indicators of interest were created to classify patients according to the POSEIDON criteria based upon AFC and AMH values. Patients who did not fit any of the four POSEIDON groups were classified as non-POSEIDON. AFC was determined in the early follicular phase using two-dimensional (2D) transvaginal ultrasonography, whereas AMH values were based on the modified Beckman Coulter generation II enzyme-linked immunosorbent assay. Agreement rates were computed between AFC and AMH to classify patients using Cohen's kappa statistics. Logistic regression analyzes were carried out to examine the association between ovarian markers and low (<4) and suboptimal (4-9) oocyte yield. MAIN RESULTS AND THE ROLE OF CHANCE: The degree of agreement in classifying patients according to POSEIDON groups was strong overall (kappa = 0.802; 95% CI: 0.792-0.811). A total of 73.8% of individuals were classified under the same group using both biomarkers. The disagreement rates were ∼26% and did not diverge when AFC or AMH was used as the primary biomarker criterion. Significant regression equations were found between ovarian markers and oocyte yield (P < 0.0001). For low oocyte yield, the optimal AFC and AMH cutoff values were 5 and 1.27 ng/ml with sensitivities of 0.61 and 0.66, specificities of 0.81 and 0.72, and AUC receiver operating characteristics of 0.791 and 0.751, respectively. For suboptimal oocyte yield respective AFC and AMH cutoffs were 12 and 2.97 ng/ml with sensitivities of 0.74 and 0.69, specificities of 0.76 and 0.66 and AUCs of 0.81 and 0.80. LIMITATIONS, REASONS FOR CAUTION: Our study relied on 2D transvaginal sonography to quantify the AFC and manual Gen II assay for AMH determination and classification of patients. AMH data must be interpreted in an assay-specific manner. Treatment protocols varied across centers potentially affecting patient classification. WIDER IMPLICATIONS OF THE FINDINGS: Three of four patients will be classified the same using either AFC or AMH values. Both biomarkers provide acceptable and equivalent accuracy in predicting oocyte yield further supporting their use and proposed thresholds in daily clinical practice for patient classification according to the POSEIDON criteria. However, the sensitivity of POSEIDON thresholds in predicting low oocyte yield is low. Clinicians should adopt the biomarker that may best reflect their clinical setting. STUDY FUNDING/COMPETING INTEREST(S): Unrestricted investigator-sponsored study grant (MS200059_0013) from Merck KGaA, Darmstadt, Germany. The funder had no role in study design, data collection, analysis, decision to publish or manuscript preparation. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. H.Y. declares receipt of payment for lectures from Merck and Ferring. L.N.V. receives speaker fees and conferences from Merck, Merck Sharp and Dohme (MSD) and Ferring and research grants from MSD and Ferring. T.M.H. received speaker fees and conferences from Merck, MSD and Ferring. The remaining authors have nothing to disclose. TRIAL REGISTRATION NUMBER: not applicable.

Cumulative delivery rate per aspiration IVF/ICSI cycle in POSEIDON patients: a real-world evidence study of 9073 patients.

STUDY QUESTION: What is the cumulative delivery rate (CDR) per aspiration IVF/ICSI cycle in low-prognosis patients as defined by the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria? SUMMARY ANSWER: The CDR of POSEIDON patients was on average ∼50% lower than in normal responders and varied across POSEIDON groups; differences were primarily determined by female age, number of embryos obtained, number of embryo transfer (ET) cycles per patient, number of oocytes retrieved, duration of infertility, and BMI. WHAT IS KNOWN ALREADY: The POSEIDON criteria aim to underline differences related to a poor or suboptimal treatment outcome in terms of oocyte quality and quantity among patients undergoing IVF/ICSI, and thus, create more homogenous groups for the clinical management of infertility and research. POSEIDON patients are presumed to be at a higher risk of failing to achieve a live birth after IVF/ICSI treatment than normal responders with an adequate ovarian reserve. The CDR per initiated/aspiration cycle after the transfer of all fresh and frozen-thawed/warmed embryos has been suggested to be the critical endpoint that sets these groups apart. However, no multicenter study has yet substantiated the validity of the POSEIDON classification in identifying relevant subpopulations of patients with low-prognosis in IVF/ICSI treatment using real-world data. STUDY DESIGN, SIZE, DURATION: Multicenter population-based retrospective cohort study involving 9073 patients treated in three fertility clinics in Brazil, Turkey and Vietnam between 2015 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were women with infertility between 22 and 42 years old in their first IVF/ICSI cycle of standard ovarian stimulation whose fresh and/or frozen embryos were transferred until delivery of a live born or until all embryos were used. Patients were retrospectively classified according to the POSEIDON criteria into four groups based on female age, antral follicle count (AFC), and the number of oocytes retrieved or into a control group of normal responders (non-POSEIDON). POSEIDON patients encompassed younger (<35 years) and older (35 years or above) women with an AFC ≥5 and an unexpected poor (<4 retrieved oocytes) or suboptimal (4-9 retrieved oocytes) response to stimulation, and respective younger and older counterparts with an impaired ovarian reserve (i.e. expected poor responders; AFC <5). Non-POSEIDON patients were those with AFC ≥5 and >9 oocytes retrieved. CDR was computed per one aspirated cycle. Logistic regression analysis was carried out to examine the association between patient classification and CDR. MAIN RESULTS AND ROLE OF CHANCE: The CDR was lower in the POSEIDON patients than in the non-POSEIDON patients (33.7% vs 50.6%; P < 0.001) and differed across POSEIDON groups (younger unexpected poor responder [Group 1a; n = 212]: 27.8%, younger unexpected suboptimal responder [Group 1b; n = 1785]: 47.8%, older unexpected poor responder [Group 2a; n = 293]: 14.0%, older unexpected suboptimal responder [Group 2b; n = 1275]: 30.5%, younger expected poor responder [Group 3; n = 245]: 29.4%, and older expected poor responder [Group 4; n = 623]: 12.5%. Among unexpected suboptimal/poor responders (POSEIDON Groups 1 and 2), the CDR was twice as high in suboptimal responders (4-9 oocytes retrieved) as in poor responders (<4 oocytes) (P = 0.0004). Logistic regression analysis revealed that the POSEIDON grouping, number of embryos obtained, number of ET cycles per patient, number of oocytes collected, female age, duration of infertility and BMI were relevant predictors for CDR (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Our study relied on the antral follicle count as the biomarker used for patient classification. Ovarian stimulation protocols varied across study centers, potentially affecting patient classification. WIDER IMPLICATIONS OF THE FINDINGS: POSEIDON patients exhibit lower CDR per aspirated IVF/ICSI cycle than normal responders; the differences are mainly determined by female age and number of oocytes retrieved, thereby reflecting the importance of oocyte quality and quantity. Our data substantiate the validity of the POSEIDON criteria in identifying relevant subpopulations of patients with low-prognosis in IVF/ICSI treatment. Efforts in terms of early diagnosis, prevention, and identification of specific interventions that might benefit POSEIDON patients are warranted. STUDY FUNDING/COMPETING INTEREST(S): Unrestricted investigator-sponsored study grant (MS200059_0013) from Merck KGaA, Darmstadt, Germany. The funder had no role in study design, data collection, analysis, decision to publish or manuscript preparation. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. H.Y. declares receipt of payment for lectures from Merck and Ferring. L.N.V. receives speaker fees and conferences from Merck, Merck Sharp and Dohme (MSD) and Ferring and research grants from MSD and Ferring. J.F.C. declares receipt of statistical services fees from ANDROFERT Clinic. T.M.H. received speaker fees and conferences from Merck, MSD and Ferring. P.H. declares receipt of unrestricted research grants from Merck, Ferring, Gedeon Richter and IBSA and lecture fees from Merck, Gedeon Richter and Med.E.A. C.A. declares receipt of unrestricted research grants from Merck and lecture fees from Merck. The remaining authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Micronized progesterone plus dydrogesterone versus micronized progesterone alone for luteal phase support in frozen-thawed cycles (MIDRONE): a prospective cohort study.

STUDY QUESTION: Does the addition of oral dydrogesterone to vaginal progesterone as luteal phase support improve pregnancy outcomes during frozen embryo transfer (FET) cycles compared with vaginal progesterone alone? SUMMARY ANSWER: Luteal phase support with oral dydrogesterone added to vaginal progesterone had a higher live birth rate and lower miscarriage rate compared with vaginal progesterone alone. WHAT IS KNOWN ALREADY: Progesterone is an important hormone that triggers secretory transformation of the endometrium to allow implantation of the embryo. During IVF, exogenous progesterone is administered for luteal phase support. However, there is wide inter-individual variation in absorption of progesterone via the vaginal wall. Oral dydrogesterone is effective and well tolerated when used to provide luteal phase support after fresh embryo transfer. However, there are currently no data on the effectiveness of luteal phase support with the combination of dydrogesterone with vaginal micronized progesterone compared with vaginal micronized progesterone after FET. STUDY DESIGN, SIZE, DURATION: Prospective cohort study conducted at an academic infertility center in Vietnam from 26 June 2019 to 30 March 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1364 women undergoing IVF with FET. Luteal support was started when endometrial thickness reached ≥8 mm. The luteal support regimen was either vaginal micronized progesterone 400 mg twice daily plus oral dydrogesterone 10 mg twice daily (second part of the study) or vaginal micronized progesterone 400 mg twice daily (first 4 months of the study). In women with a positive pregnancy test, the appropriate luteal phase support regimen was continued until 7 weeks' gestation. The primary endpoint was live birth after the first FET of the started cycle, with miscarriage <12 weeks as one of the secondary endpoints. MAIN RESULTS AND THE ROLE OF CHANCE: The vaginal progesterone + dydrogesterone group and vaginal progesterone groups included 732 and 632 participants, respectively. Live birth rates were 46.3% versus 41.3%, respectively (rate ratio [RR] 1.12, 95% CI 0.99-1.27, P = 0.06; multivariate analysis RR 1.30 (95% CI 1.01-1.68), P = 0.042), with a statistically significant lower rate of miscarriage at <12 weeks in the progesterone + dydrogesterone versus progesterone group (3.4% versus 6.6%; RR 0.51, 95% CI 0.32-0.83; P = 0.009). Birth weight of both singletons (2971.0 ± 628.4 versus 3118.8 ± 559.2 g; P = 0.004) and twins (2175.5 ± 494.8 versus 2494.2 ± 584.7; P = 0.002) was significantly lower in the progesterone plus dydrogesterone versus progesterone group. LIMITATIONS, REASONS FOR CAUTION: The main limitations of the study were the open-label design and the non-randomized nature of the sequential administration of study treatments. However, our systematic comparison of the two strategies was able to be performed much more rapidly than a conventional randomized controlled trial. In addition, the single ethnicity population limits external generalizability. WIDER IMPLICATIONS OF THE FINDINGS: Our findings study suggest a role for oral dydrogesterone in addition to vaginal progesterone as luteal phase support in FET cycles to reduce the miscarriage rate and improve the live birth rate. Carefully planned prospective cohort studies with limited bias could be used as an alternative to randomized controlled clinical trials to inform clinical practice. STUDY FUNDING/COMPETING INTERESTS: This study received no external funding. LNV has received speaker and conference fees from Merck, grant, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring; TMH has received speaker fees from Merck, Merck Sharp and Dohme, and Ferring; R.J.N. has received scientific board fees from Ferring and receives grant funding from the National Health and Medical Research Council (NHMRC) of Australia; BWM has acted as a paid consultant to Merck, ObsEva and Guerbet, and is the recipient of grant money from an NHMRC Investigator Grant. TRIAL REGISTRATION NUMBER: NCT0399876.

In-vitro maturation versus IVF: a cost-effectiveness analysis.

RESEARCH QUESTION: How do costs and effects of in-vitro maturation (IVM) compare to IVF in women with a high antral follicle count (AFC)? DESIGN: This cost-effectiveness analysis (CEA) was based on data of a previous retrospective cohort study at IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam. Between July 2015 and December 2017, 608 women underwent IVM and 311 women IVF. The effectiveness measure for the CEA was cumulative live birth rate (LBR) after one completed cycle including subsequent cryo-cycles within 12 months of inclusion. Data were collected on resource use related to treatment, medication and pregnancy from the case report forms. The mean costs and effects, average cost differences and incremental cost-effectiveness ratios (ICER) were calculated using non-parametric bootstrap resampling to assess the effect of uncertainty in the estimates. RESULTS: Cumulative LBR after one completed cycle were 239/608 (39.3%) in the IVM group versus 155/311 (49.8%) in the IVF group (adjusted odds ratio 0.52, 95% confidence interval [CI] 0.30-0.89). Ovarian hyperstimulation syndrome (OHSS) did not occur in the IVM group versus 11/311 (3.5%) in the IVF group. The mean costs per couple were €4300 (95% CI €1371-18,798) for IVM and €6493 (95% CI €2204-20,136) for IVF. The ICER per additional live birth with IVF was €20,144 (95% CI €9116-50,418). Results were robust over a wide range of assumptions. CONCLUSIONS: IVM is less expensive than IVF in women with a high AFC undergoing treatment with assisted reproductive technology, while leading to a slightly lower effectiveness in terms of cumulative LBR.

Fresh embryo transfer versus freeze-only after in vitro maturation with a pre-maturation step in women with high antral follicle count: a randomized controlled pilot study.

PURPOSE: In vitro maturation (IVM) is an alternative to in vitro fertilization (IVF) for women at high risk of developing ovarian hyperstimulation syndrome (OHSS). This study determined the effectiveness and safety of a freeze-only strategy versus fresh embryo transfer (ET) after IVM with a pre-maturation step (CAPA-IVM) in women with a high antral follicle count (AFC). METHODS: This randomized, controlled pilot study (NCT04297553) was conducted between March and November 2020. Forty women aged 18-37 years with a high AFC (≥24 follicles in both ovaries) undergoing one cycle of CAPA-IVM were randomized to a freeze-only strategy with subsequent frozen ET (n = 20) or to fresh ET (n = 20). The primary endpoint was ongoing pregnancy resulting in live birth after the first ET of the started treatment cycle. RESULTS: The ongoing pregnancy rate in the freeze-only group (65%) was significantly higher than that in the fresh ET group (25%; p = 0.03), as was the live birth rate (60% versus 20%; p = 0.02). Clinical pregnancy rate was numerically, but not significantly, higher after frozen versus fresh ET (70% versus 35%; p = 0.06), while the number of day 3 or good quality embryos, endometrial thickness on the day of oocyte pick-up, implantation rate, and positive pregnancy test rate did not differ significantly between groups. No cases of OHSS were observed, and miscarriage and multiple pregnancy rates were similar in the two groups. CONCLUSIONS: These findings suggest that the effectiveness of CAPA-IVM could be improved considerably by using a freeze-only strategy followed by frozen ET in subsequent cycles. TRIAL REGISTRATION NUMBER: NCT04297553 ( www.clinicaltrials.gov ).