Diagnostic accuracy of hysterosalpingo-foam sonography for assessment of fallopian tube patency in infertile women.

RESEARCH QUESTION: What is the diagnostic accuracy of hysterosalpingo-foam sonography (HyFoSy), using two-dimensional ultrasound in tubal patency assessment in infertile women compared with laparoscopy with dye chromotubation? DESIGN: This prospective study was conducted at My Duc Hospital, Vietnam. Infertile women aged 18 years or older, who were scheduled for laparoscopy, were included. Visual Analogue Scale (VAS) score for perception of pain during HyFoSy was used. Laparoscopy was carried out on the same day. Clinicians undertaking laparoscopy were blinded to HyFoSy results. Sensitivity, specificity, negative and positive predictive value, and 95% confidence intervals were calculated. A sample size of 455 women (n = 910 fallopian tubes) was needed to demonstrate a fluctuation hypothesis, not exceeding 6%, for sensitivity and specificity (power 0.80, two-sided alpha 5%, loss to follow-up 5%). RESULTS: Between 2019 and 2022, 455 participants were recruited. Hysterosalpingo-foam sonography was unsuccessfully carried out in six participants. Two withdrew their consent. Data analysis was conducted on the remaining 447 participants (n = 868 fallopian tubes). The sensitivity and specificity of hysterosalpingo-foam sonography compared with laparoscopy were 0.75 (95% CI 0.71 to 0.79) and 0.70 (95% CI 0.65 to 0.74), respectively. Hysterosalpingo-foam sonography gave a positive predictive value of 0.76 (95% CI 0.73 to 0.80) and negative predictive value of 0.68 (95% CI 0.64 to 0.73). A total of 42.8% of women reported a VAS score of no pain. No adverse event was reported. CONCLUSION: Compared with laparoscopy with dye chromotubation, two-dimensional HyFoSy is a well-tolerated, reliable technique for assessing tubal patency.

Live birth after vitrification of oocytes from capacitation in vitro maturation.

Female fertility preservation is a rapidly growing field in medicine. Oocyte cryopreservation and assisted reproductive technique with vitrified-warmed oocytes have been successful with in vivo matured oocytes after conventional ovarian stimulation protocols. The use of in vitro matured oocytes after vitrification and warming has been limited. Capacitation in vitro maturation (CAPA-IVM) represents the latest refinement of IVM protocols and provides in vitro matured oocytes with improved competence. This case report describes the first successful live birth following oocyte vitrification from a CAPA-IVM cycle. This milestone achievement holds a significant promise to expand fertility preservation options and improve accessibility for women wishing to cryopreserve their eggs for future use.

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).

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.

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.

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.

Embryological and clinical outcomes in couples with severe male factor infertility versus normozoospermia.

OBJECTIVE: This study evaluated embryological and clinical outcomes in couples with severe male factor infertility versus those with normozoospermia undergoing ICSI and in vitro fertilisation. METHODS: This multicentre, retrospective cohort study included all couples who had undergone autologous ICSI cycles at My Duc Hospital and My Duc Phu Nhuan Hospital in Vietnam between January 2018 and January 2021 (female age < 35 years and males with severe male factor or normozoospermia based on the World Health Organization 2010 criteria). The primary outcome was the cumulative live birth rate after the first ICSI cycle. RESULTS: A total of 1296 couples were included, including 648 with severe male factor infertility and 648 with normozoospermia. The number of two pronuclei zygotes, embryos, and frozen embryos was significantly lower in couples with severe male factor infertility compared with normozoospermia (p < 0.05). In contrast, there were no significant differences between the two groups with respect to cumulative pregnancy outcomes, including the live birth rate, and secondary outcomes including clinical pregnancy rate, ongoing pregnancy rate, and miscarriage rate. CONCLUSION: Severe male factor infertility appeared to have an impact on the fertilisation and early developmental potential of embryos, but sperm quality did not affect cumulative clinical fertility outcomes.

A fresh start for IVM: capacitating the oocyte for development using pre-IVM.

BACKGROUND: While oocyte IVM is practiced sporadically it has not achieved widespread clinical practice globally. However, recently there have been some seminal advances in our understanding of basic aspects of oocyte biology and ovulation from animal studies that have led to novel approaches to IVM. A significant recent advance in IVM technology is the use of biphasic IVM approaches. These involve the collection of immature oocytes from small antral follicles from minimally stimulated patients/animals (without hCG-priming) and an ∼24 h pre-culture of oocytes in an advanced culture system ('pre-IVM') prior to IVM, followed by routine IVF procedures. If safe and efficacious, this novel procedure may stand to make a significant impact on human ART practices. OBJECTIVE AND RATIONALE: The objectives of this review are to examine the major scientific advances in ovarian biology with a unique focus on the development of pre-IVM methodologies, to provide an insight into biphasic IVM procedures, and to report on outcomes from animal and clinical human data, including safety data. The potential future impact of biphasic IVM on ART practice is discussed. SEARCH METHODS: Peer review original and review articles were selected from PubMed and Web of Science searches for this narrative review. Searches were performed using the following keywords: oocyte IVM, pre-IVM, biphasic IVM, CAPA-IVM, hCG-triggered/primed IVM, natural cycle IVF/M, ex-vivo IVM, OTO-IVM, oocyte maturation, meiotic competence, oocyte developmental competence, oocyte capacitation, follicle size, cumulus cell (CC), granulosa cell, COC, gap-junction communication, trans-zonal process, cAMP and IVM, cGMP and IVM, CNP and IVM, EGF-like peptide and IVM, minimal stimulation ART, PCOS. OUTCOMES: Minimizing gonadotrophin use means IVM oocytes will be collected from small antral (pre-dominant) follicles containing oocytes that are still developing. Standard IVM yields suboptimal clinical outcomes using such oocytes, whereas pre-IVM aims to continue the oocyte's development ex vivo, prior to IVM. Pre-IVM achieves this by eliciting profound cellular changes in the oocyte's CCs, which continue to meet the oocyte's developmental needs during the pre-IVM phase. The literature contains 25 years of animal research on various pre-IVM and biphasic IVM procedures, which serves as a large knowledge base for new approaches to human IVM. A pre-IVM procedure based on c-type natriuretic peptide (named 'capacitation-IVM' (CAPA-IVM)) has undergone pre-clinical human safety and efficacy trials and its adoption into clinical practice resulted in healthy live birth rates not different from conventional IVF. WIDER IMPLICATIONS: Over many decades, improvements in clinical IVM have been gradual and incremental but there has likely been a turning of the tide in the past few years, with landmark discoveries in animal oocyte biology finally making their way into clinical practice leading to improved outcomes for patients. Demonstration of favorable clinical results with CAPA-IVM, as the first clinically tested biphasic IVM system, has led to renewed interest in IVM as an alternative, low-intervention, low-cost, safe, patient-friendly ART approach, and especially for patients with PCOS. The same new approach is being used as part of fertility preservation in patients with cancer and holds promise for social oocyte freezing.

Epigenetic variation in neonatal tissues in infants conceived using capacitation-in vitro maturation vs. in vitro fertilization.

OBJECTIVE: To investigate alterations of the global DNA methylation profile in placenta, cord blood, and neonatal buccal smears in infants conceived using in vitro maturation (IVM) with a prematuration step (capacitation-IVM [CAPA-IVM]) vs. in vitro fertilization (IVF). DESIGN: Analysis of data from the offspring of participants in a randomized controlled trial. SETTING: Private clinic. PATIENTS: Forty-six women with polycystic ovary syndrome and/or high antral follicle count and their offspring (58 newborns). INTERVENTION(S): Women with polycystic ovary syndrome and/or a high antral follicle count participating in the clinical trial were randomized to undergo CAPA-IVM or conventional IVF. MAIN OUTCOME MEASURE(S): At delivery, biological samples including cord blood, placental tissue, and a neonatal buccal smear were collected. Genome-wide DNA methylation was determined using the Illumina Infinium MethylationEPIC BeadChip. Variability in methylation was also considered, and mean variances for the two treatment categories were compared. RESULTS: In neonatal buccal smears, there were no significant differences between the CAPA-IVM and conventional IVF groups on the basis of the CpG probe after linear regression analysis using a significant cut-off of false-discovery rate <0.05 and |Δß|≥0.05. In cord blood, only one CpG site showed a significant gain of methylation in the CAPA-IVM group. In the placenta, CAPA-IVM was significantly associated with changes in methylation at five CpG sites. Significantly more variable DNA methylation was found in five probes in the placenta, 54 in cord blood, and two in buccal smears after IVM of oocytes. In cord blood samples, 20 CpG sites had more variable methylation in the conventional IVF vs. IVM group. Isolated CpG sites showing differences in methylation in cord blood were not associated with changes in gene expression of the overlapping genes. CONCLUSION(S): Capacitation-IVM appeared to be associated with only a small amount of epigenetic variation in cord blood, placental tissue, and neonate buccal smears. CLINICAL TRIAL REGISTRATION NUMBER: NCT03405701 (www. CLINICALTRIALS: gov).

Association between sequence variants in the FSHR gene and reproductive outcomes following IVF in predicted normoresponders.

RESEARCH QUESTION: Is there an association between FSHR sequence variants and reproductive outcomes following IVF in predicted normoresponders? DESIGN: Multicentre prospective cohort study conducted from November 2016 to June 2019 in Vietnam, Belgium and Spain including patients aged <38 years, and undergoing IVF with a predicted normal response with fixed-dose 150 IU rFSH in an antagonist protocol. Genotyping was performed for three FSHR (c.919A>G, c.2039A>G, c.-29G>A) and one FSHB sequence variants (c.-211G>T). Clinical pregnancy rate (CPR), live birth rate (LBR) and miscarriage rate in the first embryo transfer and cumulative live birth rate (CLBR) were compared between the different genotypes. RESULTS: A total of 351 patients underwent at least one embryo transfer. Genetic model analysis that adjusted for patient age, body mass index, ethnicity, type of embryo transfer, embryo stage and number of top-quality embryos transferred revealed a higher CPR for homozygous patients for the variant allele G of c.919A>G when compared to patients with genotype AA (60.3% versus 46.3%, adjusted odds ratio [ORadj] 1.96, 95% confidence interval [CI] 1.09-3.53). Also, c.919A>G genotypes AG and GG presented a higher CPR and LBR when compared with genotype AA (59.1% versus 46.3%, ORadj 1.80, 95% CI 1.08-3.00, and 51.3% versus 39.0%, ORadj 1.69, 95% CI 1.01-2.80, respectively). Cox regression models revealed a statistically significantly lower CLBR for c.2039A>G genotype GG in the codominant model (hazard ratio [HR] 0.66, 95% CI 0.43-0.99). CONCLUSION: These results demonstrate a previously unreported association between variant c.919A>G genotype GG and higher CPR and LBR in infertile patients and reinforce a potential role for genetic background in predicting the reproductive prognosis following IVF.

Outcomes of clinical in vitro maturation programs for treating infertility in hyper responders: a systematic review.

Oocyte in vitro maturation (IVM) has been proposed as an alternative to conventional ovarian stimulation (COS) in subfertile women with polycystic ovary syndrome. To evaluate the effectiveness and safety of IVM compared with COS in women with predicted hyperresponse to gonadotropins, we searched the published literature for relevant studies comparing any IVM protocol with any COS protocol followed by in vitro fertilization or intracytoplasmic sperm injection. A systematic review was undertaken on 3 eligible prospective studies. Live birth rate was not significantly lower after IVM vs. COS (odds ratio [95% confidence interval] of 0.56 [0.32-1.01] overall, 0.83 [0.63-1.10] for human chorionic gonadotropin (hCG)-triggered IVM [hCG-IVM] and 0.45 [0.18-1.13] for non-hCG-triggered IVM [non-hCG-IVM]), irrespective of the stage of transferred embryos. Data from nonrandomized studies generally showed either significantly low or statistically comparable rates of live birth with IVM vs. COS. Most studies have not identified any significant difference between IVM and COS with respect to the rates of obstetric or perinatal complications, apart from a potentially higher rate of hypertensive disorders during pregnancy. The development of offspring from IVM and COS with in vitro fertilization or intracytoplasmic sperm injection appears to be similar. Additional research is needed to identify which patient populations will benefit most from IVM, to define the appropriate clinical protocol, and to develop the optimal culture system.

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.

Endocrine Responses to Triptorelin in Healthy Women, Women With Polycystic Ovary Syndrome, and Women With Hypothalamic Amenorrhea.

CONTEXT: Limited data exist regarding whether the endocrine response to the gonadotropin-releasing hormone receptor agonist (GnRHa) triptorelin differs in women with polycystic ovary syndrome (PCOS) compared with healthy women or those with hypothalamic amenorrhea (HA). OBJECTIVE: We compared the gonadotropin response to triptorelin in healthy women, women with PCOS, or those with HA without ovarian stimulation, and in women with or without polycystic ovaries undergoing oocyte donation cycles after ovarian stimulation. METHODS: The change in serum gonadotropin levels was determined in (1) a prospective single-blinded placebo-controlled study to determine the endocrine profile of triptorelin (0.2 mg) or saline-placebo in healthy women, women with PCOS, and those with HA, without ovarian stimulation; and (2) a retrospective analysis from a dose-finding randomized controlled trial of triptorelin (0.2-0.4 mg) in oocyte donation cycles after ovarian stimulation. RESULTS: In Study 1, triptorelin induced an increase in serum luteinizing hormone (LH) of similar amplitude in all women (mean peak LH: healthy, 52.3; PCOS, 46.2; HA, 41.3 IU/L). The AUC of change in serum follicle-stimulating hormone (FSH) was attenuated in women with PCOS compared with healthy women and women with HA (median AUC of change in serum FSH: PCOS, 127.2; healthy, 253.8; HA, 326.7 IU.h/L; P = 0.0005). In Study 2, FSH levels 4 hours after triptorelin were reduced in women with at least one polycystic morphology ovary (n = 60) vs normal morphology ovaries (n = 91) (34.0 vs 42.3 IU/L; P = 0.0003). Serum anti-Müllerian hormone (AMH) was negatively associated with the increase in FSH after triptorelin, both with and without ovarian stimulation. CONCLUSION: FSH response to triptorelin was attenuated in women with polycystic ovaries, both with and without ovarian stimulation, and was negatively related to AMH levels.

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.

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.

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.

Perspectives on the development and future of oocyte IVM in clinical practice.

Oocyte in vitro maturation (IVM) is an assisted reproductive technology designed to obtain mature oocytes following culture of immature cumulus-oocyte complexes collected from antral follicles. Although IVM has been practiced for decades and is no longer considered experimental, the uptake of IVM in clinical practice is currently limited. The purpose of this review is to ensure reproductive medicine professionals understand the appropriate use of IVM drawn from the best available evidence supporting its clinical potential and safety in selected patient groups. This group of scientists and fertility specialists, with expertise in IVM in the ART laboratory and/or clinic, explore here the development of IVM towards acquisition of a non-experimental status and, in addition, critically appraise the current and future role of IVM in human ART.

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.