Cumulative Clinical Pregnancy Research Articles

O-099 The use of cumulus cells (CCs) to select spermatozoa for intracytoplasmic sperm injection improves blastocyst development and quality

Abstract Study question Is there a role for sperm selection based on the capacity to pass through cumulus oophorous column in improving the laboratory outcomes in ICSI cycles? Summary answer A higher rate of blastocyst formation and quality are obtained with the use of CCs to select spermatozoa for ICSI compared to conventional density gradients. What is known already The sperm selection for ICSI is an operator-dependent procedure based on sperm morphology and motility. ICSI bypasses all natural barriers of sperm selection, which may impact embryo development. During natural fertilization, only the spermatozoa that pass-through cumulus cells will have the chance to fertilize the egg. Spermatozoa capable of traverse COCs have better morphology, higher chromatin integrity and greater acrosomal reaction. Hyaluronic acid is an important component of these cells and plays a key role in the selection of spermatozoa with intact DNA. However, there is scarce data regarding this selection method for ICSI on the development of the embryo. Study design, size, duration This is a prospective randomized sibling oocyte pilot study (February-December 2021). A total of 996 metaphase II (MII) oocytes were randomized into two groups. In the control group (Group 0, n = 489 MII), ICSI was performed with sperm selected by conventional density gradients. In the study group (Group 1, n = 507 MII) the oocytes were microinjected with sperm selected through CCs. The main outcome was blastocyst formation rate and quality. Reproductive results were analyzed as secondary outcomes. Participants/materials, setting, methods Ninety-eight couples undergoing ICSI (private center) with ≥6 fresh own MII obtained after ovarian stimulation, embryo culture until blastocyst stage and ejaculated sperm samples were included in the study. All seminal samples were processed using density gradients and those in the study group were additionally passed through CCs (the patient's own CCs were used in all cases). Fertilization and day 5 blastocyst formation rates were assessed. Embryo quality was scored according to Gardner's criteria. Main results and the role of chance Data was similar with regards to cause of infertility, maternal age (36.47 vs 36.63 y.o.), sperm count (60.53 vs 58.25 mill/ml) and progressive motility (57.45 vs 57.50%) between group 0 vs 1, respectively. Fertilization rate was similar between groups (74.0% vs 78.7%; p = 0.419. Group 0 vs 1, respectively). However, the blastocyst formation rate was significantly higher in the study group compared to control (70.9% vs 60.1%; p = 0.002). In addition, high-quality blastocyst rate was significantly higher in the CCs compared to the control group (49.6% vs 38.5%; p = 0.003). After the analysis of 145 treatments (131 frozen vs 14 fresh transfers) the cumulative clinical pregnancy rate in the study group was 47.2%, higher than in the control group (32.1%), but without reaching statistical difference (p = 0.07). Limitations, reasons for caution This is an exploratory study, aimed to evaluate the effectiveness of CCs as a more “physiologic” selection of spermatozoa for ICSI treatments in terms of laboratory outcomes (blastocyst formation rate and quality). Albeit not reaching statistical significance, the higher cumulative pregnancy rate in the study group seems clinically relevant. Wider implications of the findings Our results suggest that CCs can select more competent sperm for ICSI. This “physiologic-resembling”, operator-independent selection method has the potential of increasing pregnancy outcomes in ICSI cycles, pending of confirmation in larger studies including cumulative embryo-transfer cycles. Trial registration number NA

P-554 Impact of genotype and phenotype on ICSI outcomes of cystic fibrosis (CF) men patients: a cohort study about 107 ICSI from 1999 to 2019

Abstract Study question Is there an impact of CFTR (cystic fibrosis transmembrane-conductance regulator) gene mutation type and/or general health condition of men with CF and the ICSI outcomes? Summary answer Neither genetic severity nor clinical severity seems to have a negative impact on the biological or clinical ICSI issues for cystic fibrosis men patients. What is known already CFTR protein regulates electrolyte and fluid transport in many tissues with exocrine function, including male reproductive tract. Mutation of CFTR gene causes CF, which affects the function of several organs, and impairs male fertility. CF is generally associated to an obstructive azoospermia because of bilateral absence of vas deferens and seminal vesicles degeneration. CFTR protein is detected in human fetus at the early developmental stages and highly expressed in testis and epididymis. CFTR provides establishment of specific fluid environment for germ cell differentiation and maturation. According to literature, it seems likely that CFTR mutations affect sperm quality and embryo development. Study design, size, duration This cohort study was conducted in the Assisted Reproduction Center of an university hospital on 52 patients, for whom a CF has been diagnosed and monitored in the same hospital. The CF diagnosis was based on CFTR genetic tests and clinical symptoms. All men were azoospermic and underwent on a microscopic epididymal sperm aspiration (MESA) and/or a testicular sperm extraction (TESE). 52 couples underwent in total 107 ICSI with frozen sperm between 1999 and 2019. Participants/materials, setting, methods Clinical data- one year preceding surgical sperm collection and freeze - related to the severity of the CF were collected: respiratory spirometry data, Pseudomonas aeruginosa colonization, number of antibiotic treatment, BMI and Pancreatic insufficiency, as well as CFTR mutations. Linear regression tests (fisher and χ²) were carried out to establish or not correlation between biological and clinical ICSI outcomes and on the other hand genotype and/ or each clinical parameter. Main results and the role of chance The mean age of patients at sperm retrieval was 31.3 years [21-55]. Mean BMI was 21.3. Patients with severe genotype represented 67.8% and likely (67.3%) with external pancreatic deficiency. P.aeroginosa colonization was revealed in 30% of cases and 45.6% patients received at least one IV antibiotic treatment. Respiratory function has been impaired in 18 cases, with a maximal expiratory volume per second < 40%. Spermatozoa were found and frozen for all patients after surgical sperm retrieval (20 MESA and 32 MESA + TESE). The mean number of epididymal motile progressive spermatozoa was satisfactory (10.2±18.83 million). Women mean age was 30 years at ICSI and female infertility was associated in 15.4%. Fertilization and cleavage rates were 66% both. Mean number of transferred and/or frozen embryos per attempt was 3. Implantation rate was 20%. A total of 50 pregnancies and 44 live births were obtained (35.5% of cumulative clinical pregnancy rate per ICSI and 29.1% of live birth rate per transfer). Fertilization rate, absence of pregnancy or absence of live birth were not affected by the genetic severity (p = 0.63, p = 0.46 and p = 0.16 respectively). Likewise, and after several univariate analyses there was no statistically significant correlation between clinical severity and ICSI outcomes. Limitations, reasons for caution Practices of assisted reproduction have constantly evolved during the study period, this concerns the controlled ovarian stimulation protocols, IVF techniques, equipment and culture media used. Our study needs to be completed by a multivariate analyse Wider implications of the findings Regarding to better quality of life of CF patients nowadays and to our results- with no significant correlation between genetic and/or clinical severity and ICSI outcomes, surgical sperm collection can be proposed only in case of a conceptional project or before transplantation and immunosuppressive agents in order to perform ICSI. Trial registration number for non-clinical trials

P-781 Elective single cleavage-stage embryo transfer in IVF patients with suboptimal ovarian response is not detrimental to cumulative pregnancy and reduces multiple pregnancy rates

Abstract Study question To compare elective single embryo transfer (eSET) with double embryo transfer (DET) in patients with suboptimal response to ovarian stimulation in terms of pregnancy rates. Summary answer Elective single embryo transfer in patients with suboptimal response to ovarian stimulation is not detrimental to cumulative pregnancy and delivery rates. What is known already Even though higher-order pregnancies in in vitro fertilization (IVF) programs have dropped significantly in recent years, the incidence of twin pregnancies is currently not negligible. The greatest efforts to promote eSET have been made in the IVF population with a good prognosis but results obtained in this population can hardly be extrapolated to patients with lower chances of success, such as those with low oocyte yield. Although still under discussion, it has been suggested that in patients with poor or suboptimal response to ovarian stimulation, eSET could achieve acceptable cumulative live birth rates with negligible risk of twin pregnancy. Study design, size, duration A matched case-control pre and post intervention study including IVF patients with poor or sub-optimal response to ovarian stimulation (≤9 oocytes) receiving a double embryo transfer (2016-2018) or elective single embryo transfer (2018-2020). Matching was performed 1:1 for female age (±18 months), AMH ≥1.2 or < 1.2 ng/ml and number of previous cycles. A sample size of 215 patients per group was foreseen to obtain ±5% variability of the main outcome (clinical pregnancy rate per cycle). Participants/materials, setting, methods A strict policy regarding single embryo transfer was introduced in our clinic from September 2018 to reduce twin pregnancy rates independently from ovarian response or embryo quality. Couples undergoing standard IVF or ICSI with ≤9 oocytes and at least 2 viable embryos were divided in two groups and matched for main variables known for influencing results: pre-intervention with DET (controls) and post-intervention with eSET (cases). In both groups, cryopreserved supernumerary embryos were always transferred individually. Main results and the role of chance A total of 463 patients with at least 2 viable embryos undergoing fresh embryo transfer after the recovery of 2 to 9 oocytes were retrospectively evaluated and, according to matching criteria, 212 cases (eSET) and 212 matched controls (DET) were included for data analysis. The cumulative clinical pregnancy rate per cycle was the same in the two groups (26%, 95%CI: 20-32%) with a crude OR = 1.00 (95%CI: 0.65-1.54), p = 1.00 and a mean female age of 37.4 and 38.0 years, respectively. The mean number of mature oocytes was 4 ±2 in both groups. Live birth rate was similar in cases and controls (22% and 21%, respectively) while twin pregnancies were significantly reduced in women receiving single embryo transfer (18% versus 0%, p = 0.008). Women receiving eSET were more likely to undergo a subsequent frozen embryo transfer (26% versus 14%, p = 0.002). Considering the main confounding factors, a binomial logistic model indicated that the cumulative clinical pregnancy rate was not significantly affected when a single embryo transfer was performed in women recovering up to nine oocytes. Similar results were obtained comparing cases and controls within subgroups: 2-4 or 5-9 oocytes; <35 or 35–39 or > 39 years female age). Limitations, reasons for caution This study does not have the statistical power to highlight small differences between the two groups. It was conducted on a specific population of women with 9 or less oocytes therefore results cannot be generalized to other populations, particularly those with a better or poorer prognosis. Wider implications of the findings eSET results are mainly based on good prognosis couples. Despite a trend for better success after fresh DET, cumulative results are not affected by eSET at the cleavage stage with significantly reduced incidence of twins and moderate delay in time to pregnancy also in poor/suboptimal responders. Trial registration number not applicable

P-788 A proof-of-concept study evaluating the effect of personalized dosages of follitropin delta in intra-uterine insemination (IUI): Personalized IUI Treatment Study (PITS)

Abstract Study question Would a personalized dosing regimen of follitropin delta based on AMH and body weight allow better management of women’s IUI cycle? Summary answer A personalized regimen of follitropin delta based on AMH and body weight has increased pregnancy rate without having increased multiple pregnancies in our studied population. What is known already IUI has been widely used as a common treatment for infertile couples due to its simplicity and low cost. Some studies have shown that cumulative live birth rate (LBR) can be increased by use of controlled ovarian stimulation. A recent meta-analysis reported that a protocol based on exogenous gonadotropins increases the LBR. Hence, this technique remains a treatment option reaching a LBR ranging from 8.5 to 12.2%. Nevertheless, this increase in LBR is associated with a non-negligible rate of adverse events, including ovarian hyper-stimulation syndrome (OHSS) and multiple pregnancies (7.2% - 9% of twins and 0.4% - 0.5% of triplets). Study design, size, duration This prospective, phase 2, open-label study enrolled 110 women 18 - 42 years of age from January 2020 to January 2021. Participants had received up to 3 IUIs. The primary efficacy variable was the number of cycles where target number of 2 or 3 mature follicles (MII) were reached. The secondary objective and safety variable were the incidence of cycle cancellations, the clinical pregnancy rate and the proportion of multiple pregnancies over 3 consecutive cycles. Participants/materials, setting, methods Follitropin delta dosing algorithm is modeled to achieve 8-14 oocytes in IVF cycles. To achieve 2-3 mature follicles, the algorithmically derived dose was divided by 4. Follitropin delta adjustment for subsequent IUIs were based on number of MII at previous IUI and age. Dose modification was made when excessive or no response were observed at stimulation day 8 during ultrasound monitoring. If urine pregnancy test was positive, a viability ultrasound was prescribed at 6-8 weeks. Main results and the role of chance Descriptive statistics were used in this proof-of-concept study. The mean age of all subjects was 34.46 years (± 4.5). The mean weight was 69.2 kg (± 11.24), AMH - 3.84 ng/ml (± 13), FSH - 6.3 IU (± 2.61), antral follicular count - 15 (± 8.6). The mean number of years of infertility was 2.48 ± 3.57. The percentage of patients who obtained 2 or 3 follicles during the 3 consecutive IUI was 34%, 37% and 47% respectively. The percentage of patients who reached ≥3 follicles was 1.9%, 0% and 1.4% respectively, demonstrating the ability of the proposed dosing regimen to achieve the desired goal. The percentage of cycle cancelation was stable throughout the 3 cycles: 8.5%, 2.4% and 8.8% respectively. Only 6 multiple pregnancies over 40 clinical pregnancies (15%) were observed, showing the proposed dosing regimen’s safe approach. The cumulative clinical pregnancy rate over the 3 cycles among patients completing the study was 37.7%, and the cumulative live birth rate (calculated ad hoc, as it was not part of the study protocol) was 33%, leading to the personalized dosing regimen proposed in this study to be considered for use in clinical practice. Limitations, reasons for caution The study’s limitations are its exploratory nature, open-label design and small sample size. Wider implications of the findings PITS study is the first one using follitropin delta for stimulation in intra-uterine insemination. It confirms the initial hypothesis of a potential benefit of a personalized dosing regimen of follitropin delta. A larger, randomized controlled study will be needed to confirm these initial findings. Trial registration number NCT03830723

P-299 Impact of endometriosis on responsiveness to ovarian hyperstimulation and embryo development: quantitative and qualitative aspects

Abstract Study question The present study was designed to better elucidate if endometriosis may affect follicologenesis and embryo development within a cycle of ovarian hyperstimulation for IVF (In Vitro Fertilization). Summary answer Endometriosis women showed fewer oocytes retrieved and a higher rate of unexpected poor response albeit number of patients without good quality embryos was similar. What is known already The pathogenetic mechanisms explaining the association between endometriosis and infertility are not fully explained. Pelvic adhesions and inflammation may play a role but other detrimental effects are presumably involved. They include reduced ovarian reserve, altered oocyte competence, impaired endometrial receptivity and association with other conditions affecting fertility such as adenomyosis. To note, even if in vitro fertilization is expected to overcome the pelvic detrimental milieu, the success rate of the procedure is lower in women with endometriosis. Study design, size, duration We designed a clinical retrospective study in order to analyse the impact of the disease on ovarian hyperstimulation and embryo development. Women were selected among those undergoing IVF cycles between January 2014 and December 2020. The primary outcome was the number of women without top quality embryos. Secondary outcomes included the rate of unexpected poor response (retrieval of ≤ 3 oocytes), cumulative clinical pregnancy rate and cumulative birth rate. Participants/materials, setting, methods Our study was performed at the Infertility Unit of the Fondazione IRCSS Ca’ Granda Ospedale Maggiore Policlinico of Milan. We included 496 subjects with a good ovarian reserve as demonstrated by serum Anti-mullerian hormone (AMH) > 1,1 ng/ml. Two hundreds and forty-eight women with endometriosis were identified and matched with two hundreds and forty-eight women without the disease according to age, pharmacological regimen, study period and AMH levels. Main results and the role of chance The number of women without good quality embryos did not differ between exposed and unexposed subjects (16% vs 16%, p = 1.00). The adjusted OR was 0.85 (95%CI: 0.51-1.44, p = 0.56). The clinical pregnancy rate and the live birth rate were also similar. We observed a lower number of oocytes retrieved and a higher rate of unexpected poor response (23% vs 13%, p = 0.005) in women with endometriosis. At subgroup analysis, the higher rate of unexpected poor responders persisted only in previously operated women (27% vs 13%, p = 0.02). Limitations, reasons for caution The evaluation of embryo quality was only based on morphological criteria. The histological diagnosis of endometriosis was lacking in unoperated women (128 subjects). Finally, our conclusions concern ovarian hyperstimulation and may not be extrapolated to natural reproductive processes. Wider implications of the findings Despite being generally reassuring, our findings do not completely exclude some mild negative effects on folliculogenesis. Effects demonstrated could be due to anatomical distortions of the pelvis causing an inefficient response of the ovarian parenchyma to hyperstimulation. We cannot exclude that the post-surgical healing process may alter local vascular supply. Trial registration number NA

P-580 Cumulative live birth rate of oocyte in-vitro maturation with a pre-maturation step in women with polycystic ovary syndrome or high antral follicle count

Abstract Study question What is the cumulative live birth rate (CLBR) at 24 months of women undergoing oocyte in vitro maturation (IVM) a with pre-maturation step (CAPA-IVM)? Summary answer The CLBR at 24 months with CAPA-IVM was 38.2%. What is known already IVM with a pre-maturation step, known as capacitation IVM (CAPA-IVM) improves the competence of oocytes matured in-vitro by sustaining meiotic arrest to allow the synchronization of cytoplasmic and genetic maturation of the oocytes. Results from a randomized controlled trial showed that CAPA-IVM resulted in a live birth rate after the first transfer of 35.2% which was non-inferior to IVF. There is a lack of data on cumulative live birth following CAPA-IVM. Study design, size, duration A multi-center, retrospective study, performed at IVFMD, My Duc Hospital and IVFMD Phu Nhuan, My Duc Phu Nhuan Hospital from 1 January 2017 to 31 December 2019. Participants/materials, setting, methods All women with polycystic ovary syndrome (PCOS) or high antral follicle count (AFC) treated with a CAPA-IVM cycle were recruited to the study. All embryos were frozen at day 3. Cumulative live birth was difined as at least one live birth resulting from initiated CAPA-IVM cycle. If the women did not return for embryo transfer, outcomes were followed up until 24 months from aspiration day. Logistic regression was performed to assess which factors predicted CLBR. Main results and the role of chance Between 1 January 2019 and 31 December 2019, there were 374 eligible women included in the study, among them, 368 patients had embryos for transfer (98.4%) and six patients had no embryo for transfer (1.6%). A total of 496 frozen embryo transfer (FET) cycles from 368 patients were performed. Mean age and body max index (BMI) were 29.5±3.21 years and 22.3±3.09, respectively. The maturation rate was 63.2%. The median number of embryos was 4.0 [2.00; 6.00]. The cumulative clinical pregnancy rate was 60.4%, cumulative ongoing pregnancy rate was 51.6%. At 24 months after starting the treatment, the CLBR of CAPA-IVM was 38.2%. Multivariate analysis showed that patient age and number of metaphase II oocytes were the predictive factors for cumulative live birth after CAPA-IVM. Limitations, reasons for caution The study limitation derives from its retrospective nature. The generalizability of the study may be limited due to the single ethnicity group. Wider implications of the findings In patients with PCOS or high AFC, CAPA-IVM was viable and resulted in acceptable CLBR. CAPA-IVM may be the first-line treatment for women with PCOS or high AFC requiring assisted reproduction. Trial registration number not applicable

Hysteroscopic resection of type 3 fibroids could improve the pregnancy outcomes in infertile women: a case–control study

BackgroundType 3 fibroids are a special subtype of intramural fibroids that are likely to affect the pregnancy outcomes of assisted reproductive techniques. Hysteroscopic resection is a treatment for type 3 fibroids, but there has few study of its efficacy to date. In this study we evaluated the effect of hysteroscopic resection of type 3 fibroids on the pregnancy outcomes in infertile women.MethodsThis retrospective case–control study was conducted from January 1, 2014 to June 30, 2021. Patients who underwent IVF-ICSI in our unit were divided into a type 3 fibroid group and a hysteroscopic myomectomy group. The inclusion criteria for the type 3 fibroid group and the hysteroscopic myomectomy group were as follows: 1) age ≤ 40 years; 2) fibroid diameter or total fibroid diameter > 2.0 cm. The following exclusion criteria were used: 1) oocyte donor treatment cycles and 2) presence of chromosomal abnormalities; 3) history of other uterine surgery; 4) presence of intracavitary lesions, including submucosal fibroids; 5) single fibroid > 5.0 cm; 6) cervical fibroids; 7) unclear ultrasound description of fibroids; 8) preimplantation genetic testing was performed and 9) congenital or acquired uterine malformations. The control group in our study was selected from patients who were treated with IVF only because of fallopian tube factors. According to the age of the type 3 fibroid group and hysteroscopic myomectomy group, random sampling was carried out in the patients between 25 and 47 years of age to determine a control group. The outcomes measured included the average transfer times to live birth, cumulative clinical pregnancy rate, and cumulative live birth rate.ResultsA total of 302 cycles were enrolled in our study, including 125 cycles with type 3 fibroids, 122 cycles with hysteroscopic myomectomy, and 139 cycles of control patients. The average transfer times to live birth were significantly higher in the type 3 fibroid group than in the other two groups. The frequency of cumulative live births in the type 3 fibroid group was significantly lower than that in the control group. Compared with the control group, the hysteroscopic myomectomy patients had no statistically significant differences in the cumulative clinical pregnancy rate and cumulative live birth rate.ConclusionsType 3 fibroids significantly reduced the cumulative live birth rate of IVF patients. Ultrasound-guided hysteroscopic myomectomy can be used as a treatment for type 3 fibroids and could improve the pregnancy outcomes in infertile women.

Embryological Characteristics of Human Oocytes With Agar-Like Zona Pellucida and Its Clinical Treatment Strategy.

Zona pellucida (ZP) abnormalities are the cause of low fertility or infertility, agar-like ZP is more common in abnormal ZP. The purpose of this exploration is to systematically analyze the fertilization competence of agar-like ZP oocytes, the development characteristics of subsequent embryos as well as the results of embryo transfer, aiming to explore effective clinical treatment strategies. A total of 58 patients with agar-like ZP were set as the case group and the control group involved 3866 patients, in which the patients’ oocytes presented normal ZP. BMI, basal hormone levels, and hormone levels were similar in both groups. The case patients suffered significantly longer infertility years than control (p<0.05), and most patients were diagnosed with pelvic inflammatory diseases. A distinct difference was observed in the structure of oocyte corona cumulus complexes between the two groups. The embryo development parameters, which include the rates of cleavage, high-quality embryo, blastocyst, and high-quality blastocyst in the case group were greatly lower than that in the control group (p<0.05). The rates of cumulative clinical pregnancy and live birth were comparable between the two groups. In the subsequent follow-up, thirty-four of the 58 patients receiving intracytoplasmic single sperm injection (ICSI) or early rescue ICSI (R-ICSI) treatment successfully gave birth to babies, and all of the newborns were with no neonatal defects. In addition, the fertilization rate of the R-ICSI group was significantly lower than that of the ICSI group (p<0.05). The occurrence of agar-like ZP impairs the development competence of human oocytes, however, the human oocytes with agar-like ZP can develop into healthy offspring, and an ICSI regimen is the optimal treatment strategy for them.

The effect of the Ontario Fertility Program on IVF utilization and outcomes in women of advanced reproductive age

Research questionAre the demographics and clinical outcomes similar for patients aged ≥40 but <43 years seeking IVF in Ontario, Canada, before and after implementation of the Ontario Fertility Program (OFP), which supports public funding of IVF up to age 43? DesignRetrospective database review using the Canadian Assisted Reproductive Technologies Registry Plus (CARTR Plus) and Better Outcomes Registry & Network (BORN) Ontario databases. Cycles from women who underwent autologous IVF and who were aged ≥40 and <43 years were analysed during a 2-year period prior to (2014–2015) and after (2016–2017) introduction of publicly funded IVF through the OFP. ResultsThere was an almost doubling of treatment cycles in women aged 40–42 in Ontario after the OFP launch. Clinical pregnancy rate per cycle start (17.0% versus 13.3%, P < 0.001) and cumulative clinical pregnancy rate per stimulation cycle (20.5% versus 16.8%, P < 0.001) were statistically higher in women before OFP implementation. While cumulative live birth rate per cycle start was statistically lower after funding was introduced (12.5% versus 10.5%, P = 0.027), the clinical importance of this difference appears small. Outcomes were above the 10% live birth per cycle threshold recommended by the Advisory Process for Infertility Services panel, commissioned by the Ministry of Health, to determine access to publicly funded IVF. ConclusionsUse of IVF in women over age 40 doubled with access to OFP funding; however, eligibility criteria based on age still meet the target of achieving a cumulative live birth rate of at least 10%.

Increased versus standard gonadotrophin dosing in predicted poor responders of IVF: an open-label randomized controlled trial.

Does an increased dosing of FSH improve the live birth rate as compared to standard FSH dosing in expected poor responders who undergo IVF? In this trial, women with an expected poor response allocated to increased FSH dosing did not have a statistically significant increase in cumulative live births as compared to a standard FSH dose. Poor ovarian reserve leads to worse IVF outcomes owing to the low number and quality of oocytes. Clinicians often individualize the FSH dose using ovarian reserve tests, including antral follicle count (AFC), and basal plasma FSH or anti-Müllerian hormone level. However, the evidence that increased FSH dosing improves fertility outcomes in women with an expected poor response is lacking. We performed a parallel, open-label randomized controlled trial between March 2019 and October 2021 in an assisted reproduction centre. Women <43 years of age with AFC <10 referred for their first IVF cycle were randomized for increased or standard FSH dosing. In participants allocated to increased FSH dosing, women with AFC 1-6 started with 300 IU/day, while women with AFC 7-9 started with 225 IU/day. In participants allocated to the standard care, women started with 150 IU/day. The primary outcome was cumulative live birth attributable to the first IVF cycle including fresh and subsequent frozen-thawed cycles within 18 months of randomization. Live birth was defined as the delivery of one or more living infants ≥24 weeks' gestation. This trial was powered to detect an 11% difference in live birth attributable to the first IVF cycle. Outcomes were evaluated from an intention-to-treat perspective. We randomized 661 women to start FSH at increased dosing (n = 328) or standard dosing (n = 333). The primary outcome cumulative live birth occurred in 162/328 (49.4%) women in the increased group versus 141/333 (42.3%) women in the standard group [risk ratio (RR) 1.17 (95% CI, 0.99-1.38), risk difference 0.07 (95% CI, -0.005, 0.15), P = 0.070]. The live birth rate after the first embryo transfer in the increased versus standard group was 125/328 (38.1%) versus 117/333 (35.1%), respectively [RR 1.08 (95% CI, 0.83-1.33), P = 0.428]. Cumulative clinical pregnancy rates were 59.1% versus 57.1% [RR 1.04 (95% CI, 0.91-1.18), P = 0.586] with miscarriage rates of 9.8% versus 14.4% [RR 0.68 (95% CI, 0.44-1.03), P = 0.069] in the increased versus standard group, respectively. Other secondary outcomes, including biochemical pregnancy, ongoing pregnancy, multiple pregnancy and ectopic pregnancy, were not significantly different between the two groups both from the first and cumulative embryo transfer. As this study is open-label, potential selective cancelling and small dose adjustments could have influenced the results. In women with predicted poor response, we did not find evidence that increased FSH dosing improves live birth rates. A standard dose of 150 IU/day is recommended at the start of IVF in these women to reduce potential adverse effects and costs. This study was funded by the General Projects of Social Development in Shaanxi Province (No. 2022SF-565). B.W.M. is supported by NHMRC (GNT1176437). B.W.M. reports personal fees from ObsEva, and funding from Merck and Ferring outside the submitted work. Registered at Chinese clinical trial registry (www.chictr.org.cn). Registration number ChiCTR1900021944. 17 March 2019. 20 March 2019.

Outcomes of a GnRH Agonist Trigger Following a GnRH Antagonist or Flexible Progestin-Primed Ovarian Stimulation Cycle.

A suggested explanation for the pituitary-suppressive effects of progestin-primed ovarian stimulation cycles (PPOS) is pituitary luteinizing hormone (LH) depletion with progestin exposure during the follicular phase. The GnRH agonist (GnRHa) trigger releases endogenous LH from the pituitary, and if the LH depletion theory is correct, the response to the agonist trigger would be dampened in PPOS cycles. In this study, we compared the performance of the GnRHa trigger after PPOS and GnRH antagonist ovarian stimulation cycles. All women who underwent ovarian stimulation with the GnRH antagonist or flexible PPOS (fPPOS) and received a GnRH agonist trigger were eligible for inclusion. Outcomes included number of metaphase-II (MII) oocytes retrieved per cycle, rates of empty follicle syndrome, maturation, fertilization, blastulation, and cumulative clinical pregnancy per stimulation cycle. During the screening period, there were 166 antagonists and 58 fPPOS cycles triggered with a GnRH agonist. Groups were matched for potential confounders using propensity score matching. Progestin-downregulated cycles had 19% high mature oocyte yield (median: 14 vs. 19 MII oocytes, P = 0.03). Cumulative ongoing pregnancy or live birth rates were estimated after matching for transferred embryo count, and rates were similar between GnRH antagonist and fPPOS group (57.0% vs. 62.1%, P = 0.68). However, the number of remaining blastocysts was higher in the fPPOS group (median: 5.0 vs. 6.0, P < 0.001). LH levels were higher in fPPOS cycles compared to GnRH antagonist cycles up to the trigger day (P < 0.001). After the GnRHa trigger, fPPOS cycles were associated with a steeper LH surge compared with antagonist cycles (P = 0.02). Higher endogenous gonadotropin levels through the stimulation period and an LH surge of higher magnitude following a GnRHa trigger suggest a milder pituitary suppression by fPPOS, which needs to be confirmed in larger samples. It appears that progestins do not deplete pituitary LH reserves and a GnRHa trigger is usable after PPOS in women with high ovarian reserve.

Cleavage-stage versus blastocyst-stage embryo transfer in assisted reproductive technology.

Advances in embryo culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage-stage embryo transfer to blastocyst-stage embryo transfer. The rationale for blastocyst-stage transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates. To determine whether blastocyst-stage (day 5 to 6) embryo transfer improves the live birth rate (LBR) per fresh transfer, and other associated outcomes, compared with cleavage-stage (day 2 to 3) embryo transfer. We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL, from inception to October 2021. We also searched registers of ongoing trials and the reference lists of studies retrieved. We included randomised controlled trials (RCTs) which compared the effectiveness of IVF with blastocyst-stage embryo transfer versus IVF with cleavage-stage embryo transfer. We used standard methodological procedures recommended by Cochrane. Our primary outcomes were LBR per fresh transfer and cumulative clinical pregnancy rates (cCPR). Secondary outcomes were clinical pregnancy rate (CPR), multiple pregnancy, high-order multiple pregnancy, miscarriage (all following first embryo transfer), failure to transfer embryos, and whether supernumerary embryos were frozen for transfer at a later date (frozen-thawed embryo transfer). We assessed the overall quality of the evidence for the main comparisons using GRADE methods. We included 32 RCTs (5821 couples or women). The live birth rate following fresh transfer was higher in the blastocyst-stage transfer group (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06 to 1.51; I2 = 53%; 15 studies, 2219 women; low-quality evidence). This suggests that if 31% of women achieve live birth after fresh cleavage-stage transfer, between 32% and 41% would do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR. A post hoc analysis showed that vitrification could increase the cCPR. This is an interesting finding that warrants further investigation when more studies using vitrification are published. The CPR was also higher in the blastocyst-stage transfer group, following fresh transfer (OR 1.25, 95% CI 1.12 to 1.39; I2 = 51%; 32 studies, 5821 women; moderate-quality evidence). This suggests that if 39% of women achieve a clinical pregnancy after fresh cleavage-stage transfer, between 42% and 47% will probably do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer increases multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; I2 = 30%; 19 studies, 3019 women; low-quality evidence) or miscarriage rates (OR 1.12, 95% CI 0.90 to 1.38; I2 = 24%; 22 studies, 4208 women; low-quality evidence). This suggests that if 9% of women have a multiple pregnancy after fresh cleavage-stage transfer, between 8% and 12% would do so after fresh blastocyst-stage transfer. However, a sensitivity analysis restricted only to studies with low or 'some concerns' for risk of bias, in the subgroup of equal number of embryos transferred, showed that blastocyst transfer probably increases the multiple pregnancy rate. Embryo freezing rates (when there are frozen supernumerary embryos for transfer at a later date) were lower in the blastocyst-stage transfer group (OR 0.48, 95% CI 0.40 to 0.57; I2 = 84%; 14 studies, 2292 women; low-quality evidence). This suggests that if 60% of women have embryos frozen after cleavage-stage transfer, between 37% and 46% would do so after blastocyst-stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; I2 = 36%; 17 studies, 2577 women; moderate-quality evidence). This suggests that if 1% of women have no embryos transferred in planned fresh cleavage-stage transfer, between 2% and 4% probably have no embryos transferred in planned fresh blastocyst-stage transfer. The evidence was of low quality for most outcomes. The main limitations were serious imprecision and serious risk of bias, associated with failure to describe acceptable methods of randomisation. There is low-quality evidence for live birth and moderate-quality evidence for clinical pregnancy that fresh blastocyst-stage transfer is associated with higher rates of both than fresh cleavage-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR derived from fresh and frozen-thawed cycles following a single oocyte retrieval. Although there is a benefit favouring blastocyst-stage transfer in fresh cycles, more evidence is needed to know whether the stage of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage. They should also evaluate women with a poor prognosis to enable those undergoing assisted reproductive technology (ART) and service providers to make well-informed decisions on the best treatment option available.

The impact of endometriosis on IVF efficacy: qualitative and quantitative assessment of ovarian response and embryo development

Research questionThe detrimental effects of endometriosis on IVF success are well known, but the underlying mechanisms are still uncertain. The objective of this study was to investigate the possible detrimental effects of the disease on ovarian response and embryo development. DesignIVF cycles performed in the authors’ unit between 2014 and 2020 were retrospectively reviewed. Women with a good ovarian reserve who underwent their first IVF cycle were included. A total of 248 women with endometriosis were identified and matched to 248 women without the disease, according to age, type of stimulation, anti-Müllerian hormone concentration and study period. The primary outcome was the number of women without good-quality embryos. Secondary outcomes included the rate of unexpected poor response (retrieval of ≤3 oocytes), the cumulative clinical pregnancy rate and the cumulative live birth rate. ResultsThe number of women without good-quality embryos did not differ between women with endometriosis (exposed group) and those without it (unexposed group). The adjusted odds ratio was 0.85 (95% CI 0.51–1.44, P = 0.56). The clinical pregnancy rate and the live birth rate were also similar. Conversely, the rate of unexpected poor response was higher among women with endometriosis (23% versus 13%, P = 0.005). ConclusionsOverall, endometriosis does not markedly affect folliculogenesis and embryo development in the context of IVF. Only an increased risk of unexpected poor response emerged.

Stimulation Duration in Patients with Early Oocyte Maturation Triggering Criteria Does Not Impact IVF-ICSI Outcomes.

Results from studies reporting the optimal stimulation duration of IVF-ICSI cycles are inconsistent. The aim of this study was to determine whether, in the presence of early ovulation-triggering criteria, prolonged ovarian stimulation modified the chances of a live birth. This cross-sectional study included 312 women presenting triggering criteria beginning from D8 of ovarian stimulation. Among the 312 women included in the study, 135 were triggered for ovulation before D9 (D ≤ nine group) and 177 after D9 (D > nine group). The issues of fresh +/− frozen embryo transfers were taken into consideration. Cumulative clinical pregnancy and live-birth rates after fresh +/− frozen embryo transfers were similar in both groups (37% versus 46.9%, p = 0.10 and 19.3% versus 28.2%, p = 0.09, respectively). No patient characteristics were found to be predictive of a live birth depending on the day of ovulation trigger. Postponing of ovulation trigger did not impact pregnancy or live-birth rates in early responders. A patient’s clinical characteristics should not influence the decision process of ovulation trigger day in early responders. Further prospective studies should be conducted to support these findings.

Fine-tuning IVF laboratory key performance indicators of the Vienna consensus according to female age.

To test the validity of the Vienna consensus laboratory key performance indicators (KPIs) to monitor the outcome of treatments involving women of different age ranges. The retrospective cohort study included 862 complete IVF/ICSI cycles carried out between January 2014 and May 2021. All embryos of each cycle cohort were subject to extended culture. The overall population was divided into two groups according to female age: the Vienna consensus (≤ 39years) and older female age (≥ 40years). We compared outcomes of a selection of the Vienna performance indicators (PIs) and KPIs, with a focus on measures relevant to embryo cleavage and blastocyst formation. A possible association between total good blastocyst development rate (TGBDR) and cumulative clinical pregnancy rate (CPR) was also assessed. No differences were observed in fertilization and embryo cleavage KPIs between the Vienna consensus and the older female age group (standard IVF fertilization, 67.2 vs. 67.3; ICSI fertilization, 72.3 vs. 75.3; day 2 development, 57.6% vs 58.7%; day 3 development, 52.4% vs. 50.7%, respectively). TGBDR was lower in the older female age group (45.5% vs. 33.4% p < 0.001). Multivariate logistic regression analysis indicated female age as a factor independently associated with TGBDR. Clinical outcomes significantly decreased with increasing female age. The study suggests that, while most laboratory outcome measures are reliably applicable irrespective of female age, KPIs describing extended embryo culture should be fine-tuned in consideration of older female age.

Use of Triggers on in vitro Fertilization and Evaluation of Risk Factors for Sub-Optimal Maturation Rate.

To compare the oocyte maturation rate in the treatment of in vitro fertilization (IVF) in terms of the use of human chorionic gonadotropin (hCG), agonist gonadotropin-releasing hormone (GnRH) and dual trigger and to evaluate the associated risk factors for sub-optimal maturation rates. A retrospective cohort study with 856 women who underwent IVF. They performed oocyte retrieval and were classified into 3 groups (1 - hCG, 2 - GnRH agonist, 3 - dual trigger). The primary outcome was maturation rate per trigger, and the secondary outcomes were the pregnancy rate per oocyte retrieval and the correlations between low maturation rate as well as the clinical and treatment characteristics of women. The maturation rate was 77% in group 1; 76% in group 2, and 83% in group 3 (p = 0.003). Group 2 showed women with better ovarian reserve, greater number of oocytes collected, and more mature oocytes and embryos compared with the other groups (p < 0.001). The cumulative clinical pregnancy rate was no different between the groups (p = 0.755). Low ovarian reserve and low doses of follicle-stimulating hormone (FSH) administered during the stimulus were associated with a higher chance of null maturation rate. The oocyte maturation rates and IVF results were similar in all groups. Low ovarian reserve is associated with the worst treatment results.

The effect of endometrial scratching on pregnancy rate after failed intrauterine insemination: A Randomised Controlled Trail

IntroductionEndometrial injury (ES) has been suggested as intervention to increase probability of pregnancy in women undergoing assisted reproductive technologies. Majority of studies reported that ES improves outcome in Invitro fertilisation,Intrauterine Insemination(IUI) and natural conceptions: however, the size and quality of studies are poor which questions the presence of any beneficial effect. The present study was done to evaluate the effect of endometrial scratching on pregnancy rate after previous failed Intrauterine Insemination and to assess the pain and bleeding following the procedure. Material and methodsRandomized controlled trial. One hundred sixty-eight women (Eighty-four in each group) with primary/secondary infertility were recruited and randomized into intervention and control group using block randomization. Intervention group underwent ES using pipelle’s canula on D8 or D9 of menstrual cycle. Three cycles of ovulation induction with Clomiphene citrate and gonadotrophins followed by IUI was done. The primary end point was clinical pregnancy rate. Pain and bleeding after the procedure were evaluated as secondary outcomes.The study was conducted from June 2017 to June 2019.Main results.The cumulative clinical pregnancy rate in ES group was 22.2 % in comparison 9.8 % in control group. In the intent to treat analysis, with a p value of 0.03 calculated from Chi-square test(p < 0.05) there was statistically significant difference in the pregnancy rate between Intervention and Control group. Efficacy of intervention was found to be Fourteen Percent (14 %). Fifty-one women (63 %) had marked a VAS pain score of 4–5 and Twelve women(12.2 %) experienced mild spotting post procedure. Two patients in ES group had miscarriage and no case of multiple pregnancy in both the groups. ConclusionEndometrial Scratching improves clinical pregnancy rate in patients with Unexplained infertility and mild male factor infertility with previous failed IUI cycles. ES will be an inexpensive alternative to IVF for couples after IUI failures especially in developing countries, with an acceptable pregnancy rate and does not demand any special qualification or equipment and can be trained easily in primary settings. Larger and adequately powered studies are needed to elucidate the beneficial effects of endometrial scratching on implantation.

A decision tree analysis applied to women aged 43–45: who should be referred for ovum donation?

Research questionIn women at the advanced age of 43–45 years undergoing repeated IVF cycles with autologous oocytes, who has the highest chance for birth and who should be referred early to receive donor oocytes? DesignA retrospective cohort study was conducted at a university hospital reproductive centre. The computerized database of 394 women aged 43–45 years undergoing 1528 non-donor IVF or intracytoplasmic sperm injection cycles between 2010 and 2019 was analysed. A decision tree was developed, enabling a comprehensive study of a set of clinical parameters and the expected outcomes. ResultsThe cumulative clinical pregnancy rate was 15.0% (59/394) and the cumulative live birth rate was 8.4% (33/394). The decision tree developed to predict women who should be offered egg donation included age, poor ovarian response to stimulation, the number of top-quality embryos, dominant follicles, previous pregnancy or live birth, fertilized oocytes and body mass index. The model showed that a good ovarian response in the first cycle was the best predictor for live birth (13.3% gave birth). However, among women with poor responses, 7.1% of those who were younger than 43.5 years gave birth, and none of the women who were older than 43.5 years did. ConclusionsWomen over 43.5 years old with fewer than four oocytes collected in their first IVF cycle should be offered ovum donation, since their live birth rate in subsequent cycles is negligible.

Efficacy of the depot gonadotropin-releasing hormone agonist protocol on in vitro fertilization outcomes in young poor ovarian responders from POSEIDON group 3.

To investigate whether the depot gonadotropin-releasing hormone (GnRH) agonist protocol could improve in vitro fertilization (IVF) outcomes for young poor responders from POSEIDON group 3. This retrospective cohort study was carried out from June 2017 to June 2020. A total of 451 patients were assigned to three groups depending on the ovarian stimulation protocols. The outcome parameters of IVF were compared in each group. Patients who received the depot GnRH agonist had significantly higher cumulative clinical pregnancy rates (50.88%, 32.02%, and 31.88%, respectively; P=0.009 and P=0.007) and cumulative live birth rate (48.25%, 26.97%, and 28.99%, respectively; P=0.004 and P=0.009) compared with mild ovarian stimulation protocol and GnRH antagonist protocol. They also had higher live birth rate per fresh embryo transfer cycle (47.78%, 32.35%, and 36.62%, respectively), but these differences were not statistically significant. Moreover, duration of stimulation, total dose of gonadotropins and endometrial thickness were significantly higher among women who received the depot GnRH agonist (P<0.001). However, they had lower embryo transfer cancellation rate, and abnormal endometrium rate (P<0.001). The depot GnRH agonist protocol may improve cumulative clinical pregnancy rate and cumulative live birth rate for young women with poor ovarian response from POSEIDON group 3.

DELAYING OVULATION TRIGGERING DOESN'T COMPROMISE CUMULATIVE PREGNANCY RATES IN FROZEN EMBRYO TRANSFER

Defining optimal ovulation trigger criteria has been a persistent concern in assisted reproduction technology. The commonly used ultrasound parameter has been the presence of at least 3 follicles ≥17 mm. The impact of delaying ovulation triggering has been studied in fresh embryo transfers with discordant results. Therefore, we queried whether using larger ultrasound criteria and delaying ovulation triggering– by one or two days – increased the number of metaphase II oocytes (MII), usable blastocysts and cumulative clinical pregnancy rates (cCPR) in frozen embryo transfers. All patients performing their first autologous In Vitro Fertilization (IVF) cycle between 1/2017 and 12/2019 with antagonist protocol and frozen embryo transfers in our center were considered. We included only patients with blastocysts transfers. We divided patients into 3 groups constituted as: control group with patients whose ovulation was triggered when > 3 follicles reached >17 mm; the group 1 and 2 had ovulation triggered one and two days, respectively after the forementioned ultrasound criteria were reached. The primary outcome was cCPR. The secondary outcomes were: MIIs number, fertilization, blastulation, implantation and miscarriage rates. Comparisons between the 3 treatment groups were assessed using statistical analysis Chi2 and ANOVA. 1180 patients (598, 449 and 133 in the control group and group 1 and 2, respectively) were analyzed. Patients in group 2 were significantly younger (34.1 years) than those in the control group (35.4) and group 1 (34.9) p=0.01. Ovarian reserve parameters, type of infertility and BMI were similar between the groups. Ovarian stimulation length was approximately 11 days. Analysis of cCPR showed no difference but yet, a trend toward higher values in group 1 (47,7%) and in group 2 (51,1%), as compared to controls (45,3%) p=0.44, paralleling a trend toward more MII (11.4, 11.8 and 12.3 p=0.44) and vitrified blastocysts (3.2, 3.4 and 3.7 p=0.29) in controls and group 1 and 2 respectively. Fertilization, blastulation, implantation and miscarriage rates were similar in all 3 groups. Likewise, no difference was found after adjustment for age. Using larger ultrasound criteria for triggering ovulation in ovarian stimulation doesn’t compromise oocyte quantity nor cCPR when frozen embryos are transferred. Interestingly, using larger ultrasound criteria for triggering ovulation didn’t lengthen ovarian stimulation thereby suggesting that clinicians adjust their judgment when triggering ovulation according to ovarian stimulation duration.