Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number Research Articles

P-122 The impact of severe male factor on morphokinetic embryo development in low-prognosis patients according to the POSEIDON criteria: an analysis of 10366 injected oocytes

Abstract Study question Does severe male factor infertility (SMF) impact embryo morphokinetic behavior in low-prognosis women as stratified by the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria? Summary answer Embryos from SMF patients showed lower KIDScore ranking than those from non-SMF (nSMF) patients, which may justify the reduced clinical outcomes contrasted to Control group. What is known already It has been reported that 37.1% of poor responder patients (POR) have infertile male partners. While the maternal influence has been well-investigated, the role of seminal quality on reproductive outcomes in POR remains questionable. Embryo monitoring with timelapse imaging (TLI) may be a valuable approach to evaluate whether sperm quality relates to association between POSEIDON classification and the competences of developing embryos. The aim of this study was to investigate whether SMF impacts embryo quality and morphokinetic behavior in the four groups of low-prognosis women as stratified by the POSEIDON criteria. Study design, size, duration This historical cohort-study was performed in a private university–affiliated IVF center, between Mar/2019 and Apr/2022. Kinetic data were analyzed in 10366 embryos cultured in a TLI incubator until day five, derived from 2272 patients undergoing ICSI. Patients were split into eight groups according to the POSEIDON criteria and the presence or absence of SMF (<5 × 106 sperms/mL). Embryo morphokinetics were compared among the groups (post hoc achieved power > 90%). Participants/materials, setting, methods Injected oocytes were cultured in the EmbryoScope+ incubator, which recorded the following kinetic markers: timing to pronuclei appearance and fading (tPNa and tPNf), two (t2), three (t3), four (t4), five (t5), six (t6), seven (t7), and eight cells (t8), morulae (tM), start of blastulation (tSB) and blastulation (tB). Durations of second and third cell cycles (cc2 and cc3) and timing to complete synchronous divisions s1, s2, and s3 were calculated. The KIDScore ranking was recorded. Main results and the role of chance POSEIDON group 1 embryos showed significantly slower tPNa, tPNf, t2, t3, t4, t6, and t7 compared to those from Control group. POSEIDON group 2 embryos showed significantly slower tPNa, t4, t6, t7, t8, and tM compared to those from Control group. Embryos in POSEIDON 2 SMF subgroup took longer than those in POSEIDON 2 nSMF subgroup, and those in both Control subgroups, to achieve tPNf, t2, t3, t5, tSB. POSEIDON group 3 embryos showed significantly slower t8, and cc2 compared to those from Control group. POSEIDON group 4 embryos showed significantly slower tPNf, t2, t3, t4, t5, t6, t7, t8, s2, and s3 compared to those from Control group. For POSEIDON groups 1, 2 and 4, and Control group, the KIDScore ranking was significantly different between SMF and nSFM subgroups. KIDScore ranking was significantly different across all the subgroups in POSEIDON 3. Irrespective of sperm quality, implantation and miscarriage rates were significantly improved in Control subgroups compared to POSEIDON 2 subgroups, there were trends toward improved clinical outcomes in Control subgroups compared to POSEIDON 3 subgroups, and pregnancy, implantation and miscarriage rates were significantly improved in Control subgroups compared to POSEIDON 4 subgroups. Limitations, reasons for caution The use of historical cohort groups is a drawback. Despite the eligibility criteria for inclusion in the analysis, potential differences in the baseline characteristics cannot be ruled out. Wider implications of the findings The results presented contribute to the understating of the relationship between sperm quality and embryo morphokinetic behavior in POSEIDON patients. Embryo quality, as assessed by TLI-imaging, and clinical outcomes were significantly lower in POSEIDON SMF patients, suggesting that both oocyte (quantity and quality) and sperm are determinant of embryo development. Trial registration number N/A

P-710 Comparison of cumulative delivery rates per aspiration cycle in patients fulfilling Bologna and POSEIDON criteria

Abstract Study question Do cumulative delivery rates (CDRs) per aspiration cycle differ in low-prognosis patients according to the Bologna and POSEIDON (Patient-Oriented-Strategies-Encompassing IndividualizeD-Oocyte-Number) classification criteria? Summary answer The CDR was 8.7% in Bologna and 22.7% in POSEIDON. The odds of achieving live-birth were ∼3-fold higher in POSEIDON than in the Bologna group. What is known already Bologna criteria were generated to address the heterogeneity in the definition of the Poor Ovarian Response (POR). However, patients meeting these criteria may not be homogeneous in terms of the number of oocytes retrieved and live birth rate. Subsequently, as a more inclusive classification, the POSEIDON criteria were proposed to stratify low-prognosis patients according to female age and suboptimal response to ovarian stimulation. To our knowledge, there is a paucity of data comparing CDRs between the POSEIDON and Bologna groups. Study design, size, duration Retrospective cohort study including 1250 patients undergoing their first ovarian egg retrieval cycle at Hacettepe University IVF Center in Ankara between 2017 and 2023. Exclusion criteria were female age >45 years old, body mass index >35 kg/m2, azoospermia, pre-implantation genetic testing (PGT) for structural rearrangement or monogenic disorders, fertility preservation cycles, dual-stimulation cycles, premature ovarian insufficiency, and hypogonadotropic hypogonadism. The primary outcome measured was CDR defined by ICMART (International Committee for Monitoring Assisted Reproductive Technologies). Participants/materials, setting, methods The Bologna patients have at least two of the following three features; female-age ≥40 or prior ovarian surgery, AMH<1.1ng/ml or antral-follicle-count (AFC)<5-7, and obtaining ≤3 oocytes in prior conventional stimulation. POSEIDON patients were categorized into four groups; younger(<35) and older(≥35) women with AMH≥1.2/AFC≥5 experiencing an unexpected poor(<4 oocytes-retrieved) or suboptimal(4–9 oocytes-retrieved) response, along with respective younger and older counterparts with AMH<1.1/AFC<5. Non-POSEIDON patients were those with AMH≥1.2/AFC≥5 and >9 oocytes-retrieved. General-Estimated-Equation(GEE) analysis was employed. Main results and the role of chance Out of 1250 patients, 79.6% were classified as POSEIDON, with sub-groups as follows: 5.28% Group 1a, 23.4% Group 1b, 3.6% Group 2a, 10.1% Group 2b, 14.64% Group 3, and 22.48% Group 4. The number of patients meeting Bologna criteria was 17.4% (218). For POSEIDON patients, median[IQR] values were: age 34 [30-38], AMH 1.33 [0.65-2.69], oocytes retrieved 4 [2-6], and embryo transfers 1 [1-2]. For non-POSEIDON patients: age 30 [27-33], AMH 4.63 [2.93-7.07], oocytes retrieved 13 [11-15], and embryo transfers 2 [1-3]. In Bologna patients: age 40 [36-42], AMH 0.46 [0.20-0.76], oocytes retrieved 2 [1-3], and embryo transfers 1 [0-1]. For non-Bologna patients: age 31 [28-36], AMH 2.30 [1.17-4.29], oocytes retrieved 6 [3-9], and embryo transfers 1 [1-2]. CDR for non-POSEIDON: 49.8%; Group 1a, 24.2%; Group 1b, 34.1%; Group 2a, 15.6%; Group 2b, 27.6%; Group 3, 20.8%; Group 4, 10.7%. In clustered-GEE analysis, using non-POSEIDON as reference, odds ratios (ORs) for live birth were: Group 1a OR 0.32 [0.18 - 0.60]; Group 1b OR 0.52 [0.37-0.74]; Group 2a OR 0.19 [0.08-0.43]; Group 2b OR 0.38 [0.24-0.61]; Group 3 OR 0.26 [0.17-0.41]; Group 4 OR 0.12 [0.08-0.19]. CDR for the Bologna group: 8.7% (OR: 0.10, 0.06-0.16); non-Bologna patients: 32.4% [OR: 0.48, 0.39-0.60]. Limitations, reasons for caution The limitations of the study encompass its retrospective cohort design and the variability introduced by different individuals conducting antral follicle counts using 2D ultrasonography. Wider implications of the findings Significant CDR differences exist between Bologna and Poseidon groups. POSEIDON patients show ∼2-fold lower CDR than normal responders, and Bologna patients exhibit ∼4-fold lower CDR than non-Bologna patients. Poseidon criteria cover a broader range of low-prognosis patients, while meeting Bologna criteria indicates a narrower, more specific group with poorer outcomes. Trial registration number N/A

Effectiveness of oestrogen pretreatment in patients with expected poor ovarian response (POSEIDON groups 3 and 4) undergoing GnRH antagonist protocol: study protocol for a randomised controlled trial

IntroductionWomen characterised by diminished ovarian reserve are considered to have poor ovarian response (POR) according to Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria. Patients in this population often have...

Conventional follicular-phase ovarian stimulation vs. luteal-phase stimulation in suboptimal responders: a randomized controlled trial

To compare the oocyte yield between follicular-phase stimulation (FPS) and luteal-phase stimulation (LPS) in suboptimal responders. Prospective, randomized, crossover clinical trial. Forty-one patients with infertility according to the POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria (1b/2b). Crossover study on 2 assigned ovarian stimulations that started randomly in the follicular or luteal phase. The invitro fertilization cycles were not consecutive but separated in time (45 days to 6 months). The random crossover design ensured that all subjects received the first treatment by chance. The primary objective was the number of cumulus-oocyte complexes retrieved in each cycle. Secondary objectives were number of metaphase II and fertilized oocytes, additional doses of recombinant follicle-stimulating hormone, and the duration of ovarian stimulation (days). The mean number of cumulus-oocyte complexes retrieved was similar between the FPS and LPS groups (7.5 ± 4.6 vs. 7.0 ± 4.1; 95% confidence interval [CI] for the mean, 5.8-8.7 vs. 5.6-8.3, respectively; the difference between means, -0.5; 95% CI, -1.8 to +1.5). Similarly, the mean number of metaphase II oocytes retrieved was not different between the FPS and LPS groups (5.4 ± 3.6 vs. 5.2 ± 2.8; 95% CI for the mean, 4.2-6.5 vs. 4.3-6.1, respectively; the difference between means, -0.2; 95% CI, -1.2 to +1.1). Moreover, the secondary objectives were similar between FPS and LPS groups. In this study, the oocyte yield in LPS did not increase in suboptimal responders compared with that in FPS when the onset of LPS was separated in time from FPS. NCT039393990 https://beta.clinicaltrials.gov/study/NCT03939390.

O-118 Morphokinetic embryo behavior in low-prognosis patients according to the POSEIDON criteria: an analysis of 3326 injected oocytes

Abstract Study question Do embryo quality and morphokinetic behavior differ in the four groups of low-prognosis women as stratified by the POSEIDON criteria? Summary answer Embryo quality and morphokinetic behavior differ across the POSEIDON groups, being more favorable in POSEIDON group 1, as well as were implantation and miscarriage rates. What is known already Poor ovarian responders (POR) represent 9-24% of patients undergoing ovarian stimulation, and the clinical management of these patients remains a challenge in everyday practice. In an attempt to standardize the diagnosis of POR, the medical community developed the Bologna Criteria and then shifted to the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON). Embryo monitoring with timelapse imaging (TLI) may allow the identification of morphokinetic events potentially affected by ovarian response. The aim of this study was to compare embryo quality, and speed and pattern of cell divisions in the four groups of POR as stratified by the POSEIDON criteria. Study design, size, duration This cohort study included low-prognosis patients undergoing their first intracytoplasmic sperm injection (ICSI) from Mar/2019 to Apr/2022 at a private-university affiliated IVF center, who met the POSEIDON criteria. A total of 3326 injected oocytes from 846 women were analyzed. Kinetic markers from the point of insemination were recorded. Generalized mixed models followed by Bonferroni post hoc were used to compare morphokinetics among the POSEIDON groups. The post hoc achieved power was > 80%. Participants/materials, setting, methods Injected oocytes were cultured in the EmbryoScope+ incubator, which recorded the following kinetic markers: timing to pronuclei appearance and fading (tPNa and tPNf), two (t2), three (t3), four (t4), five (t5), six (t6), seven (t7), and eight cells (t8), morulae (tM), start of blastulation (tSB) and blastulation (tB). Durations of second and third cell cycles (cc2 and cc3) and timing to complete synchronous divisions s1, s2, and s3 were calculated. The KIDScore ranking was recorded. Main results and the role of chance The results from the generalized mixed models followed by Bonferroni post hoc for the comparison of means among groups showed that embryos derived from patients in the POSEIDON groups 2, 3 and 4 showed significantly slower divisions compared to those from POSEIDON 1 group (Table 1). The KIDScore rank was significantly lower for embryos derived from POSEIDON groups 2, 3 and 4 (2: 4.4 ± 0.7 vs. 3: 4.2 ± 0.2 vs. 4: 3.0 ± 0.4) compared to those derived from POSEIDON 1 group (4.8 ± 0.1, p < 0.001). Group POSEIDON 1 also showed improved implantation (26.9% vs. 2: 22.4% vs. 3: 20.0% vs. 4: 14.0, p < 0.001) and miscarriage rates (5.6% vs. 2: 31.2% vs. 4: 50.0%, p = 0.013). Limitations, reasons for caution The use of historical cohort groups is a drawback. Despite the eligibility criteria for inclusion in the analysis, potential differences in the baseline characteristics cannot be ruled out. Wider implications of the findings Embryo development was more favorable in POSEIDON group 1, suggesting a direct relationship between oocyte quantity and quality, and that oocyte quality is determinant of embryo development. These show the reasonability of classifying POR by the POSEIDON criteria, providing information for the appropriate counselling of POR regarding their possible prognosis. Trial registration number N/A

Comparison of Cumulative Live Birth Rate (CLBR) According to Patient Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) Stratification Among Low Prognosis Women Undergoing IVF-ICSI Cycles.

The purpose of the current study was to evaluate patient-oriented strategies encompassing individualized oocyte number (POSEIDON) criteria, validate stratification of low prognosis women, and prognosticate their reproductive potential in terms of cumulative live birth rate (CLBR) in Indian women. Out of 4048 women who underwent IVF/ICSI, 3287 women met the criteria for final evaluation of CLBR. They criteria were divided into (a) group 1a as cases with <4 oocytes retrieved and 1b with 4-9 oocytes retrieved; (b) group 2a as cases with <4 oocytes retrieved and 2b with 4-9 oocytes retrieved; (c) group 3 (<35 years, AMH <1.2 ng/ml, AFC <5); and (d) group 4 (≥35 years, AMH <1.2 ng/ml, AFC <5). Non-POSEIDON group was sub-divided into normo-responders (10-20 oocytes) and hyper-responder (>20 oocytes). Overall CLBR was two-fold lower in POSEIDON group as compared to non-POSEIDON group (p<0.001). For every one-year increase in the age, the odds of CLBR decreased by 4% (OR 0.96, CI 0.93-0.99) in POSEIDON group and by 5% (OR 0.95, CI 0.92-0.98) in non-POSEIDON group. For every unit increase in number of oocytes retrieved, the odds of CLBR increased by 1.22 times (OR1.22, CI 1.16-1.28) in POSEIDON group and by 1.08 times (OR 1.08, CI 1.05-1.11) in non-POSEIDON group. Among POSEIDON groups, the highest values in CLBR belonged to group 1b followed by 3, 2b, 4, 1a, and 2a. POSEIDON stratification of low-prognosis women undergoing IVF may be considered valid to prognosticate and counsel women undergoing IVF. Prospective studies will strengthen its validity among different ethnic populations.

Determination of serum anti-Mullerian hormone levels in a low-prognosis women treated in-vitro fertilization/intracytoplasmic sperm injection: A cohort study.

Outcome prediction of participants treated with in-vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) using anti-Mullerian hormone (AMH) concentration has been widely used. According to the patient-oriented strategies encompassing individualized oocyte number (POSEIDON) definition, low prognosis Bologna responders have changed from poor. This definition divides low prognosis into 4 groups. The purpose of this study was to assess blood AMH levels in the group of women treated with IVF/ICSI who were thought to have a low prognosis. A retrospective cohort study among 252 suspected low-prognosis group participants was assessed between January 2016 and December 2019 at Morula IVF, National hospital, Surabaya, Indonesia. Observed AMH serum levels and pregnancy rates were compared among 4 subgroups. The AMH cutoff value was 1.7 ng/mL with a sensitivity of 86.7% and a specificity of 70% for diagnosing low-prognosis women using POSEIDON criteria. There was no difference in the pregnancy rate between those groups (p 0.05). AMH levels may indicate a poor prognosis for women having IVF/ICSI in accordance with POSEIDON guidelines. To predict the poor prognosis in women, the cutoff value must be identified.

Efficacy of progestin-primed ovarian stimulation (PPOS) versus minimal stimulation in women of advanced maternal age with poor ovarian response under the Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) criteria

We investigated the efficacy of progestin-primed ovarian stimulation (PPOS) and minimal stimulation using clomiphene citrate (CC) + gonadotropin (Gn) for in-vitro fertilization-embryo transfer (IVF-ET) in advanced maternal age (AMA) women with poor ovarian response (POR) according to the Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) criteria. A retrospective analysis was performed using the data of AMA patients who had received IVF-ET due to a low ovarian reserve. The enrolled patients were screened according to the POSEIDON group 4 criteria. 102 patients were included in the study, including 52 in the PPOS group and 50 in the minimal stimulation group (who received CC + Gn). The duration of Gn administration, Gn dose, estradiol (E2), and luteinizing hormone (LH) levels on the day of trigger, the cancellation rate of the oocyte retrieval cycle, the number of oocytes retrieved, the number of metaphase II (MII) oocytes, and IVF laboratory outcomes during ovarian stimulation were compared between the 2 groups. No significant differences were found in terms of age, infertility, body mass index (BMI), and basal follicle-stimulating hormone, LH, E2, AFC, and AMH between the 2 groups (all P>0.05). The duration of ovarian stimulation [(9.43±2.44) vs. (7.48±3.09) days, P<0.05] was significantly longer and the total Gn dose [(2,423.22±738.66) vs. (1,579.68±728.86) IU, P<0.05] were significantly higher in the PPOS group than the minimal stimulation group. The LH value on the day of trigger in the PPOS group (3.28 mIU/mL) was significantly lower than that in the minimal stimulation group (5.57 mIU/mL) (P<0.05). The number of oocytes retrieved, normal fertilization rate, number of good-quality embryos on day 3, number of transferable embryos, and number of frozen blastocysts did not differ significantly between the 2 groups (all P>0.05). The proportion of MII oocytes was significantly higher in the PPOS group than the minimal stimulation group (94.05% vs. 81.40%, P<0.05). For patients in the POSEIDON group 4, PPOS effectively blocked the premature LH surge and increased the proportion of mature oocytes. Thus, it is a feasible ovulation stimulation protocol for AMA women with POR.

Ovarian Stimulation in Patient-oriented Strategies Encompassing Individualised Oocyte Number-4 Category; Antagonist versus Short-agonist Protocols.

Recently POSEIDON (Patient-Oriented Strategies Encompassing Individualized Oocyte Number) classification was proposed to categorize patients with expected poor response to conventional stimulation. Searching for the ideal management of poor responders in IVF is still an active research area. This study compares GnRH-antagonist and GnRH-agonist short protocols in ICSI cycles for the POSEIDON-4 group. This retrospective study was conducted in a tertiary infertility unit between January 2016 and December 2020. Infertile women who met the criteria for POSEIDON 4 group and underwent fresh ICSI-ET in using GnRH-antagonist and GnRH-agonist short protocols was performed. POSEIDON-4 includes patients ≥ 35 years with poor ovarian reserve markers; AFC < 5 and AMH < 1.2 ng/ml. Numerical variables were compared between both groups by student's t test and Mann Whitney test when appropriate. Chi-square test used to compare categorical variables. Multivariate logistic regression models were utilized to adjust for the effect of the different study confounders on live birth rate. One hundred ninety fresh ICSI cycles were analyzed. Of the total cohort, 41.6 % (79) patients pursued antagonist protocol compared to 58.4% (111) underwent short agonist protocol. Fresh embryo transfer was accomplished in 55.7 % (44/79) vs. 61.3 % (68/111), P = 0.44 in antagonist vs. short protocol respectively. Cycle cancellation due to poor ovarian response was encountered in (32.9%vs. 27.9%, P = 0.50) in the antagonist and short groups, whereas no good-quality embryos were developed after ovum pickup in 11.4% vs. 10.8%, P>0.05. Comparable total gonadotropins dose, number of retrieved and mature oocytes, and good-quality embryos were found in both groups. Likewise, clinical pregnancy rate was not different for the antagonist and short groups [11/79 (13.9%) vs. 20/111 (18%), P = 0.45]. The live birth rate was comparable between both groups (8.9% vs. 10.8%, P = 0.659) for antagonist and short groups respectively. No significant impact for the protocol type on live birth rate was revealed after adjusting to cycle confounders in multivariate analysis (OR: 0.439, 95%CI 0.134-1.434, P = 0.173). This study shows comparable pregnancy outcomes for antagonist and short-agonist protocols in IVF/ICSI cycles for POSEIDON-4 category.

POSEIDON groups and their distinct reproductive outcomes: Effectiveness and cost-effectiveness insights from real-world data research.

The Patient-Oriented Strategies Encompassing IndividualizeDOocyte Number (POSEIDON) criteria identify and classify the so-called 'low-prognosis' patients undergoing assisted reproductive technology (ART). Recent large-scale studies using real-world data (RWD) have shown that patients classified under this system have distinct reproductive outcomes. Moreover, these studies also confirm that POSEIDON patients are commonly found in fertility centers. RWD has substantiated the validity of the POSEIDON biomarkers' thresholds (antral follicle count [AFC] and/or anti-Müllerian hormone [AMH]) for patient classification. Lastly, a predictive model has been developed and validated to estimate the POSEIDON metric of success (i.e., number of oocytes needed to achieve at least one euploid blastocyst). Although more evidence is needed in this area, current insights from RWD research indicate that infertility patients can be counseled and managed more effectively under the POSEIDON scope, with potential gains for all parties involved.

Comparison of ART outcome in patients with poor ovarian response according to POSEIDON criteria

The aim of this study is to evaluate whether the patient-oriented strategies encompassing individualized oocyte number (POSEIDON) criteria can reflect the prognosis of controlled ovarian stimulation (COS) by comparing the results of assisted reproductive technologies (ART) between four POSEIDON and normal responder (NR) groups. In total, 225 patients were included in this retrospective observational study. The patients underwent various COS protocols and in vitro fertilization or intracytoplasmic sperm injection, followed by fresh or frozen embryo transfer. Based on their clinical and demographic data, patients were divided into four groups according to the POSEIDON classification, and their ART outcomes were evaluated. Statistical analyses were performed using R version 4.0.5, and a p-value of < 0.05 was considered significant. The NR group had the highest number of total oocytes retrieved and total embryos obtained, as well as the best ART outcome in terms of clinical pregnancy rate ([CPR], 47.6%). The POSEIDON groups 1 and 2 had better COS and ART outcomes than groups 3 and 4 (CPR, 22.6%, 22.1%, 16.7%, and 4.8% in groups 1–4, respectively); the patients in group 3 were younger than those in group 2 by definition, but their CPR was lower than that of patients in group 2. When comparing young and old women with low anti-Müllerian hormone (AMH) levels, the younger group (POSEIDON group 2) had better COS and ART outcomes than their older counterparts, especially POSEIDON group 4. A binary logistic regression adjusted for body mass index (BMI) comparing the ART outcomes of patients that did not get pregnant in the POSEIDON groups compared to the NR group showed odds ratios (ORs) (95% confidence interval) of 2.938 (1.496–5.768), 3.376 (1.848–6.167), 6.801 (2.740–16.881), and 20.497 (8.284–50.713) for groups 1, 2, 3, and 4, respectively. Ovarian reserve still seems to outweigh patients’ age when predicting the ART outcomes of low-responder infertile women, as suggested by the results of POSEIDON groups 2 and 3. However, when there are no differences in ovarian reserve, as in POSEIDON groups 2 and 4, younger women with low AMH have a higher probability of pregnancy than their AMH-matched older counterparts.

Transcriptomic landscape of granulosa cells and peripheral blood mononuclear cells in women with PCOS compared to young poor responders and women with normal response.

STUDY QUESTIONAre transcriptomic profiles altered in ovarian granulosa cells (GCs) and peripheral blood mononuclear cells (PBMNCs) of women with polycystic ovary syndrome (PCOS) compared to young poor responders (YPR) and women with normal response to ovarian stimulation?SUMMARY ANSWERRNA expression profiles in ovarian GCs and PBMNCs were significantly altered in patients with PCOS compared with normoresponder controls (CONT) and YPR.WHAT IS KNOWN ALREADYPCOS is characterised by a higher number of follicles at all developmental stages. During controlled ovarian hyperstimulation, PCOS women develop a larger number of follicles as a result of an exacerbated response, with an increased risk of ovarian hyperstimulation syndrome. Despite the number of developing follicles, they are often heterogeneous in both size and maturation stage, with compromised quality and retrieval of immature oocytes. Women with PCOS appear to have a longer reproductive lifespan, with a slightly higher menopausal age than the general population, in addition to having a higher antral follicular count. As a result, the ovarian follicular dynamics appear to differ significantly from those observed in women with poor ovarian response (POR) or diminished ovarian reserve.STUDY DESIGN, SIZE, DURATIONTranscriptomic profiling with RNA-sequencing and validation using quantitative reverse transcription PCR (qRT-PCR). Women with PCOS (N = 20), YPR (N = 20) and CONT (N = 20). Five patients for each group were used for sequencing and 15 samples per group were used for validation.PARTICIPANTS/MATERIALS, SETTING, METHODSPCOS was defined using the revised Rotterdam diagnostic criteria for PCOS. The YPR group included women <35 years old with <4 mature follicles (at least 15 mm) on the day of the trigger. According to internal data, this group represented the bottom 15th percentile of patients' responses in this age group. It was consistent with Patient-Oriented Strategies Encompassing Individualize D Oocyte Number (POSEIDON) criteria for POR (Group 3). The young CONT group included women <35 years without PCOS or anovulation, who developed >14 mature follicles (at least 15 mm on transvaginal ultrasound). According to internal data, a threshold of >14 mature follicles was established to represent the top 25% of patients in this age group in this clinic.Overall, n = 60 GCs and PBMNCs samples were collected and processed for total RNA extraction. To define the transcriptomic cargo of GCs and PBMNCs, RNA-seq libraries were successfully prepared from samples and analysed by RNA-seq analysis. Differential gene expression analysis was used to compare RNA-seq results between different groups of samples. Ingenuity pathway analysis was used to perform Gene Ontology and pathways analyses.MAIN RESULTS AND THE ROLE OF CHANCEIn PBMNCs of PCOS, there were 65 differentially expressed genes (DEGs) compared to CONT, and 16 compared to YPR. In GCs of PCOS, 4 genes showed decreased expression compared to CONT, while 58 genes were differentially expressed compared to YPR. qRT-PCR analysis confirmed the findings of the RNA-seq. The functional enrichment analysis performed revealed that DEGs in GCs of PCOS compared to CONT and YPR were prevalently involved in protein ubiquitination, oxidative phosphorylation, mitochondrial dysfunction and sirtuin signaling pathways.LARGE SCALE DATAThe data used in this study is partially available at Gene Ontology database.LIMITATIONS, REASONS FOR CAUTIONThe analysis in PBMNCs could be uninformative due to inter-individual variability among patients in the same study groups. Despite the fact that we considered this was the best approach for our study's novel, exploratory nature.WIDER IMPLICATIONS OF THE FINDINGSRNA expression profiles in ovarian GCs and PBMNCs were altered in patients with PCOS compared with CONT and YPR. GCs of PCOS patients showed altered expression of several genes involved in oxidative phosphorylation, mitochondrial function and sirtuin signaling pathways. This is the first study to show that the transcriptomic landscape in GCs is altered in PCOS compared to CONT and YPR.STUDY FUNDING/COMPETING INTEREST(S)This study was partially supported by grant PI18/00322 from Instituto de Salud Carlos III, and European Regional Development Fund (FEDER), ‘A way to make Europe’ awarded to S.H. M.C., S.H., S.T., L.R., M.R., I.R., A.P. and R.C. declare no conflict of interests concerning this research. E.S. is a consultant for and receives research funding from the Foundation for Embryonic Competence.TRIAL REGISTRATION NUMBERN/A.

Euploid blastocyst rates in patients from POSEIDON groups 3 and 4 using propensity score matching

Research questionDo patients with low ovarian reserve, as defined by the patient-oriented strategies encompassing individualized oocyte number (POSEIDON) criteria, have low euploid blastocyst rates? DesignRetrospective study of 548 IVF cycles of patients with unexplained recurrent miscarriage who underwent preimplantation genetic test for aneuploidy (PGT-A). Euploid blastocyst rates were analysed to compare patients from POSEIDON groups 3 and 4 (serum anti-Müllerian hormone [AMH] levels <1.2 ng/ml) with those who have normal ovarian reserve (AMH levels ≥1.2 ng/ml) before and after using propensity score matching to match selected variables, such as female age, body mass index, the number of clinical miscarriages, ovarian stimulation protocols and PGT-A analysis platforms. Cycles of patients from POSEIDON groups 3 and 4 were then divided into four groups according to median and quartiles of serum AMH levels: <0.668 ng/ml, 0.668–0.890 ng/ml, >0.890–1.070 ng/ml and >1.070–<1.20 ng/ml. The euploid blastocyst rates were compared across these four groups. ResultsAfter using propensity score matching, no difference was found in euploid blastocyst rates between patients from POSEIDON groups 3 and 4 and those with normal ovarian reserve. Among cycles of patients from POSEIDON groups 3 and 4, no difference was found in euploid blastocyst rates between the different AMH levels. ConclusionsThe decline in ovarian reserve in patients from POSEIDON groups 3 and 4 was not related to low euploid blastocyst rates. Serum AMH levels do not seem to be a predictor of euploid blastocyst rates in such patients.

Association between different dual trigger dosages and in vitro fertilization results in patients with patient-oriented strategies encompassing individualized oocyte number group IV

ObjectiveDual trigger is used to induce final oocyte maturation during the process of controlled ovarian hyperstimulation, yet yielding controversial results. Also, there are yet no data regarding the effect of the dosage of the dual trigger on clinical outcomes. Based on the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria, this study aimed to determine the clinical difference of a single bolus versus two boluses of gonadotropin-releasing hormone agonist (GnRHa) in POSEIDON group IV patients using dual trigger.MethodsWe screened a total of 1,256 patients who underwent in vitro fertilization (IVF) cycles who met the POSEIDON group IV criteria. Six hundred and twenty-nine patients received one bolus of GnRHa, and 627 patients were given two boluses. All patients received the same dose of recombinant human chorionic gonadotropin during the dual trigger cycle.ResultsMetaphase II oocyte retrieval rate, fertilization rate and clinical pregnancy rate did not differ between the two groups. However, a lower percentage of at least one top-quality embryo transfer (34.3% vs. 26.0%, P=0.001) in the two bolus-GnRHa group was noted.ConclusionA double bolus of GnRHa did not show superior clinical results compared to a single bolus of GnRHa in the dual trigger IVF cycle. Therefore, GnRHa doses for use should be decided based on individual clinical situations considering cost-effectiveness and patient compliance, but further investigation will be needed.

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

STUDY QUESTIONWhat 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 ANSWERThe 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 ALREADYThe 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, DURATIONMulticenter 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, METHODSParticipants 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 CHANCEThe 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 CAUTIONOur 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 FINDINGSPOSEIDON 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 NUMBERN/A.

Live birth rates in different subgroups of poor ovarian responders according to Bologna and POSEIDON group classification criteria

PurposeThe present study was designed to compare the live birth rates (LBRs) according to Bologna criteria or Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) group classifications to determine the important predictive factors for LBR in patients with POR. Basic proceduresIn this cross-sectional study, the database of Royan Institute (Tehran, Iran) from December 2015 to December 2017 was evaluated and the fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles outcomes for all the patients with at least one POR after standard controlled ovarian stimulation were collected. The patients divided into five subgroups according to Bologna criteria and four groups on the basis of POSEIDON group classification. Main finding812 patients with POR diagnosis were assessed which 517 (63.6%) of them were underwent embryo transfer (ET) during the last treatment cycle. According to Bologna criteria, 41 patients were not included in any subgroup and the patients in Bologna group II had highest LBR (19.8%). In terms of POSEIDON classification, all of the patients were classified into subgroups and the women in POSEIDON group III had the highest LBR (27%). According to multivariable regression analysis, the significant independent predictive factors for LBR were the number and morphology (good and excellent) of the embryos transferred, and POSEIDON group III classification. Principal conclusionThe results indicated that the POSEIDON group classification could be more comprehensive and practical than Bologna criteria for categorizing POR patients and predicting their outcome. Moreover, the number and morphology of transferred embryos were the most important prognostic factors for live births in these patients.

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

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

Improving Reporting of Clinical Studies Using the POSEIDON Criteria: POSORT Guidelines.

The POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria were developed to help clinicians identify and classify low-prognosis patients undergoing assisted reproductive technology (ART) and provide guidance for possible therapeutic strategies to overcome infertility. Since its introduction, the number of published studies using the POSEIDON criteria has increased steadily. However, a critical analysis of existing evidence indicates inconsistent and incomplete reporting of critical outcomes. Therefore, we developed guidelines to help researchers improve the quality of reporting in studies applying the POSEIDON criteria. We also discuss the advantages of using the POSEIDON criteria in ART clinical studies and elaborate on possible study designs and critical endpoints. Our ultimate goal is to advance the knowledge concerning the clinical use of the POSEIDON criteria to patients, clinicians, and the infertility community.

A Feasible Option before Cycle Cancellation for Poor Responders; STOP-START Protocol

Despite the advances in controlled ovarian stimulation (COS), management of a subgroup of poor ovarian responder patients may still be challenging. We describe a feasible and simplified protocol, namely the STOP-START protocol, for poor responders defined as Patient-Oriented Strategies Encompassing Individualize D Oocyte Number (POSEI- DON) groups 3 and 4, who are unresponsive to COS with maximum dose gonadotrophins. Data of 11 women un- responsive to COS were reviewed. Mean age of the patients was 36.5 ± 6.0 years. Unresponsiveness was defined as no follicular growth >9 mm and/or estradiol level less than 40 pg/ml after a week of recombinant follicle stimulating hormone (rFSH, 225-300 IU) administration. In that case, COS was stopped and each woman underwent weekly ul- trasound assessment to catch a secondary follicular growth. All women showed at least one follicular growth within five to 20 days. Six women (54.5%) had spontaneous follicular growth and the other five required ovarian stimulation. At least one oocyte was retrieved from each one of seven patients (63.6%). The mean number of oocytes retrieved was 1.6 ± 1.4 and five women (45.5%) had at least one grade A embryo. Among all, two women became pregnant successfully and both gave live births (18.2%). In conclusion, STOP-START protocol may potentially be an effective, feasible, and time-saving management option for POSEIDON group 3/4 poor responders who are unresponsive to standard COS treatment with maximum dose gonadotrophins.

Cumulative live birth rate of low prognosis patients with POSEIDON stratification: a single-centre data analysis

Research questionDoes patient-oriented strategies encompassing individualized oocyte number (POSEIDON) classification help stratify the reproductive potential of patients with low prognosis more effectively from the perspective of prognosis; and as cumulative live birth rate (CLBR) is an effect indication, how is CLBR in patients stratified using POSEIDON? DesignA retrospective cohort study of 10,615 women who underwent IVF treatment at the Peking University Third Hospital between January 2017 and December 2017. Patients were stratified according to POSEIDON criteria. Clinical characteristics, fresh embryo transfer outcomes and CLBR during the first two ovarian stimulation cycles were recorded. ResultsGonadotrophin-releasing hormone antagonist protocol was the most used treatment in both ovarian stimulation cycles. After the failure of the first IVF treatment, 2063 (29.2%) women continued the second treatment, and 10.9% of them switched to the micro-stimulation protocol. Compared with the non-POSEIDON group, the CLBR of the first cycle in each POSEIDON group was lower (P < 0.001). The CLBRs of the second cycle in older patients (POSEIDON groups 2b and 4) and in younger patients with poor ovarian reserve (POSEIDON group 3) were lower than that in non-POSEIDON group (group 2b, P = 0.001; group 3, P = 0.019; group 4, P < 0.001). Subgroup analysis showed that younger patients had higher CLBR than older patients in both cycles (P < 0.001). ConclusionThe CLBRs vary among different POSEIDON groups. The results may help reproductive specialists to understand the characteristics of low prognosis patients better and to develop individualized treatment plans.