Individualized controlled ovarian stimulation in expected poor-responders: an update.

Controlled ovarian stimulation with subsequent multi-follicular development continues to be a keystone in ART. Evidence supports an individualized approach to ovarian stimulation, usually involving combinations of ovarian reserve tests, body mass index and age to tailor the exogenous gonadotropin dose, and potentially adjuvant treatment aiming for high safety and a shortening of time to live birth. While stimulation and trigger concepts have been developed successfully in normo- and hyperresponder patients, the poor responder patient remains difficult to manage. However, recent advances in definition and classification of the expected poor ovarian responder patient might enable a more accurate and clinically useful interpretation of new treatment concepts in a more homogenous study population. In the present review, we discuss the classification of the expected poor ovarian responder patient as well as clinically useful measurements of efficacy for controlled ovarian stimulation, and finally, we discuss the evidence for clinical management of patients with expected poor ovarian response, including adjuvant treatments such as growth hormone, androgens, and LH activity.In conclusion, the best available evidence supports that the treatment of the expected poor ovarian response patient should be individualized in all steps of ART, including the choice of GnRH analogue, the gonadotropin type and dose, ovulation trigger, and the possible use of adjuvant therapies.

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.

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.

Future Perspectives of POSEIDON Stratification for Clinical Practice and Research.

A total of 50% of patients undergoing IVF treatment has previously been estimated to fulfill the POSEIDON classification criteria; importantly, although the reproductive prognosis differs between patients, POSEIDON patients share the same characteristic of a low ovarian response to exogenous gonadotropin stimulation-independent of age. POSEIDON patients require focused attention as regards ovarian stimulation in order to increase the chances of having at least one euploid blastocyst for transfer-the success criterion for stimulation set forth by the POSEIDON Group. The key to success seems to be individualization in all steps of treatment. In this perspective article we discuss the future impact of the POSEIDON stratification for daily clinical practice as well as for research.

Management Strategies for POSEIDON Groups 3 and 4.

In the POSEIDON classification, patients belonging to groups 3 and 4 share the same common feature of a poor ovarian reserve which independently of age renders them at high risk of a poor reproductive outcome. Overall, POSEIDON groups 1-4 constitute approximately 47% of patients attending assisted reproductive technology (ART) treatment. With the increasing delay in childbearing, POSEIDON group 4 seems to increase in numbers now in some centers constituting more than 50% of the total POSEIDON population, whereas group 3 patients constitute approximately 10%. Both POSEIDON groups 3 and 4 patients require special attention as regards pre-treatment strategy, ovarian stimulation, adjuvant treatment, and ovulation trigger strategy in order to optimize the probability of having at least one euploid blastocyst for transfer. Although more evidence is needed, recent advances seem to have increased the reproductive outcomes in the poor prognosis patient. The key to success is individualization in all steps of ART treatment. Herein, we review the recent evidence for the management of POSEIDON groups 3 and 4.

Management of Women With an Unexpected Low Ovarian Response to Gonadotropin.

POSEIDON groups 1 and 2 patients respond poorly (<4 oocytes retrieved) or sub-optimally (4-9 oocytes retrieved) to gonadotropin stimulation despite the presence of adequate ovarian parameters, which negatively affect their cumulative chances of delivering a baby using Assisted Reproductive Technology. A polygenic trait involving gonadotropins and/or their receptors seems to be the primary pathophysiology mechanism explaining this phenomenon. The clinical management is mainly focused on maximizing oocyte yield as to increase the likelihood of having at least one euploid embryo for transfer. Indices such as FORT (follicle output rate) and FOI (follicle-to-oocyte index) may be used to determine if the ovarian reserve was properly explored during a previous ovarian stimulation. Testing for the presence of common polymorphisms affecting gonadotropins and/or their receptors can also be considered to identify patients at risk of hypo-response. An individualized estimation of the minimum number of oocytes needed to obtain at least one euploid embryo can assist counseling and treatment planning. Among currently existing pharmacological interventions, use of recombinant FSH in preference over urinary gonadotropin preparations, FSH dosage increase, and use of rLH supplementation may be considered -alone or combined- for optimally managing POSEIDON's groups 1 and 2 patients. However, given the recent introduction of the POSEIDON criteria, there is still a lack of studies examining the role of interventions specifically to patients classified as groups 1 and 2, thus making it an area for open research.

Validation of ART Calculator for Predicting the Number of Metaphase II Oocytes Required for Obtaining at Least One Euploid Blastocyst for Transfer in Couples Undergoing in vitro Fertilization/Intracytoplasmic Sperm Injection.

This multicenter study evaluated the reliability of the recently published ART calculator for predicting the minimum number of metaphase II (MII) oocytes (MIImin) to obtain at least one euploid blastocyst in patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). We used clinical and embryonic retrospective data of 1,464 consecutive infertile couples who underwent IVF/ICSI with the intention to have preimplantation genetic testing for aneuploidy. The validation procedure followed a stepwise approach. Firstly, we assessed the distribution of euploid blastocysts per patient and found that it followed a negative binomial distribution. Secondly, we used generalized linear models and applied the Lasso procedure-including MII oocytes to adjust the data-to select the factors predicting the response variable "euploid blastocyst." Third, a logistic regression model-fit to the binomial response euploid (yes/no) for each MII oocyte-was built using the relevant factors. The observational unit was the "woman" whereas the response was the pair (m, n), where n is the number of retrieved MII oocytes and m the corresponding number of euploid blastocysts. The model was internally validated by randomly splitting the data into training and validation sets. The R-squares (~0.25) and the area under the ROC curve (~0.70) did not differ between the training and validation datasets. Fourth, mathematical equations and the calculated probabilities generated by the validation model were used to determine the MIImin required for obtaining at least one euploid blastocyst according to different success probabilities. Lastly, we compared the fittings generated by the validation model and the ART calculator and assessed the predictive value of the latter using the validation dataset. The fittings were sufficiently close for both the estimated probabilities of blastocyst euploid per MII oocyte (r = 0.91) and MIImin (r = 0.88). The ART calculator positive predictive values, i.e., the frequency of patients with at least one euploid blastocyst among those who achieved the estimated MIImin, were 84.8%, 87.5%, and 90.0% for 70%, 80%, and 90% predicted probabilities of success, respectively. The ART calculator effectively predicts the MIImin needed to achieve at least one euploid blastocyst in individual patients undergoing IVF/ICSI. The prediction tool might be used for counseling and planning IVF/ICSI treatments.

The POSEIDON Criteria and Its Measure of Success Through the Eyes of Clinicians and Embryologists.

This article represents a viewpoint on the POSEIDON criteria by a group of clinicians and embryologists. Its primary objective is to contextualize the Poseidon criteria and their metric of success for the relevant Frontiers Research Topic "POSEIDON's Stratification of Low Prognosis Patients in ART: The WHY, the WHAT, and the HOW". "Low prognosis" relates with reduced oocyte number, which can be associated with low or sometimes a normal ovarian reserve and is aggravated by advanced female age. These aspects will ultimately affect the number of embryos generated and consequently, the cumulative live birth rate. The novel system relies on female age, ovarian reserve markers, ovarian sensitivity to exogenous gonadotropin, and the number of oocytes retrieved, which will both identify the patients with low prognosis and stratify such patients into one of four groups of women with "expected" or "unexpected" impaired ovarian response to exogenous gonadotropin stimulation. Furthermore, the POSEIDON group introduced a new measure of clinical success in ART, namely, the ability to retrieve the number of oocytes needed to obtain at least one euploid blastocyst for transfer in each patient. Using the POSEIDON criteria, the clinician can firstly identify and classify patients who have low prognosis in ART, and secondly, aim at designing an individualized treatment plan to maximize the chances of achieving the POSEIDON measure of success in each of the four low prognosis groups. The novel POSEIDON classification system is anticipated to improve counseling and management of low prognosis patients undergoing ART, with an expected positive effect on reproductive success and a reduction in the time to live birth.

A Novel Predictive Model to Estimate the Number of Mature Oocytes Required for Obtaining at Least One Euploid Blastocyst for Transfer in Couples Undergoing in vitro Fertilization/Intracytoplasmic Sperm Injection: The ART Calculator.

The POSEIDON group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) has introduced "the ability to retrieve the number of oocytes needed to achieve at least one euploid embryo for transfer" as an intermediate marker of successful outcome in IVF/ICSI cycles. This study aimed to develop a novel calculator to predict the POSEIDON marker. We analyzed clinical and embryonic data of infertile couples who underwent IVF/ICSI with the intention to have trophectoderm biopsy for preimplantation genetic testing for aneuploidy. We used the negative binomial distribution to model the number of euploid blastocysts and the adaptive LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection. The fitted model selected female age, sperm source used for ICSI, and the number of mature (metaphase II) oocytes as predictors (p < 0.0001). Female age was the most important factor for predicting the probability of a blastocyst being euploid given each mature oocyte (loglikelihood of age [adjusted for sperm source]: 30.9; df = 2; p < 0.0001). The final predictive model was developed using logistic regression analysis, and internally validated by the holdout method. The predictive ability of the model was assessed by the ROC curve, which resulted in an area under the curve of 0.716. Using the final model and mathematical equations, we calculated the individualized probability of blastocyst euploidy per mature retrieved oocyte and the minimum number of mature oocytes required to obtain ≥1 euploid blastocyst-with their 95% confidence interval [CI]-for different probabilities of success. The estimated predicted probabilities of a mature oocyte turn into a euploid blastocyst decreased progressively with female age and was negatively modulated overall by use of testicular sperm across age (p < 0.001). A calculator was developed to make two types of predictions automatically, one using pretreatment information to estimate the minimum number of mature oocytes to achieve ≥1 euploid blastocyst, and another based on the actual number of mature oocytes collected/accumulated to estimate the chances of having a euploid blastocyst using that oocyte cohort for IVF/ICSI. The new ART calculator may assist in clinical counseling and individualized treatment planning regarding the number of oocytes required for at least one euploid blastocyst in IVF/ICSI procedures.