Ovarian Stimulation Strategies Research Articles

Ovarian follicular waves in ovulation induction in assisted reproduction techniques

Background: A greater understanding of the menstrual cycle and multiple waves of antral ovarian follicular development has challenged traditional concepts of female reproductive physiology and the foundations of assisted reproductive technologies (ART). Approximately two-thirds of women develop two follicle waves throughout an interovulatory interval, and the remainder exhibit three waves of follicle development. Major and minor waves of follicle development have been observed. Major waves are those in which a dominant follicle develops; dominant follicles either regress or ovulate. In minor waves, the physiological selection of a dominant follicle is not manifested. Knowledge of the waves of antral follicular development has led to the global adoption of novel ovarian stimulation strategies in which stimulation can be initiated at various times throughout the cycle. Random-start and luteal-phase ovarian stimulation regimens have important clinical applications in women requiring urgent oocyte or embryo cryopreservation for fertility preservation before chemotherapy.
 Objective: To evaluate the role of multiple waves of the antral ovarian follicular in the menstrual cycle in ovulation induction in ART.
 Methods: A literature search using the keywords “multiple waves of antral ovarian follicular development, In Vitro Fertilization, Ovarian stimulation ” was performed in the PubMed database.
 Outcome: Random start and luteal phase of ovulation induction in ART offer the same results in fertilization and pregnancy rates as conventional early follicular phase start.
 Conclusion: The primary benefits of the random-start protocol include a patient-oriented approach to care, timely and efficient treatment, and a lower dropout rate. Women with poor ovarian reserve and those diagnosed with cancer will have a greater chance of successful assisted reproduction with the use of these strategies.

P-025 Optimising stimulated IUI; a systematic review and network meta-analysis

Abstract Study question What is the effectiveness and safety of various follicular phase ovarian stimulation protocols for intrauterine insemination (IUI) performed for any indication? Summary answer Significantly higher LBR/OPR was noted for gonadotrophins versus oral agents. Clomiphene+estrogen and gonadotrophins+letrozole demonstrated significantly higher OPR/LBR compared to no stimulation/stimulation with oral agents alone. What is known already Stimulated IUI is one of the most widespread fertility treatments offered for various indications. The rationale of stimulated IUI cycles follows the concept that more available oocytes for fertilisation would lead to increase chances of conception. Although several small pairwise comparisons are reported between different stimulation agents, there is no overall comparison using a network meta-analysis. Optimising the ovarian stimulation is an important step towards evidence-based guidelines. There is a cost- effect balance which should be kept in mind between achieving multi follicular growth to boost success rates and keeping the intervention safe in relation to multiple pregnancies. Study design, size, duration This review has been conducted in accordance with PRISMA guidelines and has been registered in PROSPERO (CRD42022300857). A computerized literature search was performed using EMBASE, MEDLINE and CINAHL as well as the Cochrane Central register of trials from database inception to May 2022. Randomized controlled trials (RCTs) were included. A random effects network meta-analysis within a frequentist setting was performed for the primary outcome live birth rate/ongoing pregnancy rate (LBR)/(OPR) and for multiple pregnancy rate. Participants/materials, setting, methods Couples/single women undergoing one or more cycles of stimulated IUI for various indications using partner’s or donor sperm were included. The effect sizes of the outcome were estimated as odds ratio (ORs) and presented along with their 95% confidence interval (CIs). We used network plots to illustrate head-to-head comparisons. The superiority of the interventions was assessed; we calculated the probability of being the best, the mean rank, and the surface under cumulative ranking (SUCRA). Main results and the role of chance 57 RCTs were identified comparing stimulation protocols. These included oral agents (clomiphene, letrozole, anastrozole, tamoxifene, estrogen), injectable hormones (FSH, hMG +/- GnRH agonists and GnRH antagonists), alone or in combination, compared to other stimulation agent (s). The included trials randomized 11341 participants across 14 countries between 1994 and 2020. Fourteen trials were multi-centre and 43 (75%) were single centre. Comparisons were assessed in relation to LBR/OPR and in relation to multiple pregnancy rate in order to identify which combination is superior in achieving maximum success rates without compromising safety. The comparison between ovarian stimulation with gonadotrophins and clomiphene had the most trials and participants and showed significantly higher OPR/LBR for ovarian stimulation with gonadotrophins compared to clomiphene (OR: 1.58, CI 1.24-2.02). No stimulation or stimulation with clomiphene or aromatase inhibitors demonstrated significantly lower OPR/LBR compared to clomiphene + estrogen (OR no stimulation: 0.29, CI 0.10-0.83; OR clomiphene: 0.27, CI 0.10-0.69; OR letrozole 0.30, CI 0.11-0.83) and gonadotrophins + letrozole (OR no stimulation: 0.22, CI 0.06-0.82; OR clomiphene: 0.21, CI 0.06-0.73; OR letrozole 0.23, CI 0.06-0.85).The safety of each ovarian stimulation strategy was assessed in terms of risk of multiple pregnancy. Limitations, reasons for caution Comparing different stimulation protocols for IUI is challenging in view of heterogeneity amongst included trials. Different add-ons could benefit specific patient groups but based on the available data, safe recommendations cannot be proposed according to subfertility diagnosis. Various add-ons, protocol variations and sperm preparation techniques could also affect outcomes. Wider implications of the findings Stimulation strategies aiming to increase success rates should be safe in terms of multiple pregnancy. Strict cancellation criteria and monitoring are required. Cost effectiveness, ease of administration, chances of cycle cancellation and couple’s preferences should be taken into consideration. Future trials should take into account subfertility background and patient characteristics. Trial registration number not applicable

P-657 Elecys anti-Müllerian hormone thresholds for defining ovarian response categories; comparison of published and novel values in 7,988 treatment naïve women

Abstract Study question Test the accuracy of published and novel AMH thresholds in predicting (low, sub-optimal, optimal and high) ovarian response categories in first treatment cycles. Summary answer Published AMH thresholds for poor and excessive ovarian response perform adequately, however, prediction of suboptimal or optimal oocyte yields is difficult reflecting their limited range. What is known already AMH is an established predictor of ovarian response, and can identify women at risk of poor (<4 oocytes) or excessive (>15 oocytes) response. With the development of suboptimal (4 to 9 oocytes) and optimal (10 to 14 oocytes) response categories, a series of AMH ranges for the Roche Elcesys AMH assay has been proposed to predict response for all four categories (AMH <6.4pmol/l, 4.9–11.3 pmol/l, 11.3–20.9 pmol/l, and >14.2 pmol/l). To date there has been no internal or external validation of these single centre derived thresholds, and it is unknown whether they are generalisable to other clinic populations. Study design, size, duration Observational cohort study from 8 UK clinics, incorporating 7,998 women undertaking their first ovarian stimulation cycle for assisted conception or fertility preservation between 2016 and 2022, with a pre-treatment AMH measured using the Roche Elecsys AMH assay. Both GnRH agonist and antagonist cycles were included, with triggering by either recombinant hCG or GnRH agonist once 3 follicles were ³18mm in size with oocyte retrieval performed 36h later. Participants/materials, setting, methods To give equal opportunity to the published and novel thresholds, patients were divided into training (5,330) and testing (2,668) sets. Novel cut-off points for a low, sub-optimal, optimal and high response were derived in the training set. The performance of these novel thresholds and those of published values were then assessed and compared in the testing set by their respective AUC, and precision as defined as the fraction of correct predictions for a certain class. Main results and the role of chance Baseline patient characteristics (mean, SD) were 35.1±4.7 years; BMI 25.5±4.4 kg/m2, with a median AMH 15.2 pmol/l (IQR 8, 26) and a median of 11 (IQR 6,16) oocytes retrieved. These baseline characteristics and outcomes were similar after splitting in the training and testing datasets. Baseline AMH and oocytes collected were moderately correlated (r = 0.54, p < 0.001). 465 (5.8%) cycles were cancelled due to not meeting trigger criteria and classed as poor/low responders. The novel thresholds for low oocyte yield (≤10.05 pmol/l) provided similar performance (AUC 0.70 95%CI 0.66-0.74, sensitivity 0.69, specificity 0.74) to the published thresholds (AUC 0.67, 95%CI 0.62-0.72) in the testing population. Similarly, the novel high (15.9pmol/l) threshold (AUC 0.78, 95%CI 0.75-0.81, sensitivity 0.78, specificity 0.64) exhibited similar performance to the published threshold AUC 0.77, 95%CI 0.74,0.81) in the testing population. Deriving novel thresholds for prediction of 4 categories of response (6.7, 12.9, 18.9pmol) was associated with slightly better precision for low, suboptimal and high categories (p < 0.001), with the fraction of correct predictions for a certain category of response for the novel cut-points; 69.0 % low, 11.7% suboptimal, 14.1% optimal and 78.3% high, as compared to 52.0%, 27.8%, 12.9% and 83.8% respectively for the published values. Limitations, reasons for caution While designing the ovarian stimulation strategies clinicians were aware of the baseline AMH and targeted a perceived optimal response for cumulative live birth (∼15 oocytes), which may have contributed to the performance of both the established and novel AMH thresholds. Wider implications of the findings In a large heterogenous population of women undergoing their first treatment cycle, we confirm the appropriateness of the previously published Elecsys AMH values for prediction of low (<6.4pmol/l) and high (>14.2pmol/l) oocyte yields. Trial registration number N/A

Retrospective study of influencing factors on the outcomes of luteal phase stimulation in patients with dual stimulation.

Dual/double stimulation (DS) is an ovarian stimulation strategy that has emerged in recent years; it is characterized by two rounds of ovarian stimulation and oocyte retrieval in the same menstrual cycle. DS can greatly shorten the time required to obtain valid embryos in assisted reproduction. For fertility preservation, DS can speed up oocyte storage process. However, factors influencing luteal phase ovarian stimulation (LPS) outcomes in DS have not been elucidated. A total of 156 cycles from 78 cases were studied. Patients were grouped and analyzed according to their follicular phase ovarian stimulation (FPS) types. Female ages, ovarian stimulation protocols, number of oocytes retrieved, embryo quality were recorded. Comparisons of outcomes were conducted between different groups. Our study found that LPS obtained similar outcomes to follicular phase stimulation (FPS), and that the choice of FPS protocol affected the efficiency of LPS, the antagonist protocol and progestin-primed ovarian stimulation (PPOS) protocol resulted in better embryo outcomes in LPS. In LPS of DS, sufficient stimulation duration was the guarantee of embryo quality (number of available embryos: β = 0.145, 95% CI [0.078-0.211], P = 0.000; number of high-quality embryos: β = 0.114, 95% CI [0.057-0.171], P = 0.000). This study provided ideas for the precise use of DS. We suggest to further expand the sample size of DS in the future, conduct prospective controlled studies, unify the sample size of each subgroup, include the ovarian reserve of patients in the grouping basis, and exclude the influence of male factors. We hope that this study will help further refinement of DS so as to maximize patient benefits from it. When the DS strategy is considered in the follicular phase, the antagonist protocol and PPOS protocol are more recommended for better embryo outcomes in LPS. During LPS, adequate ovarian stimulation duration is the most important guarantee for LPS efficiency.

Freeze-all embryos during treatment with assisted reproduction: Health economic aspects.

Assisted reproductive technologies are evolving, with the most recent example being the introduction of the freeze-all policy during which a fresh embryo transfer does not take place and all embryos of good quality are cryopreserved to be used in future frozen embryo transfers. As the freeze-all policy is becoming more prevalent, it is important to review the economic aspects of this approach, along with considerations of efficacy and safety, and the role of emerging freeze-all-specific ovarian stimulation strategies. Based on the available evidence, the freeze-all policy presents distinct clinical advantages, particularly for high responders. Available health economic evaluations are limited. Two good-quality cost-effectiveness analyses based on randomized controlled trials suggest that the freeze-all strategy is unlikely to be cost-effective in non-polycystic ovarian syndrome (non-PCOS), normally responding patients. However, the cost-effectiveness of the freeze-all strategy in different populations of patients and in different settings has not been evaluated, nor has the clinical and economic efficacy of modern freeze-all-specific ovarian stimulation protocols that are likely to simplify treatment and make it more affordable for patients. Economic evaluations that incorporate good practice health technology assessment (HTA) methods are needed to compare freeze-all with conventional embryo transfer strategies. Furthermore, future research should address the unique limitation of traditional HTA methods in valuing a life conceived through fertility treatment.

A higher number of oocytes retrieved is associated with an increase in fertilized oocytes, blastocysts, and cumulative live birth rates

To investigate the association between the number of oocytes retrieved and the numbers of fertilized oocytes and blastocysts and cumulative and primary transfer live birth rates (LBRs). Retrospective study. Retrieval cycles and linked embryo transfers from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. Patients in the United States undergoing autologous invitro fertilization cycles from 2014 to 2019 (n = 402,411 cycles). None. Normally fertilized oocytes, blastocysts, and cumulative and primary transfer LBRs. There was a strong positive linear correlation between oocytes and fertilized oocytes and between oocytes and blastocysts. The cumulative LBR increased rapidly with the number of oocytes retrieved to approximately 16-20 oocytes, at which point it continued to increase but with diminishing returns. The increasing trend of the cumulative LBR was observed when stratifying patients by age and antimüllerian hormone and after controlling for confounding variables using multivariate logistic regression. The primary transfer LBR also increased with the number of oocytes to approximately 16-20 oocytes, at which point it plateaued but did not decline. A higher number of oocytes retrieved improves the cumulative LBR without impairing the primary transfer LBR. Thissuggests that ovarian stimulation strategies should aim to safely maximize the number of oocytes retrieved.

Ovarian Stimulation Strategies for Intrauterine Insemination in Couples with Unexplained Infertility - A Systematic Review and Individual Participant Data Meta-analysis

Background: Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for couples with unexplained infertility. Individual participant data meta-analysis (IPD-MA) is the gold standard for evidence synthesis. Aim: To compare the effectiveness and safety of ovarian stimulation with gonadotrophin, Letrozole and clomiphene citrate (CC) and to explore treatment-covariate interactions for important baseline characteristics in women undergoing IUI. Method: We searched electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). We included randomised controlled trials (RCTs) comparing IUI-OS with gonadotropins, Letrozole or CC among couples with unexplained infertility. We excluded dose comparing studies of the same drug. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. We used a one-stage approach using a random effects model. Results: Six RCTs (n= 2299) provided IPD. Gonadotropins increased the chance of a live birth compared to both CC (5 RCTs, 1946 women, RR 1.28, 95%CI 1.10 to 1.49, I2 = 25%, moderate-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.77 95%CI 0.58 to 1.03). Gonadotropins increased the risk of a multiple pregnancy compared to both CC (4 RCTs, 1696 women, RR 2.17, 95%CI 1.33 to 3.55, I2 = 69%, low-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.71, 95%CI 0.33 to 1.56). No strong evidence on the treatment-covariate interactions (female age, BMI or primary versus secondary infertility) was found. Conclusion: Gonadotropins increased the chance of a live birth compared to both CC and Letrozole but also increased the chance of a multiple pregnancy. Further RCTs comparing Letrozole and other interventions in couples with unexplained infertility are needed.

Ovarian stimulation strategies for intrauterine insemination in couples with unexplained infertility: a systematic review and individual participant data meta-analysis.

BACKGROUNDIntrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for unexplained infertility. Gonadotrophins, letrozole and clomiphene citrate (CC) are commonly used agents during IUI-OS and have been compared in multiple aggregate data meta-analyses, with substantial heterogeneity and no analysis on time-to-event outcomes. Individual participant data meta-analysis (IPD-MA) is considered the gold standard for evidence synthesis as it can offset inadequate reporting of individual studies by obtaining the IPD, and allows analyses on treatment–covariate interactions to identify couples who benefit most from a particular treatment.OBJECTIVE AND RATIONALEWe performed this IPD-MA to compare the effectiveness and safety of ovarian stimulation with gonadotrophins, letrozole and CC and to explore treatment–covariate interactions for important baseline characteristics in couples undergoing IUI.SEARCH METHODSWe searched electronic databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO from their inception to 28 June 2021. We included randomized controlled trials (RCTs) comparing IUI-OS with gonadotrophins, letrozole and CC among couples with unexplained infertility. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA Collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Secondary outcomes were other reproductive outcomes, including time to conception leading to live birth. We performed a one-stage random effects IPD-MA.OUTCOMESSeven of 22 (31.8%) eligible RCTs provided IPD of 2495 couples (62.4% of the 3997 couples participating in 22 RCTs), of which 2411 had unexplained infertility and were included in this IPD-MA. Six RCTs (n = 1511) compared gonadotrophins with CC, and one (n = 900) compared gonadotrophins, letrozole and CC. Moderate-certainty evidence showed that gonadotrophins increased the live birth rate compared to CC (6 RCTs, 2058 women, RR 1.30, 95% CI 1.12–1.51, I2 = 26%). Low-certainty evidence showed that gonadotrophins may also increase the multiple pregnancy rate compared to CC (6 RCTs, 2058 women, RR 2.17, 95% CI 1.33–3.54, I2 = 69%). Heterogeneity on multiple pregnancy could be explained by differences in gonadotrophin starting dose and choice of cancellation criteria. Post-hoc sensitivity analysis on RCTs with a low starting dose of gonadotrophins (≤75 IU) confirmed increased live birth rates compared to CC (5 RCTs, 1457 women, RR 1.26, 95% CI 1.05–1.51), but analysis on only RCTs with stricter cancellation criteria showed inconclusive evidence on live birth (4 RCTs, 1238 women, RR 1.15, 95% CI 0.94–1.41). For multiple pregnancy, both sensitivity analyses showed inconclusive findings between gonadotrophins and CC (RR 0.94, 95% CI 0.45–1.96; RR 0.81, 95% CI 0.32–2.03, respectively). Moderate certainty evidence showed that gonadotrophins reduced the time to conception leading to a live birth when compared to CC (6 RCTs, 2058 women, HR 1.37, 95% CI 1.15–1.63, I2 = 22%). No strong evidence on the treatment–covariate (female age, BMI or primary versus secondary infertility) interactions was found.WIDER IMPLICATIONSIn couples with unexplained infertility undergoing IUI-OS, gonadotrophins increased the chance of a live birth and reduced the time to conception compared to CC, at the cost of a higher multiple pregnancy rate, when not differentiating strategies on cancellation criteria or the starting dose. The treatment effects did not seem to differ in women of different age, BMI or primary versus secondary infertility. In a modern practice where a lower starting dose and stricter cancellation criteria are in place, effectiveness and safety of different agents seem both acceptable, and therefore intervention availability, cost and patients’ preferences should factor in the clinical decision-making. As the evidence for comparisons to letrozole is based on one RCT providing IPD, further RCTs comparing letrozole and other interventions for unexplained infertility are needed.

Machine Learning-Based Modeling of Ovarian Response and the Quantitative Evaluation of Comprehensive Impact Features.

Appropriate ovarian responses to the controlled ovarian stimulation strategy is the premise for a good outcome of the in vitro fertilization cycle. With the booming of artificial intelligence, machine learning is becoming a popular and promising approach for tailoring a controlled ovarian stimulation strategy. Nowadays, most machine learning-based tailoring strategies aim to generally classify the controlled ovarian stimulation outcome, lacking the capacity to precisely predict the outcome and evaluate the impact features. Based on a clinical cohort composed of 1365 women and two machine learning methods of artificial neural network and supporting vector regression, a regression prediction model of the number of oocytes retrieved is trained, validated, and selected. Given the proposed model, an index called the normalized mean impact value is defined and calculated to reflect the importance of each impact feature. The proposed models can estimate the number of oocytes retrieved with high precision, with the regression coefficient being 0.882% and 89.84% of the instances having the prediction number ≤ 5. Among the impact features, the antral follicle count has the highest importance, followed by the E2 level on the human chorionic gonadotropin day, the age, and the Anti-Müllerian hormone, with their normalized mean impact value > 0.3. Based on the proposed model, the prognostic results for ovarian response can be predicted, which enables scientific clinical decision support for the customized controlled ovarian stimulation strategies for women, and eventually helps yield better in vitro fertilization outcomes.

Ovarian Stimulation in Assisted Reproductive Technology Cycles for Varied Patient Profiles: An Indian Perspective.

ABSTRACTControlled ovarian stimulation has been an integral part of in vitro fertilisation (IVF) treatment cycles. Availability of different gonadotropins for ovarian stimulation and gonadotropin releasing hormone (GnRH) analogues for prevention of premature rise of leutinising hormone during follicular phase offer an opportunity to utilise them for a successful outcome in women with different subsets of ovarian response. Further, use of GnRH agonist as an alternative for human chorionic gonadotropin improves safety of ovarian stimulation in hyper-responders. Mild ovarian stimulation protocols have emerged as an alternative to conventional protocols in the recent years. Individualisation plays an important role in improving safety of IVF in hyper-responders while efforts continue to improve efficacy in poor responders. Some of the follicular and peri-ovulatory phase interventions may be associated with negative impact on the luteal phase and segmentalisation of the treatment with frozen embryo transfer may be an effective strategy in such a clinical scenario. This narrative review looks at the available evidence on various aspects of ovarian stimulation strategies and their consequences. In addition, it provides a concise summary of the evidence that has emerged from India on various aspects of ovarian stimulation.

A Clinician-Friendly Machine Learning System to Predict Ovarian Response and Deploy Individualized Ovarian Stimulation Strategies in IVF

A Clinician-Friendly Machine Learning System to Predict Ovarian Response and Deploy Individualized Ovarian Stimulation Strategies in IVF

LETROZOLE CO-TREATMENT IN OVARIAN STIMULATION WITH R-FSH DELAYS EMBRYO MORPHOKINETICS AND WORSEN CLINICAL OUTCOMES

Letrozole has been considered a potential strategy to improve IVF outcomes, as inhibition of cytochrome P450 aromatase enzyme activity would increase the levels of androgens by blocking their aromatization to estrogen. Letrozole may also improve ovarian response to FSH and be a potential tool for mild ovarian stimulation strategies. Although a positive effect of letrozole in lowering the total does of FSH, key IVF outcomes have not consistently been found to be significantly improved by the supplementation with letrozole.

Leave the past behind: women’s reproductive history shows no association with blastocysts’ euploidy and limited association with live birth rates after euploid embryo transfers

Is there an association between patients' reproductive history and the mean euploidy rates per biopsied blastocysts (m-ER) or the live birth rates (LBRs) per first single vitrified-warmed euploid blastocyst transfers? Patients' reproductive history (as annotated during counselling) showed no association with the m-ER, but a lower LBR was reported after euploid blastocyst transfer in women with a history of repeated implantation failure (RIF). Several studies have investigated the association between the m-ER and (i) patients' basal characteristics, (ii) ovarian stimulation strategy and dosage, (iii) culture media and conditions, and (iv) embryo morphology and day of full blastocyst development. Conversely, the expected m-ER due to women's reproductive history (previous live births (LBs), miscarriages, failed IVF cycles and transfers, and lack of euploid blastocysts among prior cohorts of biopsied embryos) still needs investigations. Yet, this information is critical to counsel new patients about a first cycle with preimplantation genetic testing for aneuploidy (PGT-A), but even more so after former adverse outcomes to prevent treatment drop-out. This observational study included all patients undergoing a comprehensive chromosome testing (CCT)-based PGT-A cycle with at least one biopsied blastocyst in the period April 2013-December 2019 at a private IVF clinic (n = 2676 patients undergoing 2676 treatments and producing and 8151 blastocysts). m-ER were investigated according to women's reproductive history of LBs: no/≥1, miscarriages: no/1/>1; failed IVF cycles: no/1/2/>2, and implantation failures after previous transfers: no/1/2/>2. Among the 2676 patients included in this study, 440 (16%) had already undergone PGT-A before the study period; the data from these patients were further clustered according to the presence or absence of euploid embryo(s) in their previous cohort of biopsied blastocysts. The clinical outcomes per first single vitrified-warmed euploid blastocyst transfers (n =1580) were investigated according to the number of patients' previous miscarriages and implantation failures. The procedures involved in this study included ICSI, blastocyst culture, trophectoderm biopsy without hatching in Day 3, CCT-based PGT-A without reporting segmental and/or putative mitotic (or mosaic) aneuploidies and single vitrified-warmed euploid blastocyst transfer. For statistical analysis, Mann-Whitney U or Kruskal-Wallis tests, as well as linear regressions and generalised linear models among ranges of maternal age at oocyte retrieval were performed to identify significant differences for continuous variables. Fisher's exact tests and multivariate logistic regression analyses were instead used for categorical variables. Maternal age at oocyte retrieval was the only variable significantly associated with the m-ER. We defined five clusters (<35 years: 66 ± 31%; 35-37 years: 58 ± 33%; 38-40 years: 43 ± 35%; 40-42 years: 28 ± 34%; and >42 years: 17 ± 31%) and all analyses were conducted among them. The m-ER did not show any association with the number of previous LBs, miscarriages, failed IVF cycles or implantation failures. Among patients who had already undergone PGT-A before the study period, the m-ER did not associate with the absence (or presence) of euploid blastocysts in their former cohort of biopsied embryos. Regarding clinical outcomes of the first single vitrified-warmed euploid blastocyst transfer, the implantation rate was 51%, the miscarriage rate was 14% and the LBR was 44%. This LBR was independent of the number of previous miscarriages, but showed a decreasing trend depending on the number of previous implantation failures, reaching statistical significance when comparing patients with >2 failures and patients with no prior failure (36% versus 47%, P < 0.01; multivariate-OR adjusted for embryo quality and day of full blastocyst development: 0.64, 95% CI 0.48-0.86, P < 0.01). No such differences were shown for previous miscarriage rates. The sample size for treatments following a former completed PGT-A cycle should be larger in future studies. The data should be confirmed from a multicentre perspective. The analysis should be performed also in non-PGT cycles and/or including patients who did not produce blastocysts, in order to investigate a putative association between women's reproductive history with outcomes other than euploidy and LBRs. These data are critical to counsel infertile couples before, during and after a PGT-A cycle, especially to prevent treatment discontinuation due to previous adverse reproductive events. Beyond the 'maternal age effect', the causes of idiopathic recurrent pregnancy loss (RPL) and RIF are likely to be endometrial receptivity and selectivity issues; transferring euploid blastocysts might reduce the risk of a further miscarriage, but more information beyond euploidy are required to improve the prognosis in case of RIF. No funding was received and there are no competing interests. N/A.

Mild Ovarian Stimulation Strategy versus conventional ovarian Stimulation in Poor Responder Women Undergoing ICSI

Mild Ovarian Stimulation Strategy versus conventional ovarian Stimulation in Poor Responder Women Undergoing ICSI

Luteal phase after conventional stimulation in the same ovarian cycle might improve the management of poor responder patients fulfilling the Bologna criteria: a case series

To assess the clinical contribution of luteal-phase stimulation (LPS) to follicular-phase stimulation (FPS) in a single ovarian cycle (DuoStim) for poor responder patients fulfilling the Bologna criteria. Observational study (years 2015-2017) including women satisfying ≥2 of the following characteristics: maternal age ≥40 years and/or ≤3 oocytes retrieved after previous conventional stimulation and/or reduced ovarian reserve (i.e., antral follicle count <7 follicles or antimüllerian hormone <1.1 ng/mL). The LPS was started regardless of the outcome of the FPS. Private invitro fertilization center. A total of 100 of 297 patients fulfilling the Bologna criteria chose to undergo DuoStim. The FPS and LPS with the same antagonist protocol and agonist trigger, intracytoplasmic sperm injection with ejaculated sperm, preimplantation genetic testing for aneuploidies, and vitrified-warmed euploid single blastocyst transfer. The contribution of LPS to the cumulative live birth rate (CLBR) per intention-to-treat (ITT). Patients (100) underwent FPS (maternal age, 42.1 ± 1.4 y; previous invitro fertilization cycles with ≤3 collected oocytes, 0.7 ± 0.9; antral follicle count, 3.8 ± 1.2 follicles; and antimüllerian hormone, 0.56 ± 0.3 ng/mL). Ninety-one patients completed DuoStim. All patients were included in the analysis. More oocytes were obtained after LPS with similar developmental and chromosomal competence as paired FPS-derived ones. The CLBR per ITT increased from 7% after FPS to 15% after DuoStim. Conversely, the CLBR per ITT among the 197 patients that chose a conventional controlled ovarian stimulation strategy was 8%, as only 17 patients who were not pregnant returned for a second stimulation after the first attempt (drop-out rate, 81%). The LPS-derived oocytes increased the CLBR per ITT in a single ovarian cycle in patients fulfilling the Bologna criteria. The DuoStim strategy is promising to manage this thorny population of patients, especially to avoid discontinuation after a first failed attempt.

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.

Serum anti-Mullerian hormone predicts ovarian response in (Macaca fascicularis) monkeys

AMH as a promising predictor of ovarian response has been studied extensively in women undergoing assisted reproductive technology treatment, but little is known about its prediction value in monkeys undergoing ovarian stimulation. In the current study, a total of 380 cynomolgus monkeys ranging from 5 to 12 years received 699 ovarian stimulation cycles. Serum samples were collected for AMH measure with enzyme-linked immunosorbent assay. It was found that serum AMH levels were positive correlated with the number of retrieved oocytes (P < 0.01) in the first, second and third stimulation cycles. In the first cycles, area under the curve (ROCAUC) of AMH is 0.688 for low response and 0.612 for high response respectively, indicating the significant prediction values (P = 0.000 and P = 0.005). The optimal AMH cutoff value was 9.68 ng/mL for low ovarian response and 15.88 ng/mL for high ovarian response prediction. In the second stimulation cycles, the significance of ROCAUC of AMH for high response rather than the low response was observed (P = 0.001 and P = 0.468). The optimal AMH cutoff value for high ovarian response was 15.61 ng/mL. In the third stimulation cycles, AMH lost the prediction value with no significant ROCAUC. Our data demonstrated that AMH, not age, is a cycle-dependent predictor for ovarian response in form of oocyte yields, which would promote the application of AMH in assisted reproductive treatment (ART) of female cynomolgus monkeys. AMH evaluation would optimize candidate selection for ART and individualize the ovarian stimulation strategies, and consequentially improve the efficiency in monkeys.

Is gonadotropin stimulation bad for oocytes?

Gonadotrophin in IVF increases the number of oocytes retrieved, and many doctors regard a high number of oocytes as a measurement of success in IVF. Thus, the dogma of more oocytes provides better IVF success has been broadly accepted. However, some European fertility specialists have argued against this concept, saying fewer eggs might, in some instances, be a better option for the patient. The concept of 'one size fits all' stimulation in artificial reproductive technologies is not broadly supported by the current literature. The ovarian stimulation strategy has to be viewed in relation to cost, infrastructure and economics, expectations from the doctors and the patients, and more importantly the local legislation. Furthermore, also luteal phase, epigenetic factors and patient safety is a matter of concern. Studies show that in the fresh cycle, ovarian stimulation might have an impact on the epigenetics, quality of the embryo and increase the risk of ovarian hyper stimulation. Strategies like agonist triggering or 'freeze all' can help during a fresh cycle. However, there is an ongoing debate whether these strategies might increase time to pregnancy or not. In conclusion, each fertility clinic setup has its own benefits and gonadotropin hyperstimulation in IVF has to be related to this and the specific patient demographic in the clinic; however, epigenetics and time to pregnancy are still issues open to debate.

Ovarian Stimulation in Poor Responders: Have We Made Progress?

Poor ovarian responders (POR) pose a challenge to a physicians' ability to choose a stimulation protocol that maximizes the number of oocytes harvested and their chances of conception with multiple protocols aimed at improving pregnancy rates in this poor prognosis population. The Bologna criteria standardized the diagnosis of POR and allows for a more homogenous patient population in clinical trials. A structured review of the literature, which encompasses research on Bologna-defined POR, identified several proposed protocols to optimize pregnancy rates in poor responders. In addition, we reviewed the utility of utilizing oocyte quality enhancers such as luteal pre-treatment, coenzyme Q10 (CoQ10), dihydroepiandrosterone (DHEA), and growth hormone (GH). Controlled ovarian stimulation strategies with adjuvant aromatase inhibitors and clomiphene citrate have shown similar pregnancy outcomes to higher dose gonadotropin in GnRH antagonist protocols. While the standardization of Bologna defined POR has allowed for more comparable patient populations to study the effectiveness of different protocols for ovarian stimulation, there is currently no convincing data that has determined the ideal protocol for controlled ovarian stimulation in this patient population. Further research is needed to identify optimal treatment strategies.

Introduction: Contemporary approaches to alternative ovarian stimulation strategies for in vitro fertilization

In the current practice of IVF, the vast majority of cycles use some form of controlled ovarian stimulation before egg retrieval to increase the number of embryos available for transfer or cryopreservation. However, the optimal stimulation regimen has not been established. This month's Views and Reviews presents five different approaches to alternative ovarian stimulation strategies. These include mild stimulation regimens, modified natural cycles, stimulation with oral agents, invitro maturation (in the absence of stimulation), and finally, a proposal for patient-tailored ovarian stimulation. As the treatment of infertility becomes more personalized, it is likely that standard, heavy-handed stimulation protocols will give way to simpler strategies, specifically tailored to each patient's individual characteristics and needs.