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Background: The 'freeze-all' practice refers to the cryopreservation of all mature oocytes or viable embryos after ovarian stimulation. The development of the vitrification technique has been crucial to make this approach a reality, since it increases the post-thaw survival rates and permits comparable implantation rates with fresh embryos. Nonetheless, as implantation probabilities are comparable to fresh embryo transfer in normo-responder patients, the freeze- all strategy has demonstrated no benefits overall. Method: Narrative review in which we give an overview of this approach, discuss recent advances in the field, as well as for whom, when and how it is recommended to emply the freeze-all technique. Results: However, there is some clinical evidence that shows its feasibility. Thus, it has been demonstrated that elevation of progesterone at the end of ovarian stimulation decreases the implantation rates after the transfer of day 6 blastocysts in fresh and some uterine pathologies; freeze-all is also the preferred option for patients undergoing pre-implantation genetic testing, since there is an improvement of the results and it allows for inclusion of all blastocysts of the cohort. In high responders, the freeze-all strategy optimizes the response whilst also minimizing the risk of ovarian hyperstimulation syndrome. Conclusion: Due to the different cases that a reproductive expert might encounter, it is essential to highlight benefits and drawbacks of this practice.

Background In the last two decades, pregnancy rates for patients undergoing in-vitro fertilisation (IVF) have significantly increased. Some of the major advances responsible for this improvement were the introduction of controlled ovarian stimulation (COS) for the induction of multiple follicle development, and the utilisation of mid-luteal gonadotropin-releasing hormone agonists to achieve pituitary down-regulation and full control of the cycle. As a result, a combination of a gonadotropin-releasing hormone agonist with high doses (150-450 IU/day) of recombinant follicle-stimulating hormone has become the current standard approach for ovarian stimulation. However, given the heterogeneity of patients embarking on IVF, and the fact that many different drugs can be used alone or in different combinations (generating multiple potential protocols of controlled ovarian stimulation), we consider the need to identify special populations of patients and adapt treatment protocols accordingly, and to implement a more individualised approach to COS. Discussion Studies on mild, minimal and natural IVF cycles have yielded promising results, but have focused on fresh embryo transfers and included relatively young patient populations who generally have the potential for more favourable outcomes. The efficacy of these protocols in patients with a poorer prognosis remains to be tested. When comparing protocols for COS, it is important to think beyond current primary endpoints, and to consider the ideal quality and quantity of oocytes and embryos being produced per stimulated patient, in order to achieve a pregnancy. We should also focus on the cumulative pregnancy rate, which is based on outcomes from fresh and frozen embryos from the same cycle of stimulation. Individualised COS (iCOS) determined by the use of biomarkers to test ovarian reserve has the potential to optimise outcomes and reduce safety issues by adapting treatment protocols according to each patient's specific characteristics. As new objective endocrine, paracrine, functional and/or genetic biomarkers of response are developed, iCOS can be refined further still, and this will be a significant step towards a personalised approach for IVF. Conclusions A variety of COS protocols have been adopted, with mixed success, but no single approach is appropriate for all patients within a given population. We suggest that treatment protocols should be adapted for individual patients through iCOS; this approach promises to be one of the first steps towards implementing personalised medicine in reproductive science.

Purpose To explore the efficacy and safety of individualized follitropin delta dosing, based on serum anti-Müllerian hormone (AMH) concentration and bodyweight, in a long gonadotropin-releasing hormone (GnRH) agonist protocol. Methods Clinical outcomes after one treatment cycle are reported in women with AMH: 5–35 pmol/L. Oocytes were inseminated by intracytoplasmic sperm injection, blastocyst transfer was on Day 5 and remaining blastocysts were cryopreserved. Data collection included live births and neonatal health follow-up for all fresh/frozen transfers performed within one year after treatment allocation. Results In total, 104 women started stimulation, of whom 101 had oocyte recovery and 92 had blastocyst transfer. The average daily dose of follitropin delta was 11.0 ± 1.6 µg and the duration of stimulation was 10.3 ± 1.6 days. The mean number of oocytes was 12.5 ± 6.4, the mean number of blastocysts was 5.1 ± 3.4, and 85% had at least one good-quality blastocyst. Following mostly single blastocyst transfer (95%), the ongoing pregnancy rate was 43%, the live-birth rate was 43%, and the cumulative live-birth rate was 58% per started stimulation. There were 6 cases of early OHSS (5.8%) graded as mild (n = 3) and moderate (n = 3) and 6 cases of late OHSS (5.8%) graded as moderate (n = 3) and severe (n = 3). Conclusion In this first evaluation of the individualized follitropin delta dosing in a long GnRH agonist protocol, the cumulative live-birth rate was high. A randomized trial comparing follitropin delta in a long GnRH agonist protocol versus in a GnRH antagonist protocol should provide further insight into the efficacy and safety of this treatment option. Trial registration number NCT03564509; June 21, 2018.

Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels

Abstract STUDY QUESTION What is the recommended management of ovarian stimulation, based on the best available evidence in the literature? SUMMARY ANSWER The guideline development group formulated 84 recommendations answering 18 key questions on ovarian stimulation. WHAT IS KNOWN ALREADY Ovarian stimulation for IVF/ICSI has been discussed briefly in the National Institute for Health and Care Excellence guideline on fertility problems, and the Royal Australian and New Zealand College of Obstetricians and Gynaecologist has published a statement on ovarian stimulation in assisted reproduction. There are, to our knowledge, no evidence-based guidelines dedicated to the process of ovarian stimulation. STUDY DESIGN, SIZE, DURATION The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 8 November 2018 and written in English were included. The critical outcomes for this guideline were efficacy in terms of cumulative live birth rate per started cycle or live birth rate per started cycle, as well as safety in terms of the rate of occurrence of moderate and/or severe ovarian hyperstimulation syndrome (OHSS). PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE The guideline provides 84 recommendations: 7 recommendations on pre-stimulation management, 40 recommendations on LH suppression and gonadotrophin stimulation, 11 recommendations on monitoring during ovarian stimulation, 18 recommendations on triggering of final oocyte maturation and luteal support and 8 recommendations on the prevention of OHSS. These include 61 evidence-based recommendations—of which only 21 were formulated as strong recommendations—and 19 good practice points and 4 research-only recommendations. The guideline includes a strong recommendation for the use of either antral follicle count or anti-Müllerian hormone (instead of other ovarian reserve tests) to predict high and poor response to ovarian stimulation. The guideline also includes a strong recommendation for the use of the GnRH antagonist protocol over the GnRH agonist protocols in the general IVF/ICSI population, based on the comparable efficacy and higher safety. For predicted poor responders, GnRH antagonists and GnRH agonists are equally recommended. With regards to hormone pre-treatment and other adjuvant treatments (metformin, growth hormone (GH), testosterone, dehydroepiandrosterone, aspirin and sildenafil), the guideline group concluded that none are recommended for increasing efficacy or safety. LIMITATIONS, REASON FOR CAUTION Several newer interventions are not well studied yet. For most of these interventions, a recommendation against the intervention or a research-only recommendation was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides clinicians with clear advice on best practice in ovarian stimulation, based on the best evidence available. In addition, a list of research recommendations is provided to promote further studies in ovarian stimulation. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. F.B. reports research grant from Ferring and consulting fees from Merck, Ferring, Gedeon Richter and speaker’s fees from Merck. N.P. reports research grants from Ferring, MSD, Roche Diagnositics, Theramex and Besins Healthcare; consulting fees from MSD, Ferring and IBSA; and speaker’s fees from Ferring, MSD, Merck Serono, IBSA, Theramex, Besins Healthcare, Gedeon Richter and Roche Diagnostics. A.L.M reports research grants from Ferring, MSD, IBSA, Merck Serono, Gedeon Richter and TEVA and consulting fees from Roche, Beckman-Coulter. G.G. reports consulting fees from MSD, Ferring, Merck Serono, IBSA, Finox, Theramex, Gedeon-Richter, Glycotope, Abbott, Vitrolife, Biosilu, ReprodWissen, Obseva and PregLem and speaker’s fees from MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Gedeon Richter, Glycotope, Abbott, Vitrolife and Biosilu. E.B. reports research grants from Gedeon Richter; consulting and speaker’s fees from MSD, Ferring, Abbot, Gedeon Richter, Merck Serono, Roche Diagnostics and IBSA; and ownership interest from IVI-RMS Valencia. P.H. reports research grants from Gedeon Richter, Merck, IBSA and Ferring and speaker’s fees from MSD, IBSA, Merck and Gedeon Richter. J.U. reports speaker’s fees from IBSA and Ferring. N.M. reports research grants from MSD, Merck and IBSA; consulting fees from MSD, Merck, IBSA and Ferring and speaker’s fees from MSD, Merck, IBSA, Gedeon Richter and Theramex. M.G. reports speaker’s fees from Merck Serono, Ferring, Gedeon Richter and MSD. S.K.S. reports speaker’s fees from Merck, MSD, Ferring and Pharmasure. E.K. reports speaker’s fees from Merck Serono, Angellini Pharma and MSD. M.K. reports speaker’s fees from Ferring. T.T. reports speaker’s fees from Merck, MSD and MLD. The other authors report no conflicts of interest. Disclaimer This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.) †ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.

Purpose To elucidate if morning or evening start of exogenous progesterone (P4) five days before blastocyst embryo transfer (ET) impacts ongoing pregnancy rates (OPR) in artificial cycles. Methods Single-centre retrospective cohort study of 6493 artificial cycles for an ET (oestrogens and luteal phase support [LPS] with micronized vaginal progesterone [MVP] 400 mg/12 h), conducted at an infertility clinic, December 2018—July 2022. LPS was given from five days before ET. Until March 2021, LPS was started in the evening of day 0 of P4 exposure (“evening start”); since April 2021, LPS was started in the morning of day 0 (“morning start”). Results Morning start of LPS (n = 2482 cycles); evening start (n = 3983 cycles). Morning or evening start did not exert any impact in OPR (46.9% vs. 46.3%, p = 0.682), as well as after adjusting for any potential confounders (aOR (95%CI): 1.00 (0.89–1.13); p = 0.996). Regarding serum P4 levels, no differences were found between morning (13.4 ± 5.8 ng/ml) and evening start of LPS (13.2 ± 6.4 ng/ml; p = 0.181). However, s uboptimal serum P4 levels on the ET day (< 8.8 ng/ml) were registered in 16.6% (n = 411) vs. 19.8% (n = 788) of cycles with a morning and evening start, respectively (p = 0.001). Conclusions A 12-h difference in exogenous P4 initiation does not exert an impact on pregnancy outcomes in artificial cycles with MVP, as far as it is started five days before ET. Results from this study offer a great advantage in patient management, by being able to start LPS either in the morning or in the evening five days before blastocyst transfer.

This study has analysed the relationship between ovarian response and the number of euploid embryos. This is a post hoc analysis of a subset of data generated during a prospective cohort study previously published. Forty-six oocyte donors were subjected to ovarian stimulation with 150 IU of rFSH and 75 IU of hp-hMG in a GnRH agonist long protocol. Preimplantation genetic screening was performed in all viable embryos. We observed a positive relationship between ovarian response and the number of euploid embryos. When ovarian response was above the median (≥17 oocytes), the mean number of euploid embryos per donor was 5.0 ± 2.4, while when <17 oocytes were obtained the mean number of euploid embryos was 2.7 ± 1.4 (p=0.000). Aneuploidy rate did not increase with ovarian response or gonadotropin doses. Also, the number of euploid embryos was inversely related to the amount of gonadotropins needed per oocyte obtained (ovarian sensitivity index). These results suggest that the number of euploid embryos available for embryo transfer increases as the number of oocytes obtained does. Considering the total number of euploid embryos seems more relevant than the aneuploidy rate.

PurposeTo evaluate whether ICSI offers any benefit compared with IVF in different ovarian response categories in case of non-male factor infertility.MethodsThis is a retrospective multicenter analysis using individual patient data, conducted in 15 tertiary referral hospitals in Europe (1 center in Belgium and 14 in Spain). The study included the first cycle of all patients undergoing ovarian stimulation for IVF or ICSI in a GnRH antagonist protocol. Only patients having either IVF or ICSI for non-male factor infertility were included. Patients were divided into 4 groups based on their ovarian response as follows: group A, poor responders (1–3 oocytes); group B, suboptimal responders (4–9 oocytes); group C, normal responders (10–15 oocytes); group D, high responders (> 15 oocytes).ResultsIn total, 4891 patients were analyzed, of whom 4227 underwent ICSI and 664 IVF. There was no significant difference for the insemination method (ICSI vs. IVF) used among the different ovarian response categories: 87% vs. 13%, 87% vs. 13%, 86% vs. 14%, 84% vs. 16%, for groups A, B, C, and D, respectively, p value = 0.35. Mean fertilization rates and embryo utilization rates were comparable between IVF and ICSI in the whole cohort. Fresh and cumulative LBR did not differ significantly for IVF and ICSI in poor, suboptimal, normal, and high responders.ConclusionThere is no advantage of ICSI over IVF as insemination method for non-male factor infertility, irrespective of the ovarian response. The number of oocytes retrieved has no value for the selection of the insemination procedure in case of non-male infertility.

ObjectiveTo investigate whether minimal ovarian stimulation (mOS) is as effective as conventional ovarian stimulation (cOS) for older women belonging to different groups according to the Poseidon criteria.Material and methodsObservational retrospective multicentre cohort including women from Poseidon’s groups 2 and 4 that underwent in vitro fertilization (IVF). We performed a mixed-effects logistic regression model, adding as a random effect the patients and the stimulation cycle considering the dependence of data. Survival curves were employed as a measure of the cumulative live birth rate (CLBR). The primary outcomes were live birth rate per embryo transfer and CLBR per consecutive embryo transfer and oocyte consumed until a live birth was achieved.ResultsA total of 2002 patients underwent 3056 embryo transfers (mOS = 497 and cOS = 2559). The live birth rates per embryo transfer in mOS and cOS showed no significant difference in both Poseidon’s groups. Likewise, the logistic regression showed similar live birth rates between the two protocols in Poseidon’s groups 2 (OR 1.165, 95% CI 0.77–1.77; p = 0.710) and 4 (OR 1.264 95% CI 0.59–2.70; p = 0.387). However, the survival curves showed higher CLBR per oocyte in women that received mOS (Poseidon group 2: p < 0.001 and Poseidon group 4: p = 0.039).ConclusionsMinimal ovarian stimulation is a good alternative to COS as a first-line treatment for patients belonging to Poseidon’s groups 2 and 4. The number of oocytes needed to achieve a live birth seems inferior in mOS strategy than cOS.