Baris Ata

Objectives: To determine the prognostic value of serum β ‐human chorionic gonadotropin ( β ‐hCG) for predicting live birth following single euploid frozen‐embryo transfer (FET), and to develop and validate a prognostic model (iHOPE) for this purpose. Methods: This retrospective cohort study used data from two large fertility practices. The model development cohort included 1581 women with a positive β ‐hCG test after single euploid FET in the United Arab Emirates between March 2017 and June 2023. The external validation cohort comprised 1171 women who underwent FET (with or without preimplantation genetic testing for aneuploidy (PGT‐A)) resulting in a positive β ‐hCG test between January 2020 and December 2023 in the USA. β ‐hCG level was measured on approximately day 10 after FET and was repeated thereafter, allowing estimation of the daily increase in β ‐hCG. The association of clinical and embryological factors with initial β ‐hCG level and subsequent daily β ‐hCG increase was evaluated using multivariable linear regression analysis. The iHOPE prognostic model for live birth was built using repeated measurements of β ‐hCG following single euploid FET, and was validated internally and externally. Model performance was evaluated using the area under the receiver‐operating‐characteristics curve (AUC) and calibration slope. Results: Of 1581 pregnancies in the model development cohort, 1191 (75.3%) resulted in live birth. Of 1171 pregnancies in the external validation cohort, 395 were from an untested embryo, of which 261 (66.1%) resulted in live birth, and 776 were from a PGT‐A‐tested embryo, of which 566 (72.9%) resulted in live birth. In the model development cohort, trophectoderm quality was associated significantly with initial β ‐hCG level Z ‐score among pregnancies resulting in live birth (Grade B vs Grade A: β , −0.19 (95% CI, −0.34 to −0.04), P = 0.011; Grade C vs Grade A: β , −0.59 (95% CI, −0.83 to −0.35), P < 0.001). Women with a higher body mass index (BMI) had a lower initial β ‐hCG level Z ‐score and lower subsequent β ‐hCG increase among pregnancies resulting in live birth ( P < 0.001 for both). Compared with pregnancy resulting in live birth, early clinical pregnancy loss, biochemical pregnancy and pregnancy of unknown location/ectopic pregnancy had significantly lower initial β ‐hCG level Z ‐scores and lower subsequent β ‐hCG increases ( P < 0.001 for all). On internal cross‐validation, the iHOPE prognostic model based on repeated β ‐hCG measurements had a mean ± SD AUC of 0.79 ± 0.04 and good calibration for probabilistic estimation of live birth. In the external validation cohort, trophectoderm quality (Grade B vs Grade A: β , −0.19 (95% CI, −0.34 to −0.05), P = 0.007; Grade C vs Grade A: β , −0.63 (95% CI, −0.90 to −0.37), P < 0.001), time of expanded blastulation ( β , −0.02 (95% CI, −0.02 to −0.01), P < 0.001), patient BMI ( β , −0.04 (95% CI, −0.05 to −0.03), P < 0.001) and PGT‐A testing ( β , −0.16 (95% CI, −0.30 to −0.03), P = 0.017) were associated significantly with initial β ‐hCG level Z ‐score. On external validation, the AUC for the prediction of live birth using the repeated‐measurements model was 0.79 (95% CI, 0.75–0.83) and 0.84 (95% CI, 0.80–0.88) for PGT‐A‐tested and untested embryos, respectively. Calibration in the external validation cohort was better for PGT‐A‐tested embryos compared with untested embryos, as the model slightly overpredicted live‐birth probabilities in the latter group. The iHOPE model is available for use online and as a mobile application. Conclusions: Initial serum β ‐hCG level following FET is affected by PGT‐A. The iHOPE prognostic model, using repeated β ‐hCG measurements, demonstrates robust calibration and acceptable predictive capability for live birth. It may prove to be a useful tool for clinical monitoring and managing patient expectations, and could aid in the early detection of abnormal early pregnancy development. iHOPE is intended for prognostic purposes only and predicted probabilities should not be considered diagnostic. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Dear Editors, We congratulate Dhillon-Smith et al. for the retrospective study including >42 000 ART cycles comparing vaginal oil capsules with progesterone pessaries for luteal phase support. They report higher live birth rates and lower miscarriage rates with capsules ( Dhillon-Smith et al., 2026). However, we think that residual confounding due to differences in age, ovarian reserve, and embryo competence between the two groups substantially limits inference of superiority of one formulation over the other. Women in the pessary group were significantly older (median 36 vs 35 years), had lower anti-Müllerian hormone (AMH) (14.5 vs 15.2 pmol/l), and a lower antral follicle count (AFC) (13 vs 16) compared with women receiving capsules. They also had a higher prevalence of recurrent miscarriage (4.0% vs 3.5%). Despite some controversy, several studies, including our own recent study ( Lawrenz et al., 2025), suggest that diminished ovarian reserve is not only a quantitative issue but also qualitatively associated with lower euploidy rates independent of chronological age. In a pre-implantation genetic testing for aneuploidy (PGT-A) cohort, Li et al. observed that women with lower AMH had a significantly lower proportion of euploid blastocysts across age strata ( Li et al., 2023), indicating that AMH carries age-independent information about oocyte/embryo competence.

What is the recommended management of ovarian stimulation, based on the best available evidence in the literature? This updated ESHRE guideline on ovarian stimulation for IVF/ICSI provides 121 recommendations, answering 21 key questions on ovarian stimulation for IVF/ICSI. Before the ESHRE guideline on ovarian stimulation for IVF/ICSI was published in 2019, ovarian stimulation for IVF/ICSI had only been discussed briefly in the National Institute for Health and Care Excellence guideline on fertility problems and in a statement by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. The guideline was developed according to the structured methodology for ESHRE guidelines. The 18 key questions from the 2019 version of the guideline were revised by the Guideline Development Group (GDG). This resulted in the addition of one new key question, the splitting of the key question on fertility preservation in three separate key questions (fertility preservation for women facing gonadotoxic treatment, elective oocyte cryopreservation, and oocyte donation) and several new interventions being added to the existing key questions. Papers published between 31 October 2018 and 2 February 2025 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). Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the GDG. Following stakeholder review of the initial draft, the final version was approved by the GDG and ultimately by the ESHRE Executive Committee. The guideline provides a total of 121 recommendations: 42 recommendations remained unchanged in 2019, 4 recommendations were reworded for better understanding, 29 recommendations were updated in view of new evidence, and 46 new recommendations for 2025 have been formulated. The guideline provides 4 recommendations on pre-stimulation evaluation, 7 recommendations on pre-treatment therapies, 50 recommendations on pituitary suppression and ovarian stimulation, 17 recommendations on monitoring, 18 recommendations on triggering of final oocyte maturation and luteal support, and 8 recommendations on the prevention of OHSS. In addition, the guideline provides 17 recommendations on fertility preservation, both oncologic and elective, and oocyte donation. These include 90 evidence-based recommendations, of which only 42 were formulated as strong recommendations and 48 as conditional, as well as 29 good practice points and 2 research-only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, 6 by moderate-quality evidence, 36 by low-quality evidence, and 148 by very low-quality evidence. To support future research on ovarian stimulation for IVF/ICSI, a list of research recommendations was provided. 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. 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. The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive any financial incentives; all work was provided voluntarily. BA reports speaker’s fees from Gedeon-Richter, Ferring, IBSA, Intas, Merck, Organon, consulting fees from Merck, Organon, Oxolife, stock options from Global Fertility Solutions LLC (employee co-investment), and was chair of the Turkish Society of Reproductive Medicine. EB reports research grants from Roche Diagnostics and IBSA, consulting fees from MSD, Abbot, Gedeon-Richter, Roche, speaker’s fees from IBSA, MSD, Ferring Pharmaceuticals, Abbot, Gedeon-Richter, Merck, Roche, participation in the advisory board of Ferring Pharmaceuticals, IBSA and Merck, and ownership interest from IVI-RMS Valencia. GG was part of the ESHRE working group on Recurrent Implantation Failure and the ESHRE working group on clinical KPISs, reports travel support from Merck, Organon, Ferring, Theramex, Gedeon-Richter, Abbott, consulting fees from Organon, Ferring, Merck, Gedeon-Richter, Theramex, Abbott, ReproNovo, Igyxos, OxoLife, Philipps, ReprodWissen, PregLem, Guerbet, Roche, IBSA, and Besins, speaker’s fees from Organon, Ferring, Merck, Gedeon-Richter, Theramex, Abbott, ReproNovo, Igyxos, OxoLife, Philipps, ReprodWissen, PregLem, Guerbet, Roche, IBSA, and Besins, and research grants from Besin, Merck, Abbott, Ferring, Theramex. MG reports speaker’s fees from Merck Serono, Ferring, and Gedeon Richter. EK reports travel/hotel expenses from Ferring, Merck SERONO, Vianex, speaker’s fees from Ferring, Merck SERONO, Vianex, and is chair of the Greek Society of Fertility and Sterility. MK reports travel support and speaker’s fees from Ferring. ALM reports research grants from Merck, Ferring, IBSA, Roche, Organon, Theramex, Beckman Coulter, and Gedeon-Richter, consulting fees from Merck, Ferring, IBSA, Roche, Organon, Theramex, Beckman Coulter, and Gedeon-Richter, speaker’s fees from Merck, Ferring, IBSA, Roche, Organon, Theramex, Beckman Coulter, Gedeon-Richter, and participation on an advisory board of Merck, Organon, Ferring, Theramex, Gedeon Richter, and IBSA. GL reports consulting fees from Ferring and Merck, speaker’s fees from Ferring, Merck, Gedeon-Richter, Organon, and Vianex, expert testimony fees from Cook, travel support from ESHRE, Ferring, Merck, Gedeon-Richter, Organon, and Vianex, is on the advisory board of Merck and Ferring, and participated in an ESHRE committee and on the Greek Fertility and Sterility Committee. NM reports research grants from IBSA, Organon, consulting fees from Organon, Merck, GE, Ferring, Abbott, and Cooper, and speaker’s fees from Ferring, GE, Organon, IBSA, Merck, Theramex. NPP reports research grants from Besins Healthcare, Ferring Pharmaceutical, Merck Serono, Organon, Roche Diagnostics, and Theramex, consulting fees from Besins Healthcare, Alife, Ferring, IBSA, Merck Serono, Organon, Abbott, FertilAI, and speaker’s fees from Besins Healthcare, Roche Diagnostics, Ferring Pharmaceuticals, Gedeon-Richter, IBSA, Merck Serono, Organon, and Theramex. SKS reports a research grant from Ferring, travel support from Merck and INTAS, consulting fees from Merck, and speaker’s fees from Merck, MSD, INTAS, and Ferring. TT reports travel support from Merck, speaker’s fees from Merck, Organon, MSD and is editor-in-chief of a Bulgarian journal, Reproductive Health. MT reports travel support from IBSA, Ferring, and Merck, consulting fees from Abbott and is a member of the board of the Finnish Endocrine Society. JU is a member of the Steering Committee of Richter Reproduction Network and received travel support from IBSA. FB reports a research grant from Besins, is on the advisory board of Merck and Abbott, reports speaker’s fees from Ferring, Merck, Besins, Intas Fermaceuticals, PREIS School; he is the owner of FRANKSCHOOL RforL. The other authors have nothing to disclose. N/A. 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. (The full disclaimer is available at www.eshre.eu/guidelines.)

STUDY QUESTION: Do peripubertal girls with mosaic Turner’s syndrome (TS) respond to ovarian stimulation (OS) for oocyte freezing as adult women with normal ovarian reserve? SUMMARY ANSWER: Clinical and molecular reproductive/endocrine features of OS in these patients are similar to those of adult females. WHAT IS KNOWN ALREADY: OS for oocyte freezing is quite a new concept in peripubertal and young adolescent girls with TS because ovarian tissue cryopreservation (OTC) does not have proven efficacy, likely due to already diminished ovarian reserve and accelerated follicle atresia. No data are available in the literature regarding the molecular IVF characteristics of these cycles in this group of patients. We aimed to address this issue in the current study by analyzing gonadotropin receptor expression, response to gonadotropins, and steroidogenic function at the molecular level in four peripubertal patients aged 9, 12, 13, and 15 in comparison to control adult females with normal ovarian reserve undergoing OS for male factor infertility. STUDY DESIGN, SIZE, DURATION: This is a clinical and research study that simultaneously analyzes the clinical and molecular characteristics of OS in peripubertal young girls with TS between 2021 and 2023 at a university hospital and translational research center. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants underwent OS using a progestin-primed protocol with recombinant forms of FSH and LH, and final maturation was induced with recombinant hCG. Control patients who had normal ovarian reserve and underwent OS for male factor infertility were randomly recruited during the study period to simultaneously compare and analyze the clinical and molecular OS characteristics of the peripubertal TS cases. Luteinized mural granulosa cells obtained during oocyte retrieval procedures were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live-cell imaging, and hormone assays were used. MAIN RESULTS AND THE ROLE OF CHANCE: All TS cases responded to gonadotropin stimulation. Nine mature oocytes were retrieved and vitrified in the 9-year-old prepubertal mosaic TS case after four cycles of OS with r-FSH (300 IU) and r-LH (150 IU)/day after a mean stimulation period of 9.72 ± 2.1 days. Eight mature oocytes were retrieved in the case aged 13 after three rounds of OS. The other cases, aged 12 and 15, underwent only one cycle of OS, and two mature oocytes from each were retrieved. The expression of FSH/LH receptors and steroidogenic enzymes, basal and gonadotropin-induced up-regulation in the expression of the steroidogenic enzymes, and estradiol and progesterone productions of the GCs of the TS patients were similar to those of adult control patients. Confocal immunofluorescence microscopy and live imaging revealed no differences in cholesterol uptake/trafficking or in staining patterns of the steroidogenic enzymes and their co-localization with mitochondria and cholesterol-laden lipid droplets. LIMITATIONS, REASONS FOR CAUTION: Findings were obtained from a limited number of mosaic TS patients. It is unclear if these findings are reproducible in non-mosaic peripubertal cases. Furthermore, no data are available yet regarding the post-thaw survival, fertilization, embryo development competency, euploidy status, and obstetrical outcomes of the vitrified oocytes of these patients. WIDER IMPLICATIONS OF THE FINDINGS: This study provides reassuring clinical and molecular evidence that OS for oocyte freezing can be an option in young girls with mosaic TS who are not ideal candidates for OTC due to diminished ovarian reserve. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the School of Medicine, the Graduate School of Health Sciences, and the Research Center for Translational Medicine (KUTTAM) at Koç University. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.