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Background: Oocyte cryopreservation and gonadal suppression during chemotherapy with long-acting GnRH agonists (GnRHa) are standard fertility preservation (FP) methods in women with breast cancer. When both strategies are accepted by the patient, the first injection of GnRHa is frequently administered few days after oocyte retrieval in order to start oncological therapies as soon as possible. GnRHa suppress gonadal function after an initial stimulation phase due to a gonadotropins surge. Consequently, some cases of ovarian hyperstimulation (OHSS) have been described following GnRHa administration during the luteal phase of an oocyte cryopreservation cycle, as a consequence of the initial flare-up effect on recently stimulated ovaries. OHSS is associated with specific complications, such as an increased thromboembolic risk and a possible delay in the start of chemotherapy. These risks may discourage physicians from proposing gonadal suppression in combination with oocyte cryopreservation, denying women a FP opportunity with proven efficacy. However, since the same flare up effect of short-acting GnRHa (e.g. Triptorelin 0.2 mg) is commonly used to trigger ovulation in high responding infertile patients, we propose the initiation of long-acting GnRHa administration at triggering. Our hypothesis is that by inducing ovulation with long-acting GnRHa we meet the last requirement for oocytes maturation and create suppression by the time patients start chemotherapy, without the need of a further injection in the luteal phase. Methods From 2016 to 2020, 70 consecutive ovarian stimulation cycles for oocyte cryopreservation in oncological patients before chemotherapy were performed in a single university centre. Cycle outcomes were evaluated accordingly to the trigger method. Maturation rate was defined as number of cryopreserved mature oocytes/total number of oocytes retrieved. When the long-acting GnRHa was used for triggering, luteal phase hormones were assessed. Results After controlled ovarian stimulation (COS) with standard or random start antagonist protocol, ten women received the long-acting GnRHa trigger (Decapeptyl 3.75 mg, Ipsen. Group A) 36 hours before oocyte retrieval, 37 received highly purified Chorionic Gonadotrophin (Gonasi HP 10000 UI, IBSA. Group B) and 23 the short-acting GnRHa (Decapeptyl 0.2 mg, Ipsen. Group C). The groups were comparable in terms of demographic and clinical parameters. Median number of mature cryopreserved oocytes in group A was 14 (range 8-22) with a maturation rate of 81% (68-100), versus 9 (0-24) with a maturation rate of 78% (43-100) in group B, and 9 (3-34), 78% (38-100) in group C. There was no case of OHSS in Group A. Two patients developed OHSS after administration of long-acting GnRH in the luteal phase after COS, one in Group B and one in Group C. Five days after oocyte retrieval (7 days after trigger), serum FSH median level in group A was 1.28 mUI/ml (0.48-2.50) and LH median level was 1.04 mUI/ml (0.26-2.46). Conclusion We report for the first time the efficacy of long-acting GnRHa in obtaining mature oocytes and, at the same time, in guaranteeing complete suppression by chemotherapy initiation. We are aware that our data should be confirmed by more robust studies and higher numbers. Nevertheless, the feasibility of this strategy is an important step in reducing the risk of OHSS after ovarian stimulation while giving the opportunity to combine oocyte cryopreservation and ovarian suppression during chemotherapy, with proven efficacy as options to preserve fertility and ovarian function, respectively. Citation Format: Claudia Massarotti, Matteo Lambertini, Sara Stigliani, Fausta Sozzi, Paola Scaruffi, Paola Anserini. Long-acting GnRH agonist ovulation trigger to avoid ovarian hyperstimulation and to combine oocyte cryopreservation with ovarian suppression during chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-05.

BACKGROUND: With an increased lifespan, survivorship has become a crucial component of breast cancer (BC) care. Among survivorship concerns, adequate contraception counseling is needed in premenopausal patients (pts) not seeking to become pregnant. However, very limited evidence exists on attitudes and factors influencing contraception use over time in premenopausal women with early BC. METHODS: CANTO is a multicenter, prospective cohort study of 12,012 pts with stage I-III BC (NCT01993498). This analysis included women aged ≤50 years with known premenopausal status at BC diagnosis. Contraception use and type were longitudinally evaluated at diagnosis, year-1 (T1) and 2 (T2) after diagnosis. Multivariable logistic regression models assessed associations between clinical, socio-economic, treatment, toxicity (CTCAE) and pts-reported outcome (PROs, EORTC QLQ-C30/BR23) variables, with contraception use after diagnosis. RESULTS: Among 2,900 pts included, mean age at diagnosis was 43.1 (SD 5.6) years, 96.0% of pts already had children at BC diagnosis, 70.8% and 80.0% received chemotherapy and endocrine therapy (ET), respectively. Among patients treated with ET, 80.2% received tamoxifen alone and 19.8% other therapies (either tamoxifen or an aromatase inhibitor or a combination) plus ovarian function suppression (OFS). Following diagnosis, 45.0% of pts at T1 and 65.7% at T2 reported consulting a gynecologist. At diagnosis, 54.2% of pts reported contraception use, with the majority (62.6%) using hormonal methods. Prevalence of contraception use significantly decreased at T1 and T2 (38.9% and 41.2%, respectively; ptrend Citation Format: Matteo Lambertini, Claudia Massarotti, Julie Havas, Barbara Pistilli, Anne-Laure Martin, Alexandra Jacquet, Charles Coutant, Florence Coussy, Asma Dhaini Merimeche, Florence Lerebours, Olivier Tredan, Christelle Jouannaud, Olivier Rigal, Marion Fournier, Patrick Soulie, Maria Alice Franzoi, Lucia Del Mastro, Ann H. Partridge, Fabrice Andre, Ines Vaz-Luis, Antonio Di Meglio. Attitudes and factors influencing contraception use over time in premenopausal women with early breast cancer in the prospective CANTO study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-20.

Symptoms of treatment-induced menopause negatively affect quality of life and adherence to endocrine therapy of breast cancer (BC) survivors. Nevertheless, the use of systemic hormone replacement therapy (HRT) to mitigate these symptoms may be associated with an increased risk of disease recurrence in these patients. This systematic review and meta-analysis aimed to assess the safety of systemic HRT on risk of disease recurrence in BC survivors. A systematic search of PubMed up to April 20, 2021 was conducted to identify randomized controlled trials (RCTs) that investigated the risk of disease recurrence with the use of HRT in BC survivors. A random-effect model was applied to calculate the risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). A subgroup analysis was performed to estimate the risk of recurrence according to hormone receptor status. Four RCTs were included in the meta-analysis (n = 4050 patients). Overall, 2022 patients were randomized to receive HRT (estrogen/progestogen combination or tibolone) and 2023 to the control group with placebo or no HRT. HRT significantly increased the risk of BC recurrence compared to placebo (HR 1.46, 95% CI 1.12–1.91, p = 0.006). At the subgroup analysis, the risk of BC recurrence with the use of HRT was significantly increased in patients with hormone receptor-positive disease (HR 1.8, 95% CI 1.15–2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.19, 95% CI 0.80–1.77, p = 0.390). Use of HRT was associated with a detrimental prognostic effect in BC survivors, particularly in those with hormone receptor-positive disease. Alternative interventions to mitigate menopause-related symptoms should be proposed.

Background: Controlled ovarian stimulation (COS) for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors. Moreover, limited evidence exists on the safety of assisted reproductive technologies (ART) in breast cancer survivors after completion of anticancer treatments. Material and methods: A systematic literature review with no date restriction up to June 30, 2021 was conducted to identify studies reporting results of oncological outcomes in breast cancer patients and survivors who underwent COS or other ART compared to patients and survivors who did not access these techniques. From each included study, recurrence ratio, event-free survival (EFS) and mortality rate were extracted. Pooled relative risks (RRs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated using the random effects models. Results: Out of 15 included studies (n=4,643), 11 reported outcomes of patients who underwent COS for fertility preservation before starting chemotherapy, and 4 of survivors who underwent ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n=2,386), those who underwent COS (n=1,594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) or mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65).Compared to women not exposed to ART following completion of anticancer treatments (n=540), those exposed to ART (n=123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11). Conclusions: Despite including mostly retrospective studies, this meta-analysis suggests that accessing COS at diagnosis, also in hormone receptor-positive disease, or ART following treatment completion is not associated with detrimental prognostic effect in young women with breast cancer. These results are important to reassure patients and oncologists on the safety of these procedures to increase the chances of future conception. Citation Format: Luca Arecco, Eva Blondeaux, Marco Bruzzone, Marcello Ceppi, Maria Maddalena Latocca, Andrea Boutros, Camilla Marrocco, Maria Grazia Razeti, Maurizio Cosso, Stefano Spinaci, Margherita Condorelli, Claudia Massarotti, Lucia Del Mastro, Isabelle Demeestere, Matteo Lambertini. Safety of assisted reproductive technologies before and after anticancer treatments in young women with breast cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-07.

Objective This study aims to assess the factors associated with the success and failure rate of the external cephalic version (ECV) in breech fetuses. Secondary outcomes were fetal presentation in labor and mode of delivery. Methods This cross-sectional study examined the live birth certificates from 2003 through 2020 from US states and territories that implemented the 2003 revision. A total of 149,671 singleton pregnancies with information about ECV success or failure were included. The outcome was ECV success/failure, while the exposures were possible factors associated with the outcome. Results The successful ECV procedures were 96,137 (64.23%). Among the successful ECV procedures, the prevalence of spontaneous vaginal delivery was 71.63%. Among the failed ECV procedures, 24.74% had a cephalic presentation at delivery, but 63.11% of these pregnancies were delivered by cesarean section. Nulliparity, female sex, low fetal weight centile, high pre-pregnancy BMI, high BMI at delivery, and high maternal weight gain during pregnancy were associated with an increased ECV failure (p p 40 years) were significant protective factors against ECV failure (p Conclusions A high prevalence of successful ECV procedures and subsequent spontaneous vaginal delivery were found. The present results found nulliparity, maternal race, maternal age, female fetal sex, low fetal weight, and maternal anthropometric features correlated to ECV results. These findings can potentially improve the knowledge about the factors involved in ECV, allowing more informed counseling to the women undergoing this procedure.

Study question Does COVID-19 disease negatively impact on male fertility after adequate time of recovery? Summary answer COVID-19 disease did not impact on semen parameters and male reproductive potential in infertile patients, when semen was collected at least three months after recovery What is known already The male reproductive system may be a potential target for SARS-CoV-2 since the presence of ACE and TMPRS2 receptors. After a first report of the presence of SARS-CoV-2 in semen of COVID-19 patients, several papers reported that SARS-CoV-2 was not detected in the semen. However, some evidences indicated that COVID-19 disease could impair semen parameters. During the infection, or in a short period after, a reduction in sperm concentration (up to cases of azoospermia) and motility and an increase in DNA fragmentation were observed. There are no conclusive data exploring if these damages persist. Study design, size, duration In this longitudinal prospective study, performed at a tertiary level public fertility center from February 2020 to December 2021 we enrolled 20 men who had COVID-19 disease (1 severe, 15 mild/moderate, and 4 asymptomatic). We compared sperm parameters in semen samples collected before COVID-19 and at least three months after recovery (median=6 months, IQR 4-9). We also evaluated the reproductive potential of 18 men who performed ART cycles after the recovery. Participants/materials, setting, methods For each man we compared semen parameters before the COVID-19 disease and at least three months after recovery. Semen samples were analyzed following WHO guidelines. Medians and interquartile ranges (IQRs) were reported. The impact of COVID-19 on endpoints (semen volume, concentration, motility) was evaluated by Wilcoxon rank sum test. A subset of 18 patients performed ART cycles after COVID-19 recovery. Outcomes of these cycles were compared with reference performance indicators set at our center. Main results and the role of chance Comparing median semen volume and progressive motility before (2.9 ml, IQR 2.0-3.5; 38.5%, IQR 30.0-52.5) and after COVID-19 (2.5 ml, IQR 2.0-3.6; 40%, IQR 30.0-47.5) we did not find any statistical difference (p = 0.766 and p = 0.782, respectively). We observed an improvement of median sperm concentration after disease recovery (before COVID-19: 26.0 million/ml, IQR 16-37, after: 68.0 million/ml, IQR 29.5-93.5, p = 0. 003), which may be due to intra-individual variability and to patients’ management at our center (i.e., oral antioxidant treatments, other therapies, higher ejaculatory frequency). On the whole, semen parameters did not worsen although the median age of patients obviously increased (36.5 years, IQR 33.8-38 versus 37.5 years, IQR 35.9-39.6). Eighteen couples performed 29 ART cycles after recovery from COVID-19 disease of the male partners (12 IUI, 8 FIVET, 9 ICSI of which one from frozen oocytes). Fertilization, cleavage and top-quality rates were within the normal reference ranges of our center. A total of 6 clinical pregnancies were achieved (5 singletons and 1 twin). One gestation ended in a successful healthy newborn, whereas the remining 5 pregnancies are ongoing. A total of 10 blastocysts were vitrificated in 4 cycles, thus further embryo transfers will be performed. Limitations, reasons for caution The main limitations of the study are: small sample size, limited generalizability because no data were collected in fertile patients. Wider implications of the findings Our data are reassuring about the effect of COVID-19 disease on male fertility, if semen samples are collected at least three months after recovery from infection. Trial registration number not applicable

Several myths and misconceptions exist about hormones in women with familial predisposition to cancer, and there are few real-life data on their prescription and uptake. To better understand how they are prescribed and accepted in healthy carriers of a BRCA1/2 pathogenetic variant, an online survey was uploaded on Google Forms and shared through social media closed groups of patients’ associations, aBRCAcadabra and ACTO Campania. A total of 241 questionnaires were collected. Sexual quality of life was considered of the utmost importance by most of the respondents (mean score of 7 ± 2.8/10), but they felt the counseling they received by healthcare professionals on the topic was insufficient (4.9 ± 3.2/10). Only 57 women out of 233 (24.5%) had used hormonal contraception after being diagnosed as carriers of a BRCA pathogenetic variant, and 42 out of 148 (28.4%) underwent menopause hormonal therapy. The majority of women (53.6% for contraception and 61.5% for menopause) reported being dissatisfied with the counseling received, and 58.2% were not aware of the protective effect of hormonal contraception on the risk of ovarian cancer. An educational effort is desirable to guarantee healthy BRCA carriers reliable contraception and evidence-based menopause counseling.

This study aims at detecting and evaluating differences in quantitative response to controlled ovarian stimulation (COS) with high doses of gonadotropins in women with low serum anti-Müllerian hormone (AMH). About 369 first cycles in a real-life scenario in women between 21 and 43 years old and with AMH ≤0.9 ng/ml were analyzed. Older women had a significantly worse outcome with respect to young women, not only qualitatively, but also in terms of quantitative ovarian response to COS [odd ratio (OR) to obtain at least three MII oocytes with each increasing year of female age: 0.89, 95% CI: 0.85 - 0.94

In Italy during the first pandemic wave of SARS-CoV-2 the activity of fertility centers was stopped, with the exception of fertility preservation in oncological patients. We adopted telehealth and we evaluated whether it could help in the management of infertile couples at a fertility center.A longitudinal study performed at a public fertility center. Telehealth was offered to 72 couples referred to our center for a first consultation from March 17th to May 31st, 2020. Percentage of patients who performed the first assisted reproduction technology (ART) cycle or intrauterine insemination (IUI) within 6 months from the first visit and drop-out rate were analyzed during COVID-19 pandemic and compared to historical controls (couples admitted to our center in 2017-2019).Eighty-five (61/72) percent of couples accepted telehealth. Time to first treatment after online consultation in telehealth group (4.5 (1.8) months) was significantly shorter (p = 0.033) respect to time to first treatment after face-to-face visit of historical controls (7.5 (6.9) months). After telehealth consultation, we observed a significant reduction (p = 0.002) of drop-out rate from 39% in historical controls to 17% of telehealth group. Telehealth significantly diminished the drop-out rate also during the COVID-19 pandemic respect to 73% after traditional face-to-face visits (p = 0.0005), with a time to first treatment of 3.7 (2.1) months in couples who refused telehealth.Telehealth could be a useful tool to facilitate the path of patients in a fertility center.

Beneficial effects of hyaluronic acid (HA)-based selection of spermatozoa for intracytoplasmic sperm injection (ICSI) are still controversial, and further studies are needed to categorize patients that might benefit from such a method.We investigated whether HA sperm selection improved ICSI outcome of couples with previous ICSI cycle failure.In this retrospective study, we prospectively collected data of (i) Group 1: 96 couples who performed one failed ICSI cycle ("1st procedure," n = 96) followed by another ICSI cycle ("2nd procedure," n = 101); ii) Group 2: 87 couples who performed one failed ICSI cycle (n = 87) followed by an HA-ICSI cycle (n = 104). Differences between procedures and groups were measured by paired and independent statistical tests, respectively. A generalized linear mixed model analyzed the effect of procedure on the outcomes and the interaction between procedures and groups.Injection of HA-bound sperm significantly improved cleavage rate with respect to standard ICSI (p = 0.026). No evolutive pregnancies were obtained in the 1st ICSI attempts. The 2nd ICSI cycles resulted in successfully seven pregnancies. In HA-ICSI cycles, the better quality of embryos with respect to ICSI (p = 0.034) increased the choice of day 5 embryo transfer (p = 0.030), which resulted in successfully 28 pregnancies. No differences were observed in clinical outcomes of the two ICSI procedures in Group 1, while pregnancy and implantation rates were significantly higher in HA-ICSI with respect to ICSI cycles (p = 0.001, p 0.0001, respectively). No negative perinatal outcomes were recorded.In couples where previous 1st ICSI failed, selection of HA-bound spermatozoa significantly improved clinical outcomes with respect to further standard ICSI.This study identified couples with previous ICSI cycles failure as a category of infertile patients that really may benefit from HA sperm selection before ICSI.

Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment–induced gonadotoxicity. Patients and Methods: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the “biological window” of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). Results: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33–42 years). AMH values at the 3 time points differed significantly (PPPConclusions: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Background Healthy individuals and patients with cancer who are carriers of germline pathogenic variants in the BRCA1/2 genes face multiple reproductive challenges that require appropriate counseling and specific expertise. Main body On December 5th–7th, 2019, patient advocates and physicians with expertise in the field of reproductive medicine, fertility preservation, and oncology were invited to “San Giuseppe Moscati” Hospital in Avellino (Italy) for a workshop on reproductive management of women with germline pathogenic variants in the BRCA1/2 genes. From the discussion regarding the current evidence and future prospective in the field, eight main research questions were formulated and eight recommendations were developed regarding fertility, fertility preservation, preimplantation genetic testing, and pregnancy in healthy carriers and patients with cancer. Conclusion Several misconceptions about the topic persist among health care providers and patients often resulting in a discontinuous and suboptimal management. With the aim to offer patient-tailored counseling about reproductive issues, both awareness of current evidences and research should be promoted.

The COVID-19 pandemic and national lockdown from 9 March to 4 May 2020 changed social, familial, and sexual relationships, as well as how citizens interact with the health services. How these profound changes have affected sexuality, contraception and voluntary terminations of pregnancy is still largely undescribed. The main objective of this study was therefore to find out whether the COVID-19 pandemic and ensuing lockdown affected the demand for legal abortion.The study period was divided into three phases: the pre-pandemic (January and February 2020); lockdown (March and April); and post-lockdown (May and June). The number and characteristics of women requesting pregnancy termination each month during that time were compared with the stats for the same months in the preceding three years (2017-2019).Immediately after national lockdown, the number of voluntary abortions markedly declined (-40.45%). The effect was more evident in women below 20 years of age (-66.67%), employed versus unemployed women (-42.71% vs. -21.05), and non-Italian versus Italian citizens (-53.01 vs. -32.85). No difference was found in the mean time from request to execution of the procedure, or in the type of the procedure used.National lockdown reduced the number of unwanted pregnancies, especially in younger women. The Italian health service's response to the demand appears to have been unaffected by the pandemic. However, as the demand for abortion is still high, probably due to unplanned pregnancies among cohabitants within a stable relationship, contraception guidance should be improved among women traditionally deemed low-risk in terms of sexual behaviour.

Study question Does ejaculatory frequency during the three months preceding semen collection influence semen parameters in oligospermic men? Summary answer A frequency of 2–3 ejaculations/week during the three months preceding semen collection significantly optimizes sperm motility, without any reduction in sperm concentration. What is known already Male gametes undergo crucial physiological and biochemical changes during epididymal transit, but a longer storage is known to have negative effects on semen quality, especially on motility. Previous studies focused on abstinence prior to semen collection, while few data are available on the effect of ejaculation frequency. On one hand, a longer storage could increase exposure to reactive oxygen species and a pro-inflammatory environment, with a reduction in vitality and motility. On the other, an increased ejaculation frequency could cause a reduction in sperm volume and concentration. The effects of ejaculatory frequency are particularly understudied in men with oligospermia. Study design, size, duration This is a retrospective study performed at a tertiary level public infertility center. We included all semen samples, collected both for diagnostic purposes and ART cycles between September 2019 and September 2020, with a sperm concentration of 15 million/ml or less, and an abstinence of 3- 5 days. Exclusion criteria were surgically collected or collected for fertility preservation semen samples. Participants/materials, setting, methods Standard demographic and clinical data were recorded, as well as semen parameters. Ejaculation frequency was considered “optimal” (at least 2–3/week) or “reduced” ( Limitations, reasons for caution The study is retrospective and ejaculatory frequency was self-reported as an estimate of the mean of the number of ejaculations per week. Wider implications of the findings: Optimizing ejaculatory frequency may improve ART outcomes as well as success of spontaneous conceptions. There is no reason to limit ejaculatory frequency in oligospermic men for a hypothesized benefic in sperm concentration. Trial registration number Not applicable

Study question Does hyaluronic acid (HA) sperm selection improve the intracytoplasmic sperm injection outcome of couples with previous ICSI cycles failure? Summary answer In couples where previous first ICSI failed, selection of HA-bound spermatozoa significantly improved clinical outcomes respect to further standard ICSI. What is known already HA is the major component of the matrix surrounding the human oocyte and in physiological fertilization it plays an important role in sperm selection since only mature spermatozoa express specific binding protein and are able to bind to HA. Although several studies demonstrated better outcomes of ICSI with selection of mature HA-bound spermatozoa, such a beneficial effect of HA-ICSI is still controversial and to date no firm clinical guidance for the routine use of HA can be drawn. Further studies are needed to categorize patients that really might benefit from HA sperm selection before ICSI. Study design, size, duration A retrospective, longitudinal cohort study performed at a tertiary level public infertility center. We selected 164 couples who performed one or more failed ICSI cycles with low fertilization rate and poor embryo quality in the period 2010–2020 (n = 164 cycles, group A), followed by other standard ICSI (n = 99, group B) and/or HA-ICSI (n = 96 group C) cycles. We included only fresh ejaculated sperm and fresh oocytes. Participants/materials, setting, methods Endpoints were fertilization, cleavage, top quality embryo, implantation (IR), clinical pregnancy (CPR), pregnancy loss (PLR), and live birth (LBR) rates. Comparisons among groups were performed using a generalized estimating equation model performed at patient level, to take into account the correlation between observations originating from the same woman. A p-value Main results and the role of chance The three groups were similar for number of retrieved, MII and injected oocytes. As regarding embryological outcomes, there was no difference in fertilization and cleavage rates between group A and C (fertilization: 47.55 + 29.88% versus 54.10 + 28.51%, p = 0.096; cleavage: 96.19 + 12.70% versus 97.52 + 10.50%, p = 0.519), nor between group B and C (fertilization: 60.30 + 30.73% versus 53.71 + 28.61%, p = 0.112; cleavage: 92.26 + 20.540% versus 97.55 + 10.44%, p = 0.106). Selection of HA-bound spermatozoa in ICSI significantly improved the embryo quality rate (63.78 + 35.55% versus 51.42 + 34.31% p = 0.024) and the blastulation rate (43.44 + 25.55% versus 17.93 + 25.52%, p = 0.001) respect to standard ICSI. Comparisons of clinical outcomes between group B and group C highlighted significant higher IR (26.16 + 40.47% versus 7.34 + 22.16%, p = 0.0001), CPR/cycle (32.29% (31/96) versus 12.12% (12/99), p = 0.0007, chi-square test), and lower PLR (12.90% (4/31) versus 41.67% (5/12), p = 0.0398, chi-square test) in HA-ICSI respect to standard ICSI cycles. The LBR/cycle in group B was 10.10% (10/99) and in group C was 32.29% (31/96) (p = 0.0029, chi-square test). No stillbirths as well as no malformations in newborns were recorded. Limitations, reasons for caution We are aware of the retrospective nature of the study performed in a single ART center. Wider implications of the findings: This study identified couples with previous ICSI cycles failure as a category of infertile patients that really may benefit from HA sperm selection before ICSI. Trial registration number Not applicable

STUDY QUESTION Are there reasons that motivate young cancer survivors to ask for follow-up visits at an oncofertility unit? SUMMARY ANSWER Cancer survivors request oncofertility follow-up visits for the management of treatment-related side effects or ovarian reserve evaluation, even if not (or not yet) wishing for a pregnancy. WHAT IS KNOWN ALREADY Personalised oncofertility counselling before gonadotoxic therapies is considered standard of care for young women with newly diagnosed cancer. However, the long-term follow-up of these patients in an oncofertility unit is not described in the literature other than for the use of cryopreserved material. STUDY DESIGN, SIZE, DURATION We retrospectively examined rates and reasons for the first follow-up visits of 154 consecutive young female cancer patients (age range: 18–40 years) who underwent a pre-treatment consultation between January 2012 and June 2017. Demographic and clinical data were collected, as well as information about the chosen fertility preservation method, if any. PARTICIPANTS/MATERIALS, SETTING, METHODS Rates and reasons for follow-up visits were collected and expressed as percentages. Different reasons were examined in the whole cohort and stratified for type of malignancy. Possible predictive factors for return to the follow-up visit (age, nulliparity, presence of a partner, neoplasm, having cryopreserved material) were investigated through logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE Out of 154 patients, 74 returned to the oncofertility unit (48.1%) for a follow-up visit. The first visit was requested mostly at the end of anticancer therapies (51.3% versus 40.5% during therapies and 8.1% after cancer relapse). Among these patients, only 10.8% returned for the first time because they were actively desiring a pregnancy. For the others, the most common reasons for consultations were management of gynecological adverse effects of therapies (29.7%) and evaluation of ovarian reserve not linked to an immediate desire for a pregnancy (39.2%). Other patients asked for contraception (4.1%), menopause counselling (5.4%), or new fertility preservation counselling because of cancer relapse (10.8%). None of the examined factors were significantly predictive of return to the oncofertility unit. LIMITATIONS, REASONS FOR CAUTION These findings represent the experience of a single centre. A longer duration of follow-up would be needed to provide more precise information on this regard. WIDER IMPLICATION OF THE FINDINGS The role of an oncofertility unit should not be limited to proposing fertility preservation procedures. In the management of young adult cancer patients, the reproductive medical specialist should be considered a key figure not only before but also during and after anticancer treatments to explore salient aspects of gynecological and reproductive health. STUDY FUNDING/COMPETING INTEREST(S) This research did not receive any specific funding. M.L. served as a consultant for Teva and received honoraria from Theramex outside the submitted work. The other authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N.A.

In ART, embryo quality evaluation is routinely based on morphological criteria. We previously demonstrated that the mitochondrial DNA (mtDNA)/genomic DNA (gDNA) ratio in culture medium was significantly associated with embryo quality and viability potential. The purpose of this prospective, blinded, multi-centric study was to validate the use of mtDNA/gDNA ratio in Day 3 spent medium as a predictor of human embryo developmental competence. The mtDNA/gDNA ratio was assessed in Day 3 culture media (n=484) of embryos from 143 patients by quantitative PCR. A mixed effect logistic regression model was applied. We found that mtDNA/gDNA ratio in Day 3 culture medium combined with embryo morphology improves the prediction upon blastulation compared to morphology alone (P

ImportanceAs life span has increased among patients with cancer, survivorship has become an important component of breast cancer care. Among survivorship concerns, adequate contraceptive counseling is needed for premenopausal patients who are not seeking to become pregnant.ObjectiveTo examine contraceptive use and chosen methods and to assess factors associated with contraceptive use over time in patients with early breast cancer.Design, Setting, and ParticipantsThe Cancer Toxicity (CANTO) study was a multicenter nationwide prospective cohort study that enrolled women diagnosed with stage I to stage III breast cancer in France between March 2012 and December 2017. This analysis included 2900 premenopausal women who were 50 years of age or younger at diagnosis. Data were analyzed from July 2020 to July 2022.ExposuresContraceptive use and method at diagnosis, shortly after the end of primary treatment (year 1), and during follow-up (year 2).Main Outcomes and MeasuresContraceptive use and methods were longitudinally evaluated at diagnosis, year 1, and year 2 after breast cancer diagnosis. Multivariable logistic regression models were used to assess the associations of clinical, socioeconomic, treatment, adverse effect, and patient-reported outcome variables with contraceptive use after diagnosis.ResultsA total of 2900 patients (mean [SD] age, 43.1 [5.6] years) were included in the analysis; 2050 of 2894 women (70.8%) received chemotherapy, and 2305 of 2880 women (80.0%) received endocrine therapy. After diagnosis, 1182 of 2625 patients (45.0%) at year 1 and 1553 of 2363 patients (65.7%) at year 2 reported consulting with a gynecologist in the previous year. At diagnosis, 1487 of 2744 patients (54.2%) reported contraceptive use, with most patients (921 of 1470 women [62.7%]) using hormonal methods. The use of contraception significantly decreased after diagnosis (911 of 2342 patients [38.9%] at year 1 and 808 of 1961 patients [41.2%] at year 2; P Conclusions and RelevanceFindings from this study support the importance of raising awareness and improving targeted contraceptive counseling for premenopausal women with early breast cancer.

Background In assisted reproduction technology embryo competence is routinely evaluated on morphological criteria but efficacy remains relatively low. Additional information could be obtained by evaluating pronuclear (PN) morphology. Up to now controversial results have been reported about the prognostic value of PN score. One of the main limitations of literature data is the use of different PN classification methods. In this regard, in 2011 the ESHRE and Alpha Scientists in Reproductive Medicine defined three PN categories to standardize zygote assessment. In this study we evaluated whether the consensus ESHRE-Alpha system for the pronuclear scoring could be an useful additional criterion to improve prediction of embryo implantation potential. Methods This is a retrospective, longitudinal, observational, cohort study. We included 3004 zygotes from 555 women who underwent ICSI treatment at our Center between January 2014 and June 2019. The PN were categorized as score 1: symmetrical, 2: non-symmetrical, 3: abnormal. A subset of 110 zygotes did not cleaved. On day 2–3 1163 embryos were transferred, 232 arrested, and 9 were cryopreserved. Among the 1490 embryos cultured up to day 5–7, 516 became blastocysts: 123 were transferred on day 5 and 393 were cryopreserved. Comparisons of age, cleavage and blastocyst rate, quality of embryos, implantation success among PN score groups were evaluated by chi-square test or Kruskal-Wallis test as appropriate. Potential predictors of embryo implantation were first tested in univariable analysis using generalized estimating equations taking into account correlation between embryos originated from the same patient. Then, variables potentially associated with implantation success (P Results There was no significant difference in patients’age, cleavage and blastulation rates, and embryo morphology among the three PNscore groups. The PN score 1-embryos had a greater implantation success respect to score 2-3-ones (OR 1.83; 95% CI 1.34-2.50, P=0.0001). Consistently, the pronuclear score remained predictive of implantation in top quality embryos (OR 1.68; 95%CI 1.17-2.42, P= 0.005). Conclusions The consensus pronuclear score may be routinely included among criteria for embryo evaluation to increase patients’ chance of becoming pregnant.

Sir, We read with interest the recent article by Rubio Lorente et al. describing a Polymerase Chain Reaction (PCR) study of SARS-CoV-2 in amniotic fluid from two amniocenteses [1]. One case was per...

Fertility preservation for cancer patients (oncofertility) is still a relatively new discipline, given the increase in survival rates of patients undergoing chemotherapy. Ovarian stimulation followed by cryopreservation are the routine techniques recommended for post-pubertal cancer patients (The ESHRE Guideline Group on Female Fertility Preservation et al., 2020). However, there are many patients who have a contraindication for ovarian stimulation, need an urgent anticancer treatment or are pre-pubertal. Despite the impressive progress in fertility preservation in recent decades, we still lack options with proven safety and efficacy for many of these patients. [...]