Fertility preservation before cancer treatment: the dilemma of saying 'no' as the price of glory.

A great deal of work has been carried out by professionals in reproductive medicine in order to raise awareness about fertility preservation (FP) techniques, particularly for women, and to ensure that FP is included in the care of young adults treated for cancer or a pathology requiring gonadotoxic treatment. If the importance of the development of our discipline is obvious, our militancy in favour of FP and our emotional projections must not make us forget that medical thinking must be carried out not only on a case-by-case basis, weighing up the benefit-risk balance, but also without losing sight that conceiving a child with one's own gametes is not a vital issue. The cultural importance given to the genetic link with offspring may bias patients' and physicians' decisions, while other ways of achieving parenthood exist, and are often more effective. Systematic information should be provided on the existence of FP techniques, but this should not lead to their systematic implementation, nor should it obscure that early information will also allow patients to begin projecting themselves in alternative options to become parents.

Is large for gestational age in singletons born after frozen embryo transfer associated with freezing technique or endometrial preparation protocol? A longitudinal national French study.

STUDY QUESTION: Is large for gestational age (LGA) observed in babies born after frozen embryo transfer (FET) associated with either the freezing technique or the endometrial preparation protocol? SUMMARY ANSWER: Artificial cycles are associated with a higher risk of LGA, with no difference in rate between the two freezing techniques (vitrification versus slow freezing) or embryo stage (cleaved embryo versus blastocyst). WHAT IS KNOWN ALREADY: Several studies have compared neonatal outcomes after fresh embryo transfer (ET) and FET and shown that FET is associated with improved neonatal outcomes, including reduced risks of preterm birth, low birthweight, and small for gestational age (SGA), when compared with fresh ET. However, these studies also revealed an increased risk of LGA after FET. The underlying pathophysiology of this increased risk remains unclear; parental infertility, laboratory procedures (including embryo culture conditions and freezing-thawing processes), and endometrial preparation treatments might be involved. STUDY DESIGN, SIZE, DURATION: A multicentre epidemiological data study was performed through a retrospective analysis of the standardized individual clinical records of the French national register of IVF from 2014 to 2018, including single deliveries resulting from fresh ET or FET that were prospectively collected in fertility centres. Complementary data were collected from the participating fertility centres and included the vitrification media and devices, and the endometrial preparation protocols. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from 35 French ART centres, leading to the inclusion of a total of 72 789 fresh ET, 10 602 slow-freezing FET, and 39 062 vitrification FET. Main clinical outcomes were presented according to origin of the transferred embryos (fresh, slow frozen, or vitrified embryos) and endometrial preparations for FET (ovulatory or artificial cycles), comparing five different groups (fresh, slow freezing-ovulatory cycle, slow freezing-artificial cycle, vitrification-ovulatory cycle, and vitrification-artificial cycle). Foetal growth disorders were defined in live-born singletons according to gestational age and sex-specific weight percentile distribution: SGA and LGA if <10th and ≥90th percentiles, respectively. Analyses were performed using linear mixed models with the ART centres as random effect. MAIN RESULTS AND THE ROLE OF CHANCE: Transfers led to, respectively, 19 006, 1798, and 9195 deliveries corresponding to delivery rates per transfer of 26.1%, 17.0%, and 23.5% after fresh ET, slow-freezing FET, and vitrification FET, respectively. FET cycles were performed in either ovulatory cycles (n = 21 704) or artificial cycles (n = 34 237), leading to 5910 and 10 322 pregnancies, respectively, and corresponding to pregnancy rates per transfer of 31.6% and 33.3%. A significantly higher rate of spontaneous miscarriage was observed in artificial cycles when compared with ovulatory cycles (33.3% versus 21.4%, P < 0.001, in slow freezing groups and 31.6% versus 21.8%, P < 0.001 in vitrification groups). Consequently, a lower delivery rate per transfer was observed in artificial cycles compared with ovulatory cycles both in slow freezing and vitrification groups (15.5% versus 18.9%, P < 0.001 and 22.8% versus 24.9%, P < 0.001, respectively). Among a total of 26 585 live-born singletons, 16 413 babies were born from fresh ET, 1644 from slow-freezing FET, and 8528 from vitrification FET. Birthweight was significantly higher in the FET groups than in the fresh ET group, with no difference between the two freezing techniques. Likewise, LGA rates were higher and SGA rates were lower in the FET groups compared with the fresh ET group whatever the method used for embryo freezing. In a multivariable analysis, the risk of LGA following FET was significantly increased in artificial compared with ovulatory cycles. In contrast, the risk of LGA was not associated with either the freezing procedure (vitrification versus slow freezing) or the embryo stage (cleaved embryo versus blastocyst) at freezing. Regarding the vitrification method, the risk of LGA was not associated with either the vitrification medium used or the embryo stage. LIMITATIONS, REASONS FOR CAUTION: No data were available on maternal context, such as parity, BMI, infertility cause, or maternal comorbidities, in the French national database. In particular, we cannot exclude that the increased risk of LGA observed following FET with artificial cycles may, at least partially, be associated with a confounding effect of some maternal factors. No information about embryo culture and incubation conditions was available. Most of the vitrification techniques were performed using the same device and with two main vitrification media, limiting the validity of a comparison of risk for LGA according to the device or vitrification media used. WIDER IMPLICATIONS OF THE FINDINGS: Our results seem reassuring, since no potential foetal growth disorders following embryo vitrification in comparison with slow freezing were observed. Even if other factors are involved, the endometrial preparation treatment seems to have the greatest impact on LGA risk following FET. FET during ovulatory cycles could minimize the risk for foetal growth disorders. STUDY FUNDING/COMPETING INTEREST(S): This work has received funding from the French Biomedicine Agency (Grant number: 19AMP002). None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Pain after oocyte retrieval in women with endometriosis undergoing fertility preservation or IVF.

RESEARCH QUESTION: Do women with endometriosis undergoing oocyte retrieval for fertility preservation experience the same level of pain as women undergoing oocyte retrieval for IVF? DESIGN: This retrospective cohort study included 796 cycles in women with endometriosis undergoing oocyte retrieval for fertility preservation (n = 401) or IVF (n = 395) between January 2020 and October 2022. Post-operative pain assessments were compared between the two groups using a numeric rating scale (NRS). RESULTS: Women in the fertility preservation group were younger (32.1 ± 4.2 years versus 35.1 ± 4.1 years; P < 0.001), had a lower body mass index (22.8 ± 3.9 kg/m2 versus 24.6 ± 4.4 kg/m2; P < 0.001) and had a lower concentration of anti-Müllerian hormone (1.8 ± 1.5 ng/ml versus 2.15 ± 2.11 ng/ml; P = 0.026) in comparison with women in the IVF group. The oestrogen concentration on the day of ovulation trigger was higher in women in the fertility preservation group (2188 ± 1152 pg/ml versus 2081 ± 995 pg/ml; P = 0.004), and the prevalence rates of adenomyosis and digestive endometrial lesions were lower in women in the fertility preservation group (14% versus 29%, P < 0.001; 16% versus 25%, P = 0.003, respectively) compared with women in the IVF group. After oocyte puncture, more women in the fertility preservation group had an NRS pain score >3 (moderate to severe pain) compared with women in the IVF group (20% versus 14%; P = 0.018). The progestin-primed ovarian stimulation (PPOS) protocol was identified as an independent predictive factor of greater post-operative pain (adjusted OR 2.30, 95% CI 1.06-5.15; P = 0.039). CONCLUSION: Women with endometriosis undergoing fertility preservation reported more intense post-operative pain in the recovery room than women undergoing IVF. The PPOS protocol was an independent risk factor of intense pain (NRS pain score >3) in women with endometriosis, but further studies are needed to confirm this result.

Do IVF culture conditions have an impact on neonatal outcomes? A systematic review and meta-analysis.

PURPOSE: Are embryo culture conditions, including type of incubator, oxygen tension, and culture media, associated with obstetric or neonatal complications following in vitro fertilization (IVF)? METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane Library was performed from January 01, 2008, until October 31, 2021. The studies reporting quantitative data on at least one of the primary outcomes (birthweight and preterm birth) for the exposure group and the control group were included. For oxygen tension, independent meta-analysis was performed using Review Manager, comparing hypoxia/normoxia. For culture media, a network meta-analysis was carried out using R software, allowing the inclusion of articles comparing two or more culture media. RESULTS: After reviewing 182 records, 39 full-text articles were assessed for eligibility. A total of 28 studies were kept for review. Meta-analysis about the impact of incubator type on perinatal outcomes could not be carried out because of a limited number of studies. For oxygen tension, three studies were included. The pairwise meta-analysis comparing hypoxia/normoxia did not show any statistical difference for birthweight and gestational age at birth. For culture media, 18 studies were included. The network meta-analysis failed to reveal any significant impact of different culture media on birthweight or preterm birth. CONCLUSION: No difference was observed for neonatal outcomes according to the embryo culture conditions evaluated in this review. Further research is needed about the safety of IVF culture conditions as far as future children's health is concerned.

Fetal growth disorders following medically assisted reproduction: due to maternal context or techniques? A national French cohort study.

RESEARCH QUESTION: What part do maternal context and medically assisted reproduction (MAR) techniques play in the risk of fetal growth disorders? DESIGN: This retrospective nationwide cohort study uses data available in the French National Health System database and focuses on the period from 2013 to 2017. Fetal growth disorders were divided into four groups according to the origin of pregnancy: fresh embryo transfer (n = 45,201), frozen embryo transfer (FET, n = 18,845), intrauterine insemination (IUI, n = 20,179) and natural conceptions (n = 3,412,868). Fetal growth disorders were defined from the percentiles of the weight distribution according to gestational age and sex: small and large for gestational age (SGA and LGA) if <10th and >90th percentiles, respectively. Analyses were performed using univariate and multivariate logistic models. RESULTS: Compared with births following natural conception, multivariate analysis showed that the risk of SGA was higher for births following fresh embryo transfer and IUI (adjusted odds ratio [aOR] 1.26 [1.22-1.29] and 1.08 [1.03-1.12], respectively) and significantly lower following FET (aOR 0.79 [0.75-0.83]). The risk of LGA was higher for births following FET (aOR 1.32 [1.27-1.38]), especially in artificial cycles when compared with ovulatory cycles (aOR 1.25 [1.15-1.36]). In the subgroup of births without any obstetrical or neonatal morbidity, the same increased risk of SGA and LGA were observed following fresh embryo transfer or IUI and FET (aOR 1.23 [1.19-1.27] or 1.06 [1.01-1.11] and aOR 1.36 [1.30-1.43], respectively). CONCLUSIONS: An effect of MAR techniques on the risks for SGA and LGA is suggested independently from maternal context and obstetrical or neonatal morbidities. Pathophysiological mechanisms remain poorly understood and should be further evaluated, as well as the influence of embryonic stage and freezing techniques.

A Machine Learning Approach for the Prediction of Testicular Sperm Extraction in Nonobstructive Azoospermia: Algorithm Development and Validation Study.

BACKGROUND: Testicular sperm extraction (TESE) is an essential therapeutic tool for the management of male infertility. However, it is an invasive procedure with a success rate up to 50%. To date, no model based on clinical and laboratory parameters is sufficiently powerful to accurately predict the success of sperm retrieval in TESE. OBJECTIVE: The aim of this study is to compare a wide range of predictive models under similar conditions for TESE outcomes in patients with nonobstructive azoospermia (NOA) to identify the correct mathematical approach to apply, most appropriate study size, and relevance of the input biomarkers. METHODS: We analyzed 201 patients who underwent TESE at Tenon Hospital (Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris), distributed in a retrospective training cohort of 175 patients (January 2012 to April 2021) and a prospective testing cohort (May 2021 to December 2021) of 26 patients. Preoperative data (according to the French standard exploration of male infertility, 16 variables) including urogenital history, hormonal data, genetic data, and TESE outcomes (representing the target variable) were collected. A TESE was considered positive if we obtained sufficient spermatozoa for intracytoplasmic sperm injection. After preprocessing the raw data, 8 machine learning (ML) models were trained and optimized on the retrospective training cohort data set: The hyperparameter tuning was performed by random search. Finally, the prospective testing cohort data set was used for the model evaluation. The metrics used to evaluate and compare the models were the following: sensitivity, specificity, area under the receiver operating characteristic curve (AUC-ROC), and accuracy. The importance of each variable in the model was assessed using the permutation feature importance technique, and the optimal number of patients to include in the study was assessed using the learning curve. RESULTS: The ensemble models, based on decision trees, showed the best performance, especially the random forest model, which yielded the following results: AUC=0.90, sensitivity=100%, and specificity=69.2%. Furthermore, a study size of 120 patients seemed sufficient to properly exploit the preoperative data in the modeling process, since increasing the number of patients beyond 120 during model training did not bring any performance improvement. Furthermore, inhibin B and a history of varicoceles exhibited the highest predictive capacity. CONCLUSIONS: An ML algorithm based on an appropriate approach can predict successful sperm retrieval in men with NOA undergoing TESE, with promising performance. However, although this study is consistent with the first step of this process, a subsequent formal prospective multicentric validation study should be undertaken before any clinical applications. As future work, we consider the use of recent and clinically relevant data sets (including seminal plasma biomarkers, especially noncoding RNAs, as markers of residual spermatogenesis in NOA patients) to improve our results even more.

Influence of breast cancer prognostic factors on oocyte in vitro maturation outcomes performed for urgent fertility preservation.

STUDY QUESTION: Do breast cancer (BC) characteristics influence IVM of oocytes outcomes in patients undergoing fertility preservation (FP)? SUMMARY ANSWER: Scarff-Bloom-Richardson (SBR) III grade, triple-negative BC and HER2 overexpression are independent predictors of fewer oocytes or poor IVM outcomes in young women seeking FP. WHAT IS KNOWN ALREADY: SBR grade, triple-negative status and overexpression of HER2, as well as a high Ki67 proliferation index are all established prognostic factors for BC, influencing patients' therapeutic management. Yet there are also concerns about the potential impact of cancer status on ovarian reserve and function. Previous studies analysing the results of ovarian stimulation in BC patients have shown conflicting findings. Nevertheless, there is no data on the potential impact of BC status and prognostic factors on IVM outcome in women undergoing urgent FP. STUDY DESIGN, SIZE, DURATION: We studied 321 BC patients, 18 to 41 years of age, who were also candidates for oocyte cryopreservation following IVM. The number of oocytes recovered, maturation rate and total number of cryopreserved oocytes were assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve markers (antral follicle count [AFC] and serum anti-Müllerian hormone [AMH] levels) and IVM outcomes were compared according to BC characteristics (Ki67 proliferation index >20%, progesterone and/or oestrogen receptors expression, HER2 status and SBR grade). Logistic regression analysis was then performed to determine the variables that could be independently associated with poor IVM outcomes, such as oocyte retrieval rate <50%, oocyte maturation rate <60% and total number of frozen oocytes <5. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the mean age of the population was 32.3 ± 4.1 years. Mean AFC and serum AMH levels were 22.8 ± 13.9 follicles and 3.8 ± 3.1 ng/ml, respectively. AMH levels were significantly lower in case of triple-negative BC when compared with ER/PR/HER2 status positive cancer (3.1 ± 2.6 ng/ml vs 4.0 ± 3.3 ng/ml, P = 0.02). The mean number of recovered oocytes was 10.2 ± 9.1. After a mean maturation rate of 58.0 ± 26.1%, 5.8 ± 5.3 mature oocytes were cryopreserved per cycle. The number of retrieved and cryopreserved oocytes after IVM were significantly lower in patients presenting with an SBR III tumour when compared with an SBR I or II tumour (9.6 ± 8.7 vs 11.7 ± 9.8, P = 0.02 and 5.4 ± 5.4 vs 6.6 ± 5.8, P = 0.02, respectively). Multivariate statistical analysis showed that HER2 positive status was associated with a mean maturation rate <60% (odds ratio: 0.54; 95% CI (0.30-0.97)). Ki67 and hormonal status were not correlated with poor IVM outcomes. LIMITATIONS, REASONS FOR CAUTION: A weakness is the retrospective nature of the study. Moreover, as with many studies focusing on FP in oncology patients, the lack of data after reutilization of IVM oocytes prevents drawing reliable conclusions on the fate of these frozen gametes. WIDER IMPLICATIONS OF THE FINDINGS: BC prognostic factors might influence IVM outcomes. Moreover, HER2 is likely to be involved in the ovarian function and oocyte maturation process. Further investigations are needed to better understand the mechanisms at play and their possible impact on the competence of IVM oocytes. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used and there are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Obstetrical outcomes and maternal morbidities associated with COVID-19 in pregnant women in France: A national retrospective cohort study.

BACKGROUND: To the best of our knowledge, no study has exhaustively evaluated the association between maternal morbidities and Coronavirus Disease 2019 (COVID-19) during the first wave of the pandemic in pregnant women. We investigated, in natural conceptions and assisted reproductive technique (ART) pregnancies, whether maternal morbidities were more frequent in pregnant women with COVID-19 diagnosis compared to pregnant women without COVID-19 diagnosis during the first wave of the COVID-19 pandemic. METHODS AND FINDINGS: We conducted a retrospective analysis of prospectively collected data in a national cohort of all hospitalizations for births ≥22 weeks of gestation in France from January to June 2020 using the French national hospitalization database (PMSI). Pregnant women with COVID-19 were identified if they had been recorded in the database using the ICD-10 (International Classification of Disease) code for presence of a hospitalization for COVID-19. A total of 244,645 births were included, of which 874 (0.36%) in the COVID-19 group. Maternal morbidities and adverse obstetrical outcomes among those with or without COVID-19 were analyzed with a multivariable logistic regression model adjusted on patient characteristics. Among pregnant women, older age (31.1 (±5.9) years old versus 30.5 (±5.4) years old, respectively, p < 0.001), obesity (0.7% versus 0.3%, respectively, p < 0.001), multiple pregnancy (0.7% versus 0.4%, respectively, p < 0.001), and history of hypertension (0.9% versus 0.3%, respectively, p < 0.001) were more frequent with COVID-19 diagnosis. Active smoking (0.2% versus 0.4%, respectively, p < 0.001) and primiparity (0.3% versus 0.4%, respectively, p < 0.03) were less frequent with COVID-19 diagnosis. Frequency of ART conception was not different between those with and without COVID-19 diagnosis (p = 0.28). When compared to the non-COVID-19 group, women in the COVID-19 group had a higher frequency of admission to ICU (5.9% versus 0.1%, p < 0.001), mortality (0.2% versus 0.005%, p < 0.001), preeclampsia/eclampsia (4.8% versus 2.2%, p < 0.001), gestational hypertension (2.3% versus 1.3%, p < 0.03), postpartum hemorrhage (10.0% versus 5.7%, p < 0.001), preterm birth at <37 weeks of gestation (16.7% versus 7.1%, p < 0.001), <32 weeks of gestation (2.2% versus 0.8%, p < 0.001), <28 weeks of gestation (2.4% versus 0.8%, p < 0.001), induced preterm birth (5.4% versus 1.4%, p < 0.001), spontaneous preterm birth (11.3% versus 5.7%, p < 0.001), fetal distress (33.0% versus 26.0%, p < 0.001), and cesarean section (33.0% versus 20.2%, p < 0.001). Rates of pregnancy terminations ≥22 weeks of gestation, stillbirths, gestational diabetes, placenta praevia, and placenta abruption were not significantly different between the COVID-19 and non-COVID-19 groups. The number of venous thromboembolic events was too low to perform statistical analysis. A limitation of this study relies in the possibility that asymptomatic infected women were not systematically detected. CONCLUSIONS: We observed an increased frequency of pregnant women with maternal morbidities and diagnosis of COVID-19 compared to pregnant women without COVID-19. It appears essential to be aware of this, notably in populations at known risk of developing a more severe form of infection or obstetrical morbidities and in order for obstetrical units to better inform pregnant women and provide the best care. Although causality cannot be determined from these associations, these results may be in line with recent recommendations in favor of vaccination for pregnant women.

Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

Reproductive functions and fertility preservation in transgender women: a French case series.

RESEARCH QUESTION: The reproductive potential of transgender people may be impaired by gender-affirming hormone treatment (GAHT) and is obviously suppressed by gender-affirming surgery involving bilateral orchiectomy. The evolution of medical support for transgender people has made fertility preservation strategies possible. Fertility preservation in transgender women mainly relies on sperm cryopreservation. There are few studies on this subject, and the sample sizes are small, and so it difficult to know whether fertility preservation procedures are feasible and effective in trans women. DESIGN: This retrospective study reports the management of fertility preservation in transgender women referred to the study centre for sperm cryopreservation, and the semen parameters of trans women were compared with those of sperm donors. RESULTS: Ninety-six per cent of transgender women who had not started treatment benefitted from sperm cryopreservation, compared with 80% of those who attempted a therapeutic window and 50% of those receiving hormonal treatment at the time of sperm collection. No major impairment of semen parameters was observed in transgender women who had not started GAHT compared with sperm donors. However, even though the frequency of oligozoospermia was no different, two transgender women presented azoospermia. Some transgender women who had started GAHT could benefit from sperm freezing. None of them were treated with gonadotrophin-releasing hormone (GnRH) analogues. CONCLUSIONS: Parenthood strategies for transgender people have long been ignored, but this is an important issue to consider, especially because medical treatments and surgeries may be undertaken in adolescents or very young adults. Fertility preservation should ideally be offered prior to initiation of GAHT.

In vitro maturation is a viable option for urgent fertility preservation in young women with hematological conditions.

Fertility preservation embraces different techniques developed to improve young women chances of becoming mothers after healing. Among them, in vitro maturation (IVM) procedure is based on oocyte retrieval without any gonadotropin treatment, feasible under locoregional or local anesthesia, with very low operative complications. The present retrospective analysis of a preliminary case series of 25 women diagnosed with Hodgkin or non-Hodgkin lymphoma aims to evaluate the feasibility of IVM for urgent fertility preservation purposes in hematological context. A median of five mature oocytes was cryopreserved after one cycle of IVM, performed without delaying the start of the chemotherapy (median delay from histological diagnosis to start of the chemotherapy 17.5 days). No association was found between lymphomas' characteristics and the number of recovered or frozen oocytes. Although experimental, this technique could be relevant when fertility preservation has to be performed within a short time frame and without additional surgery nor any risk of malignant cells reintroduction.

Fertility preservation: should we reconsider the terminology?

The term 'fertility preservation' embraces techniques that are actually mostly based on gamete and gonadal tissue cryopreservation. While the efficiency of these techniques in terms of live births remains difficult to establish, it is remarkable that this ambiguous terminology is routinely used and seems currently well accepted. In order to limit false hopes about the real chances of truly preserving fertility, our medical community should discuss qualifying the term 'fertility preservation'. 'Gamete or gonadal tissue cryopreservation' could appear as a more unambiguous and realistic term. However, it probably captures only a segment of a more global 'fertility preservation' process. Discussing how and when to use which terminology, and even finding a more realistic and unifying term, should be further explored.

BRCA1/2 gene mutations do not affect the capacity of oocytes from breast cancer candidates for fertility preservation to mature in vitro.

STUDY QUESTION: Are the maturation rates of oocytes recovered from small antral follicles different between breast cancer patients presenting with or without a BRCA 1/2 gene mutation? SUMMARY ANSWER: BRCA 1/2 gene mutations do not affect the capacity of oocytes from breast cancer candidates for fertility preservation to mature in vitro. WHAT IS KNOWN ALREADY: Mutations in the BRCA1 and BRCA2 genes are associated with an increased risk for developing breast and ovarian cancer. Controversy exists about fertility and ovarian reserve in BRCA mutation carriers. Studies suggest that these patients may have low ovarian reserve and poor response to ovarian stimulation. The impaired ability of the mutated BRCA gene to repair double-strand breaks in DNA may prompt oocyte aging, apoptosis and meiotic errors. IVM of oocytes retrieved at germinal vesicle stage, followed by vitrification of metaphase II (MII) oocytes has recently emerged as an option for young women seeking fertility preservation, when ovarian stimulation is unfeasible. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study involving 329 breast cancer candidates for fertility preservation using IVM between January 2014 and December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were: age 18-40 years; two ovaries present; no history of chemotherapy; test for BRCA 1/2 mutations performed. Before immature oocyte retrieval, all follicles measuring 2-9 mm in diameter were precisely counted on both ovaries and serum anti-Müllerian hormone (AMH) was measured irrespective of the phase of the cycle. Number of cumulus oocyte complexes (COC) retrieved, maturation rate and number of MII oocytes cryopreserved were compared according to BRCA mutation status. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, BRCA-mutated women (n = 52) and BRCA-negative women (n = 277) were comparable in terms of age (31.7 ± 3.9 versus 32.3 ± 3.8 years, respectively, P = 0.3), BMI (23.4 ± 4.7 versus 22.6 ± 3.7 kg/m2, respectively, P = 0.3) and ovarian reserve tests (antral follicle count: 20.5 ± 11.4 versus 21.7 ± 12.1 follicles, P = 0.5; serum AMH levels: 3.6 ± 2.9 versus 4.1 ± 3.6 ng/ml, P = 0.3, respectively). The number of COCs retrieved did not differ significantly between both groups (8.9 ± 6.9 versus 9.9 ± 8.1 oocytes, P = 0.5). After similar IVM rates (67 ± 24 versus 62 ± 23%, P = 0.2), the number of MII oocytes cryopreserved was similar in patients presenting BRCA mutation or not (5.1 ± 3.8 versus 6.1 ± 5.1, P = 0.1, respectively). LIMITATIONS, REASONS FOR CAUTION: Given the low incidence of the mutation, these preliminary findings should be confirmed by further multi-center studies. WIDER IMPLICATIONS OF THE FINDINGS: Although BRCA mutations are known to alter DNA repair mechanism, it does not seem to impair oocyte capacity to mature in vitro. STUDY FUNDING/COMPETING INTEREST(s): None.

Antral follicle responsiveness to FSH, assessed by the follicular output rate (FORT), is altered in Hodgkin's lymphoma when compared with breast cancer candidates for fertility preservation.

PURPOSE: Oocyte and/or embryo cryopreservation after controlled ovarian hyperstimulation (COH) represents the most established method for female fertility preservation (FP) before cancer treatment. Whether patients suffering from malignancies, candidates for FP, have a normal ovarian capacity to respond to stimulation is controversial. Reduced responsiveness of antral follicle to exogenous FSH might be at play. The percentage of antral follicles that successfully respond to FSH administration may be estimated by the follicular output rate (FORT), which presumably reflects the health of granulosa cells. The present study aims at investigating whether the FORT differs between Hodgkin's lymphoma (HL) and breast cancer (BC) patients. METHODS: Forty-nine BC and 33 HL patient candidates for FP using oocyte vitrification following COH were prospectively studied. FORT was calculated by the ratio between the pre-ovulatory follicle count (16-22 mm) on the day of oocyte triggering × 100/antral follicle count before initiation of the stimulation. RESULTS: Overall, women in the HL group were younger in comparison with BC patients (26.4 ± 3.9 vs 33.6 ± 3.3 years, p < 0.0001, respectively). The FORT was significantly decreased in patients with HL when compared with BC group (27.0 ± 18.8 vs 39.8 ± 18.9%, p = 0.004, respectively), further leading to a comparable number of oocytes vitrified (10.8 ± 5.9 vs 10.2 ± 7.7 oocytes, p = 0.7, respectively). CONCLUSION: The present findings indicate that the percentage of antral follicles that successfully respond to FSH administration is reduced in HL when compared to BC patients, supporting the hypothesis of a detrimental effect of hemopathy on follicular health. In vitro experimentations might provide additional data to confirm this hypothesis.

Should we consider day-2 and day-3 embryo morphology before day-5 transfer when blastocysts reach a similar good quality?

Clinical outcomes of 291 day-5 blastocyst transfers carried out between January 2012 and March 2016 were retrospectively compared according to their quality at day 2 and 3. Inclusion criteria were female age younger than 37 years; first or second IVF and intracytoplasmic sperm injection cycle; quality of the transferred blastocyst: blastocoele B3 or higher; inner-cell-mass A/B; trophectoderm A/B; and known implantation outcome for each transferred blastocyst. Blastocysts were classified into good-quality and poor-quality embryo groups at day 2 and 3. Implantation (38.7% versus 41.4), clinical pregnancy (40.3% versus 45.9%), miscarriage (22.2% versus 26.7%;) and live birth rates (37.4% versus 38.8%) were comparable in day 2 good and poor-quality embryo groups. No signficiant differences in morphology of transferred blastocysts at day 3 were found. Multivariable analysis highlighted that poor or good embryo quality at day 2 and day 3 were not predictive of the implantation of good-quality blastocysts (at day 2: adjusted odds ratio = 0.82 CI 95% 0.49 to 1.38; at day 3: adjusted odds ratio = 1.39; CI 95% 0.77 to 2.52). Good-quality blastocyst transfer should, therefore, be carried out irrespective of embryo quality at cleavage stage, as it may not compromise success rates in a good-prognosis population.

History of ABVD alters the number of oocytes vitrified after in vitro maturation in fertility preservation candidates.

AIM: This retrospective case-control study aimed at analyzing the results of in vitro maturation (IVM) of oocytes, used for fertility preservation (FP), in patients with history of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) for classical Hodgkin lymphoma. PATIENTS & METHODS: A total of 22 candidates for FP, having received ABVD at least 2 years before IVM for FP were studied. IVM results were compared with those of 44 breast cancer patients, without history of chemotherapy, matched for ovarian reserve parameters. RESULTS: The number of cumulo-oocyte complexes recovered and the total number of matured oocytes vitrified was lower in patients having received AVBD (5.5 ± 4.8 vs 8.5 ± 4.4 oocytes; p = 0.03 and 3.5 ± 3.7 vs 6 ± 3.0 oocytes; p < 0.04, respectively). CONCLUSION: In light of these results, FP should be discussed before ABVD.

Should metaphase 1 and 2 stages oocytes be vitrified in the same time for fertility preservation?

AIMS: Could metaphase 1 (M1) and 2 (M2) stages oocytes from in vitro maturation (IVM) cycles and controlled-ovarian hyperstimulation (COH) cycles be frozen at the same time without any adverse effect of vitrification on further survival (SR) and maturation rates (MR)? MATERIALS & METHODS: M1 from cancer patients were prospectively included in IVM/COH groups, and in study or control subgroups if they were vitrified or not. In each study subgroup, SR were compared with that of M2 oocytes vitrified/warmed from egg donors. MR were compared with those of fresh-M1 oocytes from control IVM/COH subgroups. RESULTS: SR were not different between groups. MR compared respectively between survived- and fresh-M1 oocytes were similar when resulting from COH (85.2 vs 81.1%) but significantly lower after IVM (39.1 vs 73.3%). CONCLUSION: Simultaneous freezing of M1/M2 oocytes could be applied to COH but not to IVM during the course of fertility preservation.

The past, present and future of fertility preservation in cancer patients.

Fertility preservation strategies have been developed for men and women whose fertility is compromised for medical reasons, especially in case of cancer therapy. At present, many reliable options for preserving fertility are available. However, a part of these fertility preservation methods, despite being promising, are still considered experimental. Nevertheless, there are still situations where no methods can be offered. Remarkable scientific progress is currently underway to improve available techniques and to develop new technologies to solve problems with current fertility strategies. These new options may drastically change reproductive options for young patients facing germ cell loss and hence sterility. Therefore, oncofertility counseling by a specialist is recommended for all young cancer patients having to undergo treatment that may reduce fertility potential.

A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation.

An increasing number of couples require medical assistance to achieve a pregnancy, and more than 2% of the births in Western countries now result from assisted reproductive technologies. To identify genetic variants responsible for male infertility, we performed a whole-genome SNP scan on patients presenting with total globozoospermia, a primary infertility phenotype characterized by the presence of 100% round acrosomeless spermatozoa in the ejaculate. This strategy allowed us to identify in most patients (15/20) a 200 kb homozygous deletion encompassing only DPY19L2, which is highly expressed in the testis. Although there was no known function for DPY19L2 in humans, previous work indicated that its ortholog in C. elegans is involved in cell polarity. In man, the DPY19L2 region has been described as a copy-number variant (CNV) found to be duplicated and heterozygously deleted in healthy individuals. We show here that the breakpoints of the deletions are located on a highly homologous 28 kb low copy repeat (LCR) sequence present on each side of DPY19L2, indicating that the identified deletions were probably produced by nonallelic homologous recombination (NAHR) between these two regions. We demonstrate that patients with globozoospermia have a homozygous deletion of DPY19L2, thus indicating that DPY19L2 is necessary in men for sperm head elongation and acrosome formation. A molecular diagnosis can now be proposed to affected men; the presence of the deletion confirms the diagnosis of globozoospermia and assigns a poor prognosis for the success of in vitro fertilization.

[Artificial intelligence: to a better predictive strategy for testicular sperm extraction outcome in azoospermia]. / Intelligence artificielle : vers une meilleure stratégie de prédiction du résultat de la biopsie testiculaire dans un contexte d'azoospermie.

Azoospermia, defined as the absence of sperm in the semen, is found in 10-15 % of infertile patients. Two-thirds of these cases are caused by impaired spermatogenesis, known as non-obstructive azoospermia (NOA). In this context, surgical sperm extraction using testicular sperm extraction (TESE) is the best option and can be offered to patients as part of fertility preservation, or to benefit from in vitro fertilization. The aim of the preoperative assessment is to identify the cause of NOA and evaluate the status of spermatogenesis. Its capacity to predict TESE success remains limited. As a result, no objective and reliable criteria are currently available to guide professionals on the chances of success and enable them to correctly assess the benefit-risk balance of this procedure. Artificial intelligence (AI), a field of research that has been rapidly expanding in recent years, has the potential to revolutionize medicine by making it more predictive and personalized. The aim of this review is to introduce AI and its key concepts, and then to examine the current state of research into predicting the success of TESE.