[First-line management of infertile couple. Guidelines for clinical practice of the French College of Obstetricians and Gynecologists 2022]. / Prise en charge de première intention du couple infertile : mise à jour des RPC 2010 du CNGOF.

OBJECTIVE: To update the 2010 CNGOF clinical practice guidelines for the first-line management of infertile couples. MATERIALS AND METHODS: Five major themes (first-line assessment of the infertile woman, first-line assessment of the infertile man, prevention of exposure to environmental factors, initial management using ovulation induction regimens, first-line reproductive surgery) were identified, enabling 28 questions to be formulated using the Patients, Intervention, Comparison, Outcome (PICO) format. Each question was addressed by a working group that had carried out a systematic review of the literature since 2010, and followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) methodology to assess the quality of the scientific data on which the recommendations were based. These recommendations were then validated during a national review by 40 national experts. RESULTS: The fertility work-up is recommended to be prescribed according to the woman's age: after one year of infertility before the age of 35 and after 6months after the age of 35. A couple's initial infertility work-up includes a single 3D ultrasound scan with antral follicle count, assessment of tubal permeability by hysterography or HyFOSy, anti-Mullerian hormone assay prior to assisted reproduction, and vaginal swabbing for vaginosis. If the 3D ultrasound is normal, hysterosonography and diagnostic hysteroscopy are not recommended as first-line procedures. Chlamydia trachomatis serology does not have the necessary performance to predict tubal patency. Post-coital testing is no longer recommended. In men, spermogram, spermocytogram and spermoculture are recommended as first-line tests. If the spermogram is normal, it is not recommended to check the spermogram. If the spermogram is abnormal, an examination by an andrologist, an ultrasound scan of the testicles and hormonal test are recommended. Based on the data in the literature, we are unable to recommend a BMI threshold for women that would contraindicate medical management of infertility. A well-balanced Mediterranean-style diet, physical activity and the cessation of smoking and cannabis are recommended for infertile couples. For fertility concern, it is recommended to limit alcohol consumption to less than 5 glasses a week. If the infertility work-up reveals no abnormalities, ovulation induction is not recommended for normo-ovulatory women. If intrauterine insemination is indicated based on an abnormal infertility work-up, gonadotropin stimulation and ovulation monitoring are recommended to avoid multiple pregnancies. If the infertility work-up reveals no abnormality, laparoscopy is probably recommended before the age of 30 to increase natural pregnancy rates. In the case of hydrosalpinx, surgical management is recommended prior to ART, with either salpingotomy or salpingectomy depending on the tubal score. It is recommended to operate on polyps>10mm, myomas 0, 1, 2 and synechiae prior to ART. The data in the literature do not allow us to systematically recommend asymptomatic uterine septa and isthmoceles as first-line surgery. CONCLUSION: Based on strong agreement between experts, we have been able to formulate updated recommendations in 28 areas concerning the initial management of infertile couples.

Oocyte Vitrification for Fertility Preservation in Women with Benign Gynecologic Disease: French Clinical Practice Guidelines Developed by a Modified Delphi Consensus Process.

International guidelines are published to provide standardized information and fertility preservation (FP) care for adults and children. The purpose of the study was to conduct a modified Delphi process for generating FP guidelines for BGD. A steering committee identified 42 potential FP practices for BGD. Then 114 key stakeholders were asked to participate in a modified Delphi process via two online survey rounds and a final meeting. Consensus was reached for 28 items. Among them, stakeholders rated age-specific information concerning the risk of diminished ovarian reserve after surgery as important but rejected proposals setting various upper and lower age limits for FP. All women should be informed about the benefit/risk balance of oocyte vitrification-in particular about the likelihood of live birth according to age. FP should not be offered in rASRM stages I and II endometriosis without endometriomas. These guidelines could be useful for gynecologists to identify situations at risk of infertility and to better inform women with BGDs who might need personalized counseling for FP.

Homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anaemia trait.

BACKGROUND: Primary ovarian insufficiency (POI) affects 1% of women under 40 years and is a public health problem. The genetic causes of POI are highly heterogeneous with isolated or syndromic forms. Recently, variants in genes involved in DNA repair have been shown to cause POI. Notably, syndromic POI with Fanconi anaemia (FA) traits related to biallelic BRCA2 truncated variants has been reported. Here, we report a novel phenotype of isolated POI with a BRCA2 variant in a consanguineous Turkish family. METHODS: Exome sequencing (ES) was performed in the patient. We also performed functional studies, including a homologous recombination (HR) test, cell proliferation, radiation-induced RAD51 foci formation assays and chromosome breakage studies in primary and lymphoblastoid immortalised cells. The expression of BRCA2 in human foetal ovaries was studied. RESULTS: ES identified a homozygous missense c.8524C>T/p.R2842C-BRCA2 variant. BRCA2 defects induce cancer predisposition and FA. Remarkably, neither the patient nor her family exhibited somatic pathologies. The patient's cells showed intermediate levels of chromosomal breaks, cell proliferation and radiation-induced RAD51 foci formation compared with controls and FA cells. R2842C-BRCA2 only partially complemented HR efficiency compared with wild type-BRCA2. BRCA2 is expressed in human foetal ovaries in pachytene stage oocytes, when meiotic HR occurs. CONCLUSION: We describe the functional assessment of a homozygous hypomorphic BRCA2 variant in a patient with POI without cancer or FA trait. Our findings extend the phenotype of BRCA2 biallelic alterations to fully isolated POI. This study has a major impact on the management and genetic counselling of patients with POI.

Decrease in pregnancy rate after endometrial scratch in women undergoing a first or second in vitro fertilization. A multicenter randomized controlled trial.

STUDY QUESTION: Does endometrial scratch in women undergoing a first or second IVF/ICSI attempt improve the clinical pregnancy rate (CPR)? SUMMARY ANSWER: Endometrial scratch (ES) in women undergoing their first or second IVF/ICSI attempt does not enhance the CPR under the technical conditions of our study. WHAT IS KNOWN ALREADY: Several studies have suggested that physical scratch of the endometrium before an IVF attempt could improve embryo implantation. STUDY DESIGN, SIZE, DURATION: This was a randomized controlled multi-center, two-arm, parallel trial. Inclusions started in February 2010 and stopped prematurely in July 2014 after an unplanned interim analysis. At the time of study closure, 191 of the planned 358 patients had been included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients included in the study were randomly assigned to either the ES arm or the non-ES arm. Local ES was performed between Day 20 and Day 24 of the cycle preceding ovarian stimulation using a device for endometrial biopsy. Ovarian stimulation used a combination of recombinant FSH and either an GnRH agonist protocol or a GnRH antagonist protocol without any estrogen pre-treatment. CPR was analyzed on an intent-to-treat basis. All comparisons between the two groups were done using a logistic regression model adjusted for age, BMI and infertility etiology. Differences between the two arms were considered statistically significant at P value of less than 0.0446 for the primary outcome only. MAIN RESULTS AND THE ROLE OF CHANCE: Sixty-eight embryo transfers were performed in the ES arm and sixty-four in the non-ES arm. CPR was 23.5% (16/68) in the ES arm and 35.9% (23/64) in the non-ES arm (hazard ratio (HR) = 0.43; 95% CI, 0.18-1.02; P = 0.0568). The implantation rate was 19.1% and 24.0% in the ES arm and in the non-ES arm, respectively. Two miscarriages and one ectopic pregnancy were reported in each arm. The multiple pregnancy rate was higher in the scratch arm (50.0% vs 20.0%), but the difference was not statistically significant (odds ratio (OR) = 4.54; 95% CI, 0.50-40.93; P = 0.1349). The endometrial biopsy procedure was well tolerated in most women. Of 50 patients in the ES arm having received the embryo transfer, 40 (80.0%) patients reported having felt pain during the procedure, the pain resolving quickly for 31 of them. LIMITATIONS, REASONS FOR CAUTION: An interim analysis of the primary endpoint was conducted and an independent data monitoring committee agreed on stopping the inclusions. This analysis was prompted by the tendency towards lower pregnancy rates observed in the ES arm. Consequently, the study suffered from a lower inclusion rate and failed to reach the planned sample size. WIDER IMPLICATIONS OF THE FINDINGS: Under the technical condition employed in this study, ES in the luteal phase of the cycle preceding the ovarian stimulation does not improve CPR in patients undergoing a first or second IVF/ICSI attempt. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from Ministère de la Santé Français (Programme Hospitalier de Recherche Clinique 2009). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT01064193. TRIAL REGISTRATION DATE: 08-Feb-2010. DATE OF FIRST PATIENT'S ENROLMENT: 08-Feb-2010.

Thirteen years' experience in fertility preservation for cancer patients after in vitro fertilization and in vitro maturation treatments.

PURPOSE: This study aims to describe the experience and outcomes of in vitro maturation without ovarian stimulation (IVM-FP) and conventional in vitro fertilization after ovarian stimulation (IVF-FP) in a fertility preservation (FP) program for women with cancer. METHODS: Retrospective cohort study from 2003 to 2015 was conducted. The study population consisted of 353 women with cancer who underwent 394 FP cycles (187 IVF-FP cycles and 207 IVM-FP) for oocytes and/or embryos cryopreservation. RESULT(S): Comparatively with IVM-FP, IVF-FP had a higher median [25th-75th percentile] number of oocytes collected-12 [8-18] vs 7 [5-13]; oocytes cryopreserved-10 [6-15] vs 5 [2-8]; and, where applicable, embryos cryopreserved-5 [3-7] vs 3 [2-5] (p < 0.000001). Following FP treatment, 32 patients (9.0%) died, 18 patients (5.6%) conceived spontaneously, and 23 patients (6.5%) returned to attempt pregnancy with a median lapse of returning of 4.6 [3.1-6.1] years. Of these, cryopreserved oocytes or embryos were used in 33 cycles (19 after IVF-FP and 14 after IVM-FP). Overall, the cumulative pregnancy rate (CPR) was 47.6% (10/21) and the live birth rate (LBR) was 38.1% (8/21). Per cycle, CPR and LBR were 37 and 31% following IVF-FP and 14 and 7% following IVM-FP, although these differences did not reach statistical significance. We report the fourth live birth after IVM-FP in cancer, and the first one after IVM embryo warming resulting from in vivo oocyte retrieval and IVM procedure. CONCLUSION(S): Both IVF-FP and IVM-FP are possible options for FP women with cancer. Due to minimal data regarding ultimate outcomes, further follow-up is needed.

Immature oocyte retrieval and in vitro oocyte maturation at different phases of the menstrual cycle in women with cancer who require urgent gonadotoxic treatment.

OBJECTIVE: To evaluate the feasibility and the efficacy of in vitro maturation (IVM) when immature oocyte collection was performed in the early follicular, late follicular, or luteal phases in women with cancer who require urgent chemotherapy. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENT(S): One-hundred and sixty-four women with cancer undergoing IVM treatment for fertility preservation. INTERVENTION(S): Oocyte retrieval, IVM, cryopreservation. MAIN OUTCOME MEASURE(S): Medians (interquartile range) of oocytes collected, maturation rates after 48 hours of culture, and metaphase II oocytes cryopreserved. RESULT(S): The analysis included a total of 192 cycles grouped into early follicular phase (n = 46), late follicular phase (n = 107), or luteal phase (n = 39). Embryo cryopreservation was performed in 82 cycles, and oocyte cryopreservation in 105 cycles. Between the early follicular, late follicular, and luteal phases, no statistically significant differences were found in the number of oocytes collected (8.5 [4-15.8], 8 [5-14], and 7 [4-9], respectively), the maturation rates after 48 hours of culture (53.5% [39.8-77], 58% [44-82], and 50% [33-67], respectively), or the number of oocytes cryopreserved (3 [0-7.3], 3 [0-7], and 3 [1-5.5], respectively). Similarly, the fertilization rates (77 [62.8-92.5], 75 [60-100], and 63.5 [50-75], respectively) and number of embryos cryopreserved (3 [2-5.8], 3 [0.5-5], and 2 [1-3], respectively) were not statistically significantly different among the groups. CONCLUSION(S): Our study confirms the feasibility of IVM collection at any time during the menstrual cycle. Treatment with IVM is an alternative method when chemotherapy cannot be delayed or ovarian stimulation is contraindicated. The long-term outcomes remain to be studied.