Ovarian reserve in patients with FMR1 gene premutation and the role of fertility preservation.

INTRODUCTION: Women with premutation (PM) of the FMR1 gene may suffer from reduced ovarian reserve or even premature ovarian insufficiency (POI). We studied hormonal and ultrasound ovarian reserve, fertility and fertility preservation outcomes in these patients. PATIENTS AND METHOD: Retrospective cohort study of 63 female FMR1 premutation carriers. RESULTS: Sixty-three female patients bearing an FMR1 premutation were included. Median age was 30 years [26.5-35]. Median number of CGG triplets was 83 [77.2-92]. Before diagnosis of PM, 19 women (30%) had had in all 35 pregnancies, resulting in 20 births, including 7 affected children. After diagnosis of PM, 17 women (26.1%) had in all 23 pregnancies, at a median age of 34.5 years [32.2-36.0]: 2 after pre-implantation genetic diagnosis, 3 after oocyte donation, 18 spontaneously, and 5 ending in medical termination for fragile X syndrome. Thirty-three patients (52.4%) had POI diagnosis (median age, 30 years [27-34]) with median FSH level 84 IU/L [50.5-110] and median AMH level 0.08ng/mL [0.01-0.19]. After POI diagnosis, 8 women had in all 9 pregnancies: 3 following oocyte donation, and 6 spontaneous in 5 women (15.1%). Eight of the 9 pregnancies resulted in a live birth (including 2 affected children) and 1 in medical termination for trisomy 13. The median age of the 30 patients without POI was 31 years [25.2-35.0]. Thirteen women (20.6%) underwent fertility preservation, at a median age of 29 years [24-33]: FSH 7.7 IU/L [6.8-9.9], AMH 1.1ng/mL [0.95-2.1], antral follicle count 9.5 [7.7-14.7]. A median 15 oocytes [10-26] were cryopreserved in a median 2 cycles [1-3]. At the time of writing, no oocytes had yet been thawed for in-vitro fertilization. CONCLUSIONS: This study shows the importance of early fertility preservation after diagnosis of FMR1 premutation in women, due to early deterioration of ovarian reserve. Genetic counseling is essential in these patients, as spontaneous pregnancies are not uncommon, even in cases of impaired ovarian reserve, and can lead to birth of affected children.

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.

Fertility outcomes several years after urgent fertility preservation for patients with breast cancer.

OBJECTIVE: To study the fertility outcomes of women who tried to conceive after breast cancer (BC) treatment and fertility preservation. DESIGN: Retrospective observational, bicentric cohort study. SETTING: University hospital. PATIENTS: Patients with BC. INTERVENTION: All patients who had undergone fertility preservation before BC treatment between January 2013 and July 2019 were included (n = 844). The endpoint date was March 1, 2022. Patients with missing data on pregnancy attempts after a cancer diagnosis (n = 195) were excluded from the pregnancy analysis. MAIN OUTCOME MEASURES: Cumulative incidences of pregnancy and live birth (LB) were calculated. For women who became pregnant, the time to conception was calculated between the first fertility preservation consultation and the estimated day of conception. For those who did not conceive, we considered the time between the first fertility preservation consultation and the endpoint date, or the date of patient death. A Cox regression model was used to study the predictive factors for pregnancy and LB. RESULTS: Among the 649 patients with available data on pregnancy attempts after BC diagnosis, 255 (39.3% [35.5-43.2]) tried to conceive (median follow-up of 6.5 years). Overall, 135 (52.9% [46.6-59.2]) of these patients achieved a pregnancy, mainly through unassisted conception (79.3% [72.8-84.8]), and 99 reported an LB (representing 38.8% of patients who attempted conception). In our cohort, 48 months after the first fertility preservation consultation, the cumulative incidence of pregnancy was 33.1% ([27.6-37.9]). After adjustment for age, parity, type of chemotherapy administration, and endocrine therapy, only multiparity at diagnosis and absence of chemotherapy were positive predictive factors of pregnancy after cancer. Of the 793 patients who had vitrified oocytes and embryos, 68 used them (27% [21.3-32.5] of the patients who tried to conceive), resulting in 8 LBs (11.8% [5.2-21.9]). Women who used their cryopreserved oocytes and embryos were older at the first consultation of fertility preservation (hazard ratio 1.71 [1.42-2.21]), and chose more often to vitrify embryos (hazard ratio 1.76 [1.28-2.23]). CONCLUSION: Although pregnancy rates after fertility preservation for patients with BC are low, most conceptions are achieved without medical assistance. Our findings provide useful information to advise women on the different techniques of fertility preservation, their efficacy, and safety, as well as the relatively high chances of unassisted conception.

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.

Impact of oxygen tension during in vitro maturation: a sibling-oocyte prospective double-blinded study.

OBJECTIVE: To determine whether oxygen (O2) tension (20% vs. 5%) has an impact on oocyte maturation rates and morphology during in vitro maturation (IVM). DESIGN: A prospective, observational, monocentric, sibling-oocyte study. SETTING: University Hospital. PATIENTS: A total of 143 patients who underwent IVM for fertility preservation purposes from November 2016 to April 2021 were analyzed. Patients were included when ≥2 cumulus-oocyte complexes (COCs) were retrieved. The cohort of COCs obtained for each patient was randomly split into two groups: group 20% O2 and group 5% O2. INTERVENTION: Cumulus-oocyte complexes were incubated for 48 hours either under 5% O2 or 20% O2. After 24 and 48 hours of culture, every oocyte was assessed for maturity and morphology, to estimate oocyte quality. Morphology was evaluated considering six parameters (shape, size, ooplasm, perivitelline space, zona pellucida, and polar body characteristics), giving a total oocyte score ranging from -6 to +6. MAIN OUTCOME MEASURES: Maturation rates and total oocyte scores were compared using paired-sample analysis between group 20% O2 and group 5% O2. RESULTS: Patient median age was 31.4 [28.1-35.2] years-old. The mean serum antimüllerian hormone levels and antral follicle count were 3.2 ± 2.3 ng/mL and 27.2 ± 16.0 follicles, respectively. A mean of 10.7 COCs per cycle were retrieved, leading to 6.1 ± 2.4 metaphase II oocytes vitrified (total maturation rate = 57.3%; 991 metaphase II oocytes/1,728 COCs). A total of 864 COCs were included in each group. Oocyte maturation rates were not different between the two groups (group 20% O2: 56.82% vs. group 5% O2: 57.87%, respectively). Regarding oocyte morphology, the mean total oocyte score was significantly higher in group 5% O2 compared with group 20% O2 (3.44 ± 1.26 vs. 3.16 ± 1.32, P=.014). CONCLUSION: As culture under low O2 tension (5% O2) improves oocyte morphology IVM, our results suggest that culture under hypoxia should be standardized. Additional studies are warranted to assess the impact of O2 tension on oocyte maturation and the benefit of IVM under low O2 tension for embryo culture after utilization of frozen material.

Prospective multicenter observational real-world study to assess the use, efficacy and safety profile of follitropin delta during IVF/ICSI procedures (DELTA Study).

OBJECTIVE: To describe the use, efficacy and safety profile of follitropin delta in women undergoing IVF/ICSI in routine clinical practice after one treatment cycle. STUDY DESIGN: This was a French multicenter, prospective, observational study conducted in 14 fertility centers between June 2020 and June 2021. During this period, 248 women undergoing IVF or ICSI were treated with follitropin delta for the first time. Women were followed up to 10-11 weeks after the first fresh or frozen embryo transfer. The main outcomes were use of dosing algorithm, follitropin delta dosing patterns, ovarian response, pregnancy, and adverse drug reactions in routine clinical practice. RESULTS: The analyzable population consisted of 223 patients with mean ± SD age of 33.0 ± 4.4 years, body weight of 65.7 ± 11.8 kg, and the median (IQR) AMH level was 2.6 (1.5-4.0) ng/mL. For 193 patients (86.5 %) it was the first IVF/ICSI cycle and for 30 (13.5 %) the second. The algorithm was used for the calculation of the starting dose for 88.3 % of the patients. The mean daily starting dose of follitropin delta was 11.4 ± 4.1mcg for the whole analyzable population and 14.4 ± 5.2 mcg for the sub-group of 26 patients dosed without the algorithm. The mean duration of stimulation with follitropin delta was 10.8 ± 5.2 days. The mean total dose of follitropin delta administered was 122.2 ± 80.0 mcg. An antagonist protocol was used in 90.3 % of patients. The mean ± SD number of oocytes retrieved among patients that started stimulation was 11.3 ± 6.8 and 46.1 % of patients achieved the targeted response of the algorithm of 8-14 oocytes retrieved. A fresh transfer was performed for 77.6 % of patients; the mean ± SD number of embryos transferred was 1.3 ± 0.5. The implantation rate was 36.0 %. Per started cycle, clinical pregnancy was reported in 35.0 % of the patients and ongoing pregnancy in 29.6 %. In total, 5 patients (2.2 %) reported an event of OHSS. CONCLUSION: Clinical results as collected in routine clinical practice are promising, showing a favorable effectiveness-safety profile of follitropin delta for a very varied patient population (including anovulatory PCOS, very poor responders, or non-IVF naïve patients). These real-world data complement results from clinical trials and provide useful information for usual clinical practice within a heterogeneous population group.