[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.

Impact of the duration of oestradiol treatment on live birth rate in Hormonal Replacement Therapy cycle before frozen blastocyst transfer.

Although the duration of progesterone administration in Hormonal Replacement Therapy (HRT) cycles before frozen embryo transfer is standardized, the optimal duration of oestrogen treatment remains controversial. In this monocentric retrospective study conducted in all single frozen blastocyst transfer (FBT) performed with HRT between January 2016 and July 2019, we evaluated the association between the duration of oestradiol treatment before FBT and live birth rate (LBR) in HRT cycles. Cycles were gathered in 3 groups according to quartiles of duration of oestrogen treatment. LBR was compared across the 3 groups and multivariate analysis was performed. We included 2235 single FBT cycles; 507, 1257 and 471 with E2 treatment below 23 days, 23-30 days (reference) and more than 30 days respectively. After multivariate analysis and adjustment, no significant difference in LBR was found between below 23 or more than 30 days and reference groups (OR = 0.93 [0.68-1.27] and OR = 1.29 [0.88-1.89] respectively). Complementary sensitivity analysis led to a non-significant adjusted OR = 1.66 [IC 0.9-3.1]. In conclusion, our study showed that the duration of E2 treatment in HRT cycles before FBT is not associated with LBR.

Is low anti-Mullerian hormone (AMH) level a risk factor of miscarriage in women <37 years old undergoing in vitro fertilization (IVF)?

Anti-Mullerian Hormone (AMH) is considered to be one of the most relevant markers of ovarian reserve. However, its association with oocyte quality, pregnancy occurrence and evolution remain to be further investigated. The objective of this study was to compare miscarriage rate after fresh blastocyst(s) transfer in young women (<37 years old) with or without diminished ovarian reserve (DOR), as reflected by low serum AMH levels. This monocentric retrospective study was conducted in 669 women undergoing 1,891 blastocyst transfers. Patients were divided into 2 groups: (1) 190 transfers performed in 106 women with a 'low' serum AMH (< 10th percentile) (i.e. AMH < 0.85 ng/mL); and (2) 961 transfers performed in 563 patients with a 'normal' serum AMH (25th-75th percentile) (i.e. AMH 1.4-4 ng/mL). Miscarriage rate was comparable in both groups (9.5 and 6.8% respectively; p = 0.2) as well as implantation rate, pregnancy rate, live birth rate per transfer (p = 0.4, p = 0.07 and p = 0.6, respectively). After multivariate analysis, no significant association was found between serum AMH level and miscarriage rate (p = 0.22). In women <37 years, low serum AMH level is not associated with an increase in miscarriage rate after fresh blastocyst transfer.

A pilot study comparing corifollitropin alfa associated with hp-HMG versus high dose rFSH antagonist protocols for ovarian stimulation in poor responders.

Does corifollitropin alfa associated with hp-HMG protocol from the beginning of ovarian stimulation perform better than high dose rFSH alone for ovarian stimulation with GnRH antagonist in poor responders? This retrospective, monocentric, case-control pilot study was conducted in 65 poor responders (Bologna criteria) undergoing 2 consecutive IVF cycles. All patients underwent a first ovarian stimulation cycle with high dose rFSH (≥300 IU/day) alone in antagonist protocol, unfortunately leading to poor ovarian response and no pregnancy. The following cycle was performed with 150 µg of corifollitropin alfa associated with daily injections of hp-HMG from the beginning of the cycle. The primary outcome was the number of mature oocytes retrieved. The secondary outcomes were ovarian stimulation cancellation and embryo transfer rate per initiated cycle. The number of mature oocytes was not significantly different between the 2 groups. However, cycle cancellation rate was significantly lower and the proportion of cycles with embryo transfer was significantly higher with corifollitropin + hp-HMG protocol, leading to an encouraging clinical pregnancy rate of 24.1% per oocyte retrieval. This pilot study based on corifollitropin alfa associated with hp-HMG from the onset of stimulation appears to be promising for ovarian stimulation in poor responders.

Association between early ßhCG kinetics, blastocyst morphology and pregnancy outcome in a single-blastocyst transfer program.

OBJECTIVE(S): Beta human chorionic gonadotrophin (ß-hCG) is secreted by placenta and detectable in maternal serum a few days after embryo implantation. The evolution of ß-hCG serum levels is commonly used to confirm early pregnancy and differentiate normal pregnancies from others, either in spontaneous pregnancies or after IVF. However, little is known on the eventual link between blastocyst quality in IVF, pregnancy outcome, and ßhCG kinetics. The objective was to evaluate the association between early ßhCG rise, blastocyst morphology and pregnancy evolution in a single-blastocyst transfer program STUDY DESIGN: This retrospective cohort study was conducted in a University-affiliated IVF center in 441 couples undergoing 455 single blastocyst transfer cycles leading to a positive pregnancy test 12 days afterwards. The rate of rise of ß-hCG (ß-hCG kinetics) was calculated in each cycle and its association with blastocyst quality and pregnancy clinical outcome was evaluated. RESULTS: ß-hCG kinetics was significantly different according to blastocyst expansion, but with considerable overlap between groups. ß-hCG kinetics was also significantly different according to clinical outcome, with higher values in clinical pregnancies than in other groups. This remained true in subgroups' analysis according to blastocyst expansion and in top quality blastocysts. CONCLUSION(S): Early ß-hCG kinetics after single-blastocyst transfer is different according to pregnancy outcome and is only slightly influenced by blastocyst quality. These results confirm the interest of ß-hCG follow up in IVF pregnancies, and do not support the interest of building blastocyst-specific ß-hCG ranges in IVF cycles.

Ovarian reserve and response to stimulation in women undergoing fertility preservation according to malignancy type.

RESEARCH QUESTION: Does ovarian reserve and ovarian response to ovarian stimulation in women with cancer undergoing oocyte vitrification for fertility preservation vary according to the type of malignancy? DESIGN: Retrospective cohort study including 105 women aged between 18 and 40 years, who were referred for fertility preservation (oocyte vitrification) between 2013 and 2016. The women were divided into three groups: breast cancer, lymphoma or other cancer. All of them had been recently diagnosed with cancer, with gonadotoxic treatment scheduled, and had oocyte vitrification after ovarian stimulation with antagonist protocol. RESULTS: Baseline antral follicle count and anti-Müllerian hormone were no different between women with breast cancer, lymphoma or other cancer. The number of cancelled cycles for poor ovarian response was similar between the groups. The number of FSH units per mature oocyte, the number of mature oocytes (metaphase II) retrieved, and the oocyte maturity rate were not significantly different between the three groups. CONCLUSIONS: As the type of cancer does not seem to significantly affect ovarian reserve and ovarian response to ovarian stimulation, our results do not support the relevance of integrating this parameter when establishing ovarian stimulation protocol for oocyte vitrification cycle in women with cancer.

Proficiency in oocyte retrieval assessed by the learning curve cumulative summation test.

The number of procedures required for a trainee to reach proficiency in oocyte retrieval and the criteria applied to define performance are not well defined. To evaluate the learning curve of oocyte retrieval, this study prospectively evaluated three trainees over 6 months. Oocyte retrieval was monitored by the learning curve-cumulative summation test (LC-CUSUM), a specific statistical tool designed to indicate when a predefined level of performance is reached. Oocytes were retrieved from one ovary by the trainee and from the second ovary by a senior operator in a randomized manner. The main outcome measure was the ratio of oocytes collected and follicles aspirated. A trainee's ratio of ≥ 80% of the senior operator's defined success. From 17 to >50 procedures were necessary for the trainees to reach the predefined level of performance. Cumulative summation tests implemented after the learning phase confirmed that performance was maintained. The present study confirms the large variability in acquiring proficiency for surgical procedures. It provides an exportable model for a quantitative tailored monitoring of the learning curve and for continuous monitoring of performance in oocyte retrieval.