Risk factors for poor oocyte yield and oocyte immaturity after GnRH agonist triggering.

STUDY QUESTION: What are the potential risk factors for poor oocyte recuperation rate (ORR) and oocyte immaturity after GnRH agonist (GnRHa) ovulation triggering? SUMMARY ANSWER: Lower ovarian reserve and LH levels after GnRHa triggering are risk factors of poor ORR. Higher BMI and anti-Müllerian hormone (AMH) levels are risk factors of poor oocyte maturation rate (OMR). WHAT IS KNOWN ALREADY: The use of GnRHa to trigger ovulation is increasing. However, some patients may have a suboptimal response after GnRHa triggering. This suboptimal response can refer to any negative endpoint, such as suboptimal oocyte recovery, oocyte immaturity, or empty follicle syndrome. For some authors, a suboptimal response to GnRHa triggering refers to a suboptimal LH and/or progesterone level following triggering. Several studies have investigated a combination of demographic, clinical, and endocrine characteristics at different stages of the treatment process that may affect the efficacy of the GnRHa trigger and thus be involved in a poor endocrine response or efficiency but no consensus exists. STUDY DESIGN, SIZE, DURATION: Bicentric retrospective cohort study between 2015 and 2021 (N = 1747). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients aged 18-43 years who underwent controlled ovarian hyperstimulation and ovulation triggering by GnRHa alone (triptorelin 0.2 mg) for ICSI or oocyte cryopreservation were included. The ORR was defined as the ratio of the total number of retrieved oocytes to the number of follicles >12 mm on the day of triggering. The OMR was defined as the ratio of the number of mature oocytes to the number of retrieved oocytes. A logistic regression model with a backward selection method was used for the analysis of risk factors. Odds ratios (OR) are displayed with their two-sided 95% confidence interval. MAIN RESULTS AND THE ROLE OF CHANCE: In the multivariate analysis, initial antral follicular count and LH level 12-h post-triggering were negatively associated with poor ORR (i.e. below the 10th percentile) (OR: 0.61 [95% CI: 0.42-0.88]; P = 0.008 and OR: 0.86 [95% CI: 0.76-0.97]; P = 0.02, respectively). A nonlinear relationship was found between LH level 12-h post-triggering and poor ORR, but no LH threshold was found. A total of 25.3% of patients suffered from oocyte immaturity (i.e. OMR < 75%). In the multivariate analysis, BMI and AMH levels were negatively associated with an OMR < 75% (OR: 4.34 [95% CI: 1.96-9.6]; P < 0.001 and OR: 1.22 [95% CI: 1.03-1.12]; P = 0.015, respectively). Antigonadotrophic pretreatment decreased the risk of OMR < 75% compared to no pretreatment (OR: 0.72 [95% CI: 0.57-0.91]; P = 0.02). LIMITATIONS, REASONS FOR CAUTION: Our study is limited by its retrospective design and by the exclusion of patients who had hCG retriggers. However, this occurred in only six cycles. We were also not able to collect information on the duration of pretreatment and the duration of wash out period. WIDER IMPLICATIONS OF THE FINDINGS: In clinical practice, to avoid poor ORR, GnRHa trigger alone should not be considered in patients with higher BMI and/or low ovarian reserve, balanced by the risk of ovarian hyperstimulation syndrome. In the case of a low 12-h post-triggering LH level, practicians must be aware of the risk of poor ORR, and hCG retriggering could be considered. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Pregnancy loss: French clinical practice guidelines.

In intrauterine pregnancies of uncertain viability with a gestational sac without a yolk sac (with a mean of three orthogonal transvaginal ultrasound measurements <25mm), the suspected pregnancy loss should only be confirmed after a follow-up scan at least 14 days later shows no embryo with cardiac activity (Grade C). In intrauterine pregnancies of uncertain viability with an embryo <7mm on transvaginal ultrasound, the suspected pregnancy loss should only be confirmed after a follow-up scan at least 7 days later (Grade C). In pregnancies of unknown location after transvaginal ultrasound (i.e. not visible in the uterus), a threshold of at least 3510IU/l for the serum human chorionic gonadotrophin assay is recommended; above that level, a viable intrauterine pregnancy can be ruled out (Grade C). Postponing conception after an early miscarriage in women who want a new pregnancy is not recommended (Grade A). A work-up for women with recurrent pregnancy loss should include the following: diabetes (Grade A), antiphospholipid syndrome (Grade A), hypothyroidism with anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies (Grade A), vitamin deficiencies (B9, B12) (Grade C), hyperhomocysteinaemia (Grade C), hyperprolactinaemia (Grade B), diminished ovarian reserve (Grade C), and a uterine malformation or an acquired uterine abnormality amenable to surgical treatment (Grade C). The treatment options recommended for women with a missed early miscarriage are vacuum aspiration (Grade A) or misoprostol (Grade B); and the treatment options recommended for women with an incomplete early miscarriage are vacuum aspiration (Grade A) or expectant management (Grade A). In the absence of both chorioamnionitis and rupture of the membranes, women with a threatened late miscarriage and an open cervix, with or without protrusion of the amniotic sac into the vagina, should receive McDonald cerclage, tocolysis with indomethacin, and antibiotics (Grade C). Among women with a threatened late miscarriage and an isolated undilated shortened cervix (<25mm on ultrasound), cerclage is only indicated for those with a history of either late miscarriage or preterm delivery (Grade A). Among women with a threatened late miscarriage, an isolated undilated shortened cervix (<25mm on ultrasound) and no uterine contractions, daily treatment with vaginal progesterone up to 34 weeks of gestation is recommended (Grade A). Hysteroscopic section of the septum is recommended for women with a uterine septum and a history of late miscarriage (Grade C). Correction of acquired abnormalities of the uterine cavity (e.g. polyps, myomas, synechiae) is recommended after three early or late miscarriages (Grade C). Prophylactic cerclage is recommended for women with a history of three late miscarriages or preterm deliveries (Grade B). Low-dose aspirin and low-molecular-weight heparin at a preventive dose are recommended for women with obstetric antiphospholipid syndrome (Grade A). Glycaemic levels should be controlled before conception in women with diabetes (Grade A).

[Using an ovarian drilling by hydrolaparoscopy or recombinant follicle stimulating hormone plus metformin to treat polycystic ovary syndrome: Why a randomized controlled trial fail?]. / Drilling ovarien par fertiloscopie ou stimulation par FSH plus metformine dans le traitement du syndrome des ovaires polykystiques : pourquoi un essai thérapeutique peut être un échec.

OBJECTIVES: To evaluate pregnancy rates after randomized controlled trial (RCT) between ovarian drilling by fertiloscopy or ovarian hyperstimulation+insemination+metformine after clomifène citrate (cc) treatment fails. PATIENTS AND METHODS: Randomized controlled trial with 126 patients in each arm in 9 university centers. After 6-9 months of stimulation by cc, 2 groups were randomized: group 1, ovarian drilling with bipolar energy versus group 2: 3 months treatment by metformine followed by 3 hyperstimulation by FSH+insemination. The success rate was pregnancy rate above 12 weeks. RESULTS: RCT was stopped after the screening of 40 patients. In spite of the low number of patients, the pregnancy rate is significantly higher in medical group 8/16 versus 3/18 (p=0.04). CONCLUSION: The causes of fail of RCT were in relationship with difficulties of inclusion, with absence of final agreement by team included. Moreover, RCT between medical and surgical management is often root of difficulties for patients who decline surgical strategy. However, medical treatment appeared better than drilling in this RCT.

[The influence of exogenous LH/hCG activity on serum progesterone levels on the day of hCG administration in in vitro fertilization]. / Influence de l'activité LH/hCG exogène sur le taux sérique de progestérone le jour de l'hCG en fécondation in vitro.

OBJECTIVES: Clarifying whether the addition of recombinant LH (rLH) to recombinant FSH (rFSH) leads to progesterone (P4) levels on dhCG comparable to those obtained with stimulation with FSH and hCG (HP-hMG) MATERIALS AND METHODS: Pituitary-desensitized patients, matched for age and follicle reserve, received rFSH+LH (n=729) or HP-hMG (n=729). In the rFSH+rLH group, rLH (75 UI/day) was started at day 6. To control for the influence of ovarian response on P4, we divided serum P4 levels by the number of growing follicles (13-22 mm; "per follicle" P4 levels) and performed a multivariate analysis. RESULTS: Serum P4 levels on dHCG were lower in the HP-hMG (median: 0.63 ng/mL, max-min: 0.10-2.97) than in the rFSH+rLH group (0.91 ng/mL; 0.10-4.65, P<0.0001), as well as "per-follicle" P4 levels (0.055 ng/mL/growing follicle, 0.006-0.284 vs 0.077 ng/mL/growing follicle, 0.003-0.336; P<0.0001). CONCLUSIONS: HP-hMG led to lower P4 levels on day hCG than rFSH+rLH irrespective of the intensity of the ovarian response and the adjunction of rLH (75 IU/day from day 6 onward).

[Definition of pregnancy losses: Standardization of terminology from the French National College of Obstetricians and Gynecologists (CNGOF)]. / Standardisation de la terminologie des pertes de grossesse : consensus d'experts du Collège national des gynécologues et obstétriciens français (CNGOF).

OBJECTIVE: While a number of glossaries have been produced by various authorities in different countries, at present there is no internationally accepted common set of definitions for many terms used to describe pregnancy losses. The objective of the current study was to provide a standardized French/English terminology/glossary relating to pregnancy losses. METHODS: Literature review, construction of a glossary and rating of proposals using a formal consensus method. The glossary was subject of a critical comprehensive review by a meeting of professionals (multidisciplinary panel). RESULTS: A miscarriage is a spontaneous evacuation of an intra-uterine pregnancy<22WG. A missed early miscarriage is when ultrasound (<14WG) shows no growth of intra-uterine sac/embryo and/or loss of fetal heart activity. An early miscarriage is when spontaneous evacuation of intra-uterine pregnancy occurs <14WG. A complete early miscarriage is when there is no retained products of conception (empty uterus on ultrasound) and no bleeding nor pain. Incomplete early miscarriage is when ultrasonography shows retained products of conception in the uterine cavity (including cervical canal). Repeat miscarriage or recurrent pregnancy loss is when the woman experiences 3 or more consecutive miscarriages <14WG. A late miscarriage is when there is spontaneous evacuation of pregnancy ≥14WG and <22WG. A threatened late miscarriage is when shortening/opening of the cervix±uterine contraction occur ≥14WG and <22WG. An intra-uterine fetal demise is when there is a spontaneous loss of fetal heart activity ≥14 WG. CONCLUSION: The final current terminology should be used by all healthcare professionals.

[Epidemiology of loss pregnancy]. / Épidémiologie des pertes de grossesse.

OBJECTIVES: Study of epidemiology of pregnancy loss. MATERIALS AND METHOD: A systematic review of the literature was performed using Pubmed and the Cochrane library databases and the guidelines from main international societies. RESULTS: The occurrence of first trimester miscarriage is 12% of pregnancies and 25% of women. Miscarriage risk factors are ages of woman and man, body mass index greater than or equal to 25kg/m(2), excessive coffee drinking, smoking and alcohol consumption, exposure to magnetic fields and ionizing radiation, history of abortion, some fertility disorders and impaired ovarian reserve. Late miscarriage (LM) complicates less than 1% of pregnancies. Identified risk factors are maternal age, low level of education, living alone, history of previous miscarriage, of premature delivery and of previous termination of pregnancy, any uterine malformation, trachelectomy, existing bacterial vaginosis, amniocentesis, a shortened cervix and a dilated cervical os with prolapsed membranes. Fetal death in utero has a prevalence of 2% in the world and 5/1000 in France. Its main risk factors are detailed in the chapter.

[Early recurrent miscarriage: Evaluation and management]. / Fausses couches précoces « à répétition ¼ : bilan et prise en charge.

OBJECTIVE: To establish recommendations for early recurrent miscarriages (≥3 miscarriages before 14weeks of amenorrhea). MATERIALS AND METHODS: Literature review, establishing levels of evidence and recommendations for grades of clinical practice. RESULTS: Women evaluation includes the search for a diabetes (grade A), an antiphospholipid syndrome (APS) (grade A), a thyroid dysfunction (grade A), a hyperprolactinemia (grade B), a vitamin deficiency and a hyperhomocysteinemia (grade C), a uterine abnormality (grade C), an altered ovarian reserve (grade C), and a couple chromosome analysis (grade A). For unexplained early recurrent miscarriages, treatment includes folic acid and progesterone supplementation, and a reinsurance policy in the first quarter (grade C). It is recommended to prescribe the combination of aspirin and low-molecular-weight heparin when APS (grade A), glycemic control in diabetes (grade A), L-Thyroxine in case of hypothyroidism (grade A) or the presence of thyroid antibodies (grade B), bromocriptine if hyperprolactinemia (grade B), a substitution for vitamin deficiency or hyperhomocysteinemia (grade C), sectionning a uterine septum (grade C) and treating an uterine acquired abnormality (grade C). CONCLUSION: These recommendations should improve the management of couples faced with early recurrent miscarriages.

[Chronic maternal diseases and pregnancy losses. French guidelines]. / Pathologies maternelles chroniques et pertes de grossesse. Recommandations françaises.

AIM: To review the available data on maternal chronic diseases and pregnancy losses. MATERIAL AND METHODS: We searched PubMed and the Cochrane library with pregnancy loss, stillbirth, intrauterine fetal demise, intrauterine fetal death, miscarriage and each maternal diseases of this paper. RESULTS: Antiphospholipid antibodies (anticardiolipin, anti-beta-2-glycoprotein, lupus anticoagulant) should be measured in case of miscarriage after 10WG confirmed by ultrasound (grade B) and an antiphospholipid syndrome should be treated by a combination of aspirin and low-molecular-weight heparin during a subsequent pregnancy (grade A). We do not recommend testing for genetic thrombophilia in case of first trimester miscarriage (grade B) or stillbirth (grade C). Glycemic control should be a goal before pregnancy for women with pregestational diabetes to limit the risks of pregnancy loss (grade A) with a goal of prepregnancy HbA1c<7%. Overt and subclinical hypothyroidisms should be treated by L-thyroxin during pregnancy to reduce the risks of pregnancy loss (grade A). Women who are positive for TPOAb should have TSH concentrations follow-up during pregnancy and subsequently treated by L-thyroxin if they develop subclinical hypothyroidism (grade B). CONCLUSIONS: Prepregnancy management of most chronic maternal diseases, ideally through prepregnancy multidisciplinary counseling, reduces the risks of pregnancy loss.

[Adiana(®) hysteroscopic tubal occlusion device for the treatment of hydrosalpinx prior to in vitro fertilization: a case report]. / Obturation tubaire d'un hydrosalpinx avant fécondation in vitro par Adiana(®) : à propos d'un cas.

This case report outlines a successful pregnancy after proximal occlusion of a fallopian tube with Adiana(®) micro-insert in a patient with hydrosalpinx. A 32-year-old nulligravid patient with pelvic adhesive disease and unilateral hydrosalpinx underwent a successful occlusion of the hydrosalpinx by Adiana(®) matrix with a pregnancy after IVF cycle. Adiana(®) hysteroscopic tubal occlusion device can be used prior to IVF and seems to be an alternative to Essure(®) procedure. The theoretical advantage of Adiana(®) is the ability to maintain a uterine cavity free of all foreign matter.

[Cancer, fertility preservation and gonadotropins]. / Cancer, préservation de la fertilité et gonadotrophines.

The recent emergence of oncofertility raises the question of ovarian stimulation and its risks when performed for oocyte or/and embryo cryopreservation in a fertility preservation program. The relation between ovarian stimulation and cancer has been marked by the possible direct or indirect tumorigenic role for pituitary gonadotrophins in the tumorogenesis. Although the growth of many gonadal and extragonadal tumors is stimulated by gonadal sex hormones, whose production is regulated by gonadotrophins, there is still a lack of data to consider FSH and LH as tumor promoters. The purpose of this brief review is to present on one hand, the questions raised by the administration of exogenous gonadotrophins in cancer patients and on the other, to evaluate both experimental and clinical data about the possible relation between gonadotrophins and tumorogenesis.

Antral follicle responsiveness to follicle-stimulating hormone administration assessed by the Follicular Output RaTe (FORT) may predict in vitro fertilization-embryo transfer outcome.

BACKGROUND: Looking for a qualitative marker of ovarian function, we aimed to verify whether responsiveness of antral follicles to FSH administration, as reflected by the Follicular Output RaTe (FORT), is related to their reproductive competence. METHODS: We studied 322 IVF-ET candidates aged 25-43 years who underwent controlled ovarian hyperstimulation with similar initial FSH doses. Antral follicle (3-8 mm) count (AFC) and pre-ovulatory follicle (16-22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH treatment) and on the day of hCG administration. The FORT was calculated by PFC × 100/AFC. FORT groups were set according to tercile values: low (<42%; n= 102), average (42-58%; n= 123) and high (>58%; n= 97). RESULTS: The average FORT was 50.6% (range, 16.7-100.0%). Clinical pregnancy rates per oocyte retrieval increased progressively from the low to the high FORT groups (33.3, 51.2 and 55.7%, respectively, P< 0.003) and such a relationship assessed by logistic regression was independent of the confounding covariates, women's ages, AFC and PFC. CONCLUSIONS: The observed relationship between IVF-ET outcome and the percentage of antral follicles that effectively respond to FSH administration reaching pre-ovulatory maturation suggests that FORT may be a qualitative reflector of ovarian follicular competence. Further studies with broader inclusion criteria and more personalized protocols are needed to validate these results.

[Are mild ovarian stimulations for IVF-ET a significant progress in assisted reproductive technologies?]. / Les stimulations ovariennes modérées pour fécondation in vitro constituent-elles un réel progrès en assistance médicale à la procréation ?

Growing evidence indicates that mild ovarian stimulation for in vitro-fertilization-embryo transfer may be an interesting approach to reduce the incidence and severity of complications, the number of treatment days, cost, patient discomfort and number of patient drop-outs. However, the heterogeneity of FSH-sensitive follicles, presumably requires multiple follicular growth to improve oocyte-embryo selection. In addition, whether the acceptability probably is similar between standard ovarian stimulation and mild stimulation, per-treatment pregnancy rates with conventional stimulation is superior to mild stimulation in unselected populations. Hence, some specific indications tend to emerge such as alterations of the ovarian follicular reserve in women of less than 38 years, bad embryo qualities and implantation failure after conventional stimulation, patients with previous history of hyperstimulation syndrome or contraindications to hyperoestrogenia (estrogeno-related cancers and thromboembolic diseases). However, no randomized trials have ever been performed to compare the results of mild versus conventional stimulation in young patients and good responders. Therefore, there is insufficient scientific evidence to shift from standard stimulation to mild stimulation for all patients. Cultural standards have to be considered in the choice of the type of stimulation.

[Cancellation of IVF-ET cycles: poor prognosis, poor responder, or variability of the response to controlled ovarian hyperstimulation? An analysis of 142 cancellations]. / Annulations en fécondation in vitro : mauvais pronostic, mauvaises répondeuses, ou variabilité de la réponse à la stimulation ? Analyse de 142 annulations.

INTRODUCTION: This retrospective study aimed at analyzing IVF-ET management and outcome after cancellation of a first cycle for poor response. PATIENTS AND METHOD: One hundred and forty-two infertile patients were included in this observational study. After an overall analysis on the outcome of the second IVF-ET attempt, a sub-analysis was performed according to the presence or the absence of poor prognostic criteria defined as mentioned: patient age superior to 38 years old, antral follicle count (3-9 mm in diameter) inferior to 10 on cycle day 3 and day 3 serum AMH and FSH levels less than 1 ng/mL and more than 10 IU/mL, respectively. Main outcome measures were the cancellation rates, pregnancy and live birth rates. RESULTS: When a controlled ovarian stimulation was performed, patients with poor prognosis had higher cancellation rates (37.8% vs. 13.3%, P<0.004) and lower pregnancy and live birth rates (22.2% vs. 35.0%, P<0.05 and 11.1% vs. 26.1%, P<0.05, respectively) as compared to good prognosis women. CONCLUSION: The relatively high cancellation rate in patients with poor prognosis raises the question of the use of IVF modified natural cycle in this group.

[Serum AMH level is not a predictive value for IVF in modified natural cycle: analysis of 342 cycles]. / L'AMH sérique n'a pas de valeur prédictive en fécondation in vitro en cycle naturel modifié : analyse de 342 cycles.

The objective is to compare the IVF procedures in modified natural cycle outcomes according to serum anti-Mullerian hormone (AMH) levels. We included in this retrospective study 342 patients undergoing their first IVF in modified natural cycle. Patients were regrouped in three groups according to their serum AMH level: group 1 was defined by patients with AMH level<0.97 ng/mL (<25th percentile), group 2, patients with AMH level between 0.97 ng/mL and 2.60 ng/mL (25-75th percentile), and group 3, patients with AMH level between 2.61 ng/mL and 6.99 ng/mL (>75th percentile). The main outcomes were cancellation rate, embryo transfer rate and clinical pregnancy rate, ongoing pregnancy rate and implantation rate. No difference has been observed on cancellation rate, embryo transfer rate, clinical pregnancy rate and implantation rate. The ongoing pregnancy rate per IVF cycle was respectively: 12.8±3.6% for AMH inferior to 0.97 ng/mL versus 12.5±2.5% for AMH between 0.97 to 2.60 ng/mL and 13.4±4.2% for AMH between 2.61 ng/mL and 6.99 ng/mL. In conclusion, IVF in modified natural cycles procedures should be considered as an option for patients with an altered ovarian reserve defined by a serum AMH inferior to 1 ng/mL. Serum AMH level seems a quantitative marker of the ovary but not a quality factor. Serum AMH level does not seem to be a prognostic factor for ongoing pregnancy rated in IVF modified cycles.

[Statement: cancer treatments and ovarian reserve]. / Mise au point: traitements anticancéreux et réserve ovarienne.

PURPOSE OF REVIEW: The purpose of this review is to update the reader on the impact of cancer treatment on fertility, the options of fertility preservation, and the new markers to assess ovarian function. ESSENTIAL POINTS: The impact of chemotherapy and radiotherapy on fertility depends on the drugs and the doses used. It often affects ovarian reserve significantly, and the presence of menstruation is not a reliable reflection of it. Fertility preservation techniques, such as ovarian protection, and preferably cryopreservation combined with assisted reproductive medicine, should be individually discussed and possibly proposed to the patients. The use of new markers for ovarian reserve assessment will help to evaluate infraclinic chemotherapy and/or radiotherapy-induced effects on ovarian reserve, prior to clinical effects.

[Anti-Müllerian hormone: player and marker of folliculogenesis]. / Hormone antimüllérienne: acteur et marqueur de la folliculogenèse.

All indicates that anti-Müllerian hormone (AMH), though initially studied for its importance on male development, plays an inhibiting role on the initial and cyclic processes of follicular recruitment. The aspects involved in its regulation are still poorly understood, but the oocyte, some steroids, and follicular development itself seem to be involved. In addition, AMH has become an important clinical marker of ovarian functioning for many reasons, including its exclusive production by granulosa follicles at many stages of development, its probable FSH independence, its low inter and intracycle variability and its reliable quantitative (qualitative?) relationship with ovarian follicles and their response to exogenous FSH. The growing interest in ovarian AMH incited us to review some important fundamental and clinical publications in this field.