[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.

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.

Donated-embryo pregnancies are associated with increased risk of hypertensive disorders even for young recipients: a retrospective matched-cohort study.

OBJECTIVE: To determine whether pregnancies with donated embryos are at a higher risk of complications than the pregnancies from autologous frozen-thawed embryo transfer (FET). DESIGN: Anonymous, multicenter, comparative, observational, retrospective, matched-cohort study. SETTING: Six French assisted reproductive technique centers from 2003 to 2018. PATIENT(S): Seventy-three singleton pregnancies with donated embryos (exposed) and 136 singleton pregnancies after autologous FET (nonexposed) were matched at 7-8 weeks of gestation (pregnancy date, parity, and women's age) (2:1 ratio, respectively). In accordance with French practices, all women were <44 years old and donated embryos were discarded frozen embryos from other couples. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Percentages of hypertensive disorders of pregnancy (HDPs) with donated embryos versus autologous FET. RESULT(S): Groups were comparable (mean age: 34.5 years) and HDPs (24.6% vs. 11.9%) were significantly more frequent among the donated-embryo pregnancies, mostly in its severe forms (17.5% vs. 4.6%). In contrast, their respective isolated hypertension frequencies were comparable (7.0% vs. 7.3%). Multivariate analysis retained increased severe HDP risk with donated embryos (odds ratio 2.08 [95% confidence interval: 1.08-4.02]). No significant effect of endometrial preparation was observed. C-sections were more frequent for donated-embryo pregnancies (47.3% vs. 29.2%). Newborns from embryo donation or autologous FET were comparable for prematurity, birth weight and length, Apgar score, small for gestational age, large for gestational age, neonatal malformations, and sex ratio. CONCLUSION(S): Even for young women, the risk of severe HDP was 4 times higher for donated-embryo pregnancies than for autologous-FET pregnancies. The HDP risk must be acknowledged to inform donated-embryo recipients and provide careful pregnancy monitoring.

Comparison of predictive models for cumulative live birth rate after treatment with ART.

RESEARCH QUESTION: Can a machine learning model better predict the cumulative live birth rate for a couple after intrauterine insemination or embryo transfer than Cox regression based on their personal characteristics? STUDY DESIGN: Retrospective cohort study conducted in two French infertility centres (Créteil and Tenon Hospitals) between 2012 and 2019, including 1819 and 1226 couples at Créteil and Tenon, respectively. Two models were applied: a Cox regression, which is almost exclusively used in assisted reproductive technology (ART) predictive modelling, and a tree ensemble-based model using XGBoost implementation. Internal validations were performed on each hospital dataset separately; an external validation was then carried out on the Tenon Hospital's population. RESULTS: The two populations were significantly different, with Tenon having more severe cases than Créteil, although internal validations show comparable results (C-index of 60% for both populations). As for the external validation, the XGBoost model stands out as being more stable than Cox regression, with the latter having a higher performance loss (C-index of 60% and 58%, respectively). The explicability method indicates that the XGBoost model relies strongly on features such as the ages of a couple, causes of infertility, and the woman's body mass index or infertility duration, which is consistent with the ART literature about risk factors. CONCLUSIONS: Overall performances are still relatively modest, which is coherent with all reported ART predictive models. Explicability-based methods would allow access to new knowledge, to gain a greater comprehension of which characteristics and interactions really influence a couple's journey. These models can be used by practitioners and patients to make better informed decisions about performing ART.

Stimulation Duration in Patients with Early Oocyte Maturation Triggering Criteria Does Not Impact IVF-ICSI Outcomes.

Results from studies reporting the optimal stimulation duration of IVF-ICSI cycles are inconsistent. The aim of this study was to determine whether, in the presence of early ovulation-triggering criteria, prolonged ovarian stimulation modified the chances of a live birth. This cross-sectional study included 312 women presenting triggering criteria beginning from D8 of ovarian stimulation. Among the 312 women included in the study, 135 were triggered for ovulation before D9 (D ≤ nine group) and 177 after D9 (D > nine group). The issues of fresh +/− frozen embryo transfers were taken into consideration. Cumulative clinical pregnancy and live-birth rates after fresh +/− frozen embryo transfers were similar in both groups (37% versus 46.9%, p = 0.10 and 19.3% versus 28.2%, p = 0.09, respectively). No patient characteristics were found to be predictive of a live birth depending on the day of ovulation trigger. Postponing of ovulation trigger did not impact pregnancy or live-birth rates in early responders. A patient's clinical characteristics should not influence the decision process of ovulation trigger day in early responders. Further prospective studies should be conducted to support these findings.

Secondary infertility with a history of vaginal childbirth: Ready to have another one?

INTRODUCTION: Up to 30% of couples may face secondary infertility. The impact of ectopic pregnancy, spontaneous abortion, pregnancy termination or live birth with caesarean section may impair further fertility in different ways. However, secondary infertility after physiological vaginal life childbirth has been little studied. The aim of this study was to describe the population and the fertility issues and analyze the predictive factors of success in in vitro fertilization in women presenting secondary infertility after a physiological vaginal childbirth. MATERIAL AND METHODS: This single-centre retrospective study included women aged 18-43 years consulting between 2013 and 2020 for secondary infertility in a couple having already had previous vaginal life childbirth. Couples' characteristics, management decision after the first consultation and IVF outcomes were analyzed. RESULTS: Secondary infertility was found in 286 couples, out of whom 138 had a history of vaginal life childbirth. Population was characterized by an advanced female age and overweight. After the first consultation, IVF was performed in only 40% of couples. No predictive factor of live birth was found. CONCLUSION: Our study shows that in couples with secondary infertility after prior physiological delivery cigarette smoking is frequent in male partners, and ovarian reserve markers are altered. However, no statistically significant predictive factor of live birth after IVF treatment has been identified. Further large prospective studies are necessary.

Mild COVID-19 infection does not alter the ovarian reserve in women treated with ART.

RESEARCH QUESTION: Does mild COVID-19 infection affect the ovarian reserve of women undergoing an assisted reproductive technology (ART) protocol? DESIGN: A prospective observational study was conducted between June and December 2020 at the ART unit of Tenon Hospital, Paris. Women managed at the unit for fertility issues by in-vitro fecundation, intracytoplasmic sperm injection (IVF/ICSI), fertility preservation, frozen embryo transfer or artificial insemination, and with an anti-Müllerian hormone (AMH) test carried out within 12 months preceding ART treatment, were included. All the women underwent a COVID rapid detection test (RDT) and AMH concentrations between those who tested positive (RDT positive) and those who tested negative (RDT negative). RESULTS: The study population consisted of 118 women, 11.9% (14/118) of whom were COVID RDT positive. None of the tested women presented with a history of severe COVID-19 infection. The difference between the initial AMH concentration and AMH concentration tested during ART treatment was not significantly different between the COVID RDT positive group and COVID RDT negative group (-1.33 ng/ml [-0.35 to -1.61) versus -0.59 ng/ml [-0.15 to -1.11], P = 0.22). CONCLUSION: A history of mild COVID-19 infection does not seem to alter the ovarian reserve as evaluated by AMH concentrations. Although these results are reassuring, further studies are necessary to assess the effect of COVID-19 on pregnancy outcomes in women undergoing ART.

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.

High-Dose Supplementation of Folic Acid in Infertile Men Improves IVF-ICSI Outcomes: A Randomized Controlled Trial (FOLFIV Trial).

Dietary supplementation is commonly used in men with male infertility but its exact role is poorly understood. The aim of this multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the impact of high-dose folic acid supplementation on IVF-ICSI outcomes. 162 couples with male infertility and an indication for IVF-ICSI were included for one IVF-ICSI cycle. Male partners of couples wishing to conceive, aged 18-60 years old, with at least one abnormal spermatic criterion were randomized in a 1:1 ratio to receive daily supplements containing 15 mg of folic acid or a placebo for 3 months from Day 0 until semen collection for IVF-ICSI. Sperm parameters and DNA fragmentation before and after the treatment and the biochemical and clinical pregnancy rates after the fresh embryo transfer were analyzed. We observed an increase in the biochemical pregnancy rate and a trend for a higher clinical pregnancy rate in the folic acid group compared to placebo (44.1% versus 22.4%, p = 0.01 and 35.6% versus 20.4%, p = 0.082, respectively). Even if no changes in sperm characteristics were observed, a decrease in DNA fragmentation in the folic acid group was noted (8.5 ± 4.5 vs. 6.4 ± 4.6, p < 0.0001). High-dose folic acid supplementation in men requiring IVF-ICSI for male infertility improves IVF-ICSI outcomes.

Unexplained recurrent implantation failures: Predictive factors of pregnancy and therapeutic management from a French multicentre study.

INTRODUCTION: Recurrent implantation failure is defined as the absence of pregnancy after at least three transfers of good-quality embryos after in vitro fecundation/intracytoplasic sperm injection. AIM: The aim of this study was to describe a multicentre cohort of women with unexplained RIF, to analyse the factors associated with clinical pregnancy and to evaluate the immunomodulatory therapies efficacy. METHODS: Women were consecutively recruited from university departments with unexplained RIF. RESULTS: Sixty-four women were enrolled with mean age 36 ± 3 years. The rates of clinical pregnancy in 64 women were compared in untreated and treated cycles and according to therapies used during the last prospectively followed embryo transfer. A clinical pregnancy after the transfer was noted in 56 % pregnancies on intralipids and in 50 % on prednisone, versus 5 % in untreated ones (p < 0.001). The 340 embryo transfers of these 64 women resulted in 68 clinical pregnancies and 18 live births. Clinical pregnancies were significantly more frequent in treated versus untreated embryo transfers (44 % vs 9 %; p < 0.001) with odds ratio at 8.13 (95 % CI 4.49-14.72, p < 0.0001). Cumulative pregnancy rates were higher for steroid-treated transfers than for untreated transfers when considering overall transfers before and after using steroids and also only those under steroids. Cumulative pregnancy rates were not different from steroid- and intralipid-treated embryo transfers CONCLUSIONS: In this multicentre study of women with unexplained RIF, use of immunomodulatory treatments before embryo transfer resulted in higher clinical pregnancy. Randomised, well-designed studies in well-defined population of RIF women are necessary to confirm our preliminary data.

Unexplained recurrent miscarriages: predictive value of immune biomarkers and immunomodulatory therapies for live birth.

INTRODUCTION: Recurrent miscarriages are defined as three or more early miscarriages before 12 weeks of gestation. The aim of this study was to describe a cohort of women with unexplained recurrent miscarriages, evaluate several potential biomarkers of immune origin, and describe the outcome of pregnancies under immunomodulatory therapies. METHODS: Women having a history of at least 3 early miscarriages without any etiology were recruited from 3 university hospitals. RESULTS: Among 101 women with recurrent miscarriages, overall, 652 pregnancies have been included in the analysis. Women which experienced miscarriages were older (33.3 ± 5.4 versus 31.9 ± 6.7; p = 0.03), with history of more pregnancies (4 (2-6) versus 3.5 (1-5.75); p 0.0008), and less frequently the same partner (406 (74%) versus 79 (86%); p=0.01). There was no difference in the level and frequencies of biomarkers of immune origin (NK, lymphocyte, gamma globulins and blood cytokine levels and endometrial uNK activation status), except the higher rates of positive antinuclear antibodies in women with live birth (12 (13%) versus 36 (7%); p=0.03). Among the 652 pregnancies, 215 (33%) have been treated and received either aspirin/low weighted molecular heparin (LMWH) and/or combined to different lines of immunomodulatory treatment. Patients with pregnancy under treatment had a significantly higher rate of cumulative live birth rate than those with untreated ones (43.0% vs 34.8%; p = 0.04). When compared to patients with untreated pregnancies, patients with steroids during the pregnancy had twice more chances to obtain live birth (OR 2.0, CI95% 1.1 - 3.7, p = 0.02). CONCLUSIONS: Unexplained recurrent miscarriages could have improved obstetrical outcome under immunomodulatory therapies and in particular steroids.

The Goto-Kakizaki rat is a spontaneous prototypical rodent model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment.

New Anti-Müllerian Hormone Target Genes Involved in Granulosa Cell Survival in Women With Polycystic Ovary Syndrome.

PURPOSE: A protective effect of anti-Müllerian hormone (AMH) on follicle atresia was recently demonstrated using long-term treatments, but this effect has never been supported by mechanistic studies. This work aimed to gain an insight into the mechanism of action of AMH on follicle atresia and on how this could account for the increased follicle pool observed in women with polycystic ovary syndrome (PCOS). METHODS: In vivo and in vitro experiments were performed to study the effects of AMH on follicle atresia and on the proliferation and apoptosis of granulosa cells (GCs). RNA-sequencing was carried out to identify new AMH target genes in GCs. The expression of some of these genes in GCs from control and PCOS women was compared using microfluidic real time quantitative RT-PCR. RESULTS: A short-term AMH treatment prevented follicle atresia in prepubertal mice. Consistent with this result, AMH inhibited apoptosis and promoted proliferation of different models of GCs. Moreover, integrative biology analyses of 965 AMH target genes identified in 1 of these GC models, confirmed that AMH had initiated a gene expression program favoring cell survival and proliferation. Finally, on 43 genes selected among the most up- and down-regulated AMH targets, 8 were up-regulated in GCs isolated from PCOS women, of which 5 are involved in cell survival. MAIN CONCLUSIONS: Our results provide for the first time cellular and molecular evidence that AMH protects follicles from atresia by controlling GC survival and suggest that AMH could participate in the increased follicle pool of PCOS patients.

Borderline ovarian tumors: French guidelines from the CNGOF. Part 1. Epidemiology, biopathology, imaging and biomarkers.

The incidence (rate per 100 000) of borderline ovarian tumors (BOTs) increases progressively with age, starting at 15-19 years and peaking at around 4.5 cases per 100 000 at an age of 55-59 years (LE3) with a median age of 46 years. The five year survival for FIGO stages I, II, III and IV is 99.7 % (95 % CI: 96.2-100 %), 99.6 % (95 % CI: 92.6-100 %), 95.3 % (95 % CI: 91.8-97.4 %) and 77.1 % (95 % CI: 58.0-88.3 %), respectively (LE3). An epidemiological association exists between the individual risk of BOT and family history of BOT and certain other cancers (pancreatic, lung, bone, leukemia) (LE3), a personal history of benign ovarian cyst (LE2), a personal history of tubo-ovarian infection (LE3), the use of a levonorgestrel intrauterine device (LE3), oral contraceptive use (LE3), multiparity (LE3), Hormonal replacement therapy (LE3), high consumption of Coumestrol (LE4), medical treatment for infertility with progesterone (LE3) and non-steroidal anti-inflammatory drug use (LE3). Screening for BOTs is not recommended for patients (Grade C). The overall risk of recurrence of BOTs varies between 2% and 24 %, with an overall survival greater than 94 % at 10 years, and the risk of an invasive recurrence of a BOT ranges from 0.5 % to 3.8 %. The use of scores and nomograms can be useful in assessing the risk of recurrence, and providing patients with information (Grade C). The WHO classification is recommended for classifying BOTs. It is recommended that the presence of a microinvasive focus (<5 mm) and microinvasive carcinoma (<5 mm with an atypical nuclei and a desmoplastic stroma reaction) within a BOT be reported. In cases of serous BOT, it is recommended to specify the classic histological subtype or micropapillary / cribriform type (Grade C). When confronted with a BOT, it is recommended that the invasive or non-invasive nature of peritoneal implants can be investigated based solely on the invasion and destruction of underlying adipose or peritoneal tissue which has a desmoplastic stromal reaction where in contact with the invasive clusters (Grade B). For bilateral mucinous BOTs and / or in cases with peritoneal implants or peritoneal pseudomyxoma, it is recommended to also look for a primitive digestive or pancreato-biliary cancer (Grade C). It is recommended to sample ovarian tumors suspected of being BOTs by focusing samples on vegetations and solid components, with at least 1 sample per cm in tumors with a size less than 10 cm and 2 samples per cm in tumors with a size greater than 10 cm (Grade C). In cases of BOTs and in the absence of macroscopic omental involvement after careful macroscopic examination, it is recommended to perform at least 4-6 systematic sampling blocks and to include all peritoneal implants (Grade C). It is recommended to consult an expert pathologist in gynecology when a BOT suspicion requires intraoperative extemporaneous histology (grade C). Endo-vaginal and suprapubic ultrasonography are recommended for the analysis of an ovarian mass (Grade A). In case of an undetermined ovarian lesion on ultrasonography, it is recommended that a pelvic MRI be performed (Grade A). To analyze an adnexal mass with MRI, it is recommended to use an MRI protocol with T2, T1, T1 Fat Sat, dynamic and diffusion sequences as well as gadolinium injection (Grade B). To characterize an adnexal mass with MRI, it is recommended to include a score system for malignancy (ADNEX MR/O-RADS) (Grade C) in the report and to formulate a histological hypothesis (Grade C). Pelvic MRI is recommended to characterize a tumor suspected of being a BOT (Grade C). Macroscopic MRI features should be analyzed to differentiate BOT subtypes (Grade C). Pelvic ultrasound is the first-line examination for the detection and characterization of adnexal masses during pregnancy (Grade C). Pelvic MRI is recommended from 12 weeks of gestation in case of an indeterminate adnexal mass and should provide a diagnostic score (Grade C). Gadolinium injection must be minimized as fetal impairment has been proven (Grade C). It is recommended that serum levels of HE4 and CA125 be evaluated and that the ROMA score for the diagnosis of an indeterminate ovarian mass on imaging be used (grade A). In case of suspicion of a mucinous BOT on imaging, dosage of serum levels of CA 19-9 can be considered (Grade C). If the determination of tumor markers is normal preoperatively, routine dosage of tumor markers in BOT follow-up is not recommended (Grade C). In case of preoperative elevation in tumor markers, the determination of serum CA 125 levels is recommended in the follow-up of BOT (Grade B). When conservative treatment of a BOT has been adopted, the use of endovaginal and transabdominal ultrasonography is recommended during follow-up (Grade B).

Use of the EFI score in endometriosis-associated infertility: A cost-effectiveness study.

BACKGROUND: The management of endometriosis-related infertility is still under debate. The Endometriosis Fertility Index (EFI) score is performant to predict the occurrence of a spontaneous pregnancy following surgery, but was not evaluated in a cost-effectiveness perspective. Our objective was to quantify fertility outcomes, and costs of different care pathways for endometriosis-associated infertility after primary surgery, with a stratification on the EFI score. STUDY DESIGN: We conducted a cost-effectiveness analysis based on a decision-tree model in a Tertiary-care university hospital. Extracted form a prospectively maintained database, 608 patients with endometriosis-associated infertility, who underwent laparoscopic treatment with an evaluation of the EFI score, were discriminated between different strategies: natural conception, immediate IVF-ICSI, delayed IVF-ICSI. The pregnancy rate and the live birth rate were the effectiveness outcomes. We considered direct and indirect costs in each strategies. The analysis was stratified according to the EFI score. RESULTS: After surgery, 163 women with immediate IVF-ICSI (strategy I) were compared with 445 women who had natural conception attempts during a year (strategy II). After a year failure of natural conception attempts, 133 women continuing natural conception attempts (strategy III) were compared with 168 women who had delayed IVF-ICSI (strategy IV). The respective PR and LBR were 62.6 % and 52.1 % for strategy I, and 32.4 % and 23.8 % for strategy II. Compared to strategy II, strategy I was more costly and more effective (Incremental Cost Effectiveness Ratio (ICER): 31,469 €/pregnancy and 33,568 €/live birth)). No added benefit was observed for patients in strategy I with an EFI score [0-3] after two IVF-ICSI cycles. Strategy III was strongly dominant versus strategy IV for patients with an EFI score [9-10]. Compared to strategy III, strategy VI was more costly and more effective (ICER: 79,674 €/pregnancy, 53,188 €/pregnancy and 27,748 €/pregnancy respectively for patients with an EFI score [7-8], [4-6] and [0-3]). CONCLUSION: Immediate IVF-ICSI after surgery is effective but associated with substantial costs for the healthcare system. Taking into account healthcare costs, the EFI is a useful score for helping a couple decide between different care pathways -natural conception, immediate or delayed IVF-ICSI- after surgery for endometriosis-associated infertility.

Outcomes of fertility preservation in women with endometriosis: comparison of progestin-primed ovarian stimulation versus antagonist protocols.

BACKGROUND: PPOS protocols, initially described for FP in women with cancer, have many advantages compared to antagonist protocols. PPOS protocols were not evaluated for women with endometriosis. The objective of the study was to describe fertility preservation outcomes in women with endometriosis and to compare an antagonist protocol with a Progestin-Primed Ovarian Stimulation (PPOS) protocol. METHOD: We conducted a prospective cohort study associated with a cost-effectiveness analysis in a tertiary-care university hospital. The measured outcomes included the numbers of retrieved and vitrified oocytes, and direct medical costs. In the whole population, unique and multiple linear regressions analysis were performed to search for a correlation between individual characteristics and the number of retrieved oocyte. RESULTS: We included 108 women with endometriosis who had a single stimulation cycle performed with either an antagonist or a PPOS protocol. Overall, 8.1 ± 6.6 oocytes were retrieved and 6.4 ± 5.6 oocytes vitrified per patient. In the multiple regression model, age (p = 0.001), prior ovarian surgery (p = 0.035), and anti-Mullerian hormone level (p = 0.001) were associated with the number of retrieved oocytes. Fifty-four women were stimulated with an antagonist protocol, and 54 with a PPOS protocol. A mean of 7.9 ± 7.4 oocytes were retrieved in the antagonist group and 8.2 ± 5.6 in the PPOS group (p = 0.78). A mean of 6.4 ± 6.4 oocytes were vitrified in the antagonist group and 6.4 ± 4.7 in the PPOS group (p = 1). In the cost-effectiveness analysis, the PPOS protocol was strongly dominant over the antagonist protocol. CONCLUSION: Fertility preservation procedures are feasible and effective for patients affected by endometriosis. Antagonist and PPOS protocols were associated with similar results but the medico-economic analysis was in favor of PPOS protocols.

Predicting the likelihood of a live birth for women with endometriosis-related infertility.

OBJECTIVE: Endometriosis affects 10% of women in reproductive age and alters fertility. Its management is still debated notably the timing of surgery and ART in infertility. Several tools have been created to guide the practitioner and the couple yet many limitations persist. The objective is to create a nomogram to predict the likelihood of a live birth after surgery followed by assisted reproductive technology (ART) for patients with endometriosis-related infertility. STUDY DESIGN: All women in a public university hospital who attempted to conceive by ART after surgery for endometriosis-related infertility from 2004 to 2016 were included. We created a model using multivariable linear regression based on a retrospective database. RESULT: Of the 297 women included, 171 (57.6%) obtained a live birth. Age, duration of infertility, number of ICSI-IVF cycles, ovarian reserve and the revised American Fertility Society (rAFS) score were included in the nomogram. The predictive model had an area under the curve (AUC) of 0.77 (95% CI, 0.75-0.79) and was well calibrated. The external validation of the model was achieved with an AUC of 0.71 (95% CI, 0.69-0.73) and calibration was good. The staging accuracy according to AUC criteria for the nomogram compared to the currently used Endometriosis Infertility Index to predict live births were 0.77 (95% CI, 0.75-0.79) and 0.60 (95% CI: 0.57-0.63), respectively. CONCLUSION: This simple tool appears to accurately predict the likelihood of a live birth for a patient undergoing ART after surgery for endometriosis-related infertility. It could be used to counsel patients in their choice between spontaneous versus ART conception, or oocyte donation.

Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case-Control Study and Meta-analysis.

We aimed to compare the proportion of peripheral blood natural killer (NK) cells (CD3-CD56+) and T-cell large granular lymphocytes (CD8+CD57+) during preconception in a homogenous group of women with unexplained well-defined recurrent miscarriage (RM) and repeated implantation failure (RIF) vs healthy controls in relation to pregnancy outcomes. This case-control study followed by a literature review and meta-analysis was conducted in three university hospitals. Patients and controls were consecutively recruited from December 2015 to October 2017. In total, 115 women were included in the study: 54 with RM, 41 with RIF and 20 healthy controls with ≥ 2 term births. Percentages of CD3-CD56+ and CD8+CD57+ cells and sub-populations of CD3-CD56+ cells did not differ between cases and controls. The results for women with subsequent miscarriage did not differ from those with live births. The meta-analysis of the literature showed higher NK-cell proportions in RM [mean difference 3.47 (95% CI 2.94-4.00); p < 0.001] and RIF [mean difference 1.64 (95% CI 0.82-2.45); p < 0.001] than controls. However, the heterogeneity between the different studies was high. The proportion of peripheral blood CD3-CD56+ and CD8+CD57+ cells in the preconception period does not reflect the risk of implantation failure or miscarriage and should not be recommended indicators for the management of RM and RIF. Further prospective large studies are needed to develop a reliable peripheral blood marker of immune deregulation.

Nomogram predicting the likelihood of live-birth rate after surgery for deep infiltrating endometriosis without bowel involvement in women who wish to conceive: A retrospective study.

OBJECTIVE: To study the fertility and live birth (LB) rate in women after surgery for deep infiltrating endometriosis (DIE) without bowel involvement and to evaluate the predictive factors of LB after DIE surgery without bowel involvement. STUDY DESIGN: Retrospective cohort study. A total of 118 women who wished to conceive and who underwent surgery for DIE without bowel involvement were analyzed between January 2006 and December 2014. A multivariate logistic regression analysis of selected factors and a nomogram to predict the subsequent LB rate was constructed. RESULTS: Thirty-six woman had a LB (30.5%). In multivariate analysis, factors associated with a LB were: age ≤30 years (p = 0.0024), BMI ≤ 25 kg/m2 (p = 0.029) and Enzian grade 1 (p < 0.001). These factors were associated to develop a nomogram. Before and after the bootstrap sampling procedure, the predictive model had an AUC of 0.84 (95% CI, 0.82-0.86) and 0.81 (95% CI, 0.79-83), respectively, and showed a good calibration. CONCLUSIONS: This work presents the originality of describing the fertility and the LB rate after surgery for DIE without bowel involvement with a predictive model. Such tools can help clinicians to support the patient in making an informed decision about fertility treatment options, contributing to the decision-making process by defining simple risk factors of poor LB probability that can help identify good candidates for MAR.

Pregnancy outcome in Turner syndrome: A French multi-center study after the 2009 guidelines.

OBJECTIVE: This study aimed to assess the application of the French guidelines for pregnancies in Turner syndrome (TS) and their impact on perinatal prognosis. STUDY DESIGN: We performed a French multi-center retrospective study (14 centers), including TS pregnant patients (spontaneously or by Assisted Reproductive Technology (ART)) between January 2006 and July 2017. Only clinical pregnancies were analyzed. The adjustment of medical follow-up modalities to French guidelines was evaluated for all pregnancies after 2009. Pregnancies from oocyte donation (OD) after 2009 were compared to those of a cohort of TS pregnancies obtained by OD before 2009, which were reported by the French Study Group for Oocyte Donation. RESULTS: One hundred seventy pregnancies in 103 patients were included: 35 spontaneous, 5 by means of intra-conjugal ART, and 130 with OD. No serious maternal complications were observed. We reported two stillbirths and one intra uterine fetal death. The French guidelines were partially respected. The preconceptional assessment was carried out in 74% of cases. Cardiology follow-up during pregnancy was performed in accordance with guidelines in 74% of patients. Postpartum cardiac ultrasonography was performed in 45% of pregnancies but only in 11% within 8 days post-partum. When compared to the 2009 historical cohort, the rates of high blood pressure (19% vs. 38%; p < 0.005) pre-eclampsia (8% vs. 21%; p < 0.005) and prematurity <35 weeks (15% vs 38%; p < 0.0001) were lower. CONCLUSIONS: The implementation of guidelines has allowed the standardization of TS pregnancy care and improved perinatal indicators for both mothers and children. However, an effort must be done, in a postpartum survey.