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STUDY QUESTION: What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course of these pregnancies beyond the first trimester? SUMMARY ANSWER: In our cohort of pregnancies in women with a history of RPL exposed to HCQ early in pregnancy, we found that the only factor determining the success of these pregnancies was the number of previous miscarriages. WHAT IS KNOWN ALREADY: Dysregulation of the maternal immune system plays a role in RPL. HCQ, with its dual immunomodulating and vascular protective effects, is a potential treatment for unexplained RPL. STUDY DESIGN, SIZE, DURATION: The FALCO (Facteurs de récidive précoce des fausses couches) registry is an ongoing French multicenter infertility registry established in 2017 that includes women (aged from 18 to 49 years) with a history of spontaneous RPL (at least three early miscarriages (≤12 weeks of gestation (WG)) recruited from several university hospitals. PARTICIPANTS/MATERIALS, SETTING, METHODS: Spontaneous pregnancies enrolled in the FALCO registry with an exposure to HCQ (before conception or at the start of pregnancy) were included. Pregnancies concomitantly exposed to tumor necrosis factor inhibitors, interleukin-1 and -2 inhibitors, intravenous immunoglobulin, and/or intravenous intralipid infusion, were excluded. Concomitant treatment with low-dose aspirin (LDA), low-molecular weight heparin (LMWH), progesterone, and/or prednisone was allowed. All patients underwent the recommended evaluations for investigating RPL. Those who became pregnant received obstetric care in accordance with French recommendations and were followed prospectively. The main endpoint was the occurrence of a pregnancy continuing beyond 12 WG, and the secondary endpoint was the occurrence of a live birth. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred pregnancies with HCQ exposure in 74 women were assessed. The mean age of the women was 34.2 years, and the median number of previous miscarriages was 5. Concomitant exposure was reported in 78 (78%) pregnancies for prednisone, 56 (56%) pregnancies for LDA, and 41 (41%) pregnancies for LMWH. Sixty-two (62%) pregnancies ended within 12 WG, the other 38 (38%) continuing beyond 12 WG. The risk of experiencing an additional early spontaneous miscarriage increased with the number of previous miscarriages, but not with age. The distributions of anomalies identified in RPL investigations and of exposure to other drugs were similar between pregnancies lasting ≤12 WG and those continuing beyond 12WG. The incidence of pregnancies progressing beyond 12 WG was not higher among pregnancies with at least one positive autoantibody (Ab) (i.e. antinuclear Ab titer ≥1:160, ≥1 positive conventional and/or non-conventional antiphospholipid Ab, and/or positive results for ≥1 antithyroid Ab) without diminished ovarian reserve (18/51, 35.3%) than among those without such autoantibody (18/45, 40.0%) (P = 0.63). Multivariate analysis showed that having ≤4 prior miscarriages was the only factor significantly predictive for achieving a pregnancy > 12 WG, after adjustment for age and duration of HCQ use prior to conception (adjusted odds ratio (OR) = 3.13 [1.31-7.83], P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Our study has limitations, including the absence of a control group, incomplete data for the diagnostic procedure for RPL in some patients, and the unavailability of results from endometrial biopsies, as well as information about paternal age and behavioral factors. Consequently, not all potential confounding factors could be considered. WIDER IMPLICATIONS OF THE FINDINGS: Exposure to HCQ in early pregnancy for women with a history of RPL does not seem to prevent further miscarriages, suggesting limited impact on mechanisms related to the maternal immune system. STUDY FUNDING/COMPETING INTEREST(S): The research received no specific funding, and the authors declare no competing interests. TRIAL REGISTRATION NUMBER: clinicaltrial.gov NCT05557201.
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RESEARCH QUESTION: Do women with endometriosis undergoing oocyte retrieval for fertility preservation experience the same level of pain as women undergoing oocyte retrieval for IVF? DESIGN: This retrospective cohort study included 796 cycles in women with endometriosis undergoing oocyte retrieval for fertility preservation (nâ¯=â¯401) or IVF (nâ¯=â¯395) between January 2020 and October 2022. Post-operative pain assessments were compared between the two groups using a numeric rating scale (NRS). RESULTS: Women in the fertility preservation group were younger (32.1 ± 4.2 years versus 35.1 ± 4.1 years; P < 0.001), had a lower body mass index (22.8 ± 3.9 kg/m2 versus 24.6 ± 4.4 kg/m2; P < 0.001) and had a lower concentration of anti-Müllerian hormone (1.8 ± 1.5 ng/ml versus 2.15 ± 2.11 ng/ml; Pâ¯=â¯0.026) in comparison with women in the IVF group. The oestrogen concentration on the day of ovulation trigger was higher in women in the fertility preservation group (2188 ± 1152 pg/ml versus 2081 ± 995 pg/ml; Pâ¯=â¯0.004), and the prevalence rates of adenomyosis and digestive endometrial lesions were lower in women in the fertility preservation group (14% versus 29%, P < 0.001; 16% versus 25%, Pâ¯=â¯0.003, respectively) compared with women in the IVF group. After oocyte puncture, more women in the fertility preservation group had an NRS pain score >3 (moderate to severe pain) compared with women in the IVF group (20% versus 14%; Pâ¯=â¯0.018). The progestin-primed ovarian stimulation (PPOS) protocol was identified as an independent predictive factor of greater post-operative pain (adjusted OR 2.30, 95% CI 1.06-5.15; Pâ¯=â¯0.039). CONCLUSION: Women with endometriosis undergoing fertility preservation reported more intense post-operative pain in the recovery room than women undergoing IVF. The PPOS protocol was an independent risk factor of intense pain (NRS pain score >3) in women with endometriosis, but further studies are needed to confirm this result.
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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.
Subject(s)
Azoospermia , Infertility, Male , Humans , Male , Azoospermia/diagnosis , Azoospermia/therapy , Semen , Retrospective Studies , Prospective Studies , Spermatozoa , AlgorithmsABSTRACT
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.
Subject(s)
Birth Rate , Infertility , Female , Fertilization in Vitro , Humans , Infertility/therapy , Live Birth/epidemiology , Pregnancy , Pregnancy Rate , Reproductive Techniques, Assisted , Retrospective StudiesABSTRACT
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], Pâ¯=â¯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.
Subject(s)
Anti-Mullerian Hormone/blood , COVID-19/physiopathology , Ovarian Reserve , Adult , COVID-19/blood , Case-Control Studies , Female , Humans , Prospective Studies , Reproductive Techniques, AssistedABSTRACT
BACKGROUND: Blood coagulation plays a crucial role in the blastocyst implantation process and its alteration may be related to in vitro fertilization (IVF) failure. We conducted a prospective observational longitudinal study in women eligible for IVF to explore the association between alterations of coagulation with the IVF outcome and to identify the biomarkers of hypercoagulability which are related with this outcome. METHODS: Thirty-eight women eligible for IVF (IVF-group) and 30 healthy, age-matched women (control group) were included. In the IVF-group, blood was collected at baseline, 5-8 days after administration of gonadotropin-releasing hormone agonist (GnRH), before and two weeks after administration of human follicular stimulating hormone (FSH). Pregnancy was monitored by measurement of ßHCG performed 15 days after embryo transfer. Thrombin generation (TG), minimal tissue factor-triggered whole blood thromboelastometry (ROTEM®), procoagulant phospholipid clotting time (Procoag-PPL®), thrombomodulin (TMa), tissue factor activity (TFa), factor VIII (FVIII), factor von Willebrand (FvW), D-Dimers and fibrinogen were assessed at each time point. RESULTS: Positive IVF occurred in 15 women (40%). At baseline, the IVF-group showed significantly increased TG, TFa and TMa and significantly shorter Procoag-PPL versus the control group. After initiation of hormone treatment TG was significantly higher in the IVF-positive as compared to the IVF-negative group. At all studied points, the Procoag-PPL was significantly shorter and the levels of TFa were significantly higher in the IVF-negative group compared to the IVF-positive one. The D-Dimers were higher in the IVF negative as compared to IVF positive group. Multivariate analysis retained the Procoag-PPL and TG as predictors for the IVF outcome. CONCLUSIONS: Diagnosis of women with hypercoagulability and their stratification to risk of IVF failure using a model based on the Procoag-PPL and TG is a feasible strategy for the optimization of IVF efficiency that needs to be validated in prospective trials.
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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.
Subject(s)
Infertility, Female , Infertility, Male , Humans , Female , Infertility, Female/therapy , Male , France , Infertility, Male/therapy , Infertility, Male/etiology , Gynecology/methods , Obstetrics/methods , Ovulation Induction/methods , Reproductive Techniques, Assisted , Adult , Societies, Medical , Pregnancy , Obstetricians , GynecologistsABSTRACT
The phenotype and fate of fetal microchimeric cells transfered into the maternal circulation during pregnancy are not well described. Since progenitors from distal sites mobilize during wound healing, we analyzed the recruitment and plasticity of fetal progenitors into maternal wounds. Wounds were generated on normal and bleomycin-induced fibrotic skin of parous or pregnant wild-type females with fluorescent GFP(+) fetuses. Analyses were performed on skin and blood specimens through PCR, immunohistochemistry, and flow cytometry. Controls consisted of parous and pregnant females without wounds and virgin females with wounds. Fetal cells were detected in all skin specimens of parous mice as long as healing was not achieved. During early stages of wound healing, fetal cells expressed mainly leukocyte markers, while in later phases endothelial markers prevailed. Fetally derived vessels connected to maternal circulation were also found, demonstrating the transfer of fetal endothelial progenitor cells. Wounding mobilized fetal CD34(+)ckit(-) cells into the blood during pregnancy. Most of this population was CD11b(-)VEGFR2(-). Another part was CD11b(+) with a fraction expressing VEGFR2. VEGFa-spiked Matrigel plugs partially mimicked this fetal progenitor recruitment and mobilization into the blood. In summary, fetal cells that mobilize in response to wounding are mainly progenitor cells and participate in angiogenesis and inflammation.
Subject(s)
Embryonic Stem Cells/physiology , Inflammation/physiopathology , Maternal-Fetal Exchange/physiology , Neovascularization, Physiologic/physiology , Wound Healing/physiology , Animals , Chemotaxis/physiology , Chimerism/embryology , Embryonic Stem Cells/cytology , Embryonic Stem Cells/immunology , Female , Green Fluorescent Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pregnancy , Signal Transduction/physiology , Skin/cytology , Skin/injuries , Vascular Endothelial Growth Factor A/metabolismABSTRACT
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.
Subject(s)
Hypertension, Pregnancy-Induced , Pregnancy , Infant, Newborn , Female , Humans , Adult , Retrospective Studies , Hypertension, Pregnancy-Induced/diagnosis , Hypertension, Pregnancy-Induced/epidemiology , Hypertension, Pregnancy-Induced/etiology , Cohort Studies , Embryo Disposition/adverse effects , Embryo Transfer/adverse effects , Cryopreservation/methodsABSTRACT
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.
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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.
Subject(s)
Infertility, Female/etiology , Labor, Obstetric/physiology , Adolescent , Adult , Birth Rate , Female , Humans , Pregnancy , Pregnancy, Ectopic/epidemiology , Prospective Studies , Retrospective StudiesABSTRACT
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.
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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.
Subject(s)
Polycystic Ovary Syndrome/pathology , Adiposity , Animals , Animals, Newborn , Body Weight , Discriminant Analysis , Disease Models, Animal , Dyslipidemias/pathology , Endocrine System/pathology , Estrous Cycle , Female , Glucose Tolerance Test , Gonadotropins/pharmacology , Hormones/blood , Humans , Insulin Secretion , Least-Squares Analysis , Lipids/chemistry , Male , Maternal-Fetal Exchange , Multivariate Analysis , Ovary/pathology , Ovary/physiopathology , Phenotype , Polycystic Ovary Syndrome/blood , Polycystic Ovary Syndrome/physiopathology , Pregnancy , Rats, Wistar , Reproduction , Sexual MaturationABSTRACT
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.
Subject(s)
Embryo Implantation/immunology , Embryo Transfer/statistics & numerical data , Infertility, Female/therapy , Sperm Injections, Intracytoplasmic/statistics & numerical data , Adult , Biomarkers/analysis , Embryo Transfer/methods , Female , Humans , Infertility, Female/diagnosis , Infertility, Female/immunology , Pregnancy , Pregnancy Rate , Risk Assessment/statistics & numerical data , Sperm Injections, Intracytoplasmic/methods , Treatment FailureABSTRACT
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.
Subject(s)
Anti-Mullerian Hormone/pharmacology , Apoptosis , Granulosa Cells/drug effects , Polycystic Ovary Syndrome/pathology , Adult , Animals , Anti-Mullerian Hormone/metabolism , Apoptosis/drug effects , Apoptosis/genetics , Case-Control Studies , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Female , Gene Expression Regulation/drug effects , Granulosa Cells/pathology , Granulosa Cells/physiology , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Polycystic Ovary Syndrome/genetics , Polycystic Ovary Syndrome/metabolismABSTRACT
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.
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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.
Subject(s)
Abortion, Habitual/drug therapy , Aspirin/administration & dosage , Heparin, Low-Molecular-Weight/administration & dosage , Immunologic Factors/administration & dosage , Immunomodulation , Abortion, Habitual/blood , Abortion, Habitual/epidemiology , Adult , Biomarkers/blood , Female , Humans , Pregnancy , Retrospective StudiesABSTRACT
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).
Subject(s)
Carcinoma, Ovarian Epithelial , Ovarian Neoplasms , Biomarkers, Tumor , Carcinoma, Ovarian Epithelial/diagnosis , Carcinoma, Ovarian Epithelial/epidemiology , Carcinoma, Ovarian Epithelial/pathology , Diagnosis, Differential , Diagnostic Imaging , Female , Humans , Laparoscopy , Neoplasm Recurrence, Local , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/pathology , Pregnancy , Pregnancy Complications, Neoplastic/diagnosis , Risk Factors , Tissue Fixation , Tissue PreservationABSTRACT
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.
Subject(s)
Endometriosis , Infertility, Female , Infertility , Cost-Benefit Analysis , Endometriosis/complications , Endometriosis/surgery , Female , Fertility , Fertilization in Vitro , Humans , Infertility, Female/etiology , Infertility, Female/surgery , Pregnancy , Pregnancy RateABSTRACT
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.