Abstract BACKGROUND Extended embryo culture beyond Day-6 remains controversial. While a small subset of embryos reaches the blastocyst stage on Day-7, their developmental competence and reproductive potential remain uncertain. Data from previous studies have been limited and heterogeneous, particularly for meta-analytical evaluation of euploid embryo transfers. OBJECTIVE AND RATIONALE This systematic review and meta-analysis compared clinical pregnancy (CPR) and live birth rates (LBR), as well as implantation (IR), miscarriage (MR), and ongoing pregnancy rates (OPR), between Day-7 frozen blastocysts and those obtained on Day-5 and/or Day-6. Euploidy rates by day of blastocyst development and available perinatal outcomes were also assessed. SEARCH METHODS Conducted according to PRISMA guidelines, this review included full-length English-language human studies, published up to 1 April 2026, comparing frozen transfers of Day-7 versus Day-5/6 blastocysts and reporting at least clinical pregnancy and/or live birth outcomes. Random-effects models were used to estimate pooled odds ratios (ORs) with 95% confidence intervals (95% CI). Obstetric and perinatal outcomes were analysed when available. OUTCOMES A total of 17 retrospective studies were included. Across 2908 Day-7 transfers, CPR and LBR were significantly lower than for Day-5 (CPR: OR 0.26, 95% CI 0.19–0.35, I2: 76.2%, 16 studies, 2799 and 34 442 transfers at Day-7 and Day-5, respectively; LBR: OR 0.23, 95% CI 0.16–0.33, I2: 76.3%, 12 studies, 2687 and 31 630 transfers at Day-7 and Day-5, respectively) and Day-6 blastocysts (CPR: OR 0.38, 95% CI 0.31–0.48, I2: 54.4%, 16 studies, 2799 and 28 563 transfers at Day-7 and Day-6, respectively; LBR: OR 0.37, 95% CI 0.28–0.49, I2: 60.2%, 12 studies, 2687 and 26 687 transfers at Day-7 and Day-6, respectively). Similarly, IR and OPR were significantly lower in the Day-7 group than in the Day-5 or Day-6 groups, while MR was higher compared with Day-5 blastocysts (OR 1.54, 95% CI 1.04–2.30, I2: 51.1%, 14 studies, 685 and 18 609 pregnancies at Day-7 and Day-5, respectively). When considering only PGT-A euploid blastocysts, CPR and LBR remained significantly lower in the Day-7 group compared with Day-5 (CPR: OR 0.21, 95% CI 0.14–0.33, I2: 58.0%, 7 studies, 365 and 7064 transfers at Day-7 and Day-5, respectively; LBR: OR 0.21, 95% CI 0.17–0.28, I2: 0%, 6 studies, 364 and 5924 transfers at Day-7 and Day-5, respectively) and Day-6 (CPR: OR 0.36, 95% CI 0.28–0.46, I2: 40.8%, 7 studies, 365 and 4617 transfers at Day-7 and Day-6, respectively; LBR: OR 0.36, 95% CI 0.28–0.46, I2: 0%, 6 studies, 364 and 3782 transfers at Day-7 and Day-6, respectively), and MR was higher than Day-5 (OR 2.78, 95% CI 1.57–4.89, I2: 32.4%, 6 studies, 95 and 4018 pregnancies at Day-7 and Day-5, respectively). Euploid rates were also significantly reduced for Day-7 blastocysts compared with Day-5 and Day-6. Data on perinatal outcomes were limited but overall reassuring. The pooled analyses revealed low to high heterogeneity across studies. WIDER IMPLICATIONS Despite lower success rates, including for euploid embryos, Day-7 blastocysts may still contribute to cumulative live birth rates, notably in poor-prognosis patients. Prospective studies are needed to better assess perinatal and long-term outcomes. REGISTRATION NUMBER PROSPERO (CRD420251114251)

STUDY QUESTION:Does extended embryo culture (EEC) associate with an increased risk of obstetrical, perinatal, or children's health complications? SUMMARY ANSWER:After thorough adjustment, EEC was not associated with widespread increased risks, although a moderate excess risk persisted for a few specific outcomes, notably cardiac anomalies, whereas reduced risks were observed for gestational diabetes, small birthweight, and musculoskeletal-limb anomalies. WHAT IS KNOWN ALREADY:EEC is increasingly used in IVF cycles. While blastocyst transfer (day-5/6) often improves birth rates, concerns remain about its impact on maternal and child health. STUDY DESIGN, SIZE, DURATION:In this nationwide longitudinal cohort study, all live-born singletons conceived through IVF-with or without sperm microinjection-and following fresh embryo transfer between 2014 and 2019 in France were included and followed for up to 8 years. PARTICIPANTS/MATERIALS, SETTING, METHODS:Data were obtained from the French National Health System and the National Biomedicine Agency registries. A comparative study was conducted between singletons conceived at either day-2/3 (cleavage-stage embryos group) or day-5/6 (EEC group). Data from both registries were cross-linked to identify obstetrical, perinatal, and health outcomes, including major congenital malformations, hospitalizations, and surgical interventions. Multivariable logistic and survival models were used to adjust for maternal, paternal, and treatment-related factors. MAIN RESULTS AND THE ROLE OF CHANCE:A total of 41 315 singletons were included (25 816 and 15 499 from day-2/3 and day-5/6 groups, respectively). Most outcomes were similar between groups, notably the incidence of global major congenital malformations. However, EEC was associated with increased risks of placenta praevia (aOR, 1.16; 95% CI, 1.02-1.30), admission in neonatal intensive care unit (aOR, 1.16; 95% CI, 1.05-1.29), and cardiac anomalies at age 3 years (aHR, 1.78; 95% CI, 1.21-2.60). Conversely, the risk of gestational diabetes (aOR, 0.94; 95% CI, 0.88-1.00; P = 0.041) and small birthweight (aOR, 0.94; 95% CI, 0.88-1.00, P = 0.039) was lower, as was the risk of musculoskeletal-limb anomalies (aHR, 0.63; 95% CI, 0.42-0.97)-a finding that persisted up to age 7. Other health outcomes were largely comparable. LIMITATIONS, REASONS FOR CAUTION:One limitation of this study is that the data refer to live-born singletons, with stillbirths and medical terminations excluded from the analyses. Despite extensive adjustments, residual confounding cannot be excluded. Findings for specific pathologies/malformations should be interpreted with caution because the number of cases was small in some sub-groups. WIDER IMPLICATIONS OF THE FINDINGS:In this large and unique study, after adjusting for multiple maternal, paternal, and cycle-related variables, our findings provide some reassurance regarding the safety of prolonged in vitro embryo culture. A moderate risk remained for a few maternal and child health conditions following EEC-warranting further investigation-whereas the risk was notably lower compared to short embryo culture, particularly for musculoskeletal-limb anomalies. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the AOI of University Hospital of Dijon. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER:N/A.

Endometriosis is a chronic, systemic, and neuroinflammatory condition that affects approximately 10% of women of reproductive age. Despite its high prevalence, major gaps remain in diagnosis, understanding of disease progression, and recurrence prevention. Diagnosis is often delayed due to disease heterogeneity, nonspecific symptoms, and frequent overlap with other pain syndromes or coexisting adenomyosis. Transvaginal ultrasound and MRI, now increasingly standardized, have improved lesion detection and mapping. However, broader integration of complementary tools such as clinical scoring systems and molecular biomarkers, including salivary microRNAs, is still underway. Evidence suggests that endometriosis may progress in lesion depth and systemic impact, potentially leading to neuropathic pain or, rarely, malignant transformation. Recurrence rates after conservative surgery remain high, yet long-term hormonal treatment significantly reduces this risk. In this narrative review, we highlight that endometriosis is not a uniform disease but a spectrum of clinical entities requiring individualized management. Addressing these unresolved challenges through improved diagnostic tools and tailored long-term care strategies is critical to limiting progression, preventing recurrence, and improving patient outcomes.

STUDY OBJECTIVE:To describe reproductive outcomes and clinical safety considerations associated with assisted reproductive technology (ART) in women with a history of surgically treated catamenial pneumothorax (CP) (thoracic endometriosis syndrome). DESIGN:Retrospective case series conducted from January 2014 to December 2023. SETTING:Single tertiary academic center integrating reproductive medicine and thoracic surgery. PARTICIPANTS:Women aged 18 to 43 years with surgically treated CP were included. INTERVENTIONS:Exposure was ART in women with CP ultimately managed surgically, performed either before and/or after the thoracic operation; the timing of ART relative to surgery was recorded. MEASUREMENTS AND MAIN RESULTS:Primary outcomes were reproductive outcomes (including live birth rate per patient and per transfer) and safety outcomes (pneumothorax occurrence/recurrence and ART-related complications). Ten of the 11 patients (91%) had right-sided CP. Five women (45%) had undergone pelvic endometriosis surgery before thoracic management. Nineteen ovarian stimulation cycles were performed. Among infertile patients, seven of 10 (70%) achieved at least one live birth: five after in vitro fertilization with autologous oocytes, one after oocyte donation, and one after intrauterine insemination with donor sperm. Four women (36%) experienced their first pneumothorax episode within 4 months of ART. No thoracic recurrences were observed after surgery, despite subsequent ovarian stimulations. CONCLUSION:ART was associated with positive reproductive outcomes and a low rate of reported adverse events in women with a history of surgically treated CP, with no observed thoracic recurrences following treatment. Prospective studies are needed to further characterize outcomes and risks.

Introduction Endometriosis is a major cause of infertility, and Assisted Reproductive Techniques (ART) represent an effective approach for managing infertility associated with this condition. Because ART cycles allow direct evaluation of implantation outcomes, they provide a useful framework for assessing the specific impact of endometriosis on endometrial receptivity. Material and methods In this retrospective matched case-control study, we aimed to investigate the effect of endometriosis on endometrial receptivity using a design that minimizes the influence of ovarian and anatomical factors associated with the disease. A total of n = 195 women with peritoneal, ovarian and/or deep endometriosis were included and matched 1:1 with controls according to age and the number and morphological quality of cryopreserved blastocysts. All participants underwent a freeze-all ART cycle between September 2016 and September 2018 at the Reproductive Medicine Unit of Cochin Hospital and were evaluated according to the Core Outcome Measures for Infertility Trials recommendations. Results The cumulative clinical pregnancy rate was similar in women with and without endometriosis (62% vs 61%, crude OR 1.02, 95% CI 0.68 to 1.54; P =  0.92). After adjustment for variables that differed between groups (BMI, total number of retrieved oocytes and fertilization method), the OR was 1.25 (95% CI 0.79 to 2.00; P =  0.34). The cumulative live birth rate was also similar between groups (48% vs 49%, P =  0.84). Conclusions Our findings suggest that, in affected patients, endometriosis does not significantly impair endometrial receptivity.

PURPOSE OF RESEARCH: To evaluate the impact of ovulation-triggering agents on suboptimal mature oocyte yield in antagonist ICSI cycles. DESIGN: We conducted a retrospective cohort study of 2,129 antagonist ICSI cycles at a tertiary university hospital from October 2013 to October 2022. The primary outcome was suboptimal response to triggering, defined as a mature oocyte yield below the 75th percentile. Mature oocyte yield was calculated as the number of mature oocytes retrieved divided by the number of mature follicles (mean diameter ≥ 15 mm) on the trigger day. Prognostic factors for suboptimal response were analyzed using univariate and multivariate methods. RESULTS: Of the cycles, 909 (42.7%) were triggered with GnRHa, 845 (39.7%) with hCG, and 375 (17.6%) with both. The mean mature follicle count was 7.9 ± 4.3, the average number of mature oocytes was 7.0 ± 5.0, and the mean mature oocyte yield was 92.3 ± 55.2%. The 75th percentile for mature oocyte yield was 117%. Mature oocyte yield was significantly higher with GnRHa versus hCG (96.7 ± 59.1% vs. 87.6 ± 48.8%), with no significant difference compared to dual trigger (92.2 ± 58.0%; p = 0.017). Suboptimal yield was lower with GnRHa (71.6%) than hCG (80%), but not dual trigger (76.8%), p = 0.017. Multivariate analysis showed GnRHa triggering was associated with lower risk of suboptimal yield (p < 0.001). CONCLUSION: GnRHa triggering is associated with a reduced risk of suboptimal mature oocyte yield compared to hCG

Endometriosis, traditionally viewed as a gynecological condition, is increasingly recognized as a systemic disease due to its frequent association with inflammatory and autoimmune comorbidities. Recent molecular and genetic insights reveal dysregulated hormone receptor signaling, heightened inflammatory responses, and immune dysfunction as central drivers of disease progression. These discoveries offer compelling explanations for extra-pelvic symptoms and open up avenues for targeted diagnostics and therapies. This review integrates emerging evidence to highlight endometriosis as a multisystem disorder, underscoring the need for multidisciplinary care. By redefining endometriosis beyond reproductive health, this perspective encourages a broader, systemic view of women’s health and fosters innovation in precision medicine.

STUDY QUESTION:Do serum estradiol (E2) levels on the day of frozen blastocyst transfer (FBT) affect pregnancy outcomes in hormonal replacement therapy (HRT) cycles using transdermal estrogens? SUMMARY ANSWER:E2 levels ≥313 pg/ml on the day of FBT are associated with increased early miscarriage rates (EMRs), but do not significantly impact the live birth rate (LBR). WHAT IS KNOWN ALREADY:E2 plays a crucial role in endometrial receptivity and placentation. The effect of serum E2 levels measured around the time of FBT in HRT cycles remains debated, with some studies indicating a negative impact of high E2 levels and others finding no significant difference. Currently, no studies focus exclusively on HRT cycles using transdermal estrogens, which are considered safer regarding thromboembolic complications. STUDY DESIGN, SIZE, DURATION:This retrospective cohort study analyzed 2364 patients undergoing HRT-FBT cycles at a university hospital between January 2019 and December 2022. Each patient was included only once during the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS:The study involved patients undergoing single autologous FBT under HRT with transdermal estrogens and vaginal micronized progesterone. Serum E2 levels were measured in the morning of the FBT at a single laboratory. Primary outcomes included the LBR, with secondary outcomes encompassing clinical pregnancy rates, EMRs, and neonatal outcomes (birth weight and term of delivery). Patients were categorized into three groups based on E2 levels: <25th centile (<122 pg/ml), between 25th and 75th centile (122-312 pg/ml), and >75th centile (≥313 pg/ml), and analyzed using univariate and multivariate logistic regression models. MAIN RESULTS AND THE ROLE OF CHANCE:Of the 2364 patients, 590 were in the '<122 pg/ml' group, 1184 in the '122-312 pg/ml' group, and 590 in the '≥313 pg/ml' group. The median (interquartile range) E2 level in the entire study population was 195.3 pg/ml (122.1-312.8). The LBRs across the E2 level groups were 33.7%, 31.6%, and 31.0%. Crude and adjusted odds ratios (ORs) showed no significant differences in LBR between the '<122 pg/ml' and '≥313 pg/ml' groups compared to the '122-312 pg/ml' reference group (adjusted OR 0.9, 95% CI 0.72-1.14 and 0.9, 95% CI 0.69-1.09, respectively). The EMRs for the groups were 25.5%, 24.6%, and 30.3%, respectively. While crude analysis showed no differences between the groups, the multivariable analysis indicated that the '≥313 pg/ml' group had a significantly higher risk of early miscarriage compared to the reference group (adjusted OR 1.5, 95% CI 1.06-2.18). No significant differences were observed in clinical pregnancy rates or neonatal outcomes. LIMITATIONS, REASONS FOR CAUTION:The primary limitation is the study's retrospective design, which introduces risks of selection and confusion bias, although multivariable analysis was employed to mitigate these issues. WIDER IMPLICATIONS OF THE FINDINGS:Managing high serum E2 levels on the day of the FBT may enhance ART outcomes. Future research should aim to define optimal E2 thresholds for HRT-FBT cycles and develop personalized treatment protocols that account for individual patient variability. STUDY FUNDING/COMPETING INTEREST(S):No funding was received. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER:N/A.

Endometriosis affects approximately 10% of women of reproductive age and is characterized by the presence of endometrial-like tissue outside the uterine cavity, leading to chronic pelvic pain, infertility, and a significant reduction in quality of life. Beyond its local manifestations, endometriosis is increasingly recognized as a systemic, immune-mediated condition with multifactorial origins. In this narrative review, we provide an updated and comprehensive overview of the disease, including its pathophysiology, clinical features, and evolving conceptual frameworks. Considering the frequent digestive symptoms observed in affected patients, we summarize key findings from both animal and human studies that investigate alterations in the gut microbiota. We also review the profound immune dysregulation associated with endometriosis and explore its potential bidirectional relationship with the microbiota. Furthermore, we examine recent insights into the endometrial microbiota-an emerging field of interest given its early involvement in the disease process and its strong interconnection with the vaginal microbiome. Lastly, we highlight studies exploring the gynecological microbiota and present an updated discussion of novel therapeutic strategies, including microbiota-targeted approaches that may shape future management of this complex disease. Video Abstract.

Endometriosis is a frequent chronic estrogen-dependent condition that can significantly impair fertility and reduce the quality of life in affected individuals. Women with endometriosis face a 30-50% risk of infertility. Multifactorial factors such as peritoneal inflammation, altered ovarian reserve, impaired tubal function and modified endometrial receptivity have been proposed to contribute to infertility. Endometriosis has been highlighted as a condition that may require a fertility preservation to safeguard reproductive potential. This review aims to provide a comprehensive update on fertility preservation for women with endometriosis. A comprehensive literature search was conducted using PubMed, focusing on peer-reviewed studies. Key words included "endometriosis," "fertility preservation," "oocytes," and "cryopreservation." Studies in English and French that delve into FP techniques, success factors, and risks were included. Several fertility preservation techniques are available, but oocyte cryopreservation following ovarian stimulation is the most common and effective option for women affected by endometriosis. Success rates depend on factors such as age and prior surgical history. Surgery for ovarian endometriomas may reduce ovarian reserve, underscoring the importance of considering fertility preservation before surgery. All of ovarian stimulation protocols can be used and may not increase the risk of disease progression or recurrence however the use of an antagonist protocol with GnRH agonist triggering could be particularly beneficial in this context, as it may help reduce pain and minimize the risk of ovarian hyperstimulation syndrome. The number of cryopreserved oocytes is directly correlated with pregnancy success. Multiple stimulation cycles can be performed to obtain a sufficient number of oocytes, increasing the chances of achieving a successful live birth in case of reuse. FP should be routinely discussed with women with endometriosis, particularly those who may undergo surgery, however, its implementation is not systematic and should be considered on a case-by-case basis. Further research is essential to tailor FP strategies for women with endometriosis optimizing both clinical outcomes and cost-effectiveness.

OBJECTIVE:To evaluate the satisfaction of patients accompanied by hypnosis during oocyte retrieval under local anesthesia. METHODS:This cohort study included patients undergoing oocyte retrieval under local anesthesia with hypnotic support provided either by a hypnotherapist or via a virtual reality headset between November 2022 and November 2023. A questionnaire was distributed after the procedure, assessing satisfaction with hypnosis for pain and anxiety management, as well as the experience of pain (visual analog scale) and anxiety (State-Trait Anxiety Inventory) during the procedure. Incomplete questionnaires and non-French-speaking patients were excluded from the analysis. The two methods of hypnosis were compared. RESULTS:Out of 600 eligible women, 209 (34.8%) were included (mean age : 34.4±4.1 years). Hypnosis was conducted by a hypnotherapist for 167 patients (79.9%) and via a virtual reality headset for 42 patients (20.1%). Satisfaction with pain management was reported by 73.7% of the participants, and with anxiety management by 86.1%. Significantly more women found hypnosis beneficial for anxiety in the hypnotherapist group compared to the virtual reality group (148/167 [88.6%] versus 32/42 [76.2%], P=0.04). The mean visual analog scale score was 5.3±2.6, and the State-Trait Anxiety Inventory score during the oocyte retrieval was 36.7±17.8. No significant differences were found between the two groups for these scores. CONCLUSIONS:Women who received hypnosis during oocyte retrieval under local anesthesia were generally satisfied with this support, finding it beneficial for pain and anxiety management. Further research is needed to optimize the patient experience during this stressful procedure.

RESEARCH QUESTION:What is the incidence of endometrioma infections requiring surgical drainage following oocyte retrieval in women with ovarian endometrioma? DESIGN:This retrospective observational cohort study included women aged 18-43 years with a confirmed radiological diagnosis of ovarian endometrioma who underwent ovarian stimulation and oocyte retrieval for IVF/intracytoplasmic sperm injection (ICSI) or fertility preservation between January 2018 and December 2023 at a single tertiary academic centre. All procedures were performed under standardized aseptic conditions with antibiotic prophylaxis. Transcystic puncture was performed when deemed necessary. The primary outcome was the incidence of endometrioma infections requiring surgical drainage within 30 days after oocyte retrieval. RESULTS:Oocyte retrievals were performed in 1102 out of 1668 cycles (66.1%) for IVF/ICSI and in 566 cycles (33.9%) for fertility preservation. Bilateral endometriomas were present in 322 of 880 patients (36.6%), with a mean cyst (SD) diameter of 31.5 ± 22.7 mm. Endometriomas larger than 30 mm accounted for 295 of 649 cases (45.5%). Intentional transcystic puncture was performed in 76 of 1148 applicable procedures (6.6%), and endometrioma drainage during oocyte retrieval occurred in 52 cases (4.5%). Endometrioma infections requiring surgical drainage occurred in 6 of 1668 procedures (0.36%). Only one infection was reported following transcystic puncture (1.3%). No cases of sepsis or septic shock occurred. Five infections were managed with ultrasound-guided transvaginal drainage; one required laparoscopic surgery. CONCLUSIONS:The incidence of endometrioma infection requiring surgical intervention after oocyte retrieval, including after transcystic puncture, is low. These findings support the safety of assisted reproductive techniques in women with endometriomas.

STUDY QUESTION Is there an association between dydrogesterone exposure during early pregnancy and the reporting of birth defects?SUMMARY ANSWER This observational analysis based on global safety data showed an increased reporting of birth defects, mainly hypospadias and congenital heart defects (CHD), in pregnancies exposed to dydrogesterone, especially when comparing to progesterone.WHAT IS KNOWN ALREADY Intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation in ART. In recent years, randomized controlled clinical trials demonstrated that oral dydrogesterone was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone. Safety profiles in both mother and child were similar. However, concerns have been raised regarding an association between dydrogesterone usage during early pregnancy and CHD in offspring.STUDY DESIGN, SIZE, DURATION We performed a disproportionality analysis, also called case-non-case study, similar in concept to case-control studies, using the WHO global safety database, VigiBase. The study cohort consisted of individual pregnancy-related safety reports, using the ad hoc standardized query (SMQ 'Pregnancy and neonatal topics'). Cases of birth defects consisted of safety reports containing terms related to the 'congenital, familial and genetic disorders' System Organ Class from the Medical Dictionary for Regulatory Activities. Non-cases consisted of safety reports containing any other adverse event, in pregnancy-related safety reports.PARTICIPANTS/MATERIALS, SETTING, METHODS Considering reports since database inception to 31 December 2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug on the database, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% CI. For each comparison, two sensitivity analyses were performed. Finally, a case-by-case review was performed to further characterize major birth defects and sort anomalies according to classification of EUROCAT.MAIN RESULTS AND THE ROLE OF CHANCE Study cohort consisted of 362 183 safety reports in pregnant women, among which 50 653 reports were related to the use of drugs for ART, including 145 with dydrogesterone and 1222 with progesterone. Of these, 374 (0.7%) were cases of birth defects: 60 with dydrogesterone and 141 with progesterone, including 48 and 92 cases compatible with major birth defect cases according to EUROCAT classification, respectively. Major birth defects reported with dydrogesterone were mainly genital defects such as hypospadias and CHD. A significantly higher disproportionate reporting of birth defects was found with dydrogesterone when compared to any other drug (ROR 5.4, 95% CI [3.9-7.5]), to any other ART drug (ROR 6.0, 95% CI [4.2-8.5]), and to progesterone (ROR 5.4, 95% CI [3.7-7.9]). Sensitivity analyses found consistent results.LIMITATIONS, REASONS FOR CAUTION First, under-reporting, being inherent to pharmacovigilance systems, impedes the measurement of the incidence of adverse drug reactions and can limit the sensitivity of signal detection. Second, drug causality, not being the same for all cases, is challenging for such events and requires further assessment. However, sensitivity analyses showed consistent results. WIDER IMPLICATIONS OF THE FINDINGS This possible safety signal emphasizes the need for further investigation regarding the fetal safety profile of dydrogesterone.STUDY FUNDING/COMPETING INTEREST(S) No funding was received for this study. None of the authors have any financial and personal relationships with other people or organizations that could influence the design, conductor or reporting of this work.TRIAL REGISTRATION NUMBER N/A.

Les rhumatismes inflammatoires chroniques (RIC) sont un ensemble de pathologies responsables de douleurs articulaires inflammatoires et peuvent concerner des femmes jeunes avec un désir de grossesse. Les RIC peuvent affecter la fertilité des femmes, bien que l’impact exact soit encore mal compris. Certaines études rapportent une fertilité réduite, notamment par un allongement du délai de conception, lié à des facteurs multiples. Parmi ceux-ci, les dysfonctions sexuelles sont fréquentes en raison des douleurs et de la fatigue chronique. L’impact des RIC sur la réserve ovarienne reste controversé. Concernant les traitements, les traitements de fonds n’ont pas montré d’effet délétère sur la fertilité mais certains traitements tératogènes doivent être évités chez la femme avec un désir de grossesse. Par ailleurs, il semble exister un lien entre les RIC et certaines pathologies gynécologiques responsables d’infertilité. Chez les patientes atteintes de RIC, aborder précocement la question de la fertilité est nécessaire. En cas de projet de grossesse, la consultation pré-conceptionnelle est essentielle pour adapter les traitements, gérer les risques et préparer un projet de grossesse dans les meilleures conditions. En cas d’infertilité avérée, l’assistance médicale à la procréation constitue une option thérapeutique. Certaines études suggèrent que les taux de succès pourraient être inférieurs à ceux de la population générale. Une prise en charge multidisciplinaire impliquant rhumatologues, gynécologues et spécialistes de la reproduction, ainsi que l’optimisation thérapeutique en période pré-conceptionnelle, sont cruciales pour améliorer les chances de conception et assurer un suivi adapté à ces patientes.

Endometriosis is a chronic gynecologic disease of reproductive-age women, causing menstrual pain and infertility. Endocrine and inflammatory mechanisms drive its development, with estrogen/progesterone imbalance contributing to extrauterine implantation and persistence of ectopic endometrial cells. Chronic pain also induces stress-related disorders, worsening the quality of life. Infertility results from inflammatory, ovarian, and endometrial changes, and adverse pregnancy outcomes are reported. Diagnosis of endometriosis is clinical and imaging based. Furthermore, gastrointestinal, urinary, or autoimmune comorbidities complicate endometriosis management. Hormonal treatments, including progestins, estro-progestins, gonadotropin-releasing hormone analogs (GnRH-a), or oral antagonists, suppress menstruation and relieve pain. The relevant endocrine aspects and the systemic comorbidities make endometriosis a syndrome that requires a multidisciplinary diagnostic and therapeutic approach.

Objectives: The aim of this study was to investigate the clinical characteristics of women with superficial peritoneal endometriosis (SUP) diagnosed by surgery and not confirmed by histology, compared with histologically proven SUP. Design: This was a single-center, nested case-control study. Participants/Materials: Patients with a surgical report of SUP (n = 390), comprising a subgroup with histological confirmation of endometriosis (n = 245) and a subgroup without it (n = 145). In addition, we enrolled a control group (n = 390) among nonpregnant patients submitted to a laparoscopy or laparotomy for a benign gynecologic condition without any macroscopic sign of endometriosis. Setting: The review was conducted in the University hospital. Methods: Data synthesis, descriptive statistics, chi-square test, and one-way analysis of variance followed by Tukey's test. Results: All groups had similar age, body mass index, smoking prevalence, serum anti-m & uuml;llerian hormone levels and menstrual cycle patterns. However, the two SUP subgroups had the same prevalence and intensity of endometriosis symptoms. The SUP/histology-negative subgroup was more likely to have a familial history of endometriosis (14% vs. 1%) or a personal history of primary infertility (29% vs. 19%) or primary dysmenorrhea (50% vs. 33%) compared to the control group (all p <0.01). The intensity scores for dysmenorrhea, deep dyspareunia, and non-cyclic chronic pelvic pain were severer in both SUP subgroups than in the control group (p < 0.05). Limitations: The participants underwent surgery, so their symptoms may not represent groups with initial or mild disease that responded to medical treatments. Due to the retrospective design, performance bias cannot be ruled out. Conclusions: Patients with suspected SUP lesions and a negative histology had clinical characteristics resembling those with proven endometriosis. Further characterization with molecular biomarkers is needed to explain why these women are so symptomatic in the absence of histological hallmarks of the disease.

L’endométriose, maladie inflammatoire chronique définie par la présence de tissu endométrial en dehors de l’utérus, est responsable de douleurs pelviennes et d’infertilité. Observée chez 10 à 15 % des femmes, cette maladie ayant un impact majeur sur la qualité de vie des patientes avec un coût socio-économique important doit être considérée comme un véritable problème de santé publique. Les progrès considérables de l’imagerie (échographie pelvienne par voie vaginale et imagerie par résonance magnétique) ont révolutionné les modalités diagnostiques de l’endométriose. La cœlioscopie à simple visée diagnostique n’a aujourd’hui plus d’indications. Ce changement de paradigme sur le plan du diagnostic impacte la prise en charge thérapeutique. Trois options peuvent être proposées : les traitements hormonaux, la chirurgie et l’assistance médicale à la procréation (AMP). Dans la mesure où le diagnostic est aujourd’hui non chirurgical et qu’il est possible de débuter un traitement sans preuve histologique, le traitement médical est l’option thérapeutique de première intention pour les patientes souffrant de douleurs pelviennes et n’ayant pas de désir de grossesse immédiat. En cas de désir de grossesse, le choix se pose entre la chirurgie et l’AMP. Il est possible d’effectuer une AMP sans exérèse préalable des lésions endométriosiques. La chirurgie ne doit plus être considérée comme le traitement systématique de première intention des patientes infertiles. La prise en charge moderne de l’endométriose doit être individualisée grâce à une approche intégrée, multimodale et multidisciplinaire centrée sur la patiente.

Endometriosis appears to have a multilayered etiology, with genetic and epigenetic factors each contributing half of the pathogenesis. The molecular processes that underlie the onset of endometriosis are yet unclear, but it is assumed that an important contributor in the etiopathology of the disease is DNA methylation. We conducted a systematic review of the literature regarding DNA methylation in endometriosis following PRISMA guidelines. Records were obtained from PubMed and Web of Science on May 31, 2024. Original research articles analyzing regional or genome-wide DNA methylation in patients with confirmed endometriosis (by surgery and/or histological examination) were given consideration for inclusion. Only human studies were included, and there were no restrictions on the types of tissue that was analyzed (i.e., endometrium, blood, or fetal tissue). The study selection process was run by two manual reviewers. In parallel, an adapted virtual artificial intelligence-powered reviewer operated study selection and results were compared with the manual reviewers’ selection. Studies were divided into targeted (e.g., single gene or region level) and epigenome-wide association studies. For each, we extracted a list of genes studied with precise location of CpGs analyzed and the DNA methylation status according to the groups compared. Quality assessment of studies was performed following the Newcastle–Ottawa scale. Quality of evidence was graded following the Grading of Recommendations Assessment, Development and Evaluation. A total of 955 studies were screened, and 70 were identified as relevant for systematic review. Our analyses displayed that endometriosis could be polyepigenetic and with alterations in specific genes implicated in major signaling pathways contributing to the disease etiopathology (cell proliferation, differentiation, and division [PI3K-Akt and Wnt-signaling pathway], cell division [MAPK pathway], cell adhesion, cell communication, developmental processes, response to hormone, apoptosis, immunity, neurogenesis, and cancer). Our systematic review indicates that endometriosis is associated with DNA methylation modifications at specific genes involved in key endometrial biological processes, particularly in the ectopic endometrium. As DNA methylation appears to be an integral component of the pathogenesis of endometriosis, the identification of DNA methylation biomarkers would likely help better understand its causes and aggravating factors as well as potentially facilitate its diagnosis and support the development of new therapeutic approaches. DNA methylation modifications are observed in both eutopic and ectopic endometrium in endometriosis compared to the healthy endometrium, and their localization may influence important biological pathways of the female reproductive system. DMP: Differentially methylated position. DMR: Differentially methylated region.

STUDY QUESTION:Is there an association between mid-luteal serum progesterone (P) levels on the day of fresh embryo transfer (ET) at the blastocyst stage and the live birth rate (LBR)? SUMMARY ANSWER:Serum P levels between 46.6 and 72.3 ng/ml on the day of fresh ET are associated with the highest LBR. WHAT IS KNOWN ALREADY:Luteal phase monitoring is a standard practice in frozen ET cycles to personalize luteal phase support. However, the role of serum P levels in fresh ET cycles remains underexplored and inconsistent, with some studies suggesting a link to outcomes while others show no association. STUDY DESIGN, SIZE, DURATION:This retrospective, single-center cohort study included all single autologous Day-5 blastocyst fresh ETs performed between June 2020 and March 2023. Serum P levels were measured on the day of ET. PARTICIPANTS/MATERIALS, SETTING, METHODS:A total of 874 patients underwent ovarian stimulation according to standardized protocols, with ovulation triggered by human chorionic gonadotropin. All patients received the same luteal phase support regimen of vaginal micronized P (800 mg/day). Serum P levels were measured on the morning of ET in a single laboratory, with clinicians blinded to the results. Patients were divided into four quartiles based on their serum P levels: Q1 (10.2-46.5 ng/ml), Q2 (46.6-72.3 ng/ml), Q3 (72.4-106.9 ng/ml), and Q4 (107.0-364.8 ng/ml). The primary outcome was the LBR, with secondary outcomes including clinical pregnancy rates, early miscarriage rates, and neonatal outcomes (birth weight and gestational age at delivery). Univariate and multivariate logistic regression analyses were performed to identify factors associated with LBR. MAIN RESULTS AND THE ROLE OF CHANCE:The median serum P level on ET day for the entire study population was 72.3 ng/ml (range: 46.5-106.9), with a minimum value of 10.2 ng/ml and a maximum value of 364.8 ng/ml. The overall LBR was 29.4% (260/874), ranging from 21.0% in Q1 to 38.1% in Q2, 29.5% in Q3, and 30.3% in Q4. A significant association between serum P levels and LBR was observed, with Q1 showing the lowest LBR and Q2 the highest (P < 0.001). Multivariate logistic regression indicated that serum P levels in Q1, Q3, and Q4 were associated with significantly lower LBRs compared to Q2, with adjusted odds ratios of 0.52 (95% CI: 0.32-0.82, P = 0.005), 0.55 (95% CI: 0.36-0.86, P = 0.010), and 0.54 (95% CI: 0.34-0.85, P = 0.010), respectively. For secondary outcomes, clinical pregnancy rates were significantly lower in Q1 (29.2% vs 44.1%, P < 0.001). Early miscarriage rates were higher in Q3 (38.5%) and Q4 (35.6%) compared to Q2 (12.3%, P < 0.001). Preterm birth was significantly more frequent in Q1 than in Q2 (15.2% vs 3.6%, P = 0.010). LIMITATIONS, REASONS FOR CAUTION:The study's retrospective design is a key limitation, introducing potential selection and confounding biases, despite efforts to mitigate these using multivariable analysis. WIDER IMPLICATIONS OF THE FINDINGS:These findings highlight the need for prospective studies to validate the association between serum P levels and pregnancy outcomes in fresh ET cycles. Such studies could explore the benefits of personalizing luteal phase support based on serum P levels, including the potential for enhanced P supplementation in low P cases or a freeze-all approach for those with elevated P levels, to improve LBRs and optimize treatment outcomes. STUDY FUNDING/COMPETING INTEREST(S):This study received no external funding. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:N/A.