Hydroxychloroquine in recurrent pregnancy loss: data from a French prospective multicenter registry.

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.

[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.

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.

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.

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.

[Fertility and deep infiltrating endometriosis]. / Endométriose profonde et fertilité.

Deep infiltrating endometriosis is the most severe form of the disease, defined by infiltration beneath the peritoneum greater than 5mm. It affects several anatomical locations including the bladder, the vesico-uterine cul-de-sac, the torus uterinum, the uterosacral ligament, rectovaginal septum and the colon-rectum. Deep infiltrating endometriosis is associated with infertility. Surgery performed for deep infiltrating endometriosis in the context of pain offers good pregnancy rates either spontaneously or after assisted reproductive technologies. The results are less favorable when digestive tract is involved. IVF performed in the context of deep infiltrating endometriosis allows very satisfactory results and does not entail risks of aggravation of the pathology. There is currently no clear evidence to support either IVF or surgery to manage infertility associated with deep infiltrating endometriosis, but patients should be informed, although a risk of severe complication exists, that surgery is the only way to increase the chances of spontaneous fertility.

Colorectal endometriosis-associated infertility: should surgery precede ART?

OBJECTIVE: To compare the impact of first-line assisted reproductive technology (ART; intracytoplasmic sperm injection [ICSI]-IVF) and first-line colorectal surgery followed by ART on fertility outcomes in women with colorectal endometriosis-associated infertility. DESIGN: Retrospective matched cohort study using propensity score (PS) matching (PSM) analysis. SETTING: University referral centers. PATIENT(S): A total of 110 women were analyzed from January 2005 to June 2014. A PSM was generated using a logistic regression model based on the age, antimüllerian hormone (AMH) serum level, and presence of adenomyosis to compare the treatment strategy. INTERVENTION(S): First-line surgery group followed by ART versus exclusive ART with in situ colorectal endometriosis. MAIN OUTCOME MEASURE(S): After PSM, pregnancy rates (PRs), live-birth rates (LBRs), and cumulative rates (CRs) were estimated. RESULT(S): After PSM, in the whole population, the total LBR and PR were 35.4% (39/110) and 49% (54/110), respectively. The specific cumulative LBR at the first ICSI-IVF cycle in the first-line surgery group compared with the first-line ART was, respectively, 32.7% versus 13.0%; at the second cycle, 58.9% versus 24.8%; and at the third cycle, 70.6% versus 54.9%. The cumulative LBRs were significantly higher for women who underwent first-line surgery followed by ART compared with first-line ART in the subset of women with good prognosis (age ≤ 35 years and AMH ≥ 2 ng/mL and no adenomyosis) and women with AMH serum level < 2 ng/mL. CONCLUSION(S): First-line surgery may be a good option for women with colorectal endometriosis-associated infertility.

Finding the balance between surgery and medically-assisted reproduction in women with deep infiltrating endometriosis.

Deep infiltrating endometriosis (DIE) affects several anatomical locations including the bladder, torus uterinum, uterosacral ligament, rectovaginal septum and bowel. It is the most debilitating form of endometriosis and causes severe pain, digestive and urinary symptoms as well as infertility. Faced with an infertile woman suffering from DIE, the dilemma is whether to opt for first-line IVF treatment or for surgery. In the absence of high-level of evidence from randomized studies, several factors should be taken into account in the decision-making process. The main criterion is whether the patient wants in-vitro fertilization (IVF) treatment or not. Secondly, while previous reports have demonstrated the positive impact of surgery on pregnancy, they also underline the risk of severe complications requiring management in expert centers. Despite the availability of predictive models or scoring systems, the decision mainly boils down to the couple's characteristics. It seems logical to propose first-line IVF when spontaneous fertility is not possible due to associated male infertility or tubal obstruction; for women aged ≥35 years; or in women with diminished ovarian reserve. Conversely, first-line surgery could be the best option for women without these characteristics. However, this strategy is mainly based on low-level of evidence underlining the requiring of randomized trials.

Deep infiltrating endometriosis is a determinant factor of cumulative pregnancy rate after intracytoplasmic sperm injection/in vitro fertilization cycles in patients with endometriomas.

OBJECTIVE: To evaluate the cumulative pregnancy rate (CPR) per patient after in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) cycles in patients with endometriomas and to evaluate the determinant factors of CPR per patient. DESIGN: Retrospective study from January 2007 to October 2008. SETTING: Tertiary care university hospital. PATIENT(S): 103 patients who had undergone IVF treatment, comprising isolated endometriomas (n = 30) and endometriomas with associated deep infiltrating endometriosis (DIE) (n = 73). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate after IVF-ICSI cycle. RESULT(S): The total number of cycles was 162, and the median number of cycles per patient was 1 (1 to 5). Fifty-eight women (56.3%) became pregnant. The total number of endometriomas and size of the largest endometrioma and bilateral endometriomas had no impact on the CPR per patient. Using multivariable analysis, the associated DIE and antimüllerian hormone serum level (≤ 1 ng/mL) were independent factors associated with a decrease in the pregnancy rate per patient. Overall, the CPR per patient was 73.7%, and it increased until the third cycle with no benefit for additional cycles. The CPR per patient for women with isolated endometriomas and women with endometriomas and associated DIE was 82.5% and 69.4%, respectively. CONCLUSION(S): Associated DIE has a negative impact on assisted reproduction results in patients with endometriomas. Moreover, our data show that after three IVF-ICSI cycles the CPR per patient is not improved and that surgery should be considered.

Fetal progenitor cells naturally transferred through pregnancy participate in inflammation and angiogenesis during wound healing.

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.

Results of first in vitro fertilization cycle in women with colorectal endometriosis compared with those with tubal or male factor infertility.

This retrospective study of women undergoing IVF (29 with colorectal endometriosis, 157 with tubal factor infertility, and 340 with male factor infertility) found similar fertility outcomes between the groups.