A history of recurrent pregnancy loss is associated with increased perinatal complications, but not necessarily a longer birth interval: a population study spanning 18 years.

STUDY QUESTION: Is there a difference in the time interval between the first and second live births among individuals with and without recurrent pregnancy loss (RPL)? SUMMARY ANSWER: Primary RPL (two or more pregnancy losses before the first live birth) is associated with a shorter time interval between the first and second live births compared with individuals without RPL, but this association is reversed in patients with secondary RPL (RPL patients with no or one pregnancy loss before the first live birth). WHAT IS KNOWN ALREADY: There is limited information regarding the ability to have more than one child for patients with RPL. Previous studies have investigated the time to live birth and the live birth rate from the initial presentation to clinical providers. Most of the previous studies have included only patients treated at specialized RPL clinics and thus may be limited by selection bias, including patients with a more severe condition. STUDY DESIGN, SIZE, DURATION: We conducted a population-based retrospective cohort study of 184 241 participants who delivered in British Columbia, Canada, and had at least two recorded live births between 2000 and 2018. The aim was to study the differences in the time interval between the first and second live births and the prevalence of pregnancy complications in patients with and without RPL. Additionally, 198 319 individuals with their first live birth between 2000 and 2010 were studied to evaluate cumulative second live birth rates. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among individuals with at least two recorded live births between 2000 and 2018, 12 321 patients with RPL and 171 920 participants without RPL were included. RPL was defined as at least two pregnancy losses before 20 weeks gestation. Patients with primary RPL had at least two pregnancy losses occurring before the first live birth, while patients with secondary RPL had no or one pregnancy loss before the first live birth. We compared the time interval from the first to second live birth in patients with primary RPL, those with secondary RPL, and participants without RPL using generalized additive models to allow for a non-linear relationship between maternal age and time interval between first and second live births. We also compared prevalence of pregnancy complications at the first and second live births between the groups using non-parametric Kruskal-Wallis H test and Fisher's exact test for continuous and categorical variables, respectively. We assessed the cumulative second live birth rates in patients with primary RPL and those without RPL, among participants who had their first live birth between 2000 and 2010. Cox proportional hazards model was used to estimate and compare hazard ratios between the two groups using a stratified modelling approach. MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted time interval between the first and second live births was the longest in patients with secondary RPL, followed by individuals without RPL, and the shortest time interval was observed in patients with primary RPL: 4.34 years (95% CI: 4.09-4.58), 3.20 years (95% CI: 3.00-3.40), and 3.05 years (95% CI: 2.79-3.32). A higher frequency of pregnancy losses was associated with an increased time interval between the first and second live births. The prevalence of pregnancy complications at the first and second live births, including gestational diabetes, hypertensive disorder of pregnancy, preterm birth, and multiple gestations was significantly higher in patients with primary RPL compared with those without RPL. The cumulative second live birth rate was significantly lower in patients with primary RPL compared with individuals without RPL. LIMITATIONS, REASONS FOR CAUTION: This study may be limited by its retrospective nature. Although we adjusted for multiple potential confounders, there may be residual confounding due to a lack of information about pregnancy intentions and other factors, including unreported pregnancy losses. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study provide information that will help clinicians in the counselling of RPL patients who desire a second child. STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by a grant from the Canadian Institutes of Health Research (CIHR): Reference Number W11-179912. M.A.B. reports research grants from CIHR and Ferring Pharmaceutical. He is also on the advisory board for AbbVie, Pfizer, and Baxter. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT04360564.

Hysteroscopic Lysis of Complex Uterine Adhesions After Interventional Radiology-Guided Access.

OBJECTIVE: To demonstrate a novel surgical technique using hysteroscopic lysis of adhesions after interventional radiology (IR)-guided access in patients with severe intrauterine adhesions and challenging uterine access. DESIGN: This video illustrates the technique of the safe division of intrauterine adhesions after IR-guided access. SETTING: Conventional hysteroscopic adhesiolysis might be inadequate or risky in cases of severely narrowed or obstructed uterine flow tract, possibly resulting in incomplete adhesiolysis, false passages, or uterine perforation. This video presents 2 cases from a tertiary center involving a multidisciplinary team of a reproductive surgeon and an interventional radiologist. The first case involves a 38-year-old with severe Asherman syndrome, who experienced unsuccessful attempt to treat adhesions that was complicated by a false passage. The second case involves a 39-year-old with recurrent severe Asherman syndrome and a history of unsuccessful attempts at hysterosalpingogram and conventional hysteroscopic lysis of adhesions. INTERVENTIONS: In the IR suite, the patient was put in a lithotomy position on the fluoroscopy table. A vaginal speculum was inserted exposing the cervix. The procedure was performed using intravenous sedation and topical anesthetic spray applied to the cervix. Using fluoroscopy, a balloon cannula was inserted through the cervix, followed by contrast injection to assess uterine access. If there is no route, transvaginal ultrasound-guided needle cannulation of the main portion of the uterine cavity would be performed, approximating as closely as possible to the expected route of the cervical canal. A guidewire followed by a locked loop catheter was advanced through adhesions into the uterine cavity. The catheter was left protruding from the cervix to guide the hysteroscope. The patient was then transferred to the operating room for the hysteroscopic procedure. Under the guidance of the intrauterine catheter, the adhesions were carefully lysed using cold scissors. The endometrial cavity and tubal openings were inspected to ensure complete adhesiolysis and exclusion of any other copathologies. CONCLUSION: IR guidance can provide a safe and effective approach to hysteroscopic lysis of adhesions in patients with challenging intrauterine adhesions and difficult uterine access, such as patients with severe Asherman syndrome, intractable cervical stenosis, uterine wall agglutination, previous adhesiolysis failure, marked fixed retroverted retroflexed uteri, and previous false passage or uterine perforation.

Effect of the COVID-19 Pandemic on Stillbirths in Canada and the United States.

OBJECTIVE: There is uncertainty regarding the effect of the COVID-19 pandemic on population rates of stillbirth. We quantified pandemic-associated changes in stillbirth rates in Canada and the United States. METHODS: We carried out a retrospective study that included all live births and stillbirths in Canada and the United States from 2015 to 2020. The primary analysis was based on all stillbirths and live births at ≥20 weeks gestation. Stillbirth rates were analyzed by month, with March 2020 considered to be the month of pandemic onset. Interrupted time series analyses were used to determine pandemic effects. RESULTS: The study population included 18 475 stillbirths and 2 244 240 live births in Canada and 134 883 stillbirths and 22 963 356 live births in the United States (8.2 and 5.8 stillbirths per 1000 total births, respectively). In Canada, pandemic onset was associated with an increase in stillbirths at ≥20 weeks gestation of 1.01 (95% confidence interval [CI] 0.56-1.46) per 1000 total births and an increase in stillbirths at ≥28 weeks gestation of 0.35 (95% CI 0.16-0.54) per 1000 total births. In the United States, pandemic onset was associated with an increase in stillbirths at ≥20 weeks gestation of 0.48 (95% CI 0.22-0.75) per 1000 total births and an increase in stillbirths at ≥28 weeks gestation of 0.22 (95% CI 0.12-0.32) per 1000 total births. The increase in stillbirths at pandemic onset returned to pre-pandemic levels in subsequent months. CONCLUSION: The COVID-19 pandemic's onset was associated with a transitory increase in stillbirth rates in Canada and the United States.

Outcomes After Surgery at an Interdisciplinary Centre of Expertise for Endometriosis and Pelvic Pain in Canada: A Prospective Cohort Study.

OBJECTIVES: To prospectively evaluate pain-related quality-of-life (Endometriosis Health Profile-30 [EHP-30] pain subscale) after surgery at an interdisciplinary centre of expertise for endometriosis and pelvic pain. METHODS: A prospective cohort study was completed of persons undergoing surgical management for pelvic pain between December 2013 and July 2016 at an interdisciplinary tertiary referral centre for pelvic pain and endometriosis. We compared the change in EHP-30 scores for the following scenarios: (1) type of surgery (conservative surgery vs. hysterectomy), (2) stage of endometriosis (stage I/II vs. III/IV), and (3) age (age <40 vs. age ≥40 years). We used mixed-effects models to evaluate changes in pain during follow-up after surgery. RESULTS: Overall, 595 individuals met our inclusion criteria; the follow-up rate was 65.9% (392/595). In total, 436 (73.3%) underwent conservative surgery, while 159 (26.7%) underwent hysterectomy. Improvements in pain-related quality-of-life were seen for both conservative surgery and hysterectomy but greater improvements were seen with hysterectomy (P < 0.001). For conservative surgery, similar improvements in quality-of-life were observed regardless of endometriosis stage (I/II vs. III/IV) (P = 0.84) or age (<40 or ≥40 years old) (P = 0.87). We also observed similar improvements in quality-of-life regardless of stage (P = 0.24) or age (P = 0.71) after hysterectomy. CONCLUSIONS: At an interdisciplinary centre of expertise, there were significant improvements in quality-of-life after endometriosis surgery. These improvements were seen for both conservative surgery and hysterectomy (although greater improvement with the latter), for early and advanced stage disease, and younger and older patients.

Prevalence, causes, and impact of non-visualized pregnancy losses in a recurrent pregnancy loss population.

STUDY QUESTION: Does the occurrence of non-visualized pregnancy loss (NVPL) affect future reproductive outcomes in patients with recurrent pregnancy loss (RPL)? SUMMARY ANSWER: The number of previous NVPLs is a significant predictor of subsequent live birth in patients with RPL. WHAT IS KNOWN ALREADY: The number of preceding miscarriages is a strong indicator for future reproductive outcomes. However, NVPL particularly has been sparsely addressed in previous literature. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of 1981 patients attending a specialized recurrent pregnancy loss clinic (RPL) from January 2012 to March 2021. A total of 1859 patients met the inclusion criteria of the study and were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a history of RPL, defined as ≥2 pregnancy losses before 20 weeks gestation, who attended a specialized RPL clinic in a tertiary care center were included. Patients' evaluation included parental karyotyping, antiphospholipid antibodies screening, uterine cavity assessment with hysterosalpingography (HSG) or hysteroscopy, maternal thyroid stimulating hormone (TSH) testing, and serum hemoglobin A1C testing. Other investigations were performed only when indicated such as testing for inherited thrombophilias, serum prolactin, oral glucose tolerance test, and endometrial biopsy. Patients were divided into three groups; patients who experienced NVPLs only (pure NVPLs group), patients with only visualized pregnancy losses (pure VPLs group), and patients with history of both NVPLs and VPLs (mixed group). Statistical analysis was performed using Wilcoxon rank-sum tests for continuous variables and Fisher's exact tests for categorical variables. Significance was detected when P values <0.05. A logistic regression model was used to determine the impact of NVPLs and VPLs numbers on any live birth subsequent to the initial RPL clinic visit. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of patients with pure NVPLs, pure VPLs, and mixed losses was 14.7% (274/1859), 31.8% (591/1859), and 53.5% (994/1859), respectively. The prevalence of acquired and congenital uterine anomalies diagnosed by HSG or hysteroscopy was significantly different between pure NVPLs, pure VPLs, and mixed groups (16.8% versus 23.7% versus. 20.7%, respectively P = 0.05). There were no significant differences in the results of other RPL investigations or baseline demographics between the three groups. A logistic regression model controlling for maternal age at the initial RPL clinic visit and the follow-up duration showed that the numbers of NVPLs (odds ratio (OR): 0.77, CI: 0.68-0.88) and VPLs (OR: 0.75, CI: 0.64-0.86) are strong predictors for subsequent live births after the initial RPL clinic visit (P < 0.001). The odds of having a live birth decreased by 23% and 25% with each additional NVPL and VPL, respectively. LIMITATIONS, REASONS FOR CAUTION: This study may be limited by its retrospective design. Some of our data, including home pregnancy tests and obstetric history, are based on patient self-reporting, which could have overstated the true prevalence of NVPLs. Another limitation is the lack of available live birth data for all patients at the time of the analysis. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to examine and analyze the reproductive outcomes of patients with pure NVPLs in a substantial cohort of patients with RPL. NVPLs seem to affect future live births the same way as clinical miscarriages, which supports their inclusion in RPL definitions. STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by Canadian Institute Heath Grant (CIHR): Reference Number/W11-179912 and Women's Health Research Institute (WHRI), Vancouver, BC, Canada. M.A.B: Research grants from Canadian Institute for Health Research (CIHR) and Ferring Pharmaceutical. M.A.B. is on the advisory board for AbbVie and Baxter. TRIAL REGISTRATION NUMBER: N/A.

Pelvic pain comorbidities associated with quality of life after endometriosis surgery.

BACKGROUND: After endometriosis surgery, pain can persist or recur in a subset of patients. A possible reason for persistent pain after surgery is central nervous system sensitization and associated pelvic pain comorbidities. Surgery addresses the peripheral component of endometriosis pain pathophysiology (by lesion removal) but may not treat this centralized pain. Therefore, endometriosis patients with pelvic pain comorbidities related to central sensitization may experience worse pain-related outcomes after surgery, such as lower pain-related quality of life. OBJECTIVE: This study aimed to determine whether baseline (preoperative) pelvic pain comorbidities are associated with pain-related quality of life at follow-up after endometriosis surgery. STUDY DESIGN: This study used longitudinal prospective registry data from the Endometriosis Pelvic Pain Interdisciplinary Cohort at the BC Women's Centre for Pelvic Pain and Endometriosis. Participants were aged ≤50 years with confirmed or clinically suspected endometriosis, and underwent surgery (fertility-sparing or hysterectomy) for endometriosis pain. Participants completed the pain subscale of the Endometriosis Health Profile-30 quality of life questionnaire preoperatively and at follow-up (1-2 years). Linear regression was performed to measure the individual relationships between 7 pelvic pain comorbidities at baseline and follow-up Endometriosis Health Profile-30 score, controlling for baseline Endometriosis Health Profile-30 and type of surgery received. These baseline (preoperative) pelvic pain comorbidities included abdominal wall pain, pelvic floor myalgia, painful bladder syndrome, irritable bowel syndrome, Patient Health Questionnaire 9 depression score, Generalized Anxiety Disorder 7 score, and Pain Catastrophizing Scale score. Least absolute shrinkage and selection operator regression was then performed to select the most important variables associated with follow-up Endometriosis Health Profile-30 from 17 covariates (including the 7 pelvic pain comorbidities, baseline Endometriosis Health Profile-30 score, type of surgery, and other endometriosis-related factors such as stage and histologic confirmation of endometriosis). Using 1000 bootstrap samples, we estimated the coefficients and confidence intervals of the selected variables and generated a covariate importance rank. RESULTS: The study included 444 participants. The median follow-up time was 18 months. Pain-related quality of life (Endometriosis Health Profile-30) of the study population significantly improved at follow-up after surgery (P<.001). The following pelvic pain comorbidities were associated with lower quality of life (higher Endometriosis Health Profile-30 score) after surgery, controlling for baseline Endometriosis Health Profile-30 score and type of surgery (fertility-sparing vs hysterectomy): abdominal wall pain (P=.013), pelvic floor myalgia (P=.036), painful bladder syndrome (P=.022), Patient Health Questionnaire 9 score (P<.001), Generalized Anxiety Disorder 7 score (P<.001), and Pain Catastrophizing Scale score (P=.007). Irritable bowel syndrome was not significant (P=.70). Of the 17 covariates included for least absolute shrinkage and selection operator regression, 6 remained in the final model (lambda=3.136). These included 3 pelvic pain comorbidities that were associated with higher follow-up Endometriosis Health Profile-30 scores or worse quality of life: abdominal wall pain (ß=3.19), pelvic floor myalgia (ß=2.44), and Patient Health Questionnaire 9 depression score (ß=0.49). The other 3 variables in the final model were baseline Endometriosis Health Profile-30 score, type of surgery, and histologic confirmation of endometriosis. CONCLUSION: Pelvic pain comorbidities present at baseline before surgery, which may reflect underlying central nervous system sensitization, are associated with lower pain-related quality of life after endometriosis surgery. Particularly important were depression and musculoskeletal/myofascial pain (abdominal wall pain and pelvic floor myalgia). Therefore, these pelvic pain comorbidities should be candidates for a formal prediction model of pain outcomes after endometriosis surgery.

Early coronavirus disease 2019 restrictive measures and changes in maternal characteristics, use of assisted reproductive technology, and stillbirth.

BACKGROUND: The initial COVID-19 pandemic response-related effects on conceptions following the use of assisted reproductive technologies (ART), and on changes in the maternal characteristics of women who conceived during the early vs. pre-pandemic period, have been understudied. OBJECTIVES: To examine the effects of ART clinic closures in the United States (US) in March 2020 on the frequency of ART-conceived live births, multiple births and stillbirths; and to describe changes in the characteristics of women who conceived in the early pandemic period. METHODS: Population-based cohort study including all births in the US from January 2015 to December 2020 (22,907,688 live births; 134,537 stillbirths). Interrupted time series (ITS) methodology was used to estimate rate ratios (RR) of expected versus observed rates in December 2020 (i.e., among births conceived mainly in March 2020). Demographic and clinical characteristics were compared between mothers who conceived in March 2020 versus March 2015-2019. RESULTS: Overall, 1.1% of live births and 1.7% of stillbirths were conceived by ART. ART-conceived live births decreased by 57.0% in December 2020 (observed vs. expected RR 0.43, 95% confidence interval [CI] 0.40, 0.45), and these declines occurred in all subgroups of women. Multiple births also declined in December 2020. Stillbirth rates increased in December 2020 in ART-conceived births (RR 2.55, 95% CI 1.63, 3.92) but remained unchanged in the non-ART group. Maternal characteristics of women who conceived in the early pandemic versus pre-pandemic period differed and included an increased prevalence of pre-pregnancy obesity class 3 and chronic hypertension. CONCLUSIONS: The early pandemic closure of ART clinics resulted in a substantial decline in ART-conceived live births and multiple births in December 2020 and an increase in the proportion of stillbirths among ART-conceived births. Women who conceived in the early pandemic period also had an increased prevalence of obesity and chronic hypertension.

Uterine Septum and Other Müllerian Anomalies in a Recurrent Pregnancy Loss Population: Impact on Reproductive Outcomes.

STUDY OBJECTIVE: To study the impact of Müllerian anomalies on reproductive outcomes in a recurrent pregnancy loss (RPL) population and to evaluate the effect of surgical correction of uterine septum on the odds of achieving live birth in RPL patients with a septate uterus. DESIGN: A retrospective cohort study. SETTING: A specialized RPL clinic at a tertiary center. PATIENTS: RPL patients with ≥ 2 pregnancy losses before 20 weeks' gestation who attended a specialized RPL clinic. INTERVENTION: We aimed to assess the association between a possible risk factor (Müllerian anomalies) and reproductive outcomes and that between having surgery for septate uterus and achieving a live birth. MEASUREMENTS AND MAIN RESULTS: The primary outcome is live birth rate in RPL patients with Müllerian anomalies compared with those without; secondary outcome measures include rates of full-term live birth, preterm live birth, first and second trimester pregnancy loss, and stillbirth. After adjusting for patient age at the initial RPL visit, the number of pregnancy losses, and the presence of any other abnormal RPL investigation, the odds of achieving live birth were on average 49.4% lower for patients with a septate uterus than those without Müllerian anomalies (odds ratio, 0.51; 95% confidence interval, 0.30-0.86) in the studied cohort (n = 377). A subanalysis of 72 patients with septate uterus demonstrated a higher likelihood of live birth in those who underwent septum resection (46/72; 63.9%) than those who elected to go for expectant management (26/72; 36.1%), yet this study was underpowered to establish a significant difference (52.2% vs 34.6%; p = .22). CONCLUSION: In RPL patients, having a septate uterus significantly decreased the chances of achieving live birth. Patients with septate uterus who received hysteroscopic septum division had a higher tendency to achieve more live births than those who elected expectant management. However, our study was underpowered to detect a statistically significant difference.

Reproductive Outcomes Following Surgical Management for Isthmoceles: A Systematic Review.

OBJECTIVE: To evaluate the efficacy of surgical management for isthmoceles in patients presenting with secondary infertility. DATA SOURCES: A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library databases from inception to May 2020. The search was limited to studies published in English. METHODS OF STUDY SELECTION: After the removal of duplicates, 3380 articles were screened for inclusion independently by 2 authors. These 2 authors assessed for studies which focused on women of reproductive age with a diagnosed isthmocele and secondary infertility who underwent any surgical intervention for defect repair with at least 1 of the goals being fertility restoration. TABULATION, INTEGRATION, AND RESULTS: A total of 13 studies, comprising of 1 randomized controlled trial, 6 prospective case series, and 6 retrospective case series describing 234 patients who underwent surgical management for an isthmocele and secondary infertility were included. The methodologic quality of the included studies was assessed independently by both reviewers. Next, the data extraction was performed independently and then compared to ensure no discrepancies. A total of 188 patients were treated by hysteroscopy, 36 by laparoscopy, 7 by laparotomy, and 3 through a vaginal approach. In total, 153 of the 234 patients (65.4%) achieved pregnancy across all studies within their respective study periods. Pregnancy rates in the randomized controlled trial were 21 of 28 (75%) for those treated by hysteroscopy compared with 9 of 28 (32%) for those untreated. Among the studies reporting pregnancy outcomes, 101 of 116 (87.1%) pregnancies resulted in a live birth. The incidence of adverse events was 2%, including the risk of reoperation. CONCLUSION: The results of this systematic review suggest that the surgical treatment of an isthmocele, particularly through hysteroscopy, in patients with residual myometrial thickness of at least 2.5 mm, may be effective in treating isthmocele-associated secondary infertility with a relatively low complication rate. Further high-quality studies are needed because of the small sample sizes and observational nature of most available data.

Negative Sliding Sign during Dynamic Ultrasonography Predicts Low Endometriosis Fertility Index at Laparoscopy.

STUDY OBJECTIVE: Endometriosis fertility index (EFI) is a robust tool to predict the pregnancy rate in patients with endometriosis who are attempting non-in vitro fertilization conception. However, EFI calculation requires laparoscopy. Newly established imaging techniques such as sliding sign, which is used to diagnose pouch of Douglas obliteration, could provide a promising alternative. The objective of this study was to investigate the practicality of using ultrasound data to predict a low EFI (score ≤6). DESIGN: Observational study from a prospective registry (Endometriosis Pelvic Pain Interdisciplinary Cohort, clinicaltrials.gov #NCT02911090). Analyzed data were captured from December 2013 to June 2017. SETTING: Tertiary referral center at British Columbia Women's Hospital. PATIENTS: We analyzed data for 2583 participants from the Endometriosis Pelvic Pain Interdisciplinary Cohort. In this cross-sectional study, we included 86 women aged <40 years. INTERVENTIONS: Dynamic ultrasonography for the sliding sign testing and EFI calculation during laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: Logistic regression was used to obtain receiver operating characteristic area under the curve (AUC) for the prediction models. Significance was p <.05. Patients with a negative sliding sign were older and had severe endometriosis and longer duration of infertility. Patients with a negative sliding sign had significantly lower total EFI scores and lower surgical factors scores than patients with a positive sliding sign. Logistic regression showed that a negative sliding sign and EFI historic factors score can predict an EFI score ≤6 (sensitivity = 87.9%, specificity = 81.1%, AUC = 0.93 [95% confidence interval, 0.88-0.98]). Adding the diagnosis of endometrioma to the previous prediction model resulted in AUC = 0.95 (95% confidence interval, 0.90-0.995), sensitivity = 84.8%, and specificity = 92.5%. CONCLUSION: The sliding sign could be a potential alternative to the EFI surgical factors, and it could be used in combination with EFI historic factors and the diagnosis of endometrioma to predict an EFI score ≤6 for patients who are not scheduled for immediate surgery.

Intricate Connections between the Microbiota and Endometriosis.

Imbalances in gut and reproductive tract microbiota composition, known as dysbiosis, disrupt normal immune function, leading to the elevation of proinflammatory cytokines, compromised immunosurveillance and altered immune cell profiles, all of which may contribute to the pathogenesis of endometriosis. Over time, this immune dysregulation can progress into a chronic state of inflammation, creating an environment conducive to increased adhesion and angiogenesis, which may drive the vicious cycle of endometriosis onset and progression. Recent studies have demonstrated both the ability of endometriosis to induce microbiota changes, and the ability of antibiotics to treat endometriosis. Endometriotic microbiotas have been consistently associated with diminished Lactobacillus dominance, as well as the elevated abundance of bacterial vaginosis-related bacteria and other opportunistic pathogens. Possible explanations for the implications of dysbiosis in endometriosis include the Bacterial Contamination Theory and immune activation, cytokine-impaired gut function, altered estrogen metabolism and signaling, and aberrant progenitor and stem-cell homeostasis. Although preliminary, antibiotic and probiotic treatments have demonstrated efficacy in treating endometriosis, and female reproductive tract (FRT) microbiota sampling has successfully predicted disease risk and stage. Future research should aim to characterize the "core" upper FRT microbiota and elucidate mechanisms behind the relationship between the microbiota and endometriosis.

Role of interleukin-1ß in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis.

STUDY QUESTION: Does interleukin-1ß (IL-1ß) play a role in promoting nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis? SUMMARY ANSWER: IL-1ß directly stimulates nerve growth factor (NGF) expression in endometriosis and is associated with local neurogenesis around endometriosis and more severe deep dyspareunia. WHAT IS KNOWN ALREADY: Local nerve density around endometriosis (using the pan-neuronal marker PGP9.5) is associated with deep dyspareunia in endometriosis, mediated in part by NGF expression. STUDY DESIGN, SIZE, DURATION: This in vitro study included endometriotic tissue samples from 45 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted in a university hospital affiliated research institute and included 45 women with surgically excised deep uterosacral/rectovaginal endometriosis (DIE, n = 12), ovarian endometriomas (OMA, n = 14) or superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP, n = 19). Immunolocalisation of IL-1ß, IL-1 receptor type 1 (IL-1R1), NGF and PGP9.5 in endometriotic tissues was examined by immunohistochemistry (IHC), and the intensity of IHC staining in the endometriotic epithelium and stroma was semi-quantitatively evaluated using the Histoscore method (H-score). For each case, deep dyspareunia was pre-operatively rated by the patient on an 11-point numeric rating scale (0-10). In addition, primary endometriosis stromal cells were isolated and cultured from surgically excised endometriosis. These cells were treated with IL-1ß alone or in combination of Anakinra (an inhibitor of IL-1R1), small inference RNA (siRNA) against IL-1R1, siRNA against c-FOS or NGF neutralising antibody. The mRNA and protein levels of target genes (NGF and c-FOS) were assessed by reverse-transcription qPCR and western blot/ELISA, respectively. Furthermore, immunofluorescent microscopy was used to examine the neurite growth of rat pheochromocytoma PC-12 cells, as an in vitro model of neurogenesis. MAIN RESULTS AND THE ROLE OF CHANCE: For IHC, IL-1ß expression in the endometriosis epithelium was significantly associated with more severe deep dyspareunia (r = 0.37, P = 0.02), higher nerve fibre bundle density around endometriosis (r = 0.42, P = 0.01) and greater NGF expression by the endometriosis epithelium (r = 0.42, P = 0.01) and stroma (r = 0.45, P = 0.01). In primary endometriosis stromal cells, treatment with exogenous IL-1ß significantly increased the mRNA and protein levels of NGF and c-FOS. Pre-treatment with Anakinra, siRNA against IL-1R1, or siRNA against c-FOS, each attenuated IL-1 ß-induced increases of NGF expression. In addition, supernatants from IL-1ß treated endometriosis stromal cells significantly stimulated PC-12 neurite growth compared to controls, and these effects could be attenuated by pre-treatment with NGF neutralising antibody or Anakinra. LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: We did not have data from cultures of endometriosis glandular epithelium, due to the known difficulties with primary cultures of this cell type. WIDER IMPLICATIONS OF THE FINDINGS: Our study revealed a mechanism for deep dyspareunia in endometriosis, whereby IL-1ß stimulates NGF expression, promoting local neurogenesis around endometriosis, which in turn leads to tender pelvic anatomic sites and thus deep-hitting dyspareunia. There may also be potential for drug targeting of IL-1ß and/or NGF in the management of endometriosis-associated pain. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by grants from the Canadian Institutes of Health Research (MOP-142273 and PJT-156084). P.Y. is also supported by a Health Professional Investigator Award from the Michael Smith Foundation for Health Research. MB has financial affiliations with Abbvie and Allergan. Otherwise, there are no conflicts of interest to declare.

Prevalence of thyroid autoimmunity and effect of levothyroxine treatment in a cohort of 1064 patients with recurrent pregnancy loss.

RESEARCH QUESTION: Does initiating levothyroxine treatment based on thyroid-stimulating hormone (TSH) >2.5 mIU/l or thyroid autoimmunity improve pregnancy continuation rates in recurrent pregnancy loss (RPL) patients? DESIGN: A retrospective cohort study of 1064 RPL patients, in which subjects were classified as either euthyroid (TSH 0.1 to ≤2.5 mIU/l), borderline-subclinical hypothyroid (borderline-SCH, TSH 2.5 to ≤4 mIU/l) or subclinical hypothyroid (SCH, TSH 4 to ≤10 mIU/l). For subjects with ≥2 pregnancy losses and a subsequent pregnancy with known outcome, a comparison was done of the pregnancy continuation rate past 10 weeks of treated and untreated borderline-SCH (n = 98) and untreated euthyroid (n = 279) subjects, and between subjects with positive (n = 18) and negative (n = 206) thyroid peroxidase (TPOAb tests) within the borderline-SCH and euthyroid groups. RESULTS: 72.7% were euthyroid (721/992), 19.4% (192/992) were borderline-SCH, and 5.4% (54/992) were subclinically hypothyroid (SCH). Of 401 women with a subsequent pregnancy of known outcome at 10 gestational weeks, 21% received treatment with levothyroxine. 57.7% of subjects had a TPOAb test, which was positive in 9.25% (37/400) in euthyroid, 16.5% (22/133) in borderline-SCH subjects and 35.3% (12/34) in SCH subjects. Treatment did not improve pregnancy continuation rates in borderline-SCH subjects (P = 0.392). There was no difference in pregnancy outcomes based on TPOAb status and treatment for borderline-SCH subjects (P = 0.4214), or based on TPOAb status for euthyroid subjects (P = 0.2668). CONCLUSIONS: Treatment of hypothyroidism in pregnancy should be initiated based on a TSH >4 mIU/l. Treatment initiation based on thyroid autoimmunity or a TSH >2.5 mIU/l may result in overtreatment.

Phenotyping Sexual Pain in Endometriosis Using the Central Sensitization Inventory.

INTRODUCTION: Deep dyspareunia, a common symptom in endometriosis, has previously been associated with bladder and/or pelvic floor tenderness (BPFT), which suggests a role for central nervous system sensitization. The Central Sensitization Inventory (CSI, 0-100) is a validated self-reported scale for patients with central sensitization. AIM: The objective of this study was to phenotype deep dyspareunia using BPFT and the CSI. METHODS: The methods included cross-sectional analysis from a prospective registry from January 2018 to June 2018 at a tertiary center for endometriosis (ClinicalTrials.gov #NCT02911090). Included were women aged 18-50 years with endometriosis (previously surgically diagnosed, current visualized endometrioma on ultrasound, or current palpable or visualized nodule on ultrasound), who were newly or re-referred to the center. Severity of deep dyspareunia was self-reported using an 11-point numeric rating scale (0 = no pain; 10 = worst pain imaginable), categorized as no or low deep dyspareunia (0-4) and high deep dyspareunia (5-10). We identified the subgroup with high deep dyspareunia and presence of BPFT, where we hypothesized a central component of the sexual pain. This subgroup was compared with 2 other subgroups: no or low deep dyspareunia and high deep dyspareunia but no BPFT. The CSI was compared between the groups using analysis of variance, followed by post hoc testing (P < .05). MAIN OUTCOME MEASURE: The main outcome measure was the CSI score ranging from 0 to 100. RESULTS: Data from 163 women with endometriosis were analyzed. The mean age of this cohort was 36.4 ± 6.8 years, and the mean CSI score was 41.0 ± 18.6. 37 percent (61/163) had high deep dyspareunia and BPFT; 29% (47/163) had high deep dyspareunia and no BPFT; and 34% (55/163) had no or low deep dyspareunia. The CSI significantly differed between the 3 groups (analysis of variance: F = 22.4, P < .001). In post hoc testing, the CSI was higher in women with high deep dyspareunia and BPFT (51.3 ± 16.9), compared with women with no or low deep dyspareunia (30.9 ± 15.4, P < .001) and compared with women with high deep dyspareunia but no BPFT (39.4 ± 17.2, P = .001). CLINICAL IMPLICATIONS: The CSI could be used to classify and phenotype patients with endometriosis-associated sexual pain. STRENGTH & LIMITATIONS: Strengths include a prospective registry with integrated pain scores, validated questionnaires, and physical examination findings. Limitations include the lack of quantitative sensory testing for central sensitization. CONCLUSIONS: In women with endometriosis, the subgroup with high deep dyspareunia and bladder and/or pelvic floor tenderness had a significantly higher score on the CSI than other subgroups, suggesting that this group may have a central component to their sexual pain. Orr NL, Wahl KJ,Noga H, et al. Phenotyping Sexual Pain in Endometriosis Using the Central Sensitization Inventory. J Sex Med 2020;17:761-770.

Endometriosis and Ectopic Pregnancy: A Meta-analysis.

OBJECTIVE: To systematically review and perform a meta-analysis of the risk of ectopic pregnancy in endometriosis. DATA SOURCES: MEDLINE (OVID), Embase (OVID), CINAHL (EBSCO), and Cochrane Library to April 1, 2019. Inclusion criteria were cohort or case-control studies from 1990 onward. Exclusion criteria were cohort studies without controls, case reports or series, or no English full-text. METHODS OF STUDY SELECTION: A total of 1361 titles/abstracts were screened after removal of duplicates, 39 full-texts were requested, and, after 24 studies were excluded, there were 15 studies in the meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Data were extracted using standardized spreadsheets with 2 independent reviewers, and conflicts were resolved by a third reviewer. We performed random effects calculation of weighted estimated average odds ratio (OR). Heterogeneity and publication bias were assessed with the I2 metric and funnel plots/Egger's test, respectively. The Ottawa-Newcastle Quality Assessment Scale was used with a cutoff of ≥7 for higher quality. There were 10 case-control studies (17 972 ectopic pregnancy cases and 485 266 nonectopic pregnancy controls) and 5 cohort studies (30 609 women with endometriosis and 107 321 women without endometriosis). For case-control studies, endometriosis was associated with increased risk of ectopic pregnancy with an OR of 2.66 (95% confidence interval [CI] = 1.14-6.21, p = .02). For cohort studies, the OR was 0.95 (95% CI = 0.29-3.11, p = .94), but after post hoc analysis of the studies with a Ottawa-Newcastle score ≥7, the OR was 2.16 (95% CI = 1.67-2.79, p <.001). For both case-control and cohort studies, there was high heterogeneity among studies (I2 = 93.9% and I2 = 96.6%, Q test p <.001) but no obvious evidence of systematic bias in the funnel plot, and Egger's test results were not significant (p = .35, p = .70), suggesting no strong publication bias. There were insufficient data to make any conclusions with respect to anatomic characteristics of endometriosis (e.g., stage) or mode of conception (e.g., assisted reproductive technology vs spontaneous). CONCLUSION: Possible evidence of an association between endometriosis and ectopic pregnancy was observed (OR = 2.16-2.66). However, these results should be considered with caution, owing to high heterogeneity among studies. Continued research is needed to delineate the pregnancy implications of endometriosis.

Endometriosis and Negative Perception of the Medical Profession.

OBJECTIVE: This study sought to identify factors independently associated with a negative impression of the medical profession in patients with endometriosis who were presenting to a tertiary referral centre. METHODS: A cross-sectional analysis was conducted on a prospective data registry between December 2013 and June 2017 at a tertiary referral centre for pelvic pain and endometriosis. The main outcome variable, negative impression about the medical profession, was measured with the four-item subscale of the Endometriosis Health Profile-30 and divided into three groups: no (0), some (1-8), and many (9-16) negative impressions. Patients with a surgical and histological diagnosis of endometriosis were included. Postmenopausal women were excluded. Bivariate analyses determined significant associations (P < 0.05) between variables from the registry and the main outcome. Variables with a significant association were put into ordinal logistic regression with sequential backwards elimination. RESULTS: Negative impression of the medical profession was independently associated with previous surgery that did not help symptoms (adjusted odds ratio [aOR] 1.77; 95% confidence interval [CI] 1.09-2.87; P = 0.021), presentation to an emergency room in the past 3 months (aOR 1.90; 95% CI 1.17-3.07; P = 0.009), and previous visits to a complementary health care provider (aOR 2.16; 95% CI 1.42-3.29; P < 0.0005), while controlling for an endometriosis pain-related morbidity composite variable. CONCLUSION: Negative perception of the medical profession in women with endometriosis was associated with surgical treatment failure, emergency room use, and accessing complementary health care. Each identified factor offers an opportunity for intervention to improve the perception of the medical profession among women with endometriosis.

Association between sperm DNA fragmentation and idiopathic recurrent pregnancy loss: a systematic review and meta-analysis.

Sperm DNA fragmentation (sDF) has emerged as a valuable tool for evaluating male fertility, yet the relationship between DNA fragmentation in the male gamete and idiopathic recurrent pregnancy loss (RPL) remains a topic of ongoing debate. Hence, a meta-analysis was conducted of 12 prospective and 2 retrospective studies involving 530 men with a history of RPL who underwent sDF testing compared with 639 fertile control participants. The main outcome measures were sDF measured by comet assay, TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling (TUNEL), sperm chromatin dispersion (SCD) or sperm chromatin structure assay. Overall, couples with a history of idiopathic RPL demonstrated higher levels of sDF than fertile couples (average mean difference 11.98, P < 0.001). Subgroup analysis demonstrated a similar average mean difference between the RPL and control groups using SCD compared with TUNEL, while mean paternal age and mean sperm motility in the RPL groups tested by meta-regression demonstrated no significant effect on the mean differences in sDF (P > 0.10). These results support the diagnostic value of sDF over standard semen analysis, as well as a possible paternally derived genetic origin of unexplained RPL. Further prospective studies are required to further assess the predictive utility of sDF for assessing couples with unexplained RPL.

Atherosclerotic cardiovascular disease in women with endometriosis: a systematic review of risk factors and prospects for early surveillance.

Endometriosis and atherosclerotic cardiovascular disease (ASCVD) share similar pathogenic mechanisms. Hence, this systematic review evaluates the association between endometriosis and lifetime ASCVD risk including co-prevalence with dyslipidaemia, atherosclerosis and non-invasive markers of endothelial dysfunction. The electronic databases Embase, PubMed, MEDLINE, Cochrane Register of Trials and ClinicalTrials.gov were systematically searched for relevant articles. Two prospective cohort studies demonstrated an increased lifetime ASCVD risk after controlling for demographic and lifestyle confounders in women with endometriosis, as measured by higher incidence of myocardial infarction (relative risk [RR] 1.52), angiography-confirmed angina (RR 1.91), or requiring coronary artery bypass graft surgery (RR 1.35). Among 10 studies that included 407 patients with surgically proven endometriosis and 557 controls, RR of developing hypercholesterolemia and hypertension were 1.25 and 1.14, respectively, while higher serum lipoprotein a and lower paraoxonase 1 levels were found in women with endometriosis that was negatively correlated with stage of disease (r = -0.74, P < 0.0001). Hence, currently available evidence suggests that women with endometriosis are at higher lifetime risk of developing ASCVD than women without endometriosis. However, robust causal evidence is still lacking and future studies are needed to determine whether women with endometriosis represent a high-risk population for lifelong ASCVD risk.

A critical review of recent advances in the diagnosis, classification, and management of uterine adenomyosis.

PURPOSE OF REVIEW: The purpose of this review is to summarize and highlight recent critical advances in the diagnosis, classification, and management of adenomyosis. RECENT FINDINGS: Recent studies have clarified the specific mechanism through which adenomyotic lesions invade the underlying myometrium by epithelial-mesenchymal transition. Correlation studies using diagnostic MRI also strongly support the hypothesis of a different pathogenesis between the inner and outer myometrium forms of adenomyosis. Given advances in diagnostic imaging, several international organizations have also highlighted the importance of classification systems for adenomyosis. Finally, selective progesterone receptor modulators and gonadotropin-releasing hormone antagonists have demonstrated significant promise for treating pelvic pain and bleeding associated with adenomyosis, whereas novel fertility-preserving surgical techniques have been introduced to excise diffuse adenomyotic pathology while maintaining adequate uterine integrity. SUMMARY: Recent attempts at a uniform and reproducible classification system likely represent the first step for the development of a staging system for adenomyosis that can be correlated with the severity of clinical symptoms and promote an individualized therapeutic approach. Simultaneously, further insights into the etiology and pathogenesis as outlined in this review may also help in the development of targeted medical therapies.

Link between Endometriosis, Atherosclerotic Cardiovascular Disease, and the Health of Women Midlife.

Endometriosis and atherosclerotic cardiovascular disease (ASCVD) are both essentially diseases of inflammation. It is well established that inflammation is the leading mechanism in the initiation and maintenance of vascular injury and in the development and progression of atherosclerosis. Thus, if women with endometriosis do indeed have increased general inflammation, they are at increased risk of developing microvascular dysfunction and atherosclerosis. Currently available evidence suggests that young female patients with proven endometriosis may be at a higher lifetime risk of developing cardiovascular disease; this may be unrecognized due to the relatively young age of women found to have endometriosis. Other mechanisms proposed to explain the link between endometriosis and ASCVD include similarities in the genetic underpinnings of each condition, including microRNA dysfunction and the association between endometriosis and early menopause, a risk for developing ASCVD. Although physicians today primarily focus on traditional risk factors when evaluating an individual female patient's risk of developing ASCVD, we believe that a history of endometriosis should be included as a possible risk factor and needs further exploration. A better understanding of the mechanisms linking endometriosis with ASCVD will hopefully guide the implementation of new therapies to mitigate the increased cardiovascular disease burden that patients with endometriosis might face.