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Brittany MacGregor,1 Catherine Allaire,1 Mohamed A Bedaiwy,1 Paul J Yong,1,* Olga Bougie2,* 1Department of Obstetrics and Gynaecology, University of British Columbia, BC Women’s Centre for Pelvic Pain and Endometriosis, Vancouver, Canada; 2Department of Obstetrics and Gynaecology, Queen’s University, Kingston, Canada*These authors contributed equally to this workCorrespondence: Olga Bougie, 76 Stuart Street, Victory 4, Department of Obstetrics & Gynecology, Queen’s University, Kingston, Ontario, Canada, K7L 2V7, Email Ob17@queensu.ca Paul J Yong, Department of Obstetrics & Gynecology, University of British Columbia, FRCSC, F2 – 4500 Oak Street, Vancouver, British Columbia, V6H3N1, Canada, Email Paul.Yong@vch.caAbstract: Dysmenorrhea is the most common gynecologic condition among the female population and has a significant impact on life course potential. It has a widespread impact on a female’s mental and physical well-being, with longstanding impairments on quality of life, personal relationships, and education and career attainment. Furthermore, untreated dysmenorrhea can lead to hyperalgesic priming, which predisposes to chronic pelvic pain. Primary dysmenorrhea is pain in the lower abdomen that occurs before or during menses and in the absence of pelvic pathology. One possible mechanism is endometrial inflammation and increased prostaglandin release, resulting in painful uterine contractions. Dysmenorrhea may also occur secondary to pelvic pathology, such as endometriosis, adenomyosis or due to cyclic exacerbation of non-gynecologic pain conditions. A thorough patient evaluation is essential to differentiate between potential causes and guide management. Treatment must be tailored to individual patient symptoms. Pharmacologic management with non-steroidal anti-inflammatory medications and/or combined hormonal contraceptives is most common. Heat therapy, exercise, vitamins and dietary supplements have limited evidence and can be offered for patients seeking non-pharmacologic adjunctive or alternative options. Greater awareness for both health-care providers and patients allows for early intervention to reduce impact on quality of life and life course potential.Keywords: primary dysmenorrhea, adolescents, chronic pain, health trajectory, women’s health

Kelli M Braun,1 Mark Sheridan,2 Erin Z Latif,1 Lexy Regush,3 Anet Maksymowicz,4 Laura Weins,5 Mohamed A Bedaiwy,6 Nerissa Tyson,5 Marilyn J Davidson,2 Barry H Sanders7 1Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA; 2Department of Obstetrics and Gynecology, Saskatoon Obstetric and Gynecologic Consultants, 3Department of Obstetrics and Gynecology, Royal University Hospital, Saskatoon, 4Department of Obstetrics and Gynecology, Regina General Hospital, Regina, 5Department of Obstetrics and Gynecology, University of Saskatchewan, Saskatoon City Hospital, Saskatoon, SK, 6Department of Obstetrics and Gynecology, British Columbia Women’s Hospital, Vancouver, 7Department of Obstetrics and Gynecology, Division of General Gynaecology and Obstetrics and Division of Gynaecologic Specialties, Vancouver General Hospital, Vancouver, BC, Canada Purpose: Successful adoption of a new surgical procedure varies among practicing surgeons, and skill acquisition depends on the surgeon’s innate ability, the complexity of the technique, and training. We report intraoperative and near-term postoperative outcomes from the Acessa procedure conducted by minimally invasive gynecologic surgeons new to Acessa, and report the surgeons’ experiences during the training period.Patients and methods: The study was designed as a postmarket, prospective, single-arm, multicenter analysis of operative and early postoperative outcomes after proctored surgical training with the Acessa device and procedure (laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation of symptomatic fibroids) in premenopausal, menstruating women as conducted in community and university hospitals in the USA and Canada. Surgeons completed evaluation forms once they felt they could safely and comfortably conduct the operations.Results: Ten gynecologic surgeons without prior Acessa experience completed 40 Acessa procedures – all on an outpatient basis. Mean procedure time was 1.9±1.0 hours and was similar to that reported in the pivotal premarket study (2.1±1.0 hours). Two intraoperative complications occurred: a 1 cm uterine serosal laceration due to uterine manipulation and blood loss from both the probe insertion site and the lysis of uterine-omental adhesions. No postoperative complications or reinterventions for fibroid symptoms were reported. The surgeons completed the evaluation forms after two to five cases, and none found any factors affecting procedure efficiency to be inferior or needing improvement.Conclusion: Minimally invasive gynecologic surgeons new to Acessa can perform the procedure and provide acceptable outcomes after two to five proctored cases. Keywords: myoma, fibroid, leiomyoma, laparoscopic ultrasound, education, radiofrequency ablation

Background: Fallopian tube occlusion is a common cause of infertility, but the effect of unilateral tubal block (UTB) on pregnancy rates (PR) after controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) remains controversial.Objective: To evaluate PR after COH-IUI among infertile women with proximal and distal UTB diagnosed by hysterosalpingogram (HSG), compared against women with bilateral patent tubes experiencing unexplained infertility.Search Strategy: We searched EMBASE, MEDLINE, Google Scholar, Cochrane Library, and PUBMED from inception to 14 January 2018.Selection Criteria: Studies that report PR/cycle or cumulative PR among women with UTB and controls were included.Data Collection and Analysis: Two authors independently selected and extracted study characteristics and data. Methodological quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.Main Results: Among 2965 patients and 5749 IUI cycles across ten studies, no significant difference in PR/cycle (odds ratio, OR = 0.88; 95% confidence interval, 95% CI = 0.69-1.12) and cumulative PR (OR = 0.80, 95% CI = 0.62-1.04) was observed. Patients with proximal UTB demonstrated similar PR/cycle (OR = 1.06, 95% CI = 0.68-1.66) and cumulative PR (OR = 1.10, 95% CI = 0.75-1.62), compared with controls, whereas patients with distal UTB had significantly lower cumulative PR (OR = 0.49, 95% CI = 0.25-0.97, P = 0.04). Patients with proximal block also demonstrated significantly improved cumulative PR, compared with patients with distal block (OR=2.41, 95% CI = 1.37-4.25, P = 0.002).Conclusion: Infertile patients with proximal UTB diagnosed by HSG can expect similar pregnancy rates after COH-IUI, compared with those with bilateral tubal patency and unexplained infertility, whereas patients with distal UTB have lower odds of pregnancy. These differences may reflect inherent diagnostic limitations of HSG or differences in underlying pathologies.Tweetable Abstract: Meta-analysis evaluates pregnancy outcomes after COH-IUI in women with unilateral tubal block diagnosed by HSG. [ABSTRACT FROM AUTHOR]

Background: Endometriosis-associated chronic pelvic pain unresponsive to surgical menopause is a difficult clinical problem.Case: A middle-aged woman presented with endometriosis and severe pelvic pain after hysterectomy and bilateral salpingo-oopherectomy. She was first treated with exemestane without improvement of symptoms. However, another aromatase inhibitor, letrozole, relieved her pain, and concomitant treatment with estrogen relieved hot flushes without pain reactivation.Conclusion: Letrozole was superior to exemestane in relieving the endometriosis-associated pain in this postmenopausal woman. This suggests that patients may respond variably to different aromatase inhibitors. [ABSTRACT FROM AUTHOR]

Background: Pelvic pain worsened by orgasm is a poorly understood symptom in patients with endometriosis., Aim: To assess the prevalence of pelvic pain worsened by orgasm in patients with endometriosis and explore its association with potential etiologic factors, including pelvic floor myalgia, uterine tenderness and adenomyosis, and central nervous system sensitization., Methods: An analysis was done of a prospective data registry based at a tertiary referral center for endometriosis. Eligible participants were patients aged 18 to 50 years who were referred between January 1, 2018, and December 31, 2019, diagnosed with endometriosis, and subsequently underwent surgery at the center. Clinical features were compared between participants reporting worsening pelvic pain with orgasm and those without worsening pain with orgasm, including patient-reported variables, physical examination findings, and anatomic phenotyping at the time of surgery. Pelvic floor myalgia and uterine tenderness were assessed by palpation on pelvic examination, adenomyosis by ultrasound, and central nervous system sensitization via the Central Sensitization Inventory (range, 0-100)., Outcomes: Outcomes included pelvic or lower abdominal pain in the last 3 months that worsened with orgasm (yes/no)., Results: Among 358 participants with endometriosis, 14% (49/358) reported pain worsened by orgasm while 86% (309/358) did not. Pain with orgasm was significantly associated with pelvic floor myalgia (55% [27/49] vs 35% [109/309]; Cohen's h = 0.40, P = .01) and higher scores on the Central Sensitization Inventory (mean ± SD, 53.3 ± 17.0 vs 42.7 ± 18.2; Cohen's d = 0.60, P < .001) but not with uterine tenderness or adenomyosis. Other clinical features associated with pain with orgasm were poorer sexual health (higher scores: deep dyspareunia, Cohen's h = 0.60; superficial dyspareunia, Cohen's h = 0.34; and Female Sexual Distress Scale-Revised, Cohen's d = 0.68; all P < .05) and poorer mental health (higher scores: Patient Health Questionnaire-9, 12.9 ± 6.7 vs 9.1 ± 6.3, Cohen's d = 0.59, P < .001; Generalized Anxiety Disorder-7, 9.4 ± 5.6 vs 6.8 ± 5.5, Cohen's d = 0.48, P = .002). Anatomic findings at the time of surgery did not significantly differ between the groups., Clinical Implications: Interventions targeting pelvic floor myalgia and central nervous system sensitization may help alleviate pain worsened by orgasm in patients with endometriosis., Strengths and Limitations: A strength is that pain worsened by orgasm was differentiated from dyspareunia. However, pain with orgasm was assessed by only a binary question (yes/no). Also, the study is limited to a single center, and there were limited data on sexual function., Conclusion: Pelvic pain exacerbated by orgasm in people with endometriosis may be related to concurrent pelvic floor myalgia and central sensitization., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Chronic Intervillositis of Unknown Etiology (CIUE) is a rare idiopathic inflammatory disorder of the placenta. The evidence suggests an increased risk for poor obstetrical outcomes and a risk of recurrence as high as 100 %. This meta-analysis examined CIUE prevalence, recurrence, association with autoimmune disorders, reproductive outcomes, pregnancy complications, and the benefits of medical treatments. A systematic review, following PRISMA guidelines, involved a thorough search across multiple databases including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Evidence Based Medical Reviews, and Scopus. Out of 590 initially identified studies, 19 studies were included for both qualitative synthesis and meta-analysis after full-text review. Risk of bias was assessed using appropriate tools: The Risk Of Bias In Non-randomized Studies of Interventions tool was applied to twelve studies, while the Joanna Briggs Institute case series critical appraisal tool was used for seven studies. Our findings confirm that CIUE is a rare condition (0.7 %). CIUE is associated with decreased live birth rates (53 %), increased recurrent pregnancy loss (23 %), fetal loss beyond 22 weeks gestation (25 %), a higher prevalence of autoimmune diseases (14 %), and a recurrence rate of 30 % in subsequent pregnancies. Moreover, individuals with CIUE had higher rates of pregnancy complications, including gestational hypertension (19 %), intrauterine growth restriction (45 %), and preterm births (43 %). No significant improvement in live birth rate was observed among treated CIUE patients; however, caution is warranted when interpreting these findings due to the limited sample size. Future research in CIUE is crucial given its rarity and complexity., Competing Interests: Declaration of Competing Interest Dr. Mohamed A. Bedaiwy: Research grants from Canadian Institutes of Health Research (CIHR) and Ferring Pharmaceutical. He is on the advisory board for AbbVie, Pfizer, and Baxter. Other authors do not have any declarations of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To correlate pain-related phenotyping for central nervous system sensitization in endometriosis-associated pain with mental health outcomes during the COVID-19 pandemic, the prospective Endometriosis and Pelvic Pain Interdisciplinary Cohort (ClinicalTrials.gov #NCT02911090) was linked to the COVID-19 Rapid Evidence Study of a Provincial Population-Based Cohort for Gender and Sex (RESPPONSE) dataset. The primary outcomes were depression (PHQ-9) and anxiety (GAD-7) scores during the pandemic. The explanatory variables of interest were the Central Sensitization Inventory (CSI) score (0-100) and endometriosis-associated chronic pain comorbidities/psychological variables before the pandemic. The explanatory and response variables were assessed for correlation, followed by multivariable regression analyses adjusting for PHQ-9 and GAD-7 scores pre-pandemic as well as age, body mass index, and parity. A higher CSI score and a greater number of chronic pain comorbidities before the pandemic were both positively correlated with PHQ-9 and GAD-7 scores during the pandemic. These associations remained significant in adjusted analyses. Increasing the CSI score by 10 was associated with an increase in pandemic PHQ-9 by .74 points (P < .0001) and GAD-7 by .73 points (P < .0001) on average. Each additional chronic pain comorbidity/psychological variable was associated with an increase in pandemic PHQ-9 by an average of .63 points (P = .0004) and GAD-7 by .53 points (P = .0002). Endometriosis patients with a history of central sensitization before the pandemic had worse mental health outcomes during the COVID-19 pandemic. As a risk factor for mental health symptoms in the face of major stressors, clinical proxies for central sensitization can be used to identify endometriosis patients who may need additional support. PERSPECTIVE: This article adds to the growing literature of the clinical importance of central sensitization in endometriosis patients, who had more symptoms of depression and anxiety during the COVID-19 pandemic. Clinical features of central sensitization may help clinicians identify endometriosis patients needing additional support when facing major stressors., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

The utility of pre-implantation genetic testing (PGT-A) is controversial, with older meta-analyses demonstrating improved pregnancy outcomes, while newer trials have not shown benefit. Therefore, we performed a meta-analysis which aimed to evaluate the benefits of PGT-A using comprehensive chromosome screening (CCS) and its effects on in vitro fertilization (IVF) outcomes among randomized controlled trials (RCTs). We conducted a systematic search to identify RCTs comparing women undergoing PGT-A with CSS with women not undergoing PGT-A, from inception to December 2020. Random effects meta-analysis was utilized to calculate average odds ratios (OR) for clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), and miscarriage rate (MR). The heterogeneity of exposure was assessed using Forest plots and I2 statistics. Publication bias was evaluated using Egger's test. Among 1251 citations, seven RCTs met the inclusion criteria. Biopsies of embryos were carried out at various developmental stages, including polar body, day 3, and day 5-6 of culture. Data was analyzed as all studies and blastocyst only. Meta-analysis failed to show improvement in OPRs using PGT-A in the all ages, <35 years old and ≥35 years old age groups. There was also no significant difference in CPRs in any group. The MR decreased with the use of PGT-A (among all biopsy types and among blastocyst biopsies) in the all-ages group, but not when stratifying according to patient age <35 and ≥35 years old. More data regarding the risks and advantages of PGT-A are needed to make a final decision on the value of this intervention in clinical practice. The exact magnitude of the benefit of PGT-A selection cannot be correctly determined until multiple standardized protocol IVF PGT-A trials are conducted.

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2023 The Author. Published by Elsevier Inc. All rights reserved.)

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., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Importance: The prevalence of overweight and obesity (body mass index [BMI] ≥25) has increased globally, and high BMI has been linked to higher rates of twin birth. However, evidence from large population-based studies is lacking; the issue needs careful study, as women with obesity are also more likely to use assisted reproductive technology (ART), which frequently results in twin pregnancy., Objective: To examine the association between BMI and twin birth and the role of ART as a potential mediator in this association., Design, Setting, and Participants: This retrospective cohort study included all live births and stillbirths with gestational age of 20 weeks or longer in British Columbia, Canada, from 2008 to 2020, using data from the British Columbia Perinatal Database Registry. Data analysis was conducted from November 2022 to June 2023., Exposures: Prepregnancy BMI, calculated as weight in kilograms divided by height in meters squared, and use of ART., Main Outcomes and Measures: The study assessed whether prepregnancy BMI is associated with the rate of twin vs singleton delivery and whether this association is explained by the differential use of ART in women with obesity., Results: A total of 524 845 deliveries at 20 weeks' or longer gestation occurred in British Columbia during the study period, and 392 046 women had complete data on prepregnancy BMI. The median (IQR) age was 31.4 (27.7-35.0) years, approximately half were nulliparous (243 443 [46.4%]) and less than 10% smoked during pregnancy (36 894 [7.1%]). Overall, 8295 women had a twin delivery (15.8 per 1000 deliveries), and rates per 1000 deliveries by prepregnancy BMI categories were 11.9 (underweight), 15.1 (normal), 16.0 (overweight), 16.0 (obesity class I), 16.7 (obesity class II), and 18.9 (obesity class III). After adjustment for other covariates, women with underweight had relatively 16% fewer twins compared with women with normal BMI (adjusted risk ratio [aRR], 0.84; 95% CI, 0.74-0.95), while women with overweight, class I obesity, class II obesity, and class III obesity had 14% (aRR, 1.14; 95% CI, 1.07-1.21), 16% (aRR, 1.16; 95% CI, 1.06-1.27), 17% (aRR, 1.17; 95% CI, 1.02-1.34), and 41% higher rates (aRR, 1.41; 95% CI, 1.19-1.66), respectively. The proportion of women who conceived by ART increased with increasing BMI, and ART was associated with nearly a 12-fold higher rate of twin delivery (aRR, 11.80; 95% CI 11.10-12.54). ART explained about a quarter of the association between obesity class I and II and twin delivery (eg, obesity class I, 23% mediated; 95% CI, 7%-39% mediated), but none of this association was mediated by ART in women with class III obesity., Conclusions and Relevance: In this cohort study of 524 845 births, the rate of twin birth increased with increasing prepregnancy BMI. In women with a BMI between 30 and 40, approximately one-quarter of this association was explained by higher use of ART; however, there was no evidence of such mediation in women with BMI of 40 or greater.

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., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the odds of developing adverse maternal and perinatal outcomes in primiparous singleton pregnancies conceived with assisted reproductive technology (ART) compared with pregnancies conceived without ART., Study Design: A retrospective population-based cohort study using data from the British Columbia Perinatal Data Registry. The population included primiparous women with singleton live or stillbirths delivering at or after 20 weeks' gestation between April 1st 2008-March 31st, 2021. Women who conceived with ART were compared with those who conceived without ART. The main outcome measures were gestational diabetes, hypertensive disorders of pregnancy, preterm birth, low birth weight, neonatal intensive care unit admission, stillbirth, and 5-minute Apgar score. Adjusted odds ratios were calculated., Results: The study population included 191,059 primiparous women: 183,819 conceived without ART, 7,240 conceived using ART. After controlling for age, body mass index, pre-gestational diabetes, and smoking status, singleton pregnancies conceived by ART had significantly higher odds of gestational diabetes (OR 1.18, 95 % confidence interval [CI] 1.10-1.26) and hypertensive disorders of pregnancy (OR 1.39, 95 % CI 1.29-1.51). There were also significantly increased odds of preterm birth (OR 1.35, 95 % CI 1.25-1.46), low birth weight (OR 1.35, 95 % CI 1.23-1.49), and neonatal intensive care unit admission (OR 1.21, 95 % CI 1.11-1.32). There was not a statistically significant difference in the odds of stillbirth (OR 1.06, 95 % CI 0.72-1.57) or 5-minute Apgar score < 7 (OR 1.10, 95 % CI 0.97-1.26)., Conclusion: There is an increased odds of developing several adverse maternal or neonatal outcomes in primiparous singleton pregnancies conceived by ART including gestational diabetes, hypertensive disorders of pregnancy, preterm birth, low birth weight, and increased incidence of neonatal intensive care unit admissions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To quantify pandemic-related changes in obstetric intervention and perinatal outcomes in the United States., Methods: We carried out a retrospective study of all live births and fetal deaths in the United States, 2015-2021, with data obtained from the natality, fetal death, and linked live birth-infant death files of the National Center for Health Statistics. Analyses were carried out among all singletons; singletons of patients with prepregnancy diabetes, prepregnancy hypertension, and hypertensive disorders of pregnancy; and twins. Outcomes of interest included preterm birth, preterm labor induction or preterm cesarean delivery, macrosomia, postterm birth, and perinatal death. Interrupted time series analyses were used to estimate changes in the prepandemic period (January 2015-February 2020), at pandemic onset (March 2020), and in the pandemic period (March 2020-December 2021)., Results: The study population included 26,604,392 live births and 155,214 stillbirths. The prepandemic period was characterized by temporal increases in preterm birth and preterm labor induction or cesarean delivery rates and temporal reductions in macrosomia, postterm birth, and perinatal mortality. Pandemic onset was associated with absolute decreases in preterm birth (decrease of 0.322/100 live births, 95% CI 0.506-0.139) and preterm labor induction or cesarean delivery (decrease of 0.190/100 live births, 95% CI 0.334-0.047) and absolute increases in macrosomia (increase of 0.046/100 live births), postterm birth (increase of 0.015/100 live births), and perinatal death (increase of 0.501/1,000 total births, 95% CI 0.220-0.783). These changes were larger in subpopulations at high risk (eg, among singletons of patients with prepregnancy diabetes). Among singletons of patients with prepregnancy diabetes, pandemic onset was associated with a decrease in preterm birth (decrease of 1.634/100 live births) and preterm labor induction or cesarean delivery (decrease of 1.521/100 live births) and increases in macrosomia (increase of 0.328/100 live births) and perinatal death (increase of 9.840/1,000 total births, 95% CI 3.933-15.75). Most changes were reversed in the months after pandemic onset., Conclusion: The onset of the coronavirus disease 2019 (COVID-19) pandemic was associated with a transient decrease in obstetric intervention (especially preterm labor induction or cesarean delivery) and a transient increase in perinatal mortality., Competing Interests: Financial Disclosure Amelie Boutin reports receiving a Junior I Research Scholar Award from a governmental agency, the Fonds de recherche du Québec-Santé. Mohamed A. Bedaiwy disclosed receiving funding from Pfizer, and his institution received funding from Ferring. He also received a grant from CIHR to study the effects of COVID on patients with recurrent pregnancy loss. The other authors did not report any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (Copyright © 2023 AAGL. All rights reserved.)

The objective of this study was to characterize the relationship between embryonic chromosomal errors in the products of conception (POC) and maternal age, gestational age (GA) of pregnancy loss, and findings on routine recurrent pregnancy loss (RPL) workup. This is a retrospective cohort study of women with a history of ≥ 2 pregnancy losses and who underwent cytogenetic testing on the POC of a subsequent pregnancy loss at an academic tertiary RPL referral center. The association between the odds of embryonic chromosomal errors in POC and maternal age, GA of pregnancy loss, as well as RPL work up findings was investigated. A total of 1107 miscarriages were analyzed from 741 women. There was an overall linear relationship between embryonic chromosomal errors and maternal age, with a nearly twofold increase in the odds of chromosomal error with every 5-year increase in maternal age (P < 0.0001). The association between chromosomal errors and GA was also linear (P = 0.0001), with most losses having no chromosomal errors after 13 weeks' gestation. Women with ≥ 1 positive findings on routine RPL diagnostic workup had lower odds of embryonic chromosomal errors compared to those with a normal workup [OR 0.57 (95% CI = 0.41-0.80)]. Notably, the estimated prevalence of chromosomal error remained high (> 60%) in women ≥ 35 years old irrespective of findings on routine evaluation. While embryonic chromosomal errors were associated with advanced maternal age, early GA of loss, and a negative routine RPL evaluation, the prevalence of chromosomal errors remained high in all subpopulations. These findings suggest that primary cytogenetic testing on POCs should be offered at the time of second and subsequent pregnancy losses in all RPL patients., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Kisspeptin (KP) is a group of hypothalamic neuropeptides encoded by KISS-1 gene. KP-54, a 54-amino-acid peptide, helps regulate the hypothalamic-pituitary-ovarian axis and plays a potential role in implantation. C57BL/6 J female mice were superovulated via intraperitoneal injection of 5 International Units (IU) pregnant mare serum gonadotrophin (day 1). Forty-eight hours later, mice (5/group) were injected with phosphate-buffered saline (PBS) (group A), 5 IU human chorionic gonadotrophin (hCG) (group B), or 3 nmol KP-54 (group C). On day 7, mice were euthanized and uteri excised to create paraformaldehyde-fixed paraffin-embedded sections that were immunostained for the implantation markers: leukemia inhibitory factor (LIF) and integrin αVβ3 (ITG αVβ3). Slides were scored for intensity of staining in endometrial glandular epithelium (GE) and stromal cells (SCs) via histoscore (H-score). Data were analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U test for pairwise comparisons. LIF expression was significantly higher in GE and SCs of mice triggered with KP-54 compared to placebo (P = .009 for both), but only higher than hCG trigger group in SCs (P = .009). Meanwhile, ITG αVβ3 expression was significantly higher in SCs of mice triggered with KP-54 compared to placebo (P = .028). In conclusion, using KP-54 as an ovulation trigger resulted in higher expression of the implantation markers LIF and ITG αVβ3 in mice endometrium compared to hCG or placebo. This suggests a potential role for KP-54 trigger in improving embryo implantation in clinical IVF. However, further studies are needed to correlate these results with clinical implantation rates and pregnancy outcomes., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Problem: The current standard prevention of obstetric complications in patients with antiphospholipid antibody syndrome (APS) is the use of combination low-dose aspirin and low molecular weight heparin. However, 20-30% of women still experience refractory obstetrical APS. Hydroxychloroquine (HCQ) is an immunomodulatory agent that has been shown in laboratory studies to decrease thrombosis risk, support placentation, and minimize the destructive effects of antiphospholipid antibodies. The objective of this study was to evaluate the risk of pregnancy loss upon treatment with HCQ among women with refractory obstetrical APS., Method of Study: A systematic review was conducted according to PRISMA guidelines. Studies that evaluated the use of HCQ during pregnancy in women with primary APS were included. The primary outcomes of interest were live birth and pregnancy losses after treatment with HCQ., Results: Twelve studies met inclusion criteria. Three retrospective cohort studies demonstrated improved live birth rate, and four studies demonstrated a reduction in pregnancy loss rate. Two case reports also demonstrated a benefit in the use of HCQ compared to previous obstetrical outcomes., Conclusions: Our findings suggest a significant benefit of HCQ in addition to aspirin and heparin for patients with APS to mitigate the risk of antiphospholipid antibody mediated obstetrical complications. Randomized controlled trials with standardized patient selection criteria need to be conducted to corroborate these findings., (© 2023 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

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 (β=3.19), pelvic floor myalgia (β=2.44), and Patient Health Questionnaire 9 depression score (β=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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5-9 years of follow-up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I-IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re-operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02-2.11) and non-Caucasian ethnicity (RR = 0.64, 95% CI: 0.47-0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow-up. Re-operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66-4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer-driver mutations may inform a future molecular classification of endometriosis., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Competing Interests: Intérêts concurrents: Catherine Allaire déclare avoir reçu un soutien à titre de conférencière des laboratoires Hologic et a participé à des comités consultatifs pour les laboratoires AbbVie et Pfizer. Elle est membre du conseil d’administration de la Société canadienne pour l’avancement de l’excellence en gynécologie, la Société internationale pour la douleur pelvienne et la Société mondiale de l’endométriose. Mohamed Bedaiwy déclare avoir reçu un financement des Instituts de recherche en santé du Canada (IRSC) et de l’Institut de recherche Ferring sur la santé féminine, des royautés des laboratoires AbbVie et Baxter, des honoraires de consultation des laboratoires AbbVie et une participation au conseil d’administration de la Société canadienne de fertilité et d’andrologie. Paul Yong déclare avoir reçu du financement des IRSC, de l’organisme Michael Smith pour la recherche en santé de la Colombie-Britannique, de l’Institut de recherche en santé féminine de l’Université de la Colombie-Britannique et de la Société internationale pour l’étude de la santé sexuelle des femmes. Il déclare avoir reçu un soutien pour assister à des réunions de la Société canadienne pour l’avancement de l’excellence en gynécologie, de la Société internationale pour l’étude de la santé sexuelle des femmes, de la Société internationale de la douleur pelvienne et de la Société internationale de l’endométriose. Il fait aussi partie du comité de surveillance de la sécurité des données pour un essai clinique subventionné par les IRSC, du comité consultatif stratégique pour l’Institut de recherche en santé des femmes, des conseils d’administration de la Société canadienne pour l’avancement de l’excellence en gynécologie, de la Société internationale pour l’étude de la santé sexuelle féminine et de la Société internationale de l’endométriose. Aucun autre intérêt concurrent n’a été déclaré.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Competing interests: Catherine Allaire reports conference support from Hologic and participation on advisory boards with AbbVie and Pfizer. She is a board member with the Canadian Society for the Advancement of Gynecologic Excellence, the International Pelvic Pain Society and the World Endometriosis Society. Mohamed Bedaiwy reports funding from the Canadian Institutes of Health Research (CIHR) and the Ferring Women Health Research Institute, royalties from AbbVie and Baxter, consulting fees from AbbVie and participation with the board of the Canadian Fertility and Andrology Society. Paul Yong reports funding from CIHR, Michael Smith Health Research BC, the Women’s Health Research Institute, the University of British Columbia and the International Society for the Study of Women’s Sexual Health. He reports meeting support from the Canadian Society for the Advancement of Gynecologic Excellence, the International Society for the Study of Women’s Sexual Health, the International Pelvic Pain Society and the World Endometriosis Society. He also sits on the data safety monitoring board a for CIHR-funded clinical trial, the strategic advisory board for the Women’s Health Research Institute, the boards of the Canadian Society for the Advancement of Gynecologic Excellence, the International Society for the Study of Women’s Sexual Health and the World Endometriosis Society. No other competing interests were declared.

Objective: To study the role of interleukin (IL)-1β and the plasminogen activating (PA) system members in endometriotic stromal cell (ESC) migration/invasion., Design: Primary cultures of ESCs., Setting: Tertiary referral center for endometriosis and pelvic pain., Patient(s): Patients with surgically excised endometriosis., Intervention(s): Interleukin-1β stimulation of primary cultures of ESCs and knockdown of the PA system members urokinase plasminogen activator (uPA), uPA receptor, and plasminogen activator inhibitor-1 (PAI-1)., Main Outcome Measure(s): Invasion/migration assays., Result(s): In primary cultures, IL-1β-stimulated ESC production of the PA system members uPA, uPA receptor, and PAI-1. Interleukin-1β also enhanced ESC migration and invasion, and these effects were inhibited by the IL-1 receptor-1 antagonist anakinra. Knockdown of each of the 3 PA system members also inhibited ESC migration and invasion. Knockdown of these PA system members further attenuated the impact of IL-1β on migration and invasion, suggesting that they mediated the promigration and proinvasion effects of IL-1β. To supplement the cell culture work, immunohistochemistry was performed on tissue sections of endometriotic epithelium/stroma: uPA, PAI-1, and IL-1β histoscores were not found to be correlated with each other., Conclusion(s): In primary cultures of ESCs, IL-1β induces migration and invasion, which is mediated by PA system members and inhibited by the drug anakinra. However, the immunohistochemistry expression of IL-1β, urokinase plasminogen inhibitor-1, and PAI-1 were not correlated, suggesting other regulatory mechanisms for PA system members. Inhibition of IL-1β (e.g., with anakinra) may have potential as a novel treatment approach for the migration/invasion of endometriosis., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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., (© 2022 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Importance: A subset of people who undergo surgery for endometriosis have persistent pain, suggesting that other factors besides the endometriosis, such as central sensitization, may play a role in this pain. The Central Sensitization Inventory, a validated self-reported questionnaire of central sensitization symptoms, may identify individuals with endometriosis who have more pain after surgery due to pain sensitization., Objective: To examine whether greater baseline Central Sensitization Inventory scores are associated with postsurgical pain outcomes., Design, Setting, and Participants: This prospective, longitudinal cohort study performed at a tertiary center for endometriosis and pelvic pain in British Columbia, Canada, included all patients aged 18 to 50 years with diagnosed or suspected endometriosis and a baseline visit between January 1, 2018, and December 31, 2019, who underwent surgery after the baseline visit. Individuals who were menopausal, had a prior hysterectomy, or were missing data for outcomes or measures were excluded. Data analysis was performed from July 2021 to June 2022., Main Outcomes and Measures: The primary outcome was chronic pelvic pain at follow-up measured on a scale of 0 to 10, with 0 to 3 indicating no pain or mild pain, 4 to 6 indicating moderate pain, and 7 to 10 indicating severe pain. Secondary outcomes were deep dyspareunia, dysmenorrhea, dyschezia, and back pain at follow-up. The main variable of interest was baseline Central Sensitization Inventory score (measured from 0 to 100, consisting of 25 self-reported questions rated from 0 to 4 [never, rarely, sometimes, often, and always, respectively])., Results: A total of 239 patients (mean [SD] age, 34 [7] years; 189 [79.1%] White [11 (5.8%) identified as White mixed with another ethnicity], 1 [0.4%] Black or African American, 29 [12.1%] Asian, 2 [0.8%] Native Hawaiian or Pacific Islander, 16 [6.7%] other, and 2 [0.8%] mixed race or ethnicity) with follow-up data at more than 4 months after surgery were included in this study (71.0% follow-up rate). The mean (SD) baseline Central Sensitization Inventory score was 43.8 (18.2), and the mean (SD) follow-up was 16.1 (6.1) months. Higher baseline Central Sensitization Inventory scores were significantly associated with higher chronic pelvic pain (odds ratio [OR], 1.02; 95% CI, 1.00-1.03; P = .02), deep dyspareunia (OR, 1.03; 95% CI, 1.01-1.04; P = .004), dyschezia (OR, 1.03; 95% CI, 1.01-1.04; P < .001), and back pain (OR, 1.02; 95% CI, 1.00-1.03; P = .02) at follow-up, when controlling for baseline pain scores. The Central Sensitization Inventory scores themselves decreased slightly from baseline to follow-up (mean [SD] score, 43.8 [18.2] vs 41.7 [18.9]; P = .05); however, individuals with high baseline Central Sensitization Inventory scores still had high scores at follow-up., Conclusions and Relevance: In this cohort study of 239 patients with endometriosis, higher Central Sensitization Inventory scores at baseline were associated with worse pain outcomes after endometriosis surgery, when controlling for baseline pain scores. The Central Sensitization Inventory could be used to counsel patients with endometriosis on their expected outcomes after surgery.

Objective: To study choriodecidual immunoreactivity of kisspeptin (KISS1) and its receptor (KISS1R) in recurrent pregnancy loss (RPL) due to aneuploidy (AnE) and unexplained (UE) RPL in comparison to control elective abortions (EAbs)., Design: This is a case-control study., Setting: Tertiary care facility and affiliated research institute., Patient(s): Patients with either UE RPL (n = 10) or RPL due to AnE (n = 10) vs. a control group of patients who underwent EAb (n = 10)., Intervention(s): Immunohistochemistry of archived choriodecidual tissue samples., Main Outcome Measure(s): Histoscores of KISS1 and KISS1R immunoreactivity in the syncytiotrophoblast (SyT), cytotrophoblast (CyT), decidual glands (DeGs), and decidual stroma (DeS) across the 3 study groups., Result(s): There was no difference in both maternal and gestational ages among the 3 groups. Kisspeptin immunoreactivity was similar in the SyT, CyT, DeGs, and DeS of all groups. Similarly, KISS1R expression was not different in the DeGs or DeS among all study groups. In addition, there was no difference in KISS1R immunoreactivity in the SyTs and CyTs between patients with RPL due to AnE and those with UE RPL. However, KISS1R was significantly lower in the SyT and CyT of patients with RPL due to AnE and UE RPL than in those who underwent EAb., Conclusion(s): The expression of KISS1R is lower in the chorionic tissues of euploid (unexplained) and aneuploid RPLs than in the control group. The current results broaden our understanding of the role played by KISS1 and KISS1R in early placentation. Further investigation is necessary to determine whether KISS1 activity is the cause or a sequel of defective placentation., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Although racial and ethnic disparities in adverse birth outcomes have been well documented, it is unknown whether such disparities diminish in women who use medically assisted reproduction (MAR). We examined differences in the association between maternal race and ethnicity and adverse birth outcomes among women who conceived spontaneously and those who used MAR, including assisted reproduction technology (ART), eg, in-vitro fertilization, and also non-ART MAR, eg, fertility drugs., Methods: We conducted a population-based retrospective cohort study using data on all singleton births (N = 7 545 805) in the United States from 2016 to 2017. The outcomes included neonatal and fetal death, preterm birth, and serious neonatal morbidity, among others. Modified Poisson regression was used to estimate adjusted rate ratios (aRR) and 95% confidence intervals (CI) and to assess the interactions between race and ethnicity and mode of conception., Results: Overall, 93 469 (1.3%) singletons were conceived by MAR. Neonatal mortality was twofold higher among infants of non-Hispanic Black versus non-Hispanic White women in the spontaneous-conception group (aRR = 1.9, 95% CI: 1.8-1.9), whereas in the ART-conception group, neonatal mortality was more than fourfold higher in infants of non-Hispanic Black women (aRR = 4.1, 95% CI: 2.9-5.9). Racial and ethnic disparities between Hispanic versus non-Hispanic White women were also significantly larger among women who conceived using MAR with regard to preterm birth (&lt;34 weeks) and perinatal mortality., Conclusions: Compared to women who conceived spontaneously, racial and ethnic disparities in adverse perinatal outcomes were larger in women who used MAR. More research is needed to identify preventive measures for reducing risks among vulnerable women who use medically assisted reproduction., (Copyright © 2022 by the American Academy of Pediatrics.)

Objectives: The purpose of this study was to explore if thyroperoxidase antibody positivity impacts thyroid stimulating hormone levels during pregnancies following the index visit and how live birth rate is impacted when treated subclinical hypothyroidism is treated with levothyroxine or not., Study Design: A retrospective chart review of 1443 recurrent pregnancy loss patients from BC Women's Hospital recurrent pregnancy loss clinic was conducted. Thyroid stimulating hormone in pregnancies after the index visit across thyroperoxidase antibody status was analyzed using mixed-effects linear regression. Live birth rate in patients with subclinical hypothyroidism (thyroid stimulating hormone 2.5-10 mIU/L) with levothyroxine treatment was compared to those without relative to euthyroid patients using logistic regression., Results and Conclusions: There was no significant difference in patient demographics including age, body mass index, or number of previous live births or pregnancy losses between groups. The distribution of recurrent pregnancy loss causes between groups revealed no difference in proportion of patients with anti-phospholipid antibody syndrome, hereditary thrombophilia, hyperprolactinemia, or anatomic causes. There was no significant change in thyroid stimulating hormone across thyroperoxidase antibody or treatment status (p = 0.24) for up to four subsequent pregnancies. An increased live birth rate in subclinical hypothyroidism when treated with levothyroxine relative to untreated (OR = 2.25, p < 0.001) was seen. Thyroid stimulating hormone values do not change over time following the index visit for up to 4 subsequent pregnancies irrespective of the thyroxperoxidase antibody status. An increase in live birth rate was found in patients with borderline subclinical hypothyroidism when treated with levothyroxine., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohamed A. Bedaiwy is on the advisory board for AbbVie and Baxter and has received research grant funding from Ferring., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Endometriosis is a chronic, debilitating, gynecologic condition with a non-specific clinical presentation. Globally, patients can experience diagnostic delays of ~6 to 12 years, which significantly hinders adequate management and places a significant financial burden on patients and the healthcare system. Through artificial intelligence (AI), it is possible to create models that can extract data patterns to act as inputs for developing interventions with predictive and diagnostic accuracies that are superior to conventional methods and current tools used in standards of care. This literature review explored the use of AI methods to address different clinical problems in endometriosis. Approximately 1309 unique records were found across four databases; among those, 36 studies met the inclusion criteria. Studies were eligible if they involved an AI approach or model to explore endometriosis pathology, diagnostics, prediction, or management and if they reported evaluation metrics (sensitivity and specificity) after validating their models. Only articles accessible in English were included in this review. Logistic regression was the most popular machine learning method, followed by decision tree algorithms, random forest, and support vector machines. Approximately 44.4% (n = 16) of the studies analyzed the predictive capabilities of AI approaches in patients with endometriosis, while 47.2% (n = 17) explored diagnostic capabilities, and 8.33% (n = 3) used AI to improve disease understanding. Models were built using different data types, including biomarkers, clinical variables, metabolite spectra, genetic variables, imaging data, mixed methods, and lesion characteristics. Regardless of the AI-based endometriosis application (either diagnostic or predictive), pooled sensitivities ranged from 81.7 to 96.7%, and pooled specificities ranged between 70.7 and 91.6%. Overall, AI models displayed good diagnostic and predictive capacity in detecting endometriosis using simple classification scenarios (i.e., differentiating between cases and controls), showing promising directions for AI in assessing endometriosis in the near future. This timely review highlighted an emerging area of interest in endometriosis and AI. It also provided recommendations for future research in this field to improve the reproducibility of results and comparability between models, and further test the capacity of these models to enhance diagnosis, prediction, and management in endometriosis patients., (© 2022. Crown.)

Introduction: Chronic intervillositis of unknown etiology (CIUE) is a placental inflammatory process associated with pregnancy loss and high recurrence risk. The pathogenesis is unclear but involves aberrant maternal inflammation. This study assesses expression of inflammatory mediators by placenta and intervillus macrophage using digital spatial profiling, which is applicable to formalin fixed paraffin embedded tissue and provides whole transcriptome expression analysis at cellular resolution., Methods: Ethics approval was obtained and all experiments were performed in accordance with applicable guidelines and regulations. Archival tissue from early spontaneous pregnancy loss with high grade CIUE (4 cases) was compared to non-inflamed control normal placenta (4 cases) and granulomatous lymphadenitis as a macrophage inflammation control (4 cases). Differential gene expression between CIUE and relevant controls was assessed using unpaired t-test with Benjamini-Hochberg false discovery correction. Gene Set Enrichment Analysis (GSEA) was used to characterize and compare pathways active in the CIUE and relevant control samples., Results: Principal component analysis of the gene expression data showed distinct clustering with relatively little intragroup variation in the control tissues whereas the CIUE cases are more variable. Gene expression analysis showed changes in CIUE; however, no genes remained statistically significant after correction for false discovery. GSEA revealed prominent activation of IFN-related signaling pathways in CIUE placenta, particularly IFNγ signaling., Discussion: This study demonstrates that CIUE is associated with a specific profile of inflammatory mediators expressed by placenta villi that is dominated by IFN signaling, suggesting that uncontrolled IFNγ signaling may play a primary role in the pathogenetic mechanism underlying CIUE., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Abstract: A key clinical problem is identifying the patient with endometriosis whose pain is complicated by central nervous system sensitization, where conventional gynecologic treatment (eg, hormonal therapy or surgery) may not completely alleviate the pain. The Central Sensitization Inventory (CSI) is a questionnaire previously validated in the chronic pain population. The objective of this study was an exploratory proof-of-concept to identify a CSI cutoff in the endometriosis population to discriminate between individuals with significant central contributors (identified by central sensitivity syndromes [CSS]) to their pain compared to those without. We analyzed a prospective data registry at a tertiary referral center for endometriosis, and included subjects aged 18 to 50 years with endometriosis who were newly or re-referred to the center in 2018. The study sample consisted of 335 subjects with a mean age of 36.0 ± 7.0 years. An increasing number of CSS was significantly correlated with dysmenorrhea, deep dyspareunia, dyschezia, and chronic pelvic pain scores (P < 0.001), and with the CSI score (0-100) (r = 0.731, P < 0.001). Receiver operating characteristic analysis indicated that a CSI cutoff of 40 had a sensitivity of 78% (95% CI: 72.7%-84.6%) and a specificity of 80% (95% CI: 70.3%-84.5%) for identifying a patient with endometriosis with ≥3 CSS. In the group with CSI ≥ 40, 18% retrospectively self-reported pain nonresponsive to hormonal therapy and 40% self-reported daily pain, compared with 6% and 20% in the CSI < 40 group (P = 0.003 and 0.002, respectively). In conclusion, a CSI ≥ 40 may be a practical tool to help identify patients with endometriosis with pain contributors related to central nervous system sensitization., (Copyright © 2021 International Association for the Study of Pain.)

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., (Copyright © 2021 AAGL. Published by Elsevier Inc. All rights reserved.)

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.

The pathogenesis of bowel endometriosis is multifactorial. There is a predilection for disease of the rectum/sigmoid colon because refluxed endometrium is more likely to settle in the pouch of Douglas and its movement is delimited by the sigmoid colon, in addition to the close proximity of the rectum/sigmoid to posterior extrinsic uterine adenomyosis and to ovarian endometriomas. Once situated, deep bowel endometriosis has features of invasion, angiogenesis, and fibrosis (repeated tissue injury and repair), with emerging research on oxidative stress and the microbiome. Furthermore, deep bowel endometriosis is associated with neurogenesis and/or the recruitment of local nerve fibers and is capable of invading existing nerves, which in turn may also promote fibrosis. Recently, somatic cancer driver mutations (e.g., in KRAS) were identified in deep bowel endometriosis, which may play a role in the genetic/epigenetic theory of endometriosis. In the future, it is possible that bowel endometriosis could be classified based on molecular features., Competing Interests: Declaration of Competing Interest MB has financial affiliations with Abbvie and Allergan (grants and advisory boards)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)