Diagnosis and management of endometrial hyperplasia: A UK national audit of adherence to national guidance 2012-2020.

BACKGROUND: Endometrial hyperplasia (EH) is a precusor lesion for endometrial cancer (EC), the commonest gynaecological malignancy in high-income countries. EH is a proliferation of glandular tissue, classified as either non-atypical endometrial hyperplasia (NEH) or, if the cytological features are abnormal, atypical endometrial hyperplasia (AEH). The clinical significance of AEH is that patients face both a high risk of having occult EC and a high risk of progression to EC if untreated. Recommendations on the care of women with EH were introduced by United Kingdom-wide guidance (Green-top Guide No. 67, 2016). National adherence to guidance is unknown. We aimed to describe the care of patients with EH; to compare the patterns of care for those with EH with national guidance to identify opportunities for quality improvement; and to compare patterns of care prior to and following the introduction of national guidance to understand its impact. METHODS AND FINDINGS: In this UK-wide patient-level clinical audit, we included 3,307 women who received a new histological diagnosis of EH through a gynaecology service between 1 January 2012 and 30 June 2020. We described first-line management, management at 2 years, and surgical characteristics prior to and following national guidance for EH using proportions and 95% confidence intervals (CIs) and compared process measures between time periods using multilevel Poisson regression. Of the 3,307 patients, 1,570 had NEH and 1,511 had AEH between 2012 and 2019. An additional 85 patients had NEH and 141 had AEH during 2020. Prior to national guidance, 9% (95% CI [6%, 15%]) received no initial treatment for NEH compared with 3% (95% CI [1%, 5%]) post-guidance; 31% (95% CI [26%, 36%]) and 48% (95% CI [43% 53%]) received an intrauterine progestogen, respectively, in the same periods. The predominant management of women with AEH did not differ, with 68% (95% CI [61%, 74%]) and 67% (95 CI [63%, 71%]) receiving first-line hysterectomy, respectively. By 2 years, follow-up to histological regression without hysterectomy increased from 38% (95% CI [33%, 43%]) to 52% (95% CI [47%, 58%]) for those with NEH (rate ratio (RR) 1.38, 95% CI [1.18, 1.63] p < 0.001). We observed an increase in the use of total laparoscopic hysterectomy among those with AEH (RR 1.26, 95% CI [1.04, 1.52]). In the later period, 37% (95% CI [29%, 44%]) of women initially diagnosed with AEH who underwent a first-line hysterectomy, received an upgraded diagnosis of EC. Study limitations included retrospective data collection from routine clinical documentation and the inability to comprehensively understand the shared decision-making process where care differed from guidance. CONCLUSIONS: The care of patients with EH has changed in accordance with national guidance. More women received first-line medical management of NEH and were followed up to histological regression. The follow-up of those with AEH who do not undergo hysterectomy must be improved, given their very high risk of coexistent cancer and high risk of developing cancer.

The endometrial microbiota and early pregnancy loss.

The human endometrium is a dynamic entity that plays a pivotal role in mediating the complex interplay between the mother and developing embryo. Endometrial disruption can lead to pregnancy loss, impacting both maternal physical and psychological health. Recent research suggests that the endometrial microbiota may play a role in this, although the exact mechanisms are still being explored, aided by recent technological advancements and our growing understanding of host immune responses. Suboptimal or dysbiotic vaginal microbiota, characterized by increased microbial diversity and reduced Lactobacillus dominance, has been associated with various adverse reproductive events, including miscarriage. However, the mechanisms linking the lower reproductive tract microbiota with pregnancy loss remain unclear. Recent observational studies implicate a potential microbial continuum between the vaginal and endometrial niche in patients with pregnancy loss; however, transcervical sampling of the low biomass endometrium is highly prone to cross-contamination, which is often not controlled for. In this review, we explore emerging evidence supporting the theory that a dysbiotic endometrial microbiota may modulate key inflammatory pathways required for successful embryo implantation and pregnancy development. We also highlight that a greater understanding of the endometrial microbiota, its relationship with the local endometrial microenvironment, and potential interventions remain a focus for future research.

Multivariable prediction models for fetal macrosomia and large for gestational age: A systematic review.

BACKGROUND: The identification of large for gestational age (LGA) and macrosomic fetuses is essential for counselling and managing these pregnancies. OBJECTIVES: To systematically review the literature for multivariable prediction models for LGA and macrosomia, assessing the performance, quality and applicability of the included model in clinical practice. SEARCH STRATEGY: MEDLINE, EMBASE and Cochrane Library were searched until June 2022. SELECTION CRITERIA: We included observational and experimental studies reporting the development and/or validation of any multivariable prediction model for fetal macrosomia and/or LGA. We excluded studies that used a single variable or did not evaluate model performance. DATA COLLECTION AND ANALYSIS: Data were extracted using the Checklist for critical appraisal and data extraction for systematic reviews of prediction modelling studies checklist. The model performance measures discrimination, calibration and validation were extracted. The quality and completion of reporting within each study was assessed by its adherence to the TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) checklist. The risk of bias and applicability were measured using PROBAST (Prediction model Risk Of Bias Assessment Tool). MAIN RESULTS: A total of 8442 citations were identified, with 58 included in the analysis: 32/58 (55.2%) developed, 21/58 (36.2%) developed and internally validated and 2/58 (3.4%) developed and externally validated a model. Only three studies externally validated pre-existing models. Macrosomia and LGA were differentially defined by many studies. In total, 111 multivariable prediction models were developed using 112 different variables. Model discrimination was wide ranging area under the receiver operating characteristics curve (AUROC 0.56-0.96) and few studies reported calibration (11/58, 19.0%). Only 5/58 (8.6%) studies had a low risk of bias. CONCLUSIONS: There are currently no multivariable prediction models for macrosomia/LGA that are ready for clinical implementation.

Intralipid infusion at time of embryo transfer in women with history of recurrent implantation failure: A systematic review and meta-analysis.

AIM: Recurrent implantation failure (RIF) affects 10% of couples undergoing assisted conception, often due to poor endometrial receptivity. We conducted a systematic review and meta-analysis to evaluate the effectiveness of Intra-venous intralipid (IVI) in improving pregnancy rates in women with history of RIF using. METHODS: We searched MEDLINE, EMBASE, and CENTRAL for any randomized trials evaluating the use of IVI at the time of embryo transfer in women undergoing assisted conception until September 2020. We extracted data in duplicate and assessed risk of bias using the Cochrane Risk of Bias tools. We meta-analyzed data using a random effect model. RESULTS: We included five randomized trials reporting on 843 women with an overall moderate risk of bias. All trials used 20% IVI solution at the time of embryo transfer compared to normal saline infusion or no intervention (routine care). The IVI group had a higher chance of clinical pregnancy (172 vs 119, risk ratio [RR] 1.55, 95% confidence interval [CI] 1.16-2.07, I2 44.2%) and live birth (132 vs 73, RR 1.83, 95% CI 1.42-2.35, I2 0%) post treatment compared to no intervention. Our findings are limited by the small sample size and the variations in treatment protocols and population characteristics. CONCLUSION: There is limited evidence to support the use of IVI at the time of embryo transfer in women with the history of RIF. More research is needed before adopting it in clinical practice.

Assessing the Colonic Microbiota in Children: Effects of Sample Site and Bowel Preparation.

OBJECTIVES: Inflammatory bowel disease states are associated with gastrointestinal dysbiosis. Mucosal biopsy sampling, retrieving the bacterial community that most directly interacts with the host, is an invasive procedure that, we hypothesis, may be sufficiently approximated by other sampling methods. We investigate the relatedness of samples obtained by different methods and the effects of bowel preparation on the gastrointestinal community in a paediatric population. METHODS: We recruited a cohort of patients undergoing colonoscopy, collecting serial samples via differing methods (rectal swabs, biopsies, and faecal matter/luminal contents) prebowel preparation, during colonoscopy and after colonoscopy. Next-generation sequencing was used to determine the structure of the microbial community. RESULTS: The microbial community in luminal contents collected during colonoscopy was found to be more similar to that of mucosal biopsies than rectal swabs. Community traits of the mucosal biopsies could be used to segregate patients with inflammatory bowel disease from other patients, and the similarity of the communities in the luminal contents was sufficient for the segregation to be reproduced. Microbial communities sampled by rectal swabs and prebowel preparation faeces were less similar to mucosal biopsies. Bowel preparation was found to have no significant long-term effects on the microbial community, despite the transient effects evident during colonoscopy. CONCLUSIONS: A clinically relevant description of the mucosal microbial community can be obtained via the noninvasive collection of luminal contents after bowel cleansing. Bowel preparation in a paediatric population results in no consistent sustained alterations to the gastrointestinal microbiota.

Lessons learned from bovine subclinical endometritis: A systematic review exploring its potential relevance to chronic endometritis in women.

Chronic endometritis (CE) in humans is asymptomatic inflammation of the endometrium, associated with poor reproductive outcomes. Similarly asymptomatic endometrial inflammation in cows, termed subclinical endometritis (SCE), is associated with adverse reproductive outcomes. While the pathophysiology and treatment options for CE in humans remains poorly defined, the financial implications of SCE in dairy cows mean it has been intensively researched. We performed a systematic review with an emergent theme thematic analysis of studies of SCE in cows, to determine potential areas of interest in human CE research. A literature search for studies of subclinical endometritis in cows published between 1990 and November 2021 was performed across Embase, Medline, Scopus and CINAHL. Studies of symptomatic or clinical endometritis were excluded. Thematic analysis across two broad themes were explored: diagnostic methods and pathophysiology of SCE. In total, 44 bovine studies were included. 12 studies reported on diagnostic methodology. The primary emergent theme was the use of cytology for the diagnosis of SCE. This method has a lower sensitivity than histopathology but is less invasive and more specific than alternative techniques of ultrasound, vaginoscopy, or metabolic markers. The subthemes related to pathophysiology were identified as type of endometritis, metabolic stress, artificial insemination, infective causes, and altered cellular pathways. Despite the lack of symptoms, cellular pathways of inflammation including NFkB, MAPK, and inflammasomes were found to be activated. The key themes related to the diagnosis and pathophysiology of SCE in cows identified in this systematic review highlight potential areas for future research into human CE.

Preconceptual administration of doxycycline in women with recurrent miscarriage and chronic endometritis: protocol for the Chronic Endometritis and Recurrent Miscarriage (CERM) trial, a multicentre, double-blind, placebo-controlled, adaptive randomised trial with an embedded translational substudy.

INTRODUCTION: Recurrent miscarriage is a common condition with a substantial associated morbidity. A hypothesised cause of recurrent miscarriage is chronic endometritis (CE). The aetiology of CE remains uncertain. An association between CE and recurrent miscarriage has been shown. This study will aim to determine if preconceptual administration of doxycycline, in women with recurrent miscarriages, and CE, reduces first trimester miscarriages, increasing live births. METHODS AND ANALYSIS: Chronic Endometritis and Recurrent Miscarriage is a multicentre, double-blind adaptive trial with an embedded translational substudy. Women with a history of two or more consecutive first trimester losses with evidence of CE on endometrial biopsy (defined as ≥5 CD138 positive cells per 10 mm2) will be randomised to oral doxycycline or placebo for 14 days. A subset will be recruited to a mechanistic substudy in which microbial swabs and preintervention/postintervention endometrial samples will be collected. Up to 3062 women recruited from 29 National Health Service (NHS) hospital sites across the UK are expected to be screened with up to 1500 women randomised in a 1:1 ratio. Women with a negative endometrial biopsy (defined as <5 CD138 positive cells per 10 mm2) will also be followed up to test validity of the tool. The primary outcome is live births plus pregnancies ≥24 + 0 weeks gestation at the end of the trial, in the first or subsequent pregnancy. Secondary clinical outcomes will also be assessed. Exploratory outcomes will assess the effect of doxycycline treatment on the endometrial microbiota, the differentiation capacity of the endometrium and the senescent profile of the endometrium with CE. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the NHS Research Ethics Committee Northwest-Haydock (19/NW/0462). Written informed consent will be gained from all participants. The results will be published in an open-access peer-reviewed journal and reported in the National Institute for Health and Care Research journals library. TRIAL REGISTRATION NUMBER: ISRCTN23947730.

Predictive Models for Estimating the Probability of Successful Vaginal Birth After Cesarean Delivery: A Systematic Review.

OBJECTIVE: To systematically review all studies that developed or validated a vaginal birth after cesarean (VBAC) prediction model. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Library, and ClinicalTrials.gov were searched from inception until February 2022. METHODS OF STUDY SELECTION: We included observational studies that developed or validated a multivariable VBAC prediction model in women with a singleton pregnancy and one previous lower segment cesarean delivery. A total of 3,758 articles were identified and screened. TABULATION, INTEGRATION, AND RESULTS: For 57 included studies, data were extracted in duplicate using a CHARMS (Critical Appraisal and Data Extraction for Systematic Review of Prediction Modelling Studies) checklist-based tool and included participants' characteristics, sample size, predictors, timing of application, and performance. PROBAST (Prediction model Risk of Bias Assessment Tool) and TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis) were used to assess risk of bias and transparency of reporting. Several studies developed or validated more than one model. There were 38 unique prediction models, 42 external validations of 10 existing prediction models, and six modifications of existing models. Of the 38 unique models, only 19 (19/38, 50%) were internally validated in the initial study. No studies externally validated their model in the initial study. Age, previous vaginal birth, and previous cesarean delivery for labor dystocia were the commonest predictors. The area under the curve in included studies ranged from 0.61 to 0.95. Models used close to delivery generally outperformed those used earlier in pregnancy. Most studies demonstrated a high risk of bias (45/57, 79%), the remainder were unclear (7/57, 12%) and low (5/57, 9%). Median TRIPOD checklist adherence was 70% (range 32-93%). CONCLUSION: Several prediction models for VBAC success exist, but many lack external validation and are at high risk of bias. Models used close to delivery outperformed those used earlier in pregnancy; however, their generalizability and applicability remain unclear. High-quality external validation and effect studies are required to guide clinical use. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020190930.