Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

Standardising outcome reporting for clinical trials of interventions for heavy menstrual bleeding: Development of a core outcome set.

OBJECTIVE: To develop a core outcome set for heavy menstrual bleeding (HMB). DESIGN: Core outcome set (COS) development methodology described by the COMET initiative. SETTING: University hospital gynaecology department, online international survey and web-based international consensus meetings. POPULATION OR SAMPLE: An international collaboration of stakeholders (clinicians, patients, academics, guideline developers) from 20 countries and 6 continents. METHODS: Phase 1: Systematic review of previously reported outcomes to identify potential core outcomes. Phase 2: Qualitative studies with patients to identify outcomes most important to them. Phase 3: Online two-round Delphi survey to achieve consensus about which outcomes are most important. Phase 4: A consensus meeting to finalise the COS. MAIN OUTCOME MEASURES: Outcome importance was assessed in the Delphi survey on a 9-point scale. RESULTS: From the 'long list' of 114, 10 outcomes were included in the final COS: subjective blood loss; flooding; menstrual cycle metrics; severity of dysmenorrhoea; number of days with dysmenorrhoea; quality of life; adverse events; patient satisfaction; number of patients going on to have further treatment for HMB and haemoglobin level. CONCLUSIONS: The final COS includes variables that are feasible for use in clinical trials in all resource settings and apply to all known underlying causes of the symptom of HMB. These outcomes should be reported in all future trials of interventions, their systematic reviews, and clinical guidelines to underpin policy.

Evaluation of marketing authorization and clinical implementation of ulipristal acetate for uterine fibroids.

Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process.

Gynaecological management of women with inherited bleeding disorders. A UK Haemophilia Centres Doctors' Organisation Guideline.

Women with inherited bleeding disorders (IBDs) may present to healthcare professionals in a variety of ways and commonly will be encountered by either haematology or gynaecology services. Heavy menstrual bleeding is very often the first manifestation of an IBD. There is a wide variation in severity of bleeding for women with IBD and diagnosis and subsequent management of their condition requires multidisciplinary specialised care which is tailored to the individual and includes excellent cross-specialty communication between gynaecology and haematology teams. This guideline is intended for both haematologists and gynaecologists who are involved in the diagnosis and management of women with bleeding disorders. It sets out recommendations about how to investigate heavy menstrual bleeding (HMB), the commonest presentation for women with IBD to hospital services, to guide physicians about how to diagnose an IBD and covers the management of women with known IBD and HMB. The second section sets out recommendations for patients known to have IBD and covers management of patients with IBD in the setting of gynaecological surgery and management for all other non-surgical gynaecological situations.

International Consensus Statement for Recommended Terminology Describing Hysteroscopic Procedures.

OBJECTIVE: To develop a consensus statement of recommended terminology to use for describing different aspects of hysteroscopic procedures that can be uniformly used in clinical practice and research. DESIGN: Open forum discussion followed by online video meetings. SETTING: International community of hysteroscopy experts PATIENTS: Not applicable. INTERVENTIONS: Series of online video meetings to complete a previously established agenda until a final agreement for standardized nomenclature was obtained. MEASUREMENT AND MAIN RESULTS: The adoption and implementation of a common terminology to standardize reporting of hysteroscopic procedures was proposed to cover five domains: pain management, healthcare setting, model of care, type of hysteroscopic procedure and the hysteroscopic approach to the uterine cavity. A final agreement was obtained after 3 online video meetings. CONCLUSION: Hysteroscopy is the gold standard technique for the evaluation and management of uterine disorders. A clear definition and understanding of the terminology used to describe hysteroscopic procedures is lacking. The production of this international consensus statement for terminology to describe hysteroscopic procedures, covering pain management, setting, model of care, type of procedure and hysteroscopic approach, has the potential to enable more effective communication for both clinical and research purposes with the ultimate aim of improving patient care and clinical outcomes.

Pain and Operative Technologies Used in Office Hysteroscopy: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: To identify technologies associated with the least operative pain in women undergoing operative office hysteroscopic procedures. DATA SOURCES: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials were searched until January 2021 using a combination of keywords "hysteroscop*," "endometrial ablation," "outpatient," "ambulatory," "office," and associated Medical Subject Headings. METHODS OF STUDY SELECTION: Randomized controlled trials evaluating the effect of hysteroscopic devices on pain experienced by women undergoing operative office hysteroscopy were included. Data were also collected regarding efficacy, procedural time, adverse events, and patient/clinician acceptability and/or satisfaction. TABULATION, INTEGRATION, AND RESULTS: The search returned 5347 records. Ten studies provided data for review. Two trials compared endometrial ablation using bipolar radiofrequency with thermal balloon energy, with no significant difference in pain observed (p <.05). Seven trials evaluated technologies for endometrial polypectomy, of which, 4 compared energy modalities: miniature bipolar electrode resection against resectoscopy (N = 1), morcellation (N = 2), and diode laser resection (N = 1). Two studies compared hysteroscope diameter, and one study compared methods of polyp retrieval. A significant reduction in pain was found using morcellators rather than miniature bipolar electrosurgical devices (p <.001), 22Fr rather than 26Fr resectoscopes (p <.001), and 3.5-mm fiber-optic hysteroscopes with 7Fr forceps rather than 5-mm lens-based hysteroscopes with 5Fr forceps (p <.05). One study investigating septoplasty showed significant reduction in pain when cold mini-scissors, rather than a miniature bipolar electrode, were used (p = .013). Average procedural times ranged from 5 minutes 28 seconds to 22 minutes. The incidence of adverse events was low, and data regarding efficacy and acceptability/satisfaction were limited. CONCLUSION: Pain is reduced when mechanical technologies such as morcellators and scissors are used compared with electrical devices for removing structural lesions in the office. For hysteroscopic and ablative procedures, smaller and quicker devices are less painful. Large-scale RCTs investigating patient pain and experience with modern operative devices in the office setting are urgently needed.

Analgesia for Office Hysteroscopy: A Systematic Review and Meta-analysis.

OBJECTIVE: To identify the most effective analgesia for women undergoing office hysteroscopy. DATA SOURCES: We searched Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception until August 2019 for studies that investigated the effect of different analgesics on pain control in office hysteroscopy. METHODS OF STUDY SELECTION: We included randomized controlled trials that investigated the effect of analgesics on pain experienced by women undergoing diagnostic or operative hysteroscopy in an office setting compared with the control group. TABULATION, INTEGRATION, AND RESULTS: The literature search returned 561 records. Twenty-two studies were selected for a systematic review, of which 16 were suitable for meta-analysis. There was a statistically significant reduction in pain during office hysteroscopy associated with preprocedural administration of nonsteroidal anti-inflammatory drugs (NSAIDs) (standardized mean difference [SMD] -0.72; 95% confidence interval [CI] -1.27 to -0.16), opioids (SMD -0.50; 95% CI -0.97 to -0.03), and antispasmodics (SMD -1.48; 95% CI -1.82 to -1.13), as well as with the use of transcutaneous electrical nerve stimulation (TENS) (SMD -0.99; 95% CI -1.67 to -0.31), compared with the control group. Moreover, similar reduction in pain was observed after office hysteroscopy: NSAIDs (SMD -0.55; 95% CI -0.97 to -0.13), opioids (SMD -0.73; 95% CI -1.07 to -0.39), antispasmodics (SMD -1.02; 95% CI -1.34 to -0.69), and TENS (SMD -0.54; 95% CI -0.95 to -0.12). Significantly reduced pain scores with oral NSAID administration during (SMD -0.87; 95% CI -1.59 to -0.15) and after (SMD -0.56; 95% CI -1.02 to -0.10) office hysteroscopy were seen in contrast to other routes. Significantly more adverse effects were reported with the use of opioids (p <.001) and antispasmodics (p <.001) when compared with the control group, in contrast to NSAIDs (p = .97) and TENS (p = .63). CONCLUSION: Women without contraindications should be advised to take oral NSAIDs before undergoing office hysteroscopy to reduce pain during and after the procedure. TENS should be considered as an alternative analgesic in women with contraindications to NSAIDs.

A cross-sectional study on teaching pelvic examination in medical schools in the UK (the COTES study).

Gynaecological teaching associates (GTAs) appear to be effective in aiding medical students to acquire core skills in female pelvic examination (FPE). The aim was to explore the current provision for teaching and assessment of FPE in Obstetric and Gynaecological (O&G) placements across UK medical schools and in particular, the use of GTAs. An online survey was sent to undergraduate academic leads for O&G, representing 29 of the 30 UK medical schools. The response rate was 21/29 (72%). The average placement was 6.7 weeks and teaching of FPE varied including training on manikins (20/21, 95%), instruction in outpatient clinics (17/21, 81%) and instruction on anaesthetised patients (17/21, 81%). The survey revealed that anatomic pelvic models are combined with supervised instruction in outpatient clinics and operating theatres. GTAs are used by less than a third of medical schools, and where used are thought to enhance teaching in this core skill in contrast to those universities not using GTAs. Short placements, a reluctance to use GTAs and a lack of formal assessment may adversely impact upon the competency of newly qualifying medical students in FPE. Impact statement What is already known on this subject: Experience of female pelvic examination intimate is limited. Expert patients, known as Gynaecological Teaching Associates (GTAs), have been suggested as a potential solution to improve teaching of gynaecological examination, but the last survey of medical schools in the United Kingdom (UK) conducted in 1989 reported that only two were using GTAs in an average clinical placement length of 11.5 weeks. What the results of this study add: Twenty-five years after the last survey, Obstetrics and Gynaecology (O&G) clinical placements have been reduced to an average of 6 weeks with one-third requiring only an informal impression of competence in female pelvic examination. Despite published evidence since 1989 supporting the effectiveness of GTAs, just six medical schools are using GTAs for teaching and assessment with all believing them to be effective. What the implications are of these findings for clinical practice and/or further research: A combination of short placements, an apparent reluctance to use GTAs and a lack of uniform formal assessment may mean that the competency of newly qualifying medical students in basic gynaecological examination is compromised.

The feasibility, safety, and effectiveness of hysteroscopic sterilization compared with laparoscopic sterilization.

BACKGROUND: In contrast to conventional laparoscopic sterilization, newer hysteroscopic approaches avoid the need for hospital admission, general anesthesia, and prolonged recovery. However, there are concerns that the feasibility, safety, and efficacy of hysteroscopic sterilization may be lower than established laparoscopic sterilization. OBJECTIVE: We sought to evaluate the outcomes of hysteroscopic sterilization compared with laparoscopic sterilization in routine clinical practice in a comparative observational cohort study. STUDY DESIGN: This study was carried out at University of Birmingham, United Kingdom, National Health Service teaching hospital, office hysteroscopy clinics, and day-case hospital unit. In all, 1085 women underwent hysteroscopic sterilization and 2412 had laparoscopic sterilization. Hysteroscopic sterilization was carried out using the tubal implant permanent birth control system in the office setting and laparoscopic sterilization using the tubal ligation system as a day-case under general anesthesia. Outcome data were collected regarding feasibility (technical completion of the sterilization procedure, satisfactory radiological confirmation at 3 months-hysterosalpingogram or transvaginal pelvic ultrasound scan), safety events within 30 days of procedures, reoperations, and unintended pregnancies within 1 year of procedures. RESULTS: Hysteroscopic sterilization was successful in 992/1085 (91.4%; 95% confidence interval, 89.6-93.0%) at the first attempt. In comparison, bilateral tubal ligation was successfully performed in 2400/2412 (99.5%; 95% confidence interval, 99.2-99.8%) of patients who underwent laparoscopic sterilizations (odds ratio, 18.8; 95% confidence interval, 10.2-34.4). In all, 902/1085 (83.1%; 95% confidence interval, 80.8-85.2%) of successfully performed hysteroscopic procedures attended for radiological confirmation testing were considered satisfactory. The rate of adverse events within 30 days were similar: 2/1085 (0.2%) vs 3 (0.12%; 95% confidence interval, 0.04-0.36%). There were 3/1085 (0.3%; 95% confidence interval, 0.1-0.8%) unintended pregnancies after hysteroscopic sterilization compared with 5/2412 (0.2%; 95% confidence interval, 0.1-0.5%) laparoscopic sterilization (odds ratio, 1.3; 95% confidence interval, 0.3-5.6). Median length of follow-up for pregnancy outcome was 5 years. Hysteroscopic sterilization was associated with a higher risk of reoperation at 1 year compared to laparoscopic sterilization (odds ratio, 6.2; 95% confidence interval, 2.8-14.0) and the commonest reintervention was unilateral salpingectomy (12/22, 54.5%). CONCLUSION: Hysteroscopic sterilization has been introduced as a more convenient, office-based method of permanent fertility control. However, while the small risk of unintended pregnancy is comparable to conventional laparoscopic sterilization, women should also be counselled regarding its lower success rate in successfully completing the procedure and its higher rate of failed reoperation.

Three-dimensional saline infusion sonography compared to two-dimensional saline infusion sonography for the diagnosis of focal intracavitary lesions.

BACKGROUND: Focal abnormalities most commonly acquired within the uterine cavity include endometrial polyps (arising from the endometrium) and submucous fibroids (arising from the myometrium). These benign abnormalities can cause several problems, including abnormal uterine bleeding (AUB) and subfertility. Two-dimensional saline infusion sonography (2D SIS) is a minimally invasive test that can be used to diagnose these pathologies, but it is less accurate than hysteroscopy, which is a more invasive procedure by which an endoscope allows direct visualisation of the uterine cavity. Three-dimensional (3D) SIS appears to enhance sonographic visualisation within the uterine cavity, thereby offering a potentially more accurate minimally invasive diagnostic test. OBJECTIVES: Primary objectives • To evaluate the diagnostic accuracy of 3D SIS (index test 1) compared with 2D SIS for the diagnosis of focally growing lesions (presence or not) in women with AUB or subfertility, with hysteroscopy performed as the reference test. • To evaluate the diagnostic accuracy of 2D+3D SIS (index test 2) compared with 2D SIS for the diagnosis of focally growing lesions (presence or not) in women with AUB or subfertility, with hysteroscopy performed as the reference test. In this case, any abnormality on either modality was regarded as a positive result ('OR' approach). Secondary objectives • To evaluate the diagnostic accuracy of 3D SIS (index test 1) compared with 2D SIS according to type of abnormality and discrimination between uterine polyps and submucous fibroids in women with AUB or subfertility, with hysteroscopy and histology used as the reference.• To evaluate the diagnostic accuracy of 2D+3D SIS (index test 2) compared with 2D SIS according to type of abnormality and discrimination between uterine polyps and submucous fibroids in women with AUB or subfertility, with hysteroscopy and histology used as the reference. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PubMed, Cochrane Gynaecology and Fertility Group (CGF) Specialised Register and CGFG Diagnostic Test Accuracy (DTA) Specialised Register, clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Screening reference lists of appropriate studies was also performed. We screened for eligibility all studies identified from inception until March 2016. We performed searches with no date or language restrictions. SELECTION CRITERIA: The population of interest consisted of premenopausal women with AUB or subfertility and postmenopausal women with AUB. Diagnostic test accuracy studies, randomised controlled trials (RCTs) and prospective cohort studies were eligible for inclusion if they evaluated the accuracy of both 2D SIS and 3D SIS for the diagnosis of acquired intracavitary abnormalities with hysteroscopy used as the reference standard. In light of the lack of data for 3D SIS, we also included studies that evaluated the accuracy of 3D SIS alone. DATA COLLECTION AND ANALYSIS: Two review authors read all potentially eligible references after performing a first screening by title and abstract (LLN and FJRH). They independently extracted data to construct 2×2 tables from eligible studies and assessed studies for methodological quality using the QUADAS-2 tool (revised tool for quality assessment of diagnostic accuracy studies). To describe and visually present results, we produced in RevMan forest plots showing pairs of sensitivity and specificity together with 95% confidence intervals from each study, as well as raw receiver operating characteristic (ROC) plots. We displayed paired analyses in an ROC plot by linking sensitivity-specificity pairs from each study by using a dashed line. To compare 3D SIS versus 2D SIS, we restricted analyses to studies that provided 2×2 tables for both tests and used the bivariate meta-analysis of sensitivity and specificity. MAIN RESULTS: Thirteen studies (1053 women) reported the accuracy of 3D SIS for focal uterine abnormalities; 11 of these (846 women) were suitable for meta-analysis, and eight reported accuracy according to the type of focal abnormality. The design of the included studies seems applicable. The main problem involving the quality of included studies is insufficient reporting of study methods, resulting in unclear risk of bias for several of the quality domains assessed. Therefore, we considered the overall quality of the evidence as low. The summary estimate (11 studies reporting absence or presence of abnormality at 3D SIS) for sensitivity was 94.5% (95% confidence interval (CI) 90.6% to 96.9%) and for specificity 99.4% (95% CI 96.2% to 99.9%). Meta-analysis of the eight studies (N = 716) directly comparing 2D SIS versus 3D SIS showed summary sensitivity of 96.9% (95% CI 91.9% to 98.8%) and summary specificity of 99.5% (95% CI 96.1% to 100%) for 3D SIS. For 2D SIS, summary sensitivity was 90.9% (95% CI 81.2% to 95.8%) and summary specificity was 96.3% (95% CI 86.1% to 99.1%). The difference in accuracy between 2D SIS and 3D SIS was non-significant (P values of 0.07 for sensitivity and 0.10 for specificity). AUTHORS' CONCLUSIONS: Low-quality evidence suggests that 3D SIS may be very accurate in detecting intracavitary abnormalities. Meta-analysis revealed no statistically significant differences between 2D SIS and 3D SIS. Summary sensitivity and summary specificity are higher for 3D SIS, but margins of improvement are limited because 2D SIS is already very accurate. When the technology and appropriate expertise are available, 3D SIS offers an alternative to 2D SIS. Both 2D SIS and 3D SIS should be considered alternatives to diagnostic hysteroscopy when intracavitary pathology is suspected in subfertile women and in those with abnormal uterine bleeding.

The effectiveness of gynaecological teaching associates in teaching pelvic examination: a systematic review and meta-analysis.

CONTEXT: An increasing number of graduating students are unable to competently and confidently perform a pelvic examination. Gynaecology teaching associates (GTAs) teach technical and communication skills and offer immediate feedback. The objective was to perform a systematic literature review to assess whether teaching pelvic examinations using real women who are trained to give instructions on technique and feedback improves the competence, confidence and communication skills of trainees when compared with traditional teaching methods. METHODS: MEDLINE, EMBASE, the Cochrane Library, CINAHL and the ISRCTN Register of Clinical Trials were searched using selected terminology. No language restrictions were applied. The selection criteria were randomised clinical trials (RCTs) and controlled studies that investigated the use of GTAs to teach students or health-related professionals the pelvic examination. Data evaluating study outcomes, along with methodological details, were extracted in duplicate. The outcomes measured were: self-reported confidence, assessed competence and assessed communication skills. The standard mean difference (SMD) was derived for each study where possible and heterogeneity across studies was quantified using the I(2) statistic. In the presence of substantial variation, the data were pooled using a random effects model. RESULTS: Eleven studies with 856 participants were included: five RCTs and six observational studies. GTA training improved competence compared with other teaching methods and the finding of enhanced competence was consistent when the pooled analysis was restricted to RCTs. Communication skills were also improved with GTA teaching, but to a lesser degree, whereas no effect on student confidence was observed. Statistical heterogeneity was present for all outcomes when data were pooled. CONCLUSION: Our findings suggest that GTA-based teaching of pelvic examination is associated with improvement in the competence and communication skills of trainees. However, further larger-scale studies with standardised relevant educational outcomes are needed to confirm these findings.

Recurrent postmenopausal bleeding: a prospective cohort study.

STUDY OBJECTIVE: To estimate the prevalence of genital tract diseases in women with initial and recurrent postmenopausal bleeding (PMB) to help inform diagnostic pathways. DESIGN: Prospective cohort study (Canadian Task Force classification: II-2). SETTING: Large urban teaching hospital. PATIENTS: Of 1938 consecutive women with postmenopausal bleeding, 106 (5%) were investigated for a recurrent episode after having normal findings of previous investigations. INTERVENTIONS: All women underwent pelvic examination and ultrasound scanning. An endometrial biopsy was performed when endometrial thickness was >4 mm in women with a first episode of PMB, with recourse to outpatient hysteroscopy after correlation between clinical and pathologic findings. All women with a recurrent PMB episode underwent endometrial biopsy and outpatient hysteroscopy. MEASUREMENTS AND MAIN RESULTS: The risk of having endometrial cancer or hyperplasia with atypia was significantly less in women with recurrent PMB (9%) as compared with those with a first episode of PMB (8%) (p = .002), but were significantly more likely to have benign endometrial polyps (28%) compared with women with a first episode of PMB (19%) (relative risk, 1.47; 95% confidence interval, 1.07-2.02; p = .02). CONCLUSION: Recurrent PMB results in less likelihood of premalignant and malignant endometrial disease; however, in 1 of 4 women PMB is caused by endometrial polyps. First-line investigation in women with recurrent PMB should be tests that have high accuracy for enabling diagnosis of focal diseases, such as outpatient hysteroscopy or saline infusion sonography.

Surgical evacuation with intraoperative ultrasound (SEE U): A randomised controlled trial.

OBJECTIVES: To test whether intraoperative ultrasound can reduce the incidence of early and late complications following surgical removal of products of conception. DESIGN: This was a prospective, multicentre, randomised, open clinical trial to assess feasibility. It was performed in two University Teaching hospitals in the West Midlands, England. The population consisted of women aged 16 years or over who were referred for surgical management of miscarriage. Patients were randomised to surgical management of miscarriage with either continuous intraoperative ultrasound or without intraoperative ultrasound. Process outcomes included the proportion of eligible women screened and proportion of eligible women randomised, attrition rates, evaluation of outcome measurement tools and acceptability. The primary clinical outcome was a composite outcome of unsuccessful procedure or a complication. RESULTS: Fifty-nine women requiring surgical management of miscarriage were randomised. The conversion rate for entry into the trial was 59/79(75 %; 95 %CI = 64-84 %). The composite clinical outcome was attained in 5/27(19 %) patients who had surgery without ultrasound and 7/28(25 %) patients who had surgery with ultrasound (RR = 0.74;95 %CI = 0.26, 2.10). When we excluded the patients that could not attend their hysteroscopy appointment, due to COVID-19 pandemic, 5/27(19 %) of patients who had surgery without ultrasound and 5/25(20 %) of patients who had surgery with ultrasound attained the composite clinical outcome (RR = 0.93;95 %CI = 0.30, 2.90). CONCLUSIONS: This multicentre pilot study showed that a large RCT comparing surgical management of miscarriage with and without intraoperative ultrasound is feasible.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Laparoscopic removal of Essure device techniques, perioperative findings and evaluation of patient's satisfaction: A case series.

OBJECTIVE: To evaluate perioperative outcomes and symptom resolution in women undergoing Essure removal. METHODS: Single centre cohort study at a large University Teaching Hospital in the UK. Symptoms and Quality of life (QoL) were assessed using a standardised questionnaire administered at 6-months and up to 10-years following removal of Essure® devices. RESULTS: 61 women underwent surgical removal of Essure® devices representing 61/1087 (5.6%) of all women undergoing this hysteroscopic form of sterilization. Patients who had Essure® removal were more likely to have a previous caesarean section [38% vs 18%; OR 0.4, 95% CI 0.2-0.6; P <0.001]. The main indication for removal was pelvic pain (49/61, 80%). Removal was achieved by laparoscopic bilateral salpingectomy/cornuectomy (44/61,71%) or hysterectomy (17/61, 28%). At surgery, perforated device was seen in 4/61 (7%) cases. 26/61 (43%) of patients had concomitant pelvic pathology; 12/26 (46%) had fibrous adhesions, 8/26 (31%) endometriosis, 4/26 (15%) adenomyosis, and 2/26 (8%) had endometriosis and adenomyosis. 10 patients underwent further procedure following removal for ongoing symptoms. 55/61 women (90%) responded to the post removal symptom questionnaire. Most respondents to the quality of life survey 42/55 (76%) reported total or some improvement. 42/53 (79%) had total or some improvement in pelvic pain, 9/13 (69%) in mental health and 10/12 (83%) in bleeding. CONCLUSION: Surgical removal of Essure® devices appears to improve symptoms thought to be attributable to the presence of these uterine implants in most women. However, patients should be counselled that one in five women may experience persistent or even worsening symptoms.

LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial.

BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial.

Background: Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods: This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings: Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation: Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding: UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).