Preventing recurrence of endometriosis-related pain by means of long-acting progestogen therapy: the PRE-EMPT RCT.

Background: Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. Objectives: To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Design: A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women's lived experience of endometriosis and a pretrial economic model. Setting: Thirty-four United Kingdom hospitals. Participants: Women of reproductive age undergoing conservative surgery for endometriosis. Interventions: Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). Main outcome measures: The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Results: Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: -0.8, 95% confidence interval -5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval -0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations: Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. Conclusions: At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future work: Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Trial registration: This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word 'woman' is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary.

Endometriosis is a condition where cells similar to ones that line the womb are found elsewhere in the body. Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Unfortunately, symptoms often return and some women will need repeat operations. Hormonal contraceptives can prevent the return of endometriosis-related pain: either long-acting reversible contraceptives (injections or a coil, fitted inside the womb) or the combined oral contraceptive pill (often called 'the pill'). We do not know which is the best option. The aim of this trial was to find out which of these two hormone treatments was more effective in terms of symptom relief, avoidance of further surgery and costs. Four hundred and five women with endometriosis, who were not intending to get pregnant, participated in a clinical trial. Half of the participants took long-acting reversible contraceptives, and the other half took the pill for 3 years following endometriosis surgery. The choice of treatment was made at random by a computer to ensure a fair comparison, although those allocated to the long-acting contraceptive could choose between injections or the coil. Participants completed questionnaires about their symptoms and life quality at intervals up to 3 years. Both treatments were equally good at reducing pain but more women using the pill had repeat operations. The pill was a little more costly overall but associated with a slightly higher quality of life. Both treatments are equally effective in reducing pain up to 3 years after surgery for endometriosis. The differences in costs are small and the choice of treatment should be based on personal preference.

Inhaled methoxyflurane (Penthrox®) as a novel pain relief for outpatient hysteroscopy and other gynaecological procedures.

OBJECTIVE: Penthrox® (methoxyflurane) is a convenient, portable, self-administered disposable single-use handheld inhaler licenced as an emergency, rapid-onset, short-acting, analgesic in adult trauma patients. Outpatient hysteroscopy is one of the commonest procedures in contemporary gynecology but it can be associated with significant pain leading to poor patient experience and failed procedures. We evaluated the feasibility and acceptability of Penthrox® in women undergoing outpatient hysteroscopic procedures and its potential efficacy to reduce pain and improve patient experience. STUDY DESIGN: We conducted a prospective observational cohort study on women undergoing hysteroscopy or other intrauterine procedures, such as coil fitting, endometrial biopsy, polypectomy, endometrial ablation and manual vacuum aspiration in an outpatient setting. Women were offered Penthrox® inhalers for pain control, instructed how to use it and asked to record the intra-procedural pain they expected and actually experienced using a 10 cm Visual Analogue Scale. The acceptability, side effects and ease of use of the Penthrox® device were also recorded. RESULTS: 122/146 (83.6 %) women chose to use Penthrox®. 116 out of the 122 (95.1 %) underwent an intrauterine procedure, including 59 hysteroscopic polypectomies and 34 global endometrial ablations. The average pain expected during the procedure was 6.0 (SD = 2.8) and the pain experienced during the procedure was 5.1 (SD = 2.8). The intended procedure was completed in 117 (96 %) women. Penthrox® was considered easy to use by 118 (97 %) women and 111 (91 %) would use it again, although 22 (18 %) women would prefer general anaesthesia in the future. No adverse events occurred but 88 (72 %) women reported mild, self-limiting side effects. CONCLUSION: Penthrox® appears safe, feasible and acceptable as a pain relief option during outpatient hysteroscopy and other intrauterine procedures. The effectiveness of Penthrox® should be evaluated against conventional pain control in an adequately powered multicentre randomised controlled trial.

Outpatient Hysteroscopy: (Green-top Guideline no. 59).

All gynaecology departments should provide a dedicated outpatient hysteroscopy service to aid care of women and people with abnormal uterine bleeding, reproductive problems, and insertion/retrieval of intrauterine devices. [Grade A] Written information should be provided to the woman prior to their appointment. This should include details about the procedure, the benefits and risks, advice regarding pre-operative analgesia, as well as alternative options for care and contact details for the hysteroscopy unit. [Good Practice Point] Women should be made aware of other settings and modes of anaesthesia for hysteroscopy (e.g. under general or regional anaesthesia or intravenous sedation). [GPP] The woman should be advised that if they find the procedure too painful or distressing at any point, they must alert the clinical team who will stop the procedure immediately. The clinical team should alert the hysteroscopist if the woman appears to be in too much pain or is experiencing a vasovagal episode and therefore unable to voice the concerns so that the procedure can be stopped. [GPP] Women should be advised to take standard doses of oral non-steroidal anti-inflammatory agents (NSAIDs) one hour before their scheduled appointment. Vaginoscopy should be the standard technique for outpatient hysteroscopy unless the use of a vaginal speculum is required (e.g. for administering local cervical anaesthesia or dilating the cervix). [Grade A] When performing operative hysteroscopy, the smallest diameter hysteroscope should be used, with consideration given to the use of hysteroscopes with expandable outer working channels because they are associated with less pain. [Grade B] Mechanical hysteroscopic tissue removal systems should be preferred over miniature bipolar electrodes to remove endometrial polyps. [Grade A] Local anaesthesia should not be routinely administered prior to outpatient hysteroscopy where a vaginoscopic approach is used. It should be considered where use of a vaginal speculum is planned e.g. for cervical dilatation if anticipated, due to either cervical stenosis and/or the utilisation of larger-diameter hysteroscopes (≥5mm outer diameter). [Grade A] Saline should be instilled at the lowest possible pressure to achieve a satisfactory view. [Grade A] Conscious sedation should not be routinely used in outpatient hysteroscopic procedures. [Grade B].

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.

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.

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.

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).

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.

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.

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.

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.

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.

Conscious sedation for office hysteroscopy: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the role of conscious sedation on pain control in office hysteroscopy. METHODS: MEDLINE, EMBASE, CINAHL and CENTRAL were searched from inception to the 30th October 2020 in order to perform a systematic review and meta-analysis of all randomized controlled trials investigating women undergoing office hysteroscopic procedures, allocated to either conscious sedation or a suitable comparator, where the outcome was pain. Data regarding adverse events, feasibility and satisfaction/acceptability were also collected. The Risk of Bias 2 tool was used to assess study quality. Standard mean differences (SMD) or Odds Ratios (OR), and their 95% confidence intervals (CIs) were calculated for continuous (e.g. mean pain) and dichotomous (e.g. side-effects) outcomes, respectively. RESULTS: The literature search returned 339 results, of which seven studies were included for systematic review, with five studies having data suitable for meta-analysis. Intravenous conscious sedation, when compared with local anesthesia, reduced pain during (SMD -0.26, 95% CI -0.51 to -0.01), but not after (SMD -0.18, 95% CI -0.43 to 0.07) office hysteroscopy. No significant difference in side-effects were noted (OR 15.58, 95% CI 0.08 to 2891.91). Intravenous conscious sedation, when compared to an oral analgesic and antispasmodic, was associated with increased pain, both during (SMD 1.03, 95% CI 0.56 to 1.49) and after (SMD 0.49, 95% CI 0.04 to 0.93) hysteroscopy and had significantly more side-effects (OR 134.33, 95% CI 16.14 to 1118.17). Inhalational conscious sedation (70% N2O/30% O2), when compared to oral analgesia and anxiolysis, showed the greatest reduction in pain during hysteroscopy (SMD -1.04, 95% CI -1.57 to -0.52), however side-effects were not reported. Whilst patients and hysteroscopists were more satisfied with deeper levels of sedation, resulting side-effects, such as delirium, increased the level of post-procedural attention required, leading to a significantly lower level of satisfaction amongst nursing staff. CONCLUSION: The routine use of conscious sedation in contemporary hysteroscopic practice should be avoided in the absence of any clear reduction in pain and a higher risk of side-effects.

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.

COVID-19 in Women's health reducing the risk of infection to patients and staff during acute and elective hospital admission for gynaecological surgery.

The novel coronavirus SARS-Cov-2 has changed healthcare on a worldwide scale. This highly contagious respiratory virus has overwhelmed healthcare systems. Many staff were redeployed, and there was widespread cessation of non-urgent outpatient clinics and surgery. Outpatient clinics and theatre areas were converted to COVID-19 wards and intensive care units. Following the first peak, services began to recommence with new triaging and prioritisation guidance to safeguard patients and staff. Different countries and healthcare systems produced differing guidance and, in particular, variation in the best approach to continuing acute and elective surgical procedures. This chapter collates and evaluates the increasing international literature concerning the surgical management of gynaecological conditions during the pandemic, such that clear inferences, recommendations and guidance can be generated to aid clinical practice and safeguard against further major disruption arising from further COVID-19 peaks. The available data are assessed within the context of the current phase of the COVID-19 pandemic.