Tom K. Holland

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.

Background: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. Objectives: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. Design: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. Setting: A total of 48 hospitals in the UK. Participants: Women aged 16–39 years with early pregnancy bleeding. Interventions: Women aged 16–39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. Main outcome measures: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. Results: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. Trial registration: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

(Abstracted from N Engl J Med 2019;380:1815–1824) The hormone progesterone plays a critical role in preparing the endometrium for implantation of the embryo and continues to be produced throughout pregnancy. Historically, progesterone supplementation has been initiated during early pregnancies to prevent miscarriages in asymptomatic women who have a history of recurrent miscarriages or to rescue a pregnancy in women who have started to bleed during early pregnancy.

Laparoscopic surgery is progressing rapidly is becoming the normal route for many abdominal operations, even for major complex surgery. The integrated laparoscopic theatre is a state-of-the-art system in which the laparoscopic equipment and multiple flat-screen monitors are permanently installed to be operational on demand inside the theatre. These expensive systems are being widely adopted, however very little research has been published regarding which features of these systems are desired by the surgeons who use them. The study objective was to assess the strength of preference for key attributes of integrated laparoscopic theatres and to compare these preferences between Gynaecologists and General surgeons. This was an electronically distributed discrete choice experiment survey of British practicing Laparoscopic Gynaecologists and General Surgeons (Through The British Society of Gynaecology Endoscopy and The Association of Laparoscopic Surgeons of Great Britain and Ireland). An electronic survey was designed and pre-tested. This was then sent to practicing British Laparoscopic Gynaecologists and General-Surgeons. There were structured questions regarding the seven key attributes of integrated laparoscopic theatres in the standard form for a discrete choice experiment. Questionnaires from 167 respondents were analysed. One hundred three were gynaecologists and 64 were general-surgeons. Adjustable screens for height and position was the most favoured attribute and it is 4.7 times more desirable than the next most desirable attribute, which was a wire free floor. The least desirable features were piped CO2, ceiling-mounted-screens and external-transmission-of-images. Both groups favour adjustable screens for position and height above all the other features. These findings are in contrast with previous research, which showed that when asked to rank the attributes in order, gynaecologists chose ceiling mounted screens first and adjustable screens fourth. When asked to “trade off” attributes in the discrete choice experiment the adjustability of the screens became much more important than how the screens were mounted. With new wireless technology the benefits of a fully integrated theatre could be delivered with floor mounted systems at a considerably reduced cost. This information is important to manufacturers and purchasers of these systems in order to design cost effective ergonomic theatres that are fit for purpose.

The Wilcoxon-Mann-Witney test is extended to account for a second independent factor. The new test statistic’s probability mass function and normal approximation are derived. Critical-values for balanced, unbalanced and large sample designs are given. The immediate extension of this method to a wide range of non-parametric tests is explained.

STUDY QUESTION Is there any benefit to including the routine examination by ultrasound of the bladder, ureters and kidneys of women with endometriosis? SUMMARY ANSWER The benefit of examination of the complete urinary tract of women with suspected endometriosis is that ureteric endometriosis, with or without hydronephrosis, can be detected which facilitates early intervention to prevent nephropathy. WHAT IS ALREADY KNOWN Women with endometriosis can get ureteric obstruction but there is no clear consensus on the correct diagnostic technique. Ultrasound is accurate at detecting women with bladder endometriosis but ureteric involvement has not been assessed previously. STUDY DESIGN, SIZE, DURATION This was a prospective observational study, conducted at a teaching hospital over a period of 14 months. A total of 848 women presenting with chronic pelvic pain were included into the study. PARTICIPANTS/MATERIALS, SETTING, METHODS All women with chronic pelvic pain underwent a detailed transvaginal and transabdominal pelvic ultrasound examination to investigate possible causes of their symptoms. This included a systematic assessment of the urinary bladder, pelvic sections of the ureters and kidneys. The ultrasound findings were compared with findings at surgery and the results of targeted urological imaging and interventions. MAIN RESULTS AND THE ROLE OF CHANCE A total of 848 women presenting with chronic pelvic pain were included into the study. 28/848 women (3.3% 95% CI 2.1–4.5) had evidence of urinary tract abnormalities on initial ultrasound scan. Among these 17/848 (2.0% 95% CI 1.06–2.94) had evidence of urinary tract endometriosis, whilst 11/848 (1.3% 95% CI 0.54–2.06) women had other urinary tract abnormalities. Among women with urinary tract endometriosis 11/17 (65%) had evidence of ureteric involvement, 3/17 (18%) had both ureteric and bladder disease and 3/17 (18%) had bladder disease only. 12/17 (59%) women with urinary tract endometriosis also had evidence of hydronephrosis. The diagnosis of ureteral endometriosis had a sensitivity of 12/13 (92%) (95% CI 63.9–99.8), specificity 151/151 100% (95% CI 97.6–100), PPV 100% (95% CI 73.5–100), NPV 99.3% (95% CI 96.3–99.9%) LR− 0.08 (95% CI 0.01–0.39). LIMITATIONS, REASONS FOR CAUTION The routine examination of the complete urinary tract including the distal ureters is a novel technique that should be evaluated in different populations. WIDER IMPLICATIONS OF THE FINDINGS Ultrasound is an accurate test to diagnose urinary tract involvement in women with suspected pelvic endometriosis and examination of the complete urinary tract should become an integral part of ultrasound assessment of women with suspected endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The authors have no competing interests. The study was not supported by an external grant.

Endometriosis is a common condition which causes pain and reduced fertility. Treatment can be difficult, especially for severe disease, and an accurate preoperative assessment would greatly help in the managment of these patients. The objective of this study is to assess the accuracy of pre-operative transvaginal ultrasound scanning (TVS) in identifying the specific features of pelvic endometriosis and pelvic adhesions in comparison with laparoscopy.