Procedural sedation and analgesia versus general anesthesia for hysteroscopic myomectomy (PROSECCO trial): A multicenter randomized controlled trial.

BACKGROUND: Hysteroscopic resection is the first-choice treatment for symptomatic type 0 and 1 fibroids. Traditionally, this was performed under general anesthesia. Over the last decade, surgical procedures are increasingly being performed in an outpatient setting under procedural sedation and analgesia. However, studies evaluating safety and effectiveness of hysteroscopic myomectomy under procedural sedation are lacking. This study aims to investigate whether hysteroscopic myomectomy under procedural sedation and analgesia with propofol is noninferior to hysteroscopic myomectomy under general anesthesia. METHODS AND FINDINGS: This was a multicenter, randomized controlled noninferiority trial conducted in 14 university and teaching hospitals in the Netherlands between 2016 and 2021. Inclusion criteria were age ≥18 years, maximum number of 3 type 0 or 1 fibroids, maximum fibroid diameter 3.5 cm, American Society of Anesthesiologists class 1 or 2, and having sufficient knowledge of the Dutch or English language. Women with clotting disorders or with severe anemia (Hb < 5.0 mmol/L) were excluded. Women were randomized using block randomization with variable block sizes of 2, 4, and 6, between hysteroscopic myomectomy under procedural sedation and analgesia (PSA) with propofol or under general anesthesia (GA). Primary outcome was the percentage of complete resections, assessed on transvaginal ultrasonography 6 weeks postoperatively by a sonographer blinded for the treatment arm and surgical outcome. Secondary outcomes were the surgeon's judgment of completeness of procedure, menstrual blood loss, uterine fibroid related and general quality of life, pain, recovery, hospitalization, complications, and surgical reinterventions. Follow-up period was 1 year. The risk difference between both treatment arms was estimated, and a Farrington-Manning test was used to determine the p-value for noninferiority (noninferiority margin 7.5% of incomplete resections). Data were analyzed according to the intention-to-treat principle, including a per-protocol analysis for the primary outcome. A total of 209 women participated in the study and underwent hysteroscopic myomectomy with PSA (n = 106) or GA (n = 103). Mean age was 45.1 [SD 6.4] years in the PSA group versus 45.0 [7.7] years in the GA group. For 98/106 women in the PSA group and 89/103 women in the GA group, data were available for analysis of the primary outcome. Hysteroscopic resection was complete in 86/98 women (87.8%) in the PSA group and 79/89 women (88.8%) in the GA group (risk difference -1.01%; 95% confidence interval (CI) -10.36 to 8.34; noninferiority, P = 0.09). No serious anesthesiologic complications occurred, and conversion from PSA to GA was not required. During the follow-up period, 15 serious adverse events occurred (overnight admissions). All were unrelated to the intervention studied. Main limitations were the choice of primary outcome and the fact that our study proved to be underpowered. CONCLUSIONS: Noninferiority of PSA for completeness of resection was not shown, though there were no significant differences in clinical outcomes and quality of life. In this study, hysteroscopic myomectomy for type 0 and 1 fibroids with PSA compared to GA was safe and led to shorter hospitalization. These results can be used for counseling patients by gynecologists and anesthesiologists. Based on these findings, we suggest that hysteroscopic myomectomies can be performed under PSA in an outpatient setting. TRIAL REGISTRATION: The study was registered prospectively in the Dutch Trial Register (NTR 5357; registration date: 11 August 2015; Date of initial participant enrollment: 18 February 2016).

Cancer worry among BRCA1/2 pathogenic variant carriers choosing surgery to prevent tubal/ovarian cancer: course over time and associated factors.

OBJECTIVE: High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. METHODS: Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis. RESULTS: Of all 577 BRCA1/2-PV carriers, 320 (57%) had high (≥ 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis. CONCLUSIONS: Some degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support. CLINICAL TRIAL REGISTRATION: The TUBA-study is registered at ClinicalTrials.gov since December 11th, 2014. Registration number: NCT02321228.

Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy.

OBJECTIVE: Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study (NCT02321228), BRCA1/2-PV carriers are offered a choice: the standard strategy of risk-reducing salpingo-oophorectomy or the novel strategy of risk-reducing salpingectomy with delayed oophorectomy. We evaluated feasibility and effectiveness of a patient decision aid for this choice. METHODS: Premenopausal BRCA1/2-PV carriers were counselled for risk-reducing surgical options in the TUBA-study; the first cohort was counselled without and the second cohort with decision aid. Evaluation was performed using digital questionnaires for participating women and their healthcare professionals. Outcome measures included actual choice, feasibility (usage and experiences) and effectiveness (knowledge, cancer worry, decisional conflict, decisional regret and self-estimated influence on decision). RESULTS: 283 women were counselled without and 282 women with decision aid. The novel strategy was chosen less frequently in women without compared with women with decision aid (67% vs 78%, p = 0.004). The decision aid was graded with an 8 out of 10 by both women and professionals, and 78% of the women would recommend this decision aid to others. Users of the decision aid reported increased knowledge about the options and increased insight in personal values. Knowledge on cancer risk, decisional conflict, decisional regret and cancer worry were similar in both cohorts. CONCLUSIONS: The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly appreciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy.

Levonorgestrel-releasing intrauterine system versus endometrial ablation for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding affects the physical functioning and social well-being of many women. The levonorgestrel-releasing intrauterine system and endometrial ablation are 2 frequently applied treatments in women with heavy menstrual bleeding. OBJECTIVE: This study aimed to compare the effectiveness of the levonorgestrel-releasing intrauterine system with endometrial ablation in women with heavy menstrual bleeding. STUDY DESIGN: This multicenter, randomized controlled, noninferiority trial was performed in 26 hospitals and in a network of general practices in the Netherlands. Women with heavy menstrual bleeding, aged 34 years and older, without a pregnancy wish or intracavitary pathology were randomly allocated to treatment with either the levonorgestrel-releasing intrauterine system (Mirena) or endometrial ablation, performed with a bipolar radiofrequency device (NovaSure). The primary outcome was blood loss at 24 months, measured with a Pictorial Blood Loss Assessment Chart score. Secondary outcomes included reintervention rates, patient satisfaction, quality of life, and sexual function. RESULTS: We registered 645 women as eligible, of whom 270 women provided informed consent. Of these, 132 women were allocated to the levonorgestrel-releasing intrauterine system (baseline Pictorial Blood Loss Assessment Chart score, 616) and 138 women to endometrial ablation (baseline Pictorial Blood Loss Assessment Chart score, 630). At 24 months, mean Pictorial Blood Loss Assessment Chart scores were 64.8 in the levonorgestrel-releasing intrauterine system group and 14.2 in the endometrial ablation group (difference, 50.5 points; 95% confidence interval, 4.3-96.7; noninferiority, P=.87 [25 Pictorial Blood Loss Assessment Chart point margin]). Compared with 14 women (10%) in the endometrial ablation group, 34 women (27%) underwent a surgical reintervention in the levonorgestrel-releasing intrauterine system group (relative risk, 2.64; 95% confidence interval, 1.49-4.68). There was no significant difference in patient satisfaction and quality of life between the groups. CONCLUSION: Both the levonorgestrel-releasing intrauterine system and endometrial ablation strategies lead to a large decrease in menstrual blood loss in women with heavy menstrual bleeding, with comparable quality of life scores after treatment. Nevertheless, there was a significant difference in menstrual blood loss in favor of endometrial ablation, and we could not demonstrate noninferiority of starting with the levonorgestrel-releasing intrauterine system. Women who start with the levonorgestrel-releasing intrauterine system, a reversible and less invasive treatment, are at an increased risk of needing additional treatment compared with women who start with endometrial ablation. The results of this study will enable physicians to provide women with heavy menstrual bleeding with the evidence to make a well-informed decision between the 2 treatments.

Diagnostic criteria for retained products of conception-A scoping review.

INTRODUCTION: Numerous studies have been performed assessing optimal treatment regimens for evacuating (retained) products of conception from the uterus, but standardized criteria for diagnosing retained products of conception (RPOC) are still lacking. We aim to provide an overview of diagnostic criteria in current literature, used to diagnose RPOC after induced first-trimester abortion or early pregnancy loss. MATERIAL AND METHODS: Pubmed, EMBASE, and the Cochrane library were searched systematically up until March 2020 for English articles reporting on induced abortion or early pregnancy loss. Articles not specifying diagnostic criteria used to assess completeness of treatment were excluded, as were conference abstracts, expert opinions, reviews, and case reports. Four elements of diagnostic criteria were described: diagnostic tools, parameters used within these tools, applied cut-off values, and timing of follow up. Additionally, a meta-analysis was performed assessing diagnostic qualities of the most often applied diagnostic tool and parameter. RESULTS: The search strategy yielded 1233 unique articles, of which 248 were included, with a total of 339 517 participants. In the 79 included randomized controlled trials, six diagnostic tools to assess RPOC were identified, combined in 14 ways, with 55 different cut-off values. In 169 observational studies, seven diagnostic tools were identified, used in 28 combinations, applying 89 different cut-off values. Transvaginal ultrasonographic measurement of endometrial thickness with a cut-off value of at least 15 mm indicating RPOC, was used most frequently. In the timing of follow-up there was great variation, with 55 and 107 different combinations in randomized controlled trials and observational studies, respectively. Assessment of treatment success was scheduled most often around 2 weeks after treatment. Diagnostic qualities of endometrial thickness of 15 mm or more was not adequately assessed. CONCLUSIONS: There is wide variation in the way RPOC are assessed, and the criteria used to define RPOC following induced abortion and early pregnancy loss; ultrasonographic measurement of endometrial thickness, with a cut-off of 15 mm or more 2 weeks after primary treatment is the most widely used diagnostic approach. A meta-analysis on diagnostic accuracy of endometrial thickness of 15 mm or more did not lead to solid results. These findings can be a first step to develop a workable standard of establishing RPOC after induced abortion or early pregnancy loss.

Mifepristone and misoprostol versus misoprostol alone for uterine evacuation after early pregnancy failure: study protocol for a randomized double blinded placebo-controlled comparison (Triple M Trial).

BACKGROUND: Early pregnancy failure (EPF) is a common complication of pregnancy. If women do not abort spontaneously, they will undergo medical or surgical treatment in order to remove the products of conception from the uterus. Curettage, although highly effective, is associated with a risk of complications; medical treatment with misoprostol is a safe and less expensive alternative. Unfortunately, after 1 week of expectant management in case of EPF, medical treatment with misoprostol has a complete evacuation rate of approximately 50%. Misoprostol treatment results may be improved by pre-treatment with mifepristone; its effectiveness has already been proven for other indications of pregnancy termination. This study will test the hypothesis that, in EPF, the sequential combination of mifepristone with misoprostol is superior to the use of misoprostol alone in terms of complete evacuation (primary outcome), patient satisfaction, complications, side effects and costs (secondary outcomes). METHODS: The trial will be performed multi-centred, prospectively, two-armed, randomised, double-blinded and placebo-controlled. Women with confirmed EPF by ultrasonography (6-14 weeks), managed expectantly for at least 1 week, can be included and randomised to pre-treatment with oral mifepristone (600 mg) or oral placebo (identical in appearance). Randomisation will take place after receiving written consent to participate. In both arms pre-treatment will be followed by oral misoprostol, which will start 36-48 h later consisting of two doses 400 µg (4 hrs apart), repeated after 24 h if no tissue is lost. Four hundred sixty-four women will be randomised in a 1:1 ratio, stratified by centre. Ultrasonography 2 weeks after treatment will determine short term treatment effect. When the gestational sac is expulsed, expectant management is advised until 6 weeks after treatment when the definitive primary endpoint, complete or incomplete evacuation, will be determined. A sonographic endometrial thickness < 15 mm using only the allocated therapy by randomisation is considered as successful treatment. Secondary outcome measures (patient satisfaction, complications, side effects and costs) will be registered using a case report form, patient diary and validated questionnaires (Short Form 36, EuroQol-VAS, Client Satisfaction Questionnaire, iMTA Productivity Cost Questionnaire). DISCUSSION: This trial will answer the question if, in case of EPF, after at least 1 week of expectant management, sequential treatment with mifepristone and misoprostol is more effective than misoprostol alone to achieve complete evacuation of the products of conception. TRIAL REGISTRATION: Clinicaltrials.gov (d.d. 02-07-2017): NCT03212352. Trialregister.nl (d.d. 03-07-2017): NTR6550. EudraCT number (d.d. 07-08-2017): 2017-002694-19. File number Commisie Mensgebonden Onderzoek (d.d. 07-08-2017): NL 62449.091.17.

The (cost) effectiveness of procedural sedation and analgesia versus general anaesthesia for hysteroscopic myomectomy, a multicentre randomised controlled trial: PROSECCO trial, a study protocol.

BACKGROUND: In women with abnormal uterine bleeding, fibroids are a frequent finding. In case of heavy menstrual bleeding and presence of submucosal type 0-1 fibroids, hysteroscopic resection is the treatment of first choice, as removal of these fibroids is highly effective. Hysteroscopic myomectomy is currently usually performed in the operating theatre. A considerable reduction in costs and a higher patient satisfaction are expected when procedural sedation and analgesia with propofol (PSA) in an outpatient setting is applied. However, both safety and effectiveness - including the necessity for re-intervention due to incomplete resection - have not yet been evaluated. METHODS: This study is a multicentre randomised controlled trial with a non-inferiority design and will be performed in the Netherlands. Women > 18 years with a maximum of 3 symptomatic type 0 or 1 submucosal fibroids with a maximum diameter of 3.5 cm are eligible to participate in the trial. After informed consent, 205 women will be randomised to either hysteroscopic myomectomy using procedural sedation and analgesia with propofol in an outpatient setting or hysteroscopic myomectomy using general anaesthesia in a clinical setting in the operating theatre. Primary outcome will be the percentage of complete resections, based on transvaginal ultrasonography 6 weeks postoperatively. Secondary outcomes are cost effectiveness, menstrual blood loss (Pictorial blood assessment chart), quality of life, pain, return to daily activities/work, hospitalization, (post) operative complications and re-interventions. Women will be followed up to one year after hysteroscopic myomectomy. DISCUSSION: This study may demonstrate comparable effectiveness of hysteroscopic myomectomy under procedural sedation and analgesia versus general anaesthesia in a safe and patient friendly environment, whilst achieving a significant cost reduction. TRIAL REGISTRATION: Dutch trial register, number NTR5357 . Registered 11th of August 2015.

Current and future expectations of mifepristone treatment in early pregnancy failure: a survey among Dutch gynaecologists.

To investigate the current and future addition of mifepristone to misoprostol treatment in case of early pregnancy failure (EPF), a digital questionnaire was distributed to a representative sample of all Dutch hospitals (25/79). In non-teaching centres, the presence of a local protocol was significantly lower compared to academic and teaching hospitals (p=.012). If a local protocol was present, the first choice of treatment was medical in 54.5%. Four respondents (16%) always prescribed mifepristone in case of EPF. The most common reason not prescribing mifepristone was the lack of sufficient scientific evidence. An average increase in success rate of 21.7% was desired to prescribe mifepristone in the future for EPF. Completeness of evacuation of products of conception from the uterus was usually assessed after 1 week by ultrasonography combined with clinical signs. If a complete evacuation was not achieved by the initial medical treatment, expectant management was proposed just as often as surgical intervention. Impact Statement What is already known on this subject? In case of early pregnancy failure (EPF), women can choose from both expectant medical (misoprostol, whether or not combined with mifepristone) and surgical (D and C) treatment. In The Netherlands, a national guideline concerning the treatment of EPF is still lacking. A questionnaire performed by Verschoor et al. ( 2014 ) showed there was a large practice variety between Dutch clinics. What the results of this study add? In this study, a representative sample of all Dutch clinics received a questionnaire about the treatment of EPF. The results confirm a large practice variation regarding treatment of EPF. The first choice of treatment, the medical treatment regimen, and the assessment of whether or not the treatment have been variations of successful between clinics. With regards to the addition of mifepristone to the medical treatment regime with misoprostol, gynaecologists are willing to consider mifepristone if an improvement of efficacy of approximately 20% is scientifically proven. What the implications are of these findings for clinical practice and/or further research? In our opinion, these results emphasise the need for a national guideline concerning the treatment of EPF. Our results also demonstrate that, if the addition of mifepristone to medical treatment with misoprostol proves to be more efficient than misoprostol alone, gynaecologists are willing to prescribe mifepristone in the future. Whether the addition is indeed more effective than misoprostol alone, will be the subject of a multicentre, double-blind, placebo-controlled randomised controlled trial, planned to begin in the first half of 2018.

The effects of laparoscopic graspers with enhanced haptic feedback on applied forces: a randomized comparison with conventional graspers.

BACKGROUND: Haptic feedback, which enables surgeons to perceive information on interaction forces between instrument and tissue, is deficient in laparoscopic surgery. This information, however, is essential for accurate tissue manipulation and recognition of tissue consistencies. To this end, a laparoscopic grasper with enhanced haptic feedback has been developed: the force reflecting operation instrument (FROI). This study tested the effects of enhanced haptic feedback on force control, tissue consistency interpretation, and the associated surgeons' level of confidence through a randomized controlled crossover experiment. METHODS: A randomized three-period crossover trial was conducted, in which seven surgical residents and 13 medical students participated. The setup involved a box trainer in which slices of porcine organs (lung, small intestine, or liver) were presented. Participants performed three series of blinded palpation tasks involving three different graspers: the conventional grasper, the FROI with enhanced haptic feedback activated, and the FROI with enhanced haptic feedback deactivated. In each series, nine pairs of organ tissues were palpated to compare consistencies. The orders of presenting both instruments and tissues were randomized. RESULTS: The force applied during tissue palpation significantly decreased, by a mean factor of 3.1 with enhanced haptic feedback. Tissue consistency interpretation was significantly improved with more correct assessments and participants answered with significantly more confidence when enhanced haptic feedback was available. CONCLUSION: The availability of enhanced haptic feedback enabled participants to operate with significantly reduced interaction force between instrument and tissues. This observation is expected to have multiple important clinical implications, such as less tissue damage, fewer complications, shorter operation times, and improved ergonomics.

Adnexal masses in children, adolescents and women of reproductive age in the Netherlands: A nationwide population-based cohort study.

OBJECTIVE: To provide an accurate incidence of adnexal masses in children and young women which can significantly improve the performance of current risk prediction models. METHODS: We used the PALGA database, a nationwide network and registry of histopathology and cytopathology, as the primary source of our study. Reports on ovarian histology of girls, years 1991-2014, and women aged 21-39, years 2011-2013, were included. Reports were labeled using the WHO-classification and classified as benign, borderline malignant, or malignant. Surgical procedure was scored separately. RESULTS: Included were 11,595 patients. The incidence of adnexal masses increased exponentially with age, from 0.43 per 100,000womenyears at age 1 to 152 per 100,000womenyears at age 35. A (borderline) malignancy was found in 898 (7.7%) patients, ratios between benign and malignant masses varied with age and were lowest in premenarchal children. Histology varied widely with surface epithelial tumors (35.1%), germ cell tumors (29.8%), and other cysts, tumors and tumorlike lesions (32.8%) being evenly distributed while sex cord stromal tumors were rare and only represented 2.3%. The proportion of malignancies was 6.3% in germ cell tumors while the type of malignant germ cell tumor was dependent on age. Oophorectomy was more often performed in the premenarchal age group and in women approaching the end of their reproductive age. CONCLUSION: Our results show that adnexal masses in different age groups do not only differ in histological subgroups but also in malignancy rate which is of high value in presurgical risk evaluation.

Recurrence after surgery for endometrioma: a systematic review and meta-analyses.

IMPORTANCE: Endometriosis is an inflammatory disease, with different forms of expression and a variety of complaints. An endometrioma, an ovarian cyst with endometrium-like lining, is one of the most common expressions of abdominal endometriosis. These endometriomas can, in addition to medical treatment, be treated surgically. After surgery, hormonal therapy is still frequently used for the treatment of endometriosis in general and prevention of recurrence of endometriomas specifically. However, not all women want or can receive postoperative hormonal treatment. It is important for this group to determine the risk of anatomical recurrence of ovarian endometrioma after surgery for an endometrioma. OBJECTIVE: To determine the recurrence rate for surgically treated endometrioma without postoperative hormonal treatment. DATA SOURCES: We performed a systematic literature review and meta-analyses, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. MEDLINE, Embase, and the Cochrane library were searched until May 2023. The literature search was limited to women with endometrioma who received surgical treatment without postoperative hormonal treatment. STUDY SELECTION AND SYNTHESIS: A distinction was made in study design including randomized controlled trials (RCTs) and cohort and retrospective studies. For assessment of risk of bias, the Cochrane Handbook for Systematic Reviews of Interventions and Risk of Bias in Non-randomized Studies - of Interventions assessment tool were used. MAIN OUTCOMES: The outcome measure included in this review was endometrioma recurrence. RESULTS: We screened 5,367 articles, of which 97 were systematically reviewed and 55 were included in this systematic review. Twelve of these were RCTs, 11 were prospective cohort studies, and 32 were retrospective studies. Nine RCTs had a low risk of bias. For non-RCTs, only 3 studies had a low risk of bias. Data of 23 studies were pooled in meta-analyses, performed for follow-up periods of 3, 6, 12, and 24 months. These studies showed recurrence rates of 4%, 14%, 17%, and 27%, respectively. CONCLUSION AND RELEVANCE: In the meta-analysis, at 24 months after surgery, the endometrioma recurrence rate showed a weighted mean of up to 27%. In this study, we aimed to determine the recurrence rate of endometrioma after surgical treatment in women without postoperative hormonal treatment use. The recurrence rates were up to 27%.

Levonorgestrel releasing intrauterine system (Mirena) versus endometrial ablation (Novasure) in women with heavy menstrual bleeding: a multicentre randomised controlled trial.

BACKGROUND: Heavy menstrual bleeding is an important health problem. Two frequently used therapies are the levonorgestrel intra-uterine system (LNG-IUS) and endometrial ablation. The LNG-IUS can be applied easily by the general practitioner, which saves costs, but has considerable failure rates. As an alternative, endometrial ablation is also very effective, but this treatment has to be performed by a gynaecologist. Due to lack of direct comparison of LNG-IUS with endometrial ablation, there is no evidence based preferred advice for the use of one of these treatment possibilities. METHOD/DESIGN: A multicenter randomised controlled trial, organised in a network infrastructure in the Netherlands in which general practitioners and gynaecologists collaborate. DISCUSSON: This study, considering both effectiveness and cost effectiveness of LNG-IUS versus endometrial ablation may well improve care for women with heavy menstrual bleeding. TRIAL REGISTRATION: Dutch trial register, number NTR2984.

Procedural sedation and analgesia with propofol (PSA) for gynecologic surgery: A systematic review of the literature.

OBJECTIVE: To identify which gynecologic procedures are eligible to be performed under PSA with propofol and to describe safety and effectiveness of these procedures in this setting. METHODS: A systematic review of the literature was conducted in Pubmed (MEDLINE), Embase and The Cochrane Library from inception until September 21st 2022. Cohort studies and randomized controlled trials were included when they reported on clinical outcomes of gynecologic procedures under procedural sedation and analgesia in which propofol was used as an anesthetic. Studies were excluded when sedation without propofol was used, when they only mentioned the use of procedural sedation and analgesia but did not describe any clinical outcome parameters or when < 10 patients were included. The primary outcome parameter was completeness of procedure. Secondary outcome parameters were type of gynecologic procedure, intraoperative complication rate, patient satisfaction, postoperative pain, duration of hospital admission, patient's discomfort and ease of procedure as judged by the surgeon. The Cochrane risk of bias tool and the ROBINS-I tool were used for bias assessment. A narrative synthesis of the findings from the included studies was provided. Numbers and percentages were presented, as well as means with standard deviations and medians with interquartile range where applicable. RESULTS: Eight studies were included. A total of 914 patients underwent gynecologic surgical procedures with procedural sedation and analgesia with propofol. Gynecological procedures varied from hysteroscopic procedures, vaginal prolapse surgery and laparoscopic procedures. The percentage of complete procedures was 89.8%-100%. Complications occurred in 0-6.5% of patients. Other outcomes were measured in various ways, but overall patient satisfaction was high and postoperative pain was low. CONCLUSION: The use of PSA with propofol is promising for a wide range of gynecologic procedures, including hysteroscopic procedures, vaginal prolapse surgery and laparoscopic procedures. The use of PSA with propofol seems to be effective and safe and leads to high degree of patient satisfaction. More research is needed in order to determine for which types of procedures PSA can be used.

Economic evaluation of a randomized controlled trial comparing mifepristone and misoprostol with misoprostol alone in the treatment of early pregnancy loss.

BACKGROUND: In case of early pregnancy loss (EPL) women can either choose for expectant, medical or surgical management. One week of expectant management is known to lead to spontaneous abortion in approximately 50% of women. Medical treatment with misoprostol is known to be safe and less costly than surgical management, however less effective in reaching complete evacuation of the uterus. Recently, a number of trials showed that prompt treatment with the sequential combination of mifepristone with misoprostol is superior to misoprostol alone in reaching complete evacuation. In this analysis we evaluate whether the sequential combination of mifepristone with misoprostol is cost-effective compared to misoprostol alone, in the treatment of EPL. METHODS AND FINDINGS: A cost-effectiveness analysis (CEA) from a healthcare perspective was performed alongside a randomised controlled trial (RCT) in which standard treatment with misoprostol only was compared with a combination of mifepristone and misoprostol, in women with EPL after a minimum of one week of unsuccessful management. A limited societal perspective scenario was added. This RCT, the Triple M trial, was a multicentre, randomized, double-blinded, placebo-controlled trial executed at 17 hospitals in the Netherlands. The trial started on June 27th 2018, and ended prematurely in January 2020 due to highly significant outcomes from the predefined interim-analysis. We included 351 women with a diagnosis of EPL between 6 and 14 weeks gestation after at least one week of unsuccessful expectant management. They were randomized between double blinded pre-treatment with oral mifepristone 600mg (N = 175) or placebo (N = 176) taken on day one, both followed by misoprostol orally. In both groups, an intention-to-treat analysis was performed for 172 patients, showing a significant difference in success rates between participants treated with mifepristone and misoprostol versus those treated with misoprostol alone (79.1% vs 58.7% respectively). In this cost-effective analysis we measured the direct, medical costs related to treatment (planned and unplanned hospital visits, medication, additional treatment) and indirect costs based on the IMTA Productivity Cost Questionnaire (iPCQ). Quality Adjusted Life Years (QALY's) were calculated from participants' scores on the SF-36 questionnaires sent digitally at treatment start, and one, two and six weeks later. We found medical treatment with placebo followed by misoprostol to be 26% more expensive compared to mifepristone followed by misoprostol (p = 0.001). Mean average medical costs per patient were significantly lower in the mifepristone group compared to the placebo group (€528.95 ± 328.93 vs €663.77 ± 456.03, respectively; absolute difference €134.82, 95% CI 50,46-219,18, p = 0.002). Both indirect costs and QALY's were similar between both groups. CONCLUSION: The sequential combination of mifepristone with misoprostol is cost-effective compared with misoprostol alone, for treatment of EPL after a minimum of one week of unsuccessful expectant management.

STop OVarian CAncer (STOPOVCA) young: Protocol for a multicenter follow-up study to determine the long-term effects of opportunistic salpingectomy on age at menopause.

BACKGROUND: Opportunistic salpingectomy comprises additional bilateral salpingectomy during abdominal surgery as a prophylactic method to reduce the risk of ovarian cancer. However, opportunistic salpingectomy may potentially damage (micro)blood circulation to the ovaries, resulting in earlier onset of menopause. PRIMARY OBJECTIVE: To evaluate the long-term effects of opportunistic salpingectomy on the onset of menopause in women who underwent sterilization through salpingectomy compared with a control group who underwent sterilization by tubal ligation or no surgery at all. STUDY HYPOTHESIS: Opportunistic salpingectomy does not lower the mean age at onset of menopause. TRIAL DESIGN: In a multicenter observational noninferiority study, we will prospectively compare the age at menopause of women initially aged 35-45 who underwent sterilization through opportunistic salpingectomy with a similarly aged control group who underwent sterilization by tubal ligation or no sterilization. Participants will be asked to complete an annual questionnaire on onset of menopause to eventually determine whether there is more than a one-year decrease in mean age at onset of menopause in the opportunistic salpingectomy group. Follow-up will last until determination of menopause, with a maximum of 15 years. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria: pre-menopausal; age between 35 and 45; intact ovaries. EXCLUSION CRITERIA: post-menopausal; previous bilateral salpingectomy or oophorectomy; previous hysterectomy; abnormal karyotype; previous or current chemotherapy or pelvic radiation. PRIMARY ENDPOINT(S): Determination of age of menopause measured by annual questionnaire. SAMPLE SIZE: 1200 (400 intervention group; 800 control group). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated that recruitment will be completed by 2023 and results will be published by 2039. GOV IDENTIFIER: NCT04757922 PROTOCOL VERSION: : Version 1, February 2021.

Association of Salpingectomy With Delayed Oophorectomy Versus Salpingo-oophorectomy With Quality of Life in BRCA1/2 Pathogenic Variant Carriers: A Nonrandomized Controlled Trial.

IMPORTANCE: Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. OBJECTIVE: To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. DESIGN, SETTING, AND PARTICIPANTS: A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. INTERVENTIONS: Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. MAIN OUTCOMES AND MEASURES: Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. RESULTS: A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P < .001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P < .001) compared with RRS. CONCLUSIONS AND RELEVANCE: Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02321228.

Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine.

BACKGROUND: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. METHODS/DESIGN: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. DISCUSSION: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

The effectiveness of a clinically integrated e-learning course in evidence-based medicine: a cluster randomised controlled trial.

BACKGROUND: To evaluate the educational effects of a clinically integrated e-learning course for teaching basic evidence-based medicine (EBM) among postgraduates compared to a traditional lecture-based course of equivalent content. METHODS: We conducted a cluster randomised controlled trial in the Netherlands and the UK involving postgraduate trainees in six obstetrics and gynaecology departments. Outcomes (knowledge gain and change in attitude towards EBM) were compared between the clinically integrated e-learning course (intervention) and the traditional lecture based course (control). We measured change from pre- to post-intervention scores using a validated questionnaire assessing knowledge (primary outcome) and attitudes (secondary outcome). RESULTS: There were six clusters involving teaching of 61 postgraduate trainees (28 in the intervention and 33 in the control group). The intervention group achieved slightly higher scores for knowledge gain compared to the control, but these results were not statistically significant (difference in knowledge gain: 3.5 points, 95% CI -2.7 to 9.8, p = 0.27). The attitudinal changes were similar for both groups. CONCLUSION: A clinically integrated e-learning course was at least as effective as a traditional lecture based course and was well accepted. Being less costly than traditional teaching and allowing for more independent learning through materials that can be easily updated, there is a place for incorporating e-learning into postgraduate EBM curricula that offer on-the-job training for just-in-time learning. TRIAL REGISTRATION NUMBER: ACTRN12609000022268.

Factors influencing decision-making around opportunistic salpingectomy: a nationwide survey.

OBJECTIVE: To explore current practice and influencing factors on adoption of the opportunistic salpingectomy (OS), particularly regarding the decision making, to eventually enhance the development and implementation of clear guidelines. METHODS: This nationwide cross-sectional survey study was conducted in all hospitals in the Netherlands. An anonymous online survey was sent to gynecologists with special interest in gynecological oncology, gynecological endoscopy or urogynecology and all Dutch gynecology trainees. The survey mainly focused on current practice regarding OS and identification of influencing factors on the level of innovation, organization, healthcare professional and individual patient. RESULTS: The response rate was 348 out of 597 gynecologists (58.3%) and 142 out of 340 trainees (41.8%). Current practice of discussing and performing the OS varied widely, with ovarian cancer (OC) risk reduction as most important supportive factor on innovation level. Supportive factors on the level of organization and healthcare provider were; working in a non-training hospital, knowledge of current literature and extensive work experience (in years and annual number of hysterectomies). On individual patient level, a vaginal approach of hysterectomy, negative family history for OC and the presence of firm adhesions were suppressive factors for the OS. CONCLUSION: In this study we evaluated the current practice regarding the opportunistic salpingectomy in the Netherlands and identified influencing factors on different levels to raise awareness and attribute to development of a targeted implementation strategy, on both national and international level.

Harmonising evidence-based medicine teaching: a study of the outcomes of e-learning in five European countries.

BACKGROUND: We developed and evaluated the outcomes of an e-learning course for evidence based medicine (EBM) training in postgraduate medical education in different languages and settings across five European countries. METHODS: We measured changes in knowledge and attitudes with well-developed assessment tools before and after administration of the course. The course consisted of five e-learning modules covering acquisition (formulating a question and search of the literature), appraisal, application and implementation of findings from systematic reviews of therapeutic interventions, each with interactive audio-visual learning materials of 15 to 20 minutes duration. The modules were prepared in English, Spanish, German and Hungarian. The course was delivered to 101 students from different specialties in Germany (psychiatrists), Hungary (mixture of specialties), Spain (general medical practitioners), Switzerland (obstetricians-gynaecologists) and the UK (obstetricians-gynaecologists). We analysed changes in scores across modules and countries. RESULTS: On average across all countries, knowledge scores significantly improved from pre- to post-course for all five modules (p < 0.001). The improvements in scores were on average 1.87 points (14% of total score) for module 1, 1.81 points (26% of total score) for module 2, 1.9 points (11% of total score) for module 3, 1.9 points (12% of total score) for module 4 and 1.14 points (14% of total score) for module 5. In the country specific analysis, knowledge gain was not significant for module 4 in Spain, Switzerland and the UK, for module 3 in Spain and Switzerland and for module 2 in Spain. Compared to pre-course assessment, after completing the course participants felt more confident that they can assess research evidence and that the healthcare system in their country should have its own programme of research about clinical effectiveness. CONCLUSION: E-learning in EBM can be harmonised for effective teaching and learning in different languages, educational settings and clinical specialties, paving the way for development of an international e-EBM course.