The (cost-) effectiveness Of Surgical excision of Colorectal endometriosis compared to ART treatment trAjectory (TOSCA study) - a study protocol.

Currently, the optimal treatment to increase the chance of pregnancy and live birth in patients with colorectal endometriosis and subfertility is unknown. Evidence suggests that that both surgery and in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are effective in improving live birth rate (LBR) among these women. However, the available evidence is of low quality, reports highly heterogeneous results, lacks direct comparison between both treatment options and does not assess whether a combination strategy results in a higher LBR compared to IVF/ICSI-only treatment. Additionally, the optimal timing of surgery within the treatment trajectory remains unclear. The primary objective of the TOSCA study is to assess the effectiveness of surgical treatment (potentially combined with IVF/ICSI) compared to IVF/ICSI-only treatment to increase the chance of an ongoing pregnancy resulting in a live birth in patients with colorectal endometriosis and subfertility, measured by cumulative LBR. Secondary objectives are to assess and compare quality of life and cost-effectiveness in both groups. Patients will be followed for 40 months after inclusion or until live birth. The TOSCA study is expected to be completed in 6 years.

Towards reducing diagnostic delay in endometriosis in primary care: a qualitative study.

BACKGROUND: Due to a heterogeneity of symptoms, a lack of an adequate diagnostic test and a lack of awareness, diagnostic delay in endometriosis in primary care on average amounts to 35 months. AIM: To determine which interventions are most feasible to reduce time to diagnosis in primary care, focusing on GPs' preferences, the intervention's content, design and implementation. DESIGN & SETTING: We conducted a qualitative study by performing focus groups with GPs and GP trainees between July and October 2021. METHOD: Data collection was continued until saturation was obtained. Focus groups were transcribed and openly encoded. Themes were formulated by three independent researchers. RESULTS: Divided over five focus groups 22 GPs and 13 GP trainees participated. Three themes were formulated: increasing awareness, combined intervention and reaching unaware GPs.Suggestions for a combined intervention strategy were adaptation of guidelines, a diagnostic support tool and compulsory education. To reach unaware GPs, participants felt that education should be offered in regional networks and education for GP trainees should be mandatory. A guideline on menstrual symptoms should be considered, and the term endometriosis should be added to the differential diagnosis paragraphs of existing guidelines. A diagnostic support tool should be linked to a guideline and consist of a flowchart with steps starting with the first presentation of symptoms leading to the diagnosis of endometriosis. CONCLUSION: According to GPs, a combined intervention strategy consisting of an adapted guideline, a diagnostic support tool and education might be successful interventions in reduction of diagnostic delay in endometriosis.

The feasibility of an anti-inflammatory diet in endometriosis: barriers and facilitators perceived by endometriosis patients.

RESEARCH QUESTION: What is the feasibility of an anti-inflammatory diet in women diagnosed with endometriosis? DESIGN: Qualitative study using semi-structured focus groups and individual interviews among patients with endometriosis. Transcripts of the focus groups and interviews were thematically analysed using ATLAS.ti 9. To identify and structure the ideas and views from the focus groups and interviews, two behavioural change models were used. The Capability Opportunity Motivation Behaviour (COM-B) model and domains of the Theoretical Domains Framework (TDF) helped to identify factors that make adherence to an anti-inflammatory diet more or less feasible for women with endometriosis. RESULTS: The study population consisted of 23 patients with endometriosis. Numerous perceived barriers and facilitators were identified from all COM-B components and 13 out of 15 TDF domains. Knowledge and social influences were the most prominent TDF domains. Key barriers were eating with others; disbelief in a patients' own capability regarding specific dietary guidelines; concerns about taste; lack of knowledge on how to follow the diet; lack of noticeable beneficial effect; and lack of intention to follow the diet to full extent. Key facilitators were receiving social support; general confidence in a participant's own capabilities; knowing how and why to follow the diet; noticing beneficial effect; and belief that the diet would alleviate symptoms. CONCLUSION: Provision of knowledge, stimulating social support and enhancing self-efficacy should be emphasized. Overall, an anti-inflammatory diet in endometriosis patients, especially when identified barriers and facilitators are addressed in an intervention, is feasible.

Risk Factors for Adhesion-Related Readmission and Abdominal Reoperation after Gynecological Surgery: A Nationwide Cohort Study.

More than half of women in developed countries undergo surgery during their lifetime, putting them at risk of adhesion-related complications. Adhesion-related complications include small bowel obstruction, chronic (pelvic) pain, subfertility, and complications associated with adhesiolysis during reoperation. The aim of this study is to predict the risk for adhesion-related readmission and reoperation after gynecological surgery. A Scottish nationwide retrospective cohort study was conducted including all women undergoing a gynecological procedure as their initial abdominal or pelvic operation between 1 June 2009 and 30 June 2011, with a five-year follow-up. Prediction models for two- and five-year risk of adhesion-related readmission and reoperation were constructed and visualized using nomograms. To evaluate the reliability of the created prediction model, internal cross-validation was performed using bootstrap methods. During the study period, 18,452 women were operated on, and 2719 (14.7%) of them were readmitted for reasons possibly related to adhesions. A total of 2679 (14.5%) women underwent reoperation. Risk factors for adhesion-related readmission were younger age, malignancy as indication, intra-abdominal infection, previous radiotherapy, application of a mesh, and concomitant inflammatory bowel disease. Transvaginal surgery was associated with a lower risk of adhesion-related complications as compared to laparoscopic or open surgeries. The prediction model for both readmissions and reoperations had moderate predictive reliability (c-statistics 0.711 and 0.651). This study identified risk factors for adhesion-related morbidity. The constructed prediction models can guide the targeted use of adhesion prevention methods and preoperative patient information in decision-making.

Endometriosis and the effects of dietary interventions: what are we looking for?

Endometriosis is the most prevalent benign gynaecologic disease with invalidating effects on the quality of life and decreased economic productivity. As pharmacologic and surgical treatment are only partially effective, women look for self-management strategies in order to control their symptoms. Many dietary interventions have been claimed successful. But it is unclear whether these effects are caused by the idea of taking control of the symptoms by adhering to a diet or by the dietary intervention itself. In order to gain more evidence with regard to the mechanisms behind the effect of dietary intervention in the management of endometriosis, a number of issues need to be addressed for future studies. First, we need clearly defined endpoints in our studies. Secondly, we have to be aware of the difference between the effects of diet on the risk of developing endometriosis and the effects of diet on symptoms in women with already established endometriosis. Thirdly, it may be difficult to strictly define the intervention diet and the control or placebo diet. Fourthly, we have to define endometriosis-related as well as patient-related factors that may influence the success of a dietary intervention. Fifthly, we have to understand the biological mechanisms behind the perceived effects of dietary interventions. These issues will be addressed in this opinion paper. Lay summary: Endometriosis, defined as the presence of endometrium-like tissue located outside the womb, is a gynaecologic disease that affects many women. They experience severe pain, making it difficult for them to go to school or work. Medication or surgery is often not enough to relieve their pain. Therefore, these women look for ways to suppress their pain by changing their way of life. Changing their diet is an option that is often chosen by women with endometriosis. Many women experience that changing their diet helps to suppress pain symptoms. But it is not clear why changing the diet is effective. Processes in the body could be changed by taking or avoiding specific nutrients, but the effect could also be caused by the empowerment that women experience by adhering to a diet. If we want to learn more about the effect of diet on endometriosis, we have to pay attention to the following issues: first, it is important to exactly define the goal of a new study. Secondly, we have to realize that there is a difference between the study of the effect of diet on the risk of developing endometriosis and the effect of diet on endometriosis that has already developed. Thirdly, we have to realize that it can be difficult to define what the diet contains and how a control group should be defined. Fourthly, it is important to define factors that make it difficult to adhere to a diet. Fifthly, we need to try to understand what happens in the body that may cause the effect of a diet in endometriosis. In this opinion paper, these issues will be addressed.

The Promises of Natural Killer Cell Therapy in Endometriosis.

Endometriosis is a gynaecological disease defined by the growth of endometrium-like tissue outside the uterus. The disease is present in approximately 5-10% of women of reproductive age and causes pelvic pain and infertility. The pathophysiology is not completely understood, but retrograde menstruation and deficiency in natural killer (NK) cells that clear endometriotic cells in the peritoneal cavity play an important role. Nowadays, hormonal therapy and surgery to remove endometriosis lesions are used as treatment. However, these therapies do not work for all patients, and hormonal therapy prevents patients from getting pregnant. Therefore, new treatment strategies should be developed. Since the cytotoxicity of NK cells is decreased in endometriosis, we performed a literature search into the possibility of NK cell therapy. Available treatment options include the inhibition of receptor-ligand interaction for KIR2DL1, NKG2A, LILRB1/2, and PD-1/PD-L1; inhibition of TGF-ß; stimulation of NK cells with IL-2; and mycobacterial treatment with BCG. In preclinical work, these therapies show promising results but unfortunately have side effects, which have not specifically been studied in endometriosis patients. Before NK cell treatment can be used in the clinic, more research is needed.

ESHRE guideline: endometriosis.

STUDY QUESTION: How should endometriosis be diagnosed and managed based on the best available evidence from published literature? SUMMARY ANSWER: The current guideline provides 109 recommendations on diagnosis, treatments for pain and infertility, management of disease recurrence, asymptomatic or extrapelvic disease, endometriosis in adolescents and postmenopausal women, prevention and the association with cancer. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition with a plethora of presentations in terms of not only the occurrence of lesions, but also the presence of signs and symptoms. The most important symptoms include pain and infertility. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 1 December 2020 and written in English were included in the literature review. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed within specialist subgroups and then presented to the core guideline development group (GDG) until consensus was reached. A stakeholder review was organized after finalization of the draft. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help clinicians to apply best care for women with endometriosis. Although studies mostly focus on women of reproductive age, the guideline also addresses endometriosis in adolescents and postmenopausal women. The guideline outlines the diagnostic process for endometriosis, which challenges laparoscopy and histology as gold standard diagnostic tests. The options for treatment of endometriosis-associated pain symptoms include analgesics, medical treatments and surgery. Non-pharmacological treatments are also discussed. For management of endometriosis-associated infertility, surgical treatment and/or medically assisted reproduction are feasible. While most of the more recent studies confirm previous ESHRE recommendations, there are five topics in which significant changes to recommendations were required and changes in clinical practice are to be expected. LIMITATIONS REASONS FOR CAUTION: The guideline describes different management options but, based on existing evidence, no firm recommendations could be formulated on the most appropriate treatments. Also, for specific clinical issues, such as asymptomatic endometriosis or extrapelvic endometriosis, the evidence is too scarce to make evidence-based recommendations. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in endometriosis care, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in endometriosis. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payments. C.M.B. reports grants from Bayer Healthcare and the European Commission; Participation on a Data Safety Monitoring Board or Advisory Board with ObsEva (Data Safety Monitoring Group) and Myovant (Scientific Advisory Group). A.B. reports grants from FEMaLE executive board member and European Commission Horizon 2020 grant; consulting fees from Ethicon Endo Surgery, Medtronic; honoraria for lectures from Ethicon; and support for meeting attendance from Gedeon Richter; A.H. reports grants from MRC, NIHR, CSO, Roche Diagnostics, Astra Zeneca, Ferring; Consulting fees from Roche Diagnostics, Nordic Pharma, Chugai and Benevolent Al Bio Limited all paid to the institution; a pending patent on Serum endometriosis biomarker; he is also Chair of TSC for STOP-OHSS and CERM trials. O.H. reports consulting fees and speaker's fees from Gedeon Richter and Bayer AG; support for attending meetings from Gedeon-Richter, and leadership roles at the Finnish Society for Obstetrics and Gynecology and the Nordic federation of the societies of obstetrics and gynecology. L.K. reports consulting fees from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; honoraria for lectures from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; support for attending meetings from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; he also has a leadership role in the German Society of Gynecological Endocrinology (DGGEF). M.K. reports grants from French Foundation for Medical Research (FRM), Australian Ministry of Health, Medical Research Future Fund and French National Cancer Institute; support for meeting attendance from European Society for Gynaecological Endoscopy (ESGE), European Congress on Endometriosis (EEC) and ESHRE; She is an advisory Board Member, FEMaLe Project (Finding Endometriosis Using Machine Learning), Scientific Committee Chair for the French Foundation for Research on Endometriosis and Scientific Committee Chair for the ComPaRe-Endometriosis cohort. A.N. reports grants from Merck SA and Ferring; speaker fees from Merck SA and Ferring; support for meeting attendance from Merck SA; Participation on a Data Safety Monitoring Board or Advisory Board with Nordic Pharma and Merck SA; she also is a board member of medical advisory board, Endometriosis Society, the Netherlands (patients advocacy group) and an executive board member of the World Endometriosis Society. E.S. reports grants from National Institute for Health Research UK, Rosetrees Trust, Barts and the London Charity; Royalties from De Gruyter (book editor); consulting fees from Hologic; speakers fees from Hologic, Johnson & Johnson, Medtronic, Intuitive, Olympus and Karl Storz; Participation in the Medicines for Women's Health Expert Advisory Group with Medicines and Healthcare Products Regulatory Agency (MHRA); he is also Ambassador for the World Endometriosis Society. C.T. reports grants from Merck SA; Consulting fees from Gedeon Richter, Nordic Pharma and Merck SA; speaker fees from Merck SA, all paid to the institution; and support for meeting attendance from Ferring, Gedeon Richter and Merck SA. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose (Full disclaimer available at www.eshre.eu/guidelines.).

Determining the effectiveness of cognitive behavioural therapy in improving quality of life in patients undergoing endometriosis surgery: a study protocol for a randomised controlled trial.

INTRODUCTION: Endometriosis can cause chronic pain and subfertility thereby negatively affecting quality of life (QoL). Surgical removal of endometriosis lesions leads to improved health-related QoL, although not to the level of QoL of healthy controls. Pain intensity and cognitions regarding pain can play a crucial role in this health-related QoL following surgical treatment. Cognitive behavioural therapy (CBT) is a psychological treatment. In patients with chronic pain caused by a variety of medical conditions, CBT is effective in improving QoL. We designed a research protocol to investigate the effect of CBT on QoL in patients with endometriosis-associated chronic pain who are undergoing surgery. METHODS AND ANALYSIS: This is a study protocol for a randomised controlled trial in which 100 patients, undergoing endometriosis removal surgery due to endometriosis-associated chronic pain, will be randomised between post-surgery usual care with CBT and post-surgery usual care only. Participants in the CBT group will additionally receive seven sessions of CBT, focused on expectancy management, cognitions regarding pain and emotional and behavioural impact of pain. To determine the primary outcome Quality of life, both groups will complete questionnaires assessing QoL. The secondary outcomes pain intensity, pain cognitions, fatigue and perceived stress are also measured using questionnaires. Additionally, a marker for stress (cortisol extracted from a hair sample) will be assessed at T0 (baseline assessment), T1 (post-intervention; 2 weeks after completion of all CBT sessions) and T2 (follow-up; 14 weeks after T1). Statistical analysis will be performed using SPSS software. ETHICS AND DISSEMINATION: The study protocol has been approved by the Medical Ethical Committee of the region Arnhem-Nijmegen from the Radboud University Medical Centre on 2 September 2020. The findings of this study will be published in scientific journals and will be presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT04448366.

Diet quality and perceived effects of dietary changes in Dutch endometriosis patients: an observational study.

RESEARCH QUESTION: What is the current diet of women with endometriosis, in terms of adherence to dietary guidelines and use of diets, and what are the perceived effects of dietary modifications? DESIGN: In this online explorative observational study, the Dutch Healthy Diet 2015 index (DHD-15) and quality of life (QoL) with the Endometriosis Health Profile-30 questionnaire (EHP-30) were used to assess diet quality. RESULTS: The questionnaires were completed by 157 participants. Many participants made one or more dietary adaptations for their endometriosis, in the form of a specific diet (46.5%), with the use of dietary supplements (56.1%), with other dietary adjustments (64.3%), or all. Endometriosis patients had a significantly lower DHD-15 score, indicating a lower diet quality than a healthy reference group (P = 0.004). In the endometriosis group, diet users had a significantly higher total DHD-15 score than non-diet users (P < 0.0001). Diet quality was not correlated with QoL (Pearson's r = -0.010, P = 0.904). Many specific dietary adjustments (71.3%), however, were reported to reduce endometriosis pain-related symptoms. The removal of gluten, dairy or soy, as well as the addition of vegetables, showed the greatest perceived reductions of symptoms in participants. CONCLUSIONS: Although no specific dietary adjustment was found to increase QoL, endometriosis patients do feel that dietary adjustments have a beneficial effect on their symptoms. Therefore, more research is needed to gain evidence about the specific effects of nutrients on endometriosis symptoms.

The impact of the COVID-19 pandemic on infertility patients and endometriosis patients in the Netherlands.

RESEARCH QUESTION: How do infertility patients, endometriosis patients and health-care providers rate virtual care as an alternative to physical consultations during the first lockdown of the coronavirus disease 2019 (COVID-19) pandemic in the Netherlands, and how does this influence quality of life and quality of care? DESIGN: Infertility patients and endometriosis patients from a university hospital and members of national patient organizations, as well as healthcare providers in infertility and endometriosis care, were asked to participate between May and October 2020. The distributed online questionnaires consisted of an appraisal of virtual care and an assessment of fertility-related quality of life (FertiQol) and patient-centredness of endometriosis care (ENDOCARE). RESULTS: Questionnaires were returned by 330 infertility patients, 181 endometriosis patients and 101 healthcare providers. Of these, 75.9% of infertility patients, 64.8% of endometriosis patients and 80% of healthcare providers rated telephone consultations as a good alternative to physical consultations during the COVID-19-pandemic. Only 21.3%, 14.8% and 19.2% of the three groups rated telephone consultations as a good replacement for physical consultations in the future. A total of 76.6% and 35.9% of the infertility and endometriosis patients reported increased levels of stress during the pandemic. Infertility patients scored lower on the FertiQol, while the ENDOCARE results care seem comparable to the reference population. CONCLUSIONS: Virtual care seems to be a good alternative for infertility and endometriosis patients in circumstances where physical consultations are not possible. Self-reported stress is especially high in infertility patients during the COVID-19-pandemic. Healthcare providers should aim to improve their patients' ability to cope.

Strengths and weaknesses in the diagnostic process of endometriosis from the patients' perspective: a focus group study.

OBJECTIVES: Endometriosis is characterized by a long interval between onset of symptoms and diagnosis. Detailed information about the patients' perspective on the diagnostic delay of endometriosis is scarce. The aim of this study was to identify strengths and weaknesses in the diagnostic process of endometriosis from the patients' perspective. METHODS: Qualitative study with semi-structured focus groups. Participants were women between 18 and 45 years old with a recently confirmed diagnosis. The focus groups were audio recorded and fully transcribed. Grounded theory methodology was applied for data analysis. RESULTS: Six focus groups were organized, in which 23 women participated. Mean time from start of symptoms to diagnosis was 8.5 years. Dominant themes were knowledge about normal menstruation and endometriosis, being believed and acknowledged by medical staff, and collaboration between health care providers including fast referral to a gynaecologist. Barriers to a timely referral and diagnosis were young age, normalization of symptoms and a lack of awareness in general practitioners. Facilitating factors included adequate knowledge and skills of the general practitioner, a desire for pregnancy and persisting in a request for specialist consultation by the patient. CONCLUSIONS: The diagnostic process of endometriosis is hampered by delayed consultation, inadequate appraisal of symptoms by general practitioners and the interaction between patients and medical professionals. Efforts should be made to increase public awareness and to provide medical staff with sufficient knowledge and skills to adequately acknowledge presented symptoms.

Patients' perspective on cognitive behavioural therapy after surgical treatment of endometriosis: a qualitative study.

RESEARCH QUESTION: Would adding cognitive behavioural therapy (CBT) to the treatment of endometriosis improve the quality of life of patients suffering from endometriosis-associated pain? The aim of this study was to identify if patients believed CBT should be added to endometriosis treatment and which form of CBT they would prefer: face-to-face individual or group, or web-based individual, sessions. DESIGN: Between November 2019 and January 2020, semi-structured focus groups were conducted using an interview guide to ensure all topics were discussed. Data collection was continued until saturation was obtained. The focus groups were transcribed word for word and openly encoded. Finally, themes were formulated. RESULTS: All participating women believed CBT should be offered to patients undergoing endometriosis surgery. They believed it could be an asset to improve quality of life. Participants preferred either in-person individual or group therapy. They stressed the importance of being offered a custom-made treatment plan, individually tailored to the different needs of different patients. CONCLUSION: This study has shown that patients with endometriosis believe that CBT should be added to the standard treatment regimen of endometriosis in either group or individual face-to-face sessions, because they expect that CBT will improve their quality of life after surgery.

The long-term costs and effects of tubal flushing with oil-based versus water-based contrast during hysterosalpingography.

RESEARCH QUESTION: What are the long-term costs and effects of oil- versus water-based contrast in infertile women undergoing hysterosalpingography (HSG)? DESIGN: This economic evaluation of a long-term follow-up of a multicentre randomized controlled trial involved 1119 infertile women randomized to HSG with oil- (n = 557) or water-based contrast (n = 562) in the Netherlands. RESULTS: In the oil-based contrast group, 39.8% of women needed no other treatment, 34.6% underwent intrauterine insemination (IUI) and 25.6% had IVF/intracytoplasmic sperm injection (ICSI) in the 5 years following HSG. In the water-based contrast group, 35.0% of women had no other treatment, 34.2% had IUI and 30.8% had IVF/ICSI in the 5 years following HSG (P = 0.113). After 5 years of follow-up, HSG using oil-based contrast resulted in equivalent costs (mean cost difference -€144; 95% confidence interval [CI] -€579 to +€290; P = 0.515) for a 5% increase in the cumulative ongoing pregnancy rate compared with HSG using water-based contrast (80% compared with 75%, Relative Risk (RR) 1.07; 95% CI 1.00-1.14). Similarly, HSG with oil-based contrast resulted in equivalent costs (mean cost difference -€50; 95% CI -€576 to +€475; P = 0.850) for a 7.5% increase in the cumulative live birth rate compared with HSG with water-based contrast (74.8% compared with 67.3%, RR 1.11; 95% CI 1.03-1.20), making it the dominant strategy. Scenario analyses suggest that the oil-based contrast medium is the dominant strategy up to a price difference of €300. CONCLUSION: Over a 5-year follow-up, HSG with an oil-based contrast was associated with a 5% increase in ongoing pregnancy rate, a 7.5% increase in live birth rate and similar costs to HSG with water-based contrast.

Tubal flushing with oil-based or water-based contrast at hysterosalpingography for infertility: long-term reproductive outcomes of a randomized trial.

OBJECTIVE: To determine the impact of oil-based versus water-based contrast on pregnancy and live birth rates ≤5 years after hysterosalpingography (HSG) in infertile women. DESIGN: A 5-year follow-up study of a multicenter randomized trial. SETTING: Hospitals. PATIENT(S): Infertile women with an ovulatory cycle, 18-39 years of age, and having a low risk of tubal pathology. INTERVENTION(S): Use of oil-based versus water-based contrast during HSG. MAIN OUTCOME MEASURE(S): Ongoing pregnancy, live births, time to ongoing pregnancy, second ongoing pregnancy. RESULT(S): A total of 1,119 women were randomly assigned to HSG with oil-based contrast (n = 557) or water-based contrast (n = 562). After 5 years, 444 of 555 women in the oil group (80.0%) and 419 of 559 women in the water group (75.0%) had an ongoing pregnancy (relative risk [RR] 1.07; 95% confidence interval [CI] 1.00-1.14), and 415 of 555 women in the oil group (74.8%) and 376 of 559 women in the water group (67.3%) had live births (RR 1.11; 95% CI 1.03-1.20). In the oil group, 228 pregnancies (41.1%) were conceived naturally versus 194 (34.7%) pregnancies in the water group (RR 1.18; 95% CI 1.02-1.38). The time to ongoing pregnancy was significantly shorter in the oil group versus the water group (10.0 vs. 13.7 months; hazard ratio, 1.25; 95% CI 1.09-1.43). No difference was found in the occurrence of a second ongoing pregnancy. CONCLUSION(S): During a 5-year time frame, ongoing pregnancy and live birth rates are higher after tubal flushing with oil-based contrast during HSG compared with water-based contrast. More pregnancies are naturally conceived and time to ongoing pregnancy is shorter after HSG with oil-based contrast. CLINICAL TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR) 3270 and NTR6577(www.trialregister.nl).

Barriers and facilitators to the timely diagnosis of endometriosis in primary care in the Netherlands.

BACKGROUND: Endometriosis is an invalidating gynaecological condition in women of reproductive age, and a frequent cause of infertility. Unfortunately, the condition is characterized by a long interval between onset of symptoms and diagnosis. GPs in the Netherlands are educated to provide basic gynaecological care and serve as gatekeepers for specialist medical care. Therefore, it is of great importance that they recognize signs and symptoms possibly caused by endometriosis to initiate adequate actions. OBJECTIVE: The main objective of this study was to identify barriers and facilitators to the timely diagnosis of endometriosis from the GPs' perspective. METHODS: Semi-structured focus group discussions with GPs were organized throughout the Netherlands. The participants were encouraged to brainstorm about their perspective on daily practice regarding endometriosis and suggestions for interventions to enable early diagnosis and treatment. Analysis was based on grounded theory methodology. RESULTS: Forty-three GPs participated in six focus groups. Analysis of the transcripts revealed relevant determinants of practice in four main themes: professionals' experience and competence, patient characteristics, guideline factors and professional collaboration. A lack of knowledge and awareness appeared to result in a low priority for establishing the diagnosis of endometriosis, especially in young women. Infertility, patient engagement and a recent serious case or training facilitated referral. CONCLUSION: Several factors in daily primary health care contribute to the diagnostic delay in endometriosis. Future interventions to reduce this delay may be aimed at increasing awareness by means of education, incorporating the subject into national clinical guidelines and improvements in interdisciplinary collaboration.

An objective and automated method for evaluating abdominal hyperalgesia in a rat model for endometriosis.

Chronic pain and subfertility are the main symptoms of concern in women with endometriosis. In order to find new therapeutic options to suppress the pain, translational animal models are indispensable. We have developed a new automated, experimental setup, with full consideration for animal wellbeing, to determine whether operant behaviour can reveal abdominal hyperalgesia in rats with surgically-induced endometriosis, in order to assess whether abdominal hyperalgesia affect behavioural parameters. Endometriosis was induced by transplantation of uterine fragments in the abdominal cavity. Control groups consisted of sham-operated rats and non-operated rats. We have developed an operant chamber (Skinnerbox) which includes a barrier. The rat can climb the barrier in order to reach the food pellet, increasing in this way the pressure to the abdomen. We show that endometriosis rats collect significantly less sugar pellets when compared with the control rats after the introduction of the barrier. In the Skinnerbox experiment, we showed that in a positive operant setting, the introduction of a barrier results in a contrast of operant behaviour of endometriosis rats and control groups, perchance as a result of abdominal discomfort/hyperalgesia due to surgically-induced endometriosis. This is a promising start for the further development of a refined animal model to monitor abdominal discomfort/hyperalgesia in rats with surgically-induced endometriosis.

The AID study: protocol for a randomised controlled trial of intrauterine insemination in the natural cycle compared with intracervical insemination in the natural cycle.

INTRODUCTION: At present, studies comparing intrauterine insemination in the natural cycle versus intracervical insemination in the natural cycle in women undergoing artificial insemination with donor sperm are scarce. METHODS AND ANALYSIS: We perform a randomised controlled non-inferiority trial among five secondary and tertiary fertility clinics in the Netherlands and one tertiary fertility clinic in Belgium. Women eligible for artificial insemination with donor sperm are included. We perform six cycles of artificial insemination with donor sperm within a time horizon of 8 months comparing intrauterine insemination in the natural cycle with intracervical insemination in the natural cycle. The primary outcome is ongoing pregnancy leading to live birth conceived within eight months after randomisation. Secondary outcomes are clinical pregnancy rate, miscarriage rate, multiple pregnancy rate, pregnancy complications (preterm birth, birth weight <2500 g, pregnancy induced hypertension, (pre-) eclampsia, Hemolysis Elevated Liver enzymes Low Platelets (HELLP)), time to ongoing pregnancy, direct and indirect costs. To demonstrate the non-inferiority of intracervical insemination with a margin of 12%, we need 208 women per arm. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on research involving human subjects (47330-018-13). The boards of the participating hospitals approved the study. Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NTR4462.

Effective Connectivity of Beta Oscillations in Endometriosis-Related Chronic Pain During rest and Pain-Related Mental Imagery.

Using the EEG recordings of patients with endometriosis-related chronic pelvic pain, we have examined the effective connectivity within the cortical pain-related network during rest and during pain-related imagery. During rest, an altered connectivity was hypothesized between cortical somatosensory pain areas and regions involved in emotional and cognitive modulation of pain. During pain-related imagery, alterations in prefrontal-temporal connectivity were expected. The effective connectivity was estimated using the Directed Transfer Function method. Differences between endometriosis patients and controls were found in the beta band (14-25 Hz). During rest, endometriosis was associated with an increased connectivity from the left dorsolateral prefrontal cortex to the left somatosensory cortex and also from the left somatosensory cortex to the orbitofrontal cortex and the right temporal cortex. These results might be related to sustained activation of the somatosensory pain system caused by the ongoing pain. During pain-related imagery, endometriosis patients showed an increased connectivity from the left dorsolateral prefrontal cortex to the right temporal cortex. This finding might point to impaired emotional regulation when processing pain-related stimuli, or it might be related to altered memorization of pain experiences. Results of this study open up new directions in chronic pain research aimed at exploring the beta band connectivity alterations. PERSPECTIVE: This study examined the pain system's dynamics in endometriosis patients with chronic pelvic pain during resting-state and pain-related mental imagery. The results could contribute to the development of new therapies using guided mental imagery.

Health state utilities for infertility and subfertility.

BACKGROUND: Health state utility values allow for comparison of treatments across different diseases. Utility values for fertility-impaired health states are currently unavailable. Such values are necessary in order to determine the relative costs-effectiveness of fertility treatments. METHODS: This study aimed to determine utility weights for infertile and subfertile health states. In addition, it explored the Dutch general population's opinions regarding the inclusion of infertility treatments in the Dutch health insurers' basic benefit package. An online questionnaire was designed to determine the health-related quality of life values of six fertility-impaired health states. The study population consisted of a representative sample of the Dutch adult population. Respondents were asked to evaluate the health states through direct health valuation methods, i.e. the Visual Analogue Scale (VAS) and the Time Trade-Off (TTO) method. In addition, respondents were asked about their opinions regarding reimbursement of fertility-related treatments. RESULTS: The respondents' (n = 767) VAS scores ranged from 0.640 to 0.796. TTO utility values ranged from 0.792 to 0.868. Primary infertility and subfertility was valued lower than secondary infertility and subfertility. In total, 92% of the respondents stated that fertility treatments should be fully or partially reimbursed by the health insurance basic benefit package. CONCLUSIONS: Having fertility problems results in substantial disutilities according to the viewpoint of the Dutch general population. The results make it possible to compare the value for money of infertility treatment to that of treatments in other disease areas. There is strong support among the general population for reimbursing fertility treatments through the Dutch basic benefit package.