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Fundamental and translational research in ovarian cancer aims to enhance understanding of disease mechanisms and improve treatment and survival outcomes. To support this, we established the Dutch multicenter, interdisciplinary Archipelago of Ovarian Cancer Research (AOCR) infrastructure, which includes a nationwide biobank. In this study, we share our experiences in establishing the infrastructure, offer guidance for similar initiatives, and evaluate the AOCR patient cohort. Key challenges included obtaining Data Protection Impact Assessment (DPIA) clearance, drafting the consortium agreement, and securing ethical approval from all hospitals. Over three years, 1093 patients were enrolled across 17 hospitals, resulting in the collection of 1339 tissue samples and 2280 blood samples. Of the 523 patients with currently available clinical and pathological data, 74 % (n = 387) had primary ovarian cancer. Among these patients, 73.4 % was diagnosed with high-grade serous ovarian carcinoma, and 80.9 % presented with advanced-stage disease. Surgery was performed on 93 % of patients with primary ovarian cancer, and chemotherapy was administered to 90.4 % of these patients. In conclusion, the AOCR biobank has established a robust foundation for future fundamental and translational ovarian cancer research. This manuscript provides valuable insights and guidance for developing future research infrastructures and biobanks, and contains detailed information about the AOCR patient cohort to date., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate and compare the efficacy and safety of Botulinum Toxin A (BTA) injections versus placebo injections, combined with pelvic floor muscle therapy (PFMT), in women with chronic pelvic pain (CPP)., Design: Randomised, double-blinded clinical trial (January 2020-April 2023)., Setting: This multicentre study was conducted at four hospitals in the Netherlands., Population and Sample: Ninety-four women with CPP and increased pelvic floor muscle tone despite previous PFMT, were enrolled., Methods: Participants received either BTA injections (100 units) or placebo injections into the pelvic floor muscle, followed by four PFMT sessions., Main Outcomes and Measures: Primary outcomes included the number of women with at least a 33% reduction in pain and those reporting (very) much improvement of their pain. Secondary outcomes covered quality of life and pelvic floor function. Follow-up visits were scheduled at 4, 8, 12, and 26 weeks post-treatment. Mixed models for repeated measurements were used for analysis., Results: A 33% reduction or more in average pain score was reported by 15 participants (33%) after BTA treatment and 9 participants (20%) after placebo treatment (odd ratio placebo/BTA 1.88; 95% CI 0.72-4.90, p = 0.19). In both groups, 8 women (17%) reported their improvement as (very) much better (odd ratio placebo/BTA 0.947; 95% CI 0.32-2.80, p = 0.92). Pelvic floor resting activity decreased significantly after BTA treatment compared to placebo (p = 0.001)., Conclusion: The results from this study do not support the use of BTA injections in the management of CPP in women., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: Biobanks play a crucial role in fundamental and translational research by storing valuable biomaterials and data for future analyses. However, the design of their information technology (IT) infrastructures is often customized to specific requirements, thereby lacking the ability to be used for biobanks comprising other (types of) diseases. This results in substantial costs, time, and efforts for each new biobank project. The Dutch multicenter Archipelago of Ovarian Cancer Research (AOCR) biobank has developed an innovative, reusable IT infrastructure capable of adaptation to various biobanks, thereby enabling cost-effective and efficient implementation and management of biobank IT systems. Methods and Results: The AOCR IT infrastructure incorporates preexisting biobank software, mainly managed by Health-RI. The web-based registration tool Ldot is used for secure storage and pseudonymization of patient data. Clinicopathological data are retrieved from the Netherlands Cancer Registry and the Dutch nationwide pathology databank (Palga), both established repositories, reducing administrative workload and ensuring high data quality. Metadata of collected biomaterials are stored in the OpenSpecimen system. For digital pathology research, a hematoxylin and eosin-stained slide from each patient's tumor is digitized and uploaded to Slide Score. Furthermore, adhering to the Findable, Accessible, Interoperable, and Reusable (FAIR) principles, genomic data derived from the AOCR samples are stored in cBioPortal. Conclusion: The IT infrastructure of the AOCR biobank represents a new standard for biobanks, offering flexibility to handle diverse diseases and types of biomaterials. This infrastructure bypasses the need for disease-specific, custom-built software, thereby being cost- and time-effective while ensuring data quality and legislative compliance. The adaptability of this infrastructure highlights its potential to serve as a blueprint for the development of IT infrastructures in both new and existing biobanks.

Background: Vulvar lichen sclerosus (LS) is a chronic inflammatory dermatosis which can progress to precursor lesion differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar squamous cell carcinoma (VSCC). The risk of developing recurrent vulvar cancer following LS-associated VSCC is high. Evidence suggests that treatment of LS with topical corticosteroids (TCS) can prevent progression to dVIN, VSCC and recurrences. However, current guidelines do not give any recommendation on the management of LS following surgery for VSCC. The aim of this study was to conduct a survey among all registered gynaecologic oncologists (GOs) in the Netherlands to evaluate the current management of LS patients without a history of VSCC (LS noVSCC ) and patients with LS following surgery for VSCC (LS VSCC )., Methods: An online survey was distributed to all registered GOs in the Netherlands. Primary outcome measures were the frequency, type and duration of TCS treatment prescribed for LS noVSCC and LS VSCC patients, separately. As a secondary outcome measure, reasons for treating or not treating patients with LS noVSCC and LS VSCC with TCS were analysed., Results: Forty-four GOs completed the survey, resulting in a response rate of 75%. TCS were prescribed more often to patients with LS noVSCC as compared to patients with LS VSCC (86% versus 52%, respectively, p  < 0.001). If treatment was initiated, ultra-potent (class IV) TCS were most commonly prescribed for an indefinite period of time for both patient groups. The most reported reason for treating patients in both groups with TCS was symptoms, followed by clinical aspects of the lesion and prevention of progression to dVIN and VSCC., Conclusion: The majority of GOs who participated in our study endorse the utilisation of long-term ultra-potent TCS therapy in both patients with LS noVSCC and LS VSCC . Nevertheless, Dutch GOs are currently prescribing TCS more frequently to patients with LS noVSCC than to patients with LS VSCC .

Introduction: Pelvic organ prolapse is a distressing condition affecting women. Pessary therapy is a conservative and effective treatment option. However, 20-60% of women discontinue pessary treatment within 24 months., Objective: To identify patient characteristics associated with discontinuation of pessary treatment for symptomatic pelvic organ prolapse up to 24 months and to explore whether a prediction model can be developed., Study Design: Prospective observational study in 22 Dutch hospitals with a follow-up duration of 24 months., Method: Baseline patient characteristics from 6 different domains were compared between women who continued pessary therapy and women who discontinued pessary therapy within 24 months. Women with initial fitting failure were not included in analysis. Univariable and multivariable analysis were applied to identify predictors., Results: Of the 251 women included in analysis, 102 stopped using a pessary at 24 months (40.6%). After multivariable analysis, age (OR 0.95, 95% CI 0.92-0.98, p < 0.001) and the presence of patient-reported allergies (OR 2.48, 95% CI 1.32-4.66, p = 0.005) were found to be predictive for pessary discontinuation within 24 months. These two factors explain 11% of the models' variance. However, in 49% of patient-reported allergies, the allergy was not specified., Conclusion: Younger women and those who reported allergies at baseline were less likely to continue pessary use. However, the high number of unspecified reported allergies and the lack of a clear scientific explanation, suggests that a direct causal link is unlikely and warrants additional research., Competing Interests: Declarations. Conflict of interest: The authors have no financial or non-financial interests to disclose. Ethical approval: This study was approved by the Medical Research Ethics Committee (MREC), or Medisch Ethische Toetsing Commissie (METC), in Dutch. The date of approval was 22 September 2015 and the METC protocol number is 14-533/M., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: An increased interest in medical liability claims has been noticed. Nevertheless, detailed data on subject of claims and possible factors that contribute to litigation and indemnity payments are scarce and relatively dated. Insight into these data may provide valuable information to prevent both incidents and malpractice claims., Objective: To analyse the subject, outcome and costs of malpractice claims related to gynaecological care and their connection with treatment indications and treatment phases., Design: A retrospective analysis of malpractice claims related to gynaecology., Setting: All claims related to gynaecology, filed and closed by Netherlands' largest liability insurance company, Centramed between 2005 and 2022., Sample: N = 382., Methods: An in-depth analysis of claim files was performed., Results: A total of 68.6% of the claims were related to perioperative incidents. A total of 88.0% of all claims were related to treatments with a benign indication and only 12.0% were related to malignancies. The share of malignant treatment indications was high for claims related to diagnostic incidents (37.9%), compared to 7.3% for claims related to surgical treatment. Liability was accepted in 22.5% of all claims. The total costs of all claims amount €6,6mlj. Besides the indication for treatment, deficient expectation management (a lack of informed consent) contributes to dissatisfaction and increases the risk of malpractice claims. Finally, an inadequate medical file compromises legal defence and influences the judgement and settlement of malpractice claims., Conclusions: There is a connection between treatment indications and treatment phases and the risk of malpractice claims and their outcome., Competing Interests: Declarations. Ethics approval and consent to participate: This study was submitted to, and approved by, the Medical Ethics Review Committee (METC) from the MUMC + (file number METC 2021–3020). The METC confirmed that the Medical Research Involving Human Subjects Act does not apply for this study and declared that no additional ethical review was obliged. Informed consent from study participants was not obtained, since the study is based on an anonymized, retrospective analysis of medical liability files. Consent for publication: Not applicable, since the study is based on an anonymized, retrospective analysis of medical liability files. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: In the FIGO 2018 classification, women with cervical cancer and a depth of invasion ≤ 5 mm and a horizontal spread of > 7 mm in excisional biopsy with tumour-free margins, are now classified as stage IA instead of IB. This stage shift may reduce the likelihood of surgical lymph node staging. It is therefore crucial to estimate the risk and risk factors of lymph node metastasis (pN+) in this group., Methods: Women diagnosed with cervical cancer between 2005 and 2022 were identified from nationwide population-based registries from the Netherlands, Denmark, and Sweden. Inclusion criteria were squamous cell carcinoma or adenocarcinoma, FIGO 2009 stage IB1, a depth of invasion ≤ 5 mm and horizontal spread of > 7-≤ 40 mm. All cases underwent radical hysterectomy or radical trachelectomy, and surgical lymph node staging. Logistic regression was used to identify risk factors of pN+., Results: We included 992 women (pN+ 4.1 %; n = 41). Lymphovascular space invasion (LVSI) was a significant risk factor of pN+ (odds ratio 4.26, 95 % confidence interval 2.24-8.32). Accordingly, the risk of pN+ was ≥ 7.3 % in LVSI-positive tumours. The risk was lowest in LVSI-negative tumours with a size of > 7-≤ 20 mm (2.2 %), although this varied by depth of invasion and histological subtype (pN+ range 0.6-5.1 %)., Conclusion: Women with LVSI-positive FIGO 2018 IA cervical cancer and a horizontal spread > 7 mm, should undergo surgical lymph node staging. In LVSI-negative tumours, lymph node staging should not be routinely performed; tumour size, depth of invasion and histology should be considered., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HF: Board Member Surgical Science, PJ: MSD Advisory Board for cervical cancer, All other authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Asthma is the most common chronic respiratory disease in women of childbearing age and during pregnancy. This paper presents a summary of the Dutch multidisciplinary guideline on asthma and pregnancy. The aim of this guideline is to provide structured, where possible, evidence-based recommendations to optimize the management of asthma during pregnancy. The main topics covered in this guideline are preconception counseling, the safety of asthma medications during pregnancy and breastfeeding and risk assessment and monitoring of asthma during pregnancy. Because many caregivers are involved and a uniform approach is desirable, this guideline has been developed in collaboration with all relevant health care providers and patient representatives., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to assess the outcomes of patients with early stage mucinous ovarian carcinoma based on subtype (expansile vs infiltrative)., Methods: We retrospectively analyzed all surgically treated patients with mucinous ovarian carcinoma in the Netherlands (2015-2020), using data from national registries. Subtypes were determined, with any ambiguities resolved by a dedicated gynecologic pathologist. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I were categorized into full staging, fertility-sparing, or partial stagings. Outcomes were overall survival and recurrence free survival, and recurrence rates., Results: Among 409 identified patients, 257 (63%) had expansile and 152 (37%) had infiltrative tumors. Patients with expansile tumors had FIGO stage I more frequently (n=243, 95% vs n=116, 76%, p<0.001). For FIGO stage I disease, patients with expansile and infiltrative tumors underwent similar proportions of partial (n=165, 68% vs n=78, 67%), full (n=32, 13% vs n=23, 20%), and fertility-sparing stagings (n=46, 19% vs n=15, 13%) (p=0.139). Patients with expansile FIGO stage I received less adjuvant chemotherapy (n=11, 5% vs n=24, 21%, p<0.001), exhibited better overall and recurrence free survival (p=0.006, p=0.012), and fewer recurrences (n=13, 5% vs n=16, 14%, p=0.011). Survival and recurrence rates were similar across the expansile extent of staging groups. Patients undergoing fertility-sparing staging for infiltrative tumors had more recurrences compared with full or partial stagings, while recurrence free survival was similar across these groups. Full staging correlated with better overall survival in infiltrative FIGO stage I (p=0.022)., Conclusions: While most patients with FIGO stage I underwent partial staging, those with expansile had better outcomes than those with infiltrative tumors. Full staging was associated with improved overall survival in infiltrative, but not in expansile FIGO stage I. These results provide insight for tailored surgical approaches., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the various factors that influence environmentally sustainable behaviour in gynaecological surgery and examine the differences between gynaecologists and residents., Design: An interview study., Setting: Academic and non-academic hospitals in the Netherlands., Population: Gynaecologists (n = 10) and residents (n = 6)., Methods: Thematic analysis of semi-structured interviews to determine the various factors that influence environmentally sustainable behaviour in gynaecological surgery and to examine the differences between gynaecologists and residents. By using the Desmond framework and the COM-B BCW, both organisational and individual factors related to behaviour were considered., Main Outcome Measures: Factors that influence environmentally sustainable behaviour., Results: Awareness is increasing but practical knowledge is insufficient. It is crucial to integrate education on the environmental impact of everyday decisions for residents and gynaecologists. Gynaecologists make their own choices but residents' autonomy is limited. There is the necessity to provide environmentally sustainable surgical equipment without compromising other standards. There is a need for a societal change that encourages safe and open communication about environmental sustainability. To transition to environmentally sustainable practices, leadership, time, collaboration with the industry and supportive regulatory changes are essential., Conclusion: This study lays the groundwork for promoting more environmentally sustainable behaviour in gynaecological surgery. The key recommendations, addressing hospital regulations, leadership, policy revisions, collaboration with the industry, guideline development and education, offer practical steps towards a more sustainable healthcare system. Encouraging environmentally sustainable practices should be embraced to enhance the well-being of both our planet and our population, driving us closer to a more environmentally sustainable future in healthcare., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To compare the carbon footprint of caesarean and vaginal birth., Design: Life cycle assessment (LCA)., Setting: Tertiary maternity units and home births in the UK and the Netherlands., Population: Birthing women., Methods: A cradle-to-grave LCA using openLCA software to model the carbon footprint of different modes of delivery in the UK and the Netherlands., Main Outcome Measures: 'Carbon footprint' (in kgCO 2 equivalents [kgCO 2 e])., Results: Excluding analgesia, the carbon footprint of a caesarean birth in the UK was 31.21 kgCO 2 e, compared with 12.47 kgCO 2 e for vaginal birth in hospital and 7.63 kgCO 2 e at home. In the Netherlands the carbon footprint of a caesarean was higher (32.96 kgCO 2 e), but lower for vaginal birth in hospital and home (10.74 and 6.27 kgCO 2 e, respectively). Emissions associated with analgesia for vaginal birth ranged from 0.08 kgCO 2 e (with opioid analgesia) to 237.33 kgCO 2 e (nitrous oxide with oxygen). Differences in analgesia use resulted in a lower average carbon footprint for vaginal birth in the Netherlands than the UK (11.64 versus 193.26 kgCO 2 e)., Conclusion: The carbon footprint of a caesarean is higher than for a vaginal birth if analgesia is excluded, but this is very sensitive to the analgesia used; use of nitrous oxide with oxygen multiplies the carbon footprint of vaginal birth 25-fold. Alternative methods of pain relief or nitrous oxide destruction systems would lead to a substantial improvement in carbon footprint. Although clinical need and maternal choice are paramount, protocols should consider the environmental impact of different choices., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Purpose: The Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease (UCC-SMART) Study is an ongoing prospective single-centre cohort study with the aim to assess important determinants and the prognosis of cardiovascular disease progression. This article provides an update of the rationale, design, included patients, measurements and findings from the start in 1996 to date., Participants: The UCC-SMART Study includes patients aged 18-90 years referred to the University Medical Center Utrecht, the Netherlands, for management of cardiovascular disease (CVD) or severe cardiovascular risk factors. Since September 1996, a total of 14 830 patients have been included. Upon inclusion, patients undergo a standardised screening programme, including questionnaires, vital signs, laboratory measurements, an ECG, vascular ultrasound of carotid arteries and aorta, ankle-brachial index and ultrasound measurements of adipose tissue, kidney size and intima-media thickness. Outcomes of interest are collected through annual questionnaires and adjudicated by an endpoint committee., Findings to Date: By May 2022, the included patients contributed to a total follow-up time of over 134 000 person-years. During follow-up, 2259 patients suffered a vascular endpoint (including non-fatal myocardial infarction, non-fatal stroke and vascular death) and 2794 all-cause deaths, 943 incident cases of diabetes and 2139 incident cases of cancer were observed up until January 2020. The UCC-SMART cohort contributed to over 350 articles published in peer-reviewed journals, including prediction models recommended by the 2021 European Society of Cardiology CVD prevention guidelines., Future Plans: The UCC-SMART Study guarantees an infrastructure for research in patients at high cardiovascular risk. The cohort will continue to include about 600 patients yearly and follow-up will be ongoing to ensure an up-to-date cohort in accordance with current healthcare and scientific knowledge. In the near future, UCC-SMART will be enriched by echocardiography, and a food frequency questionnaire at baseline enabling the assessment of associations between nutrition and CVD and diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Congenital platelet disorders (CPDs) are rare bleeding disorders that are associated with mucocutaneous bleeds. However, data on vaginal bleeding in women with CPDs are scarce. A set of generic and bleeding-specific questionnaires were used to evaluate the prevalence of vaginal bleeding, its impact on quality of life (QoL) and sexual functioning and the consequences for pregnancy, miscarriage and delivery in a cohort of women who were referred for diagnostic evaluation for CPDs. A total of 78 women included in the study were either diagnosed with a CPD (n = 35) or were clinically suspected of a CPD (n = 43). Heavy menstrual bleeding (HMB) was reported by a large proportion of women, which mainly started at menarche. In all, 76% of women received any kind of HMB treatment, often leading to surgical prodecures. HMB was shown to have a high impact on QoL, which improved upon treatment. Even though women reported that vaginal bleeding affects sexuality, this topic is not frequently discussed with physicians. Heavy blood loss frequently occurred after miscarriage/delivery, often requiring treatment. Women with (suspected) CPDs frequently encounter HMB, negatively impacting daily life and sexual functioning. Together with peripartum bleeding, these data highlight the burden of vaginal bleeding in CPDs and importance of adequate treatment., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective: To identify, besides maternal age and the number of previous pregnancy losses, additional characteristics of couples with unexplained recurrent pregnancy loss (RPL) that improve the prediction of an ongoing pregnancy., Design: Hospital-based cohort study in couples who visited specialized RPL units of two academic centers between 2012 and 2020., Setting: Two academic centers in the Netherlands., Patients: Clinical data from 526 couples with unexplained RPL were used in this study., Intervention(s): None., Main Outcome Measures: The final model to estimate the chance of a subsequent ongoing pregnancy was determined using a backward selection process and internally validated using bootstrapping. Model performance was assessed in terms of calibration and discrimination (area under the receiver operating characteristic curve)., Results: Subsequent ongoing pregnancy was achieved in 345 of 526 couples (66%). The number of previous pregnancy losses, maternal age, paternal age, maternal body mass index, paternal body mass index, maternal smoking status, and previous in vitro fertilization/intracytoplasmic sperm injection treatment were predictive of the outcome. The optimism-corrected area under the receiver operating characteristic curve was 0.63 compared with 0.57 when using only the number of previous pregnancy losses and maternal age., Conclusions: The identification of additional predictors of a subsequent ongoing pregnancy after RPL, including male characteristics, is significant for both clinicians and couples with RPL. At the same time, we showed that the predictive ability of the current model is still limited and more research is warranted to develop a model that can be used in clinical practice., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Worldwide, hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR) and preterm birth remain the leading causes of maternal and fetal pregnancy-related mortality and (long-term) morbidity. Fetal cardiac deformation changes can be the first sign of placental dysfunction, which is associated with HDP, FGR and preterm birth. In addition, preterm birth is likely associated with changes in electrical activity across the uterine muscle. Therefore, fetal cardiac function and uterine activity can be used for the early detection of these complications in pregnancy. Fetal cardiac function and uterine activity can be assessed by two-dimensional speckle-tracking echocardiography (2D-STE), non-invasive fetal electrocardiography (NI-fECG), and electrohysterography (EHG). This study aims to generate reference values for 2D-STE, NI-fECG and EHG parameters during the second trimester of pregnancy and to investigate the diagnostic potential of these parameters in the early detection of HDP, FGR and preterm birth., Methods: In this longitudinal prospective cohort study, eligible women will be recruited from a tertiary care hospital and a primary midwifery practice. In total, 594 initially healthy pregnant women with an uncomplicated singleton pregnancy will be included. Recordings of NI-fECG and EHG will be made weekly from 22 until 28 weeks of gestation and 2D-STE measurements will be performed 4-weekly at 16, 20, 24 and 28 weeks gestational age. Retrospectively, pregnancies complicated with pregnancy-related diseases will be excluded from the cohort. Reference values for 2D-STE, NI-fECG and EHG parameters will be assessed in uncomplicated pregnancies. After, 2D-STE, NI-fCG and EHG parameters measured during gestation in complicated pregnancies will be compared with these reference values., Discussion: This will be the a large prospective study investigating new technologies that could potentially have a high impact on antepartum fetal monitoring., Trial Registration: Registered on 26 March 2020 in the Dutch Trial Register (NL8769) via https://www.trialregister.nl/trials and registered on 21 October 2020 to the Central Committee on Research Involving Human Subjects (NL73607.015.20) via https://www.toetsingonline.nl/to/ccmo&#95;search.nsf/Searchform?OpenForm ., (© 2021. The Author(s).)

Objective: To test the hypothesis that surgical site infection (SSI) risk differs, after administration of surgical antibiotic prophylaxis (SAP) within 60-30 or 30-0 minutes before incision., Background: The importance of appropriate timing of SAP before surgery has long been recognized. However, available evidence is contradictive on the best timing within a 60-0 minutes time interval before incision. Here, we aim to evaluate previous contradictions with a carefully designed observational cohort., Methods: An observational cohort study was conducted in a Dutch tertiary referral center. For 2 years, consecutive patients with SAP indication undergoing general, orthopedic, or gynecologic surgery were followed for the occurrence of superficial and deep SSI as defined by the Center of Disease Control and Prevention. The association between timing of SAP and SSI was assessed using multivariable logistic regression., Results: After 3001 surgical procedures, 161 SSIs were detected. In 87% of the procedures, SAP was administered within 60 minutes before incision. Only antibiotics with short infusion time were used. Multivariable logistic regression indicated there was no conclusive evidence of a difference in SSI risk after SAP administration 60-30 minutes or 30-0 minutes before incision [odds ratio: 0.82; 95% confidence interval (0.57-1.19)]., Conclusions: For SAP with short infusion time no clear superior timing interval within the 60-minute interval before incision could be identified in this cohort. We were unable to reproduce differences in SSI risk found in earlier studies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM)., Materials & Methods: This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis., Results: The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-risk clinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy., Conclusion: Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest. Authors have full control of all primary data. They agree to allow the journal to review the data if requested., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline., Methods: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016-1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS., Results: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles., Conclusion: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: In vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen-thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited., Methods and Analysis: We have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients' treatment burden., Ethics and Dissemination: The study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals., Trial Registration Number: Netherlands Trial Register (NL 6857)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The risk of vulvar squamous cell carcinoma (VSCC) in patients with high-grade vulvar intraepithelial neoplasia (VIN) is considered lower in high-grade squamous intraepithelial lesion (HSIL) compared to differentiated VIN (dVIN), but studies are limited. Our study investigated both the incidence of high-grade VIN and the cumulative incidence of VSCC in patients with HSIL and dVIN separately. A database of women diagnosed with high-grade VIN between 1991 and 2011 was constructed with data from the Dutch Pathology Registry (PALGA). The European standardized incidence rate (ESR) and VSCC risk were calculated, stratified for HSIL and dVIN. The effects of type of VIN (HSIL vs dVIN), age and lichen sclerosis (LS) were estimated by Cox regression. In total, 1148 patients were diagnosed with high-grade VIN between 1991 and 2011. Between 1991-1995 and 2006-2011, the ESR of HSIL increased from 2.39 (per 100 000 woman-years) to 3.26 and the ESR of dVIN increased from 0.02 to 0.08. The 10-year cumulative VSCC risk was 10.3%; 9.7% for HSIL and 50.0% for dVIN (log rank P < .001). Type of VIN, age and presence of LS were independent risk factors for progression to VSCC, with hazard ratios of 3.0 (95% confidence interval [CI] 1.3-7.1), 2.3 (95% CI 1.5-3.4) and 3.1 (95% CI 1.8-5.3), respectively. The incidence of high-grade VIN is rising. Because of the high cancer risk in patients with dVIN, better identification and timely recognition are urgently needed., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Study Question: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle?, Summary Answer: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%., What Is Known Already: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes., Study Design, Size, Duration: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate., Participants/materials, Setting, Methods: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%)., Main Results and the Role of Chance: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI)., Limitations, Reasons for Caution: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%., Wider Implications of the Findings: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials., Study Funding/competing Interest(s): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work., Trial Registration Number: Registered in the Netherlands Trial Register (NL5193/NTR 5342)., Trial Registration Date: 31 July 2015., Date of First Patient’s Enrolment: 26 January 2016., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Approximately 1 in 7 couples experience subfertility, many of whom have lifestyles that negatively affect fertility, such as poor nutrition, low physical activity, obesity, smoking, or alcohol consumption. Reducing lifestyle risk factors prior to pregnancy or assisted reproductive technology treatment contributes to the improvement of reproductive health, but cost-implications are unknown., Objective: The goal of this study was to evaluate reproductive, maternal pregnancy, and birth outcomes, as well as the costs of pre-conception lifestyle intervention programs in subfertile couples and obese women undergoing assisted reproductive technology., Methods: Using a hypothetical model based on quantitative parameters from published literature and expert opinion, we evaluated the following lifestyle intervention programs: (1) Smarter Pregnancy, an online tool; (2) LIFEstyle, which provides outpatient support for obese women; (3) concurrent use of both Smarter Pregnancy and LIFEstyle for obese women; (4) smoking cessation in men; and (5) a mindfulness mental health support program using group therapy sessions. The model population was based on data from the Netherlands., Results: All model-based analyses of the lifestyle interventions showed a reduction in the number of in vitro fertilization, intracytoplasmic sperm injection, or intrauterine insemination treatments required to achieve pregnancy and successful birth for couples in the Netherlands. Smarter Pregnancy was modeled to have the largest increase in spontaneous pregnancy rate (13.0%) and the largest absolute reduction in potential assisted reproductive technology treatments. Among obese subfertile women, LIFEstyle was modeled to show a reduction in the occurrence of gestational diabetes, maternal hypertensive pregnancy complications, and preterm births by 4.4%, 3.8%, and 3.0%, respectively, per couple. Modeled cost savings per couple per year were €41 (US $48.66), €360 (US $427.23), €513 (US $608.80), €586 (US $695.43), and €1163 (US $1380.18) for smoking cessation, mindfulness, Smarter Pregnancy, combined Smarter Pregnancy AND LIFEstyle, and LIFEstyle interventions, respectively., Conclusions: Although we modeled the potential impact on reproductive outcomes and costs of fertility treatment rather than collecting real-world data, our model suggests that of the lifestyle interventions for encouraging healthier behaviors, all are likely to be cost effective and appear to have positive effects on reproductive, maternal pregnancy, and birth outcomes. Further real-world data are required to determine the cost-effectiveness of pre-conception lifestyle interventions, including mobile apps and web-based tools that help improve lifestyle, and their effects on reproductive health. We believe that further implementation of the lifestyle app Smarter Pregnancy designed for subfertile couples seeking assistance to become pregnant is likely to be cost-effective and would allow reproductive health outcomes to be collected., (©Régine Steegers-Theunissen, Annemieke Hoek, Henk Groen, Annelies Bos, Grada van den Dool, Marieke Schoonenberg, Jesper Smeenk, Eva Creutzberg, Loes Vecht, Luc Starmans, Joop Laven. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 23.11.2020.)

Background: Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma equally benefit from these new treatments compared with patients with cutaneous melanoma (CM)., Methods: Patients with advanced MM and CM diagnosed between 2013 and 2017 were included from a nationwide population-based registry - the Dutch Melanoma Treatment Registry. Overall survival (OS) was estimated with the Kaplan-Meier method (also for a propensity score-matched cohort). A Cox model was used to analyse the association of possible prognostic factors with OS., Results: In total, 120 patients with MM and 2960 patients with CM were included. Median OS was 8.7 months and 14.5 months, respectively. Patients with MM were older (median age 70 versus 65 years) and more often female (60% versus 41%), compared with CM. In total, 77% and 2% of the MM patients were treated with first-line immunotherapy and targeted therapy, respectively, compared with 49% and 33% of the CM patients. In contrast to CM, OS for MM did not improve for patients diagnosed in 2015-2017, compared with 2013-2014. ECOG performance score ≥1 (HR = 1.99 [1.26-3.15; p = 0.003]) and elevated LDH level (HR = 1.63 [0.96-2.76]; p = 0.069) in MM were associated with worse survival., Conclusions: Within the era of immune and targeted therapies, prognosis for patients with advanced MM has not improved as much as for CM. Collaboration is necessary to enlarge sample size for research to improve immunotherapeutic strategies and identify targetable mutations., Competing Interests: Conflict of interest statement M.C.T.v.Z., F.L.B., M.I.E.v.P., L.C.d.W., M.W.J.M.W., M.J.B.S., M.J.B.A., F.W.P.J.v.d.B., D.P., R.S.v.R., A.J.t.T., G.V., J.v.d.H. have no conflicts of interest to disclose. A.J.M.v.d.E. reports having advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Novartis, MSD, and Pierre Fabre. J.W.B.d.G. reports receiving personal fees outside the submitted work from Bristol-Myers Squibb, Roche, Pierre Fabre, Servier, MSD, Novartis. G.A.P.H. reports having consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis and receiving research grants not related to this paper from Bristol-Myers Squibb, and Seerave. E.H.W.K. reports having consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Novartis, Roche, Merck, Pierre Fabre, EISAI, Bayer, Genzyme-Sanofi and receiving research grants not related to this paper from Novartis and Bristol-Myers Squibb. K.P.M.S. reports having advisory relationships with Bristol-Myers Squibb, Roche, Novartis, MSD, and Pierre Fabre. A.A.M.v.d.V. reports having consultancy relationships with Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, and Eisai. J.B.A.G.H. reports having advisory relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celsius Therapeutics, GSK, Immunocore, Ipsen, MSD, Merck Serono, Novartis, Neon Therapeutics, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics and receiving research grants not related to this paper from Novartis, Bristol-Myers Squibb, MSD, Neon Therapeutics. All grants were paid to the institutions. The funders had no role in the writing of this article or decision to submit it for publication. Authors have full control of all primary data. They agree to allow the journal to review the data if requested., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Diagnosis of congenital viral infection at birth is generally attempted by direct detection of the virus by PCR in various neonatal materials. How to reliably diagnose intrauterine infection with parvovirus B19 (B19 V) at birth is unknown., Objectives: To evaluate the performance of B19 V DNA detection in cord blood (CB) or neonatal dried blood spots (DBS) in diagnosing fetal infection., Study Design: Two cohorts of children diagnosed prenatally with an intrauterine B19 V infection were included in this study. CB samples of intrauterine B19 V infections that were sent to a reference laboratory for congenital infections in Stuttgart, Germany in the period 1995-2014 were tested in triplicate for B19 V DNA by quantitative PCR. DBS from children with intrauterine B19 V infection that underwent IUT at the LUMC, Leiden, the Netherlands in the period 2009-2014 were tested for B19 V DNA by quantitative B19 V PCR in triplicate., Results: Fourteen of twenty (70 %) CB samples tested positive for B19 V DNA. The positivity rate was 40 % (4/10) in those with a prenatal diagnosis <20 weeks gestation. When intrauterine B19 V infection was diagnosed thereafter, 100 % (10/10) samples were B19 V DNA positive. Of the thirteen available DBS, twelve (92 %) tested positive. Viral load in CB and DBS corresponded inversely with time from fetal diagnosis to birth., Conclusion: B19 V DNA can be detected in neonatal blood samples of children following intrauterine B19 V infection, although the possibility of false-negatives, even in severe infections, should be considered. B19 V viral load at birth correlates with timing of infection., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate pregnancy rates, time to pregnancy (TTP) and obstetric outcomes in female childhood cancer survivors (CCSs) and to identify specific diagnosis- and treatment-related factors associated with these outcomes., Methods: The study is part of the DCOG LATER-VEVO study, a nationwide multicenter cohort study evaluating fertility among long-term Dutch female CCSs. Data were collected by questionnaire. The current study included 1095 CCSs and 812 controls, consisting of sisters of CCSs and a random sample of women from the general population., Results: Among the subgroup of women who ever had the desire to become pregnant, the chance of becoming pregnant was significantly lower for CCSs than controls (OR 0.5, 95%CI 0.4-0.8). Moreover, TTP was 1.1 times longer for CCSs compared to controls (p = 0.09) and was significantly longer in survivors of CNS and renal tumours. Overall, no differences were found between CCSs and controls regarding the probability of ever having had a miscarriage, still birth, or induced abortion. However, CCSs had a significantly increased risk of delivering preterm (OR 2.2, 95%CI 1.3-3.7) and delivering via caesarean section (OR 1.8, 95%CI 1.2-2.6). Treatment with lower abdominal/pelvic radiotherapy was strongly associated with several adverse obstetric outcomes., Conclusion: CCSs are less likely to have ever been pregnant. Among those who do become pregnant, certain subgroups of CCSs are at increased risk of longer TTP. Moreover, as pregnant CCSs, especially those treated with lower abdominal/pelvic radiotherapy, are more likely to develop various adverse obstetric outcomes, appropriate obstetric care is highly advocated.

Study Question: Does a previous Caesarean section affect reproductive outcomes, including live birth, in women after IVF or ICSI?, Summary Answer: A previous Caesarean section impairs live birth rates after IVF or ICSI compared to a previous vaginal delivery., What Is Known Already: Rates of Caesarean sections are rising worldwide. Late sequelae of a Caesarean section related to a niche (Caesarean scar defect) include gynaecological symptoms and obstetric complications. A systematic review reported a lower pregnancy rate after a previous Caesarean section (RR 0.91 CI 0.87-0.95) compared to a previous vaginal delivery. So far, studies have been unable to causally differentiate between problems with fertilisation, and the transportation or implantation of an embryo. Studying an IVF population allows us to identify the effect of a previous Caesarean section on the implantation of embryos in relation to a previous vaginal delivery., Study Design, Size, Duration: We retrospectively studied the live birth rate in women who had an IVF or ICSI treatment at the IVF Centre, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands, between 2006 and 2016 with one previous delivery. In total, 1317 women were included, of whom 334 had a previous caesarean section and 983 had previously delivered vaginally., Participants/materials, Setting, Methods: All secondary infertile women, with only one previous delivery either by caesarean section or vaginal delivery, were included. If applicable, only the first fresh embryo transfer was included in the analyses. Patients who did not intend to undergo embryo transfer were excluded. The primary outcome was live birth. Multivariate logistic regression analyses were used with adjustment for possible confounders ((i) age; (ii) pre-pregnancy BMI; (iii) pre-pregnancy smoking; (iv) previous fertility treatment; (v) indication for current fertility treatment: (a) tubal, (b) male factor and (c) endometriosis; (vi) embryo quality; and (vii) endometrial thickness), if applicable. Analysis was by intention to treat (ITT)., Main Results and the Role of Chance: Baseline characteristics of both groups were comparable. Live birth rates were significantly lower in women with a previous caesarean section than in women with a previous vaginal delivery, 15.9% (51/320) versus 23.3% (219/941) (OR 0.63 95% CI 0.45-0.87) in the ITT analyses. The rates were also lower for ongoing pregnancy (20.1 versus 28.1% (OR 0.64 95% CI 0.48-0.87)), clinical pregnancy (25.7 versus 33.8% (OR 0.68 95% CI 0.52-0.90)) and biochemical test (36.2 versus 45.5% (OR 0.68 95% CI 0.53-0.88)). The per protocol analyses showed the same differences (live birth rate OR 0.66 95% CI 0.47-0.93 and clinical pregnancy rate OR 0.72 95% CI 0.54-0.96)., Limitations, Reasons for Caution: This study is limited by its retrospective design. Furthermore, 56 (16.3%) cases lacked data regarding delivery outcomes, but these were equally distributed between the two groups., Wider Implications of the Findings: The lower clinical pregnancy rates per embryo transfer indicate that implantation is hampered after a caesarean section. Its relation with a possible niche (caesarean scar defect) in the uterine caesarean scar needs further study. Our results should be discussed with clinicians and patients who consider an elective caesarean section., Study Funding/competing Interest(s): Not applicable., Trial Registration Number: This study has been registered in the Dutch Trial Register (Ref. No. NL7631 http://www.trialregister.nl)., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

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., (© The Author(s) 2019. Published by Oxford University Press.)

Objective: Determination of the anatomical structures that should be taught to ensure safe and competent practice among general gynaecologists., Study Design: A two-round Delphi survey, face-to-face meeting in focus groups and an individual interview. Participants were medical doctors and trainees from gynaecology, surgery, urology and radiology from academic, non-academic teaching and non-academic, non-teaching hospitals in the Netherlands. Relevant structures were collected from gynaecology surgery atlas based on most common gynaecological surgeries and diseases. These structures were supplemented and critically viewed in focus groups followed by a Delphi survey. In the Delphi survey gynaecologist and trainee's gynaecology from all over the Netherlands scored the items on a Likert scale between 1 (not relevant) and 5 (highly relevant). Consensus was defined when ≥ 70 % of the panellist scored the item as relevant or very relevant and the average rating was ≥ 4. Main outcome was clinically relevant anatomical structures., Results: Consensus on 86 clinically relevant anatomical structures divided by nine categories., Conclusions: This study identified a core list of anatomical structures that are relevant to the safe and competent practice of general gynaecologists and that can be used to guide gynaecology postgraduate education. This is the first step in a much wider and complex process of becoming a competent gynaecologist., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Given the major changes in internet use for health communication, the objective of the current study was to compare the internet use and wishes of cancer survivors between 2005 and 2017., Methods: The authors drew a sample of 390 patients in 2005 and 539 patients in 2017 who were diagnosed with breast (128 patients in 2005 and 143 patients in 2017), prostate (96 patients in 2005 and 126 patients in 2017), or gynecologic (89 patients in 2005 and 188 patients in 2017) cancer or lymphoma (77 patients in 2005 and 82 patients in 2017) in 4 different hospitals for the periods 2002 through 2004 and 2014 through 2016. These patients were sent a paper-based questionnaire that contained 45 questions regarding demographics and 4 functions of internet use: content, communication, community, and e-health., Results: The response in 2017 (53%) was lower than that in 2005 (75%). Survivors browsed the internet most frequently to search for information regarding cancer shortly after being diagnosed and while waiting for treatment. There was little change noted with regard to the relative importance attached to the various subjects. In 2017, significant increases were evident with regard to finances (+33%), health care insurance (+29%), and genetics and/or heritability (+27%). The wishes expressed in 2005 by patients were realized in part in 2017., Conclusions: A significant sample of cancer survivors in the Netherlands have indicated that the internet is an important source of information regarding their illness. However, little change was evident over the past 15 years with regard to patients' priorities regarding their wishes for internet use. The wishes of users in 2005 were found to accurately reflect the internet use of the majority of patients in 2017. The results of the current study support the belief that health care professionals should expand their online services and tailor them toward the needs and wishes of their patients., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: The increase in prevalence of colorectal cancer among young patients coupled with an older retirement age in developed countries means that more patients are being diagnosed with colorectal cancer while still at work. The aim of this study was to develop prediction models for return to work by 1 and 2 years after the start of sick leave., Methods: This was a retrospective registry-based cohort study of data from a nationwide occupational health service in the Netherlands. Only employed patients with colonic or rectal cancer treated with curative intent were included. Two predictor variable models were developed using multivariable logistic regression with backward selection. Calibration, discrimination and explained variance were used to assess model performance, and internal validation by bootstrapping was performed., Results: Median time to return to work for 317 included patients was 423 (95 per cent c.i. 379 to 467) days. Two-thirds of patients had returned to work by 2 years after the start of the sick leave. Presence of metastases, adjuvant treatment, stoma, emotional distress and postoperative complications were predictors of not returning to work in the 1-year model. In the 2-year model, presence of metastases, emotional distress, postoperative complications, company size and the trajectory of the return-to-work process were predictors., Conclusion: Almost 70 per cent of patients with colorectal cancer in this population returned to work within 2 years after the start of sick leave. The models can be used to guide patients early in colorectal cancer treatment about the likelihood of returning to work, and to identify and modify barriers that could facilitate this., (© 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Study Question: Can exome sequencing identify new genetic causes of globozoospermia?, Summary Answer: Exome sequencing in 15 cases of unexplained globozoospermia revealed deleterious mutations in seven new genes, of which two have been validated as causing globozoospermia when knocked out in mouse models., What Is Known Already: Globozoospermia is a rare form of male infertility characterised by round-headed sperm and malformation of the acrosome. Although pathogenic variants in DPY19L2 and SPATA16 are known causes of globozoospermia and explain up to 70% of all cases, genetic causality remains unexplained in the remaining patients., Study Design, Size, Duration: After pre-screening 16 men for mutations in known globozoospermia genes DPY19L2 and SPATA16, exome sequencing was performed in 15 males with globozoospermia or acrosomal hypoplasia of unknown aetiology., Participants/materials, Setting, Method: Targeted next-generation sequencing and Sanger sequencing was performed for all 16 patients to screen for single-nucleotide variants and copy number variations in DPY19L2 and SPATA16. After exclusion of one patient with DPY19L2 mutations, we performed exome sequencing for the 15 remaining subjects. We prioritised recessive and X-linked protein-altering variants with an allele frequency of <0.5% in the population database GnomAD in genes with an enhanced expression in the testis. All identified candidate variants were confirmed in patients and, where possible, in family members using Sanger sequencing. Ultrastructural examination of semen from one of the patients allowed for a precise phenotypic characterisation of abnormal spermatozoa., Main Results and Role of Chance: After prioritisation and validation, we identified possibly causative variants in eight of 15 patients investigated by exome sequencing. The analysis revealed homozygous nonsense mutations in ZPBP and CCDC62 in two unrelated patients, as well as rare missense mutations in C2CD6 (also known as ALS2CR11), CCIN, C7orf61 and DHNA17 and a frameshift mutation in GGN in six other patients. All variants identified through exome sequencing, except for the variants in DNAH17, were located in a region of homozygosity. Familial segregation of the nonsense variant in ZPBP revealed two fertile brothers and the patient's mother to be heterozygous carriers. Paternal DNA was unavailable. Immunohistochemistry confirmed that ZPBP localises to the acrosome in human spermatozoa. Ultrastructural analysis of spermatozoa in the patient with the C7orf61 mutation revealed a mixture of round heads with no acrosomes (globozoospermia) and ovoid or irregular heads with small acrosomes frequently detached from the sperm head (acrosomal hypoplasia)., Limitations, Reasons for Caution: Stringent filtering criteria were used in the exome data analysis which could result in possible pathogenic variants remaining undetected. Additionally, functional follow-up is needed for several candidate genes to confirm the impact of these mutations on normal spermatogenesis., Wider Implications of the Findings: Our study revealed an important role for mutations in ZPBP and CCDC62 in human globozoospermia as well as five new candidate genes. These findings provide a more comprehensive understanding of the genetics of male infertility and bring us closer to a complete molecular diagnosis for globozoospermia patients which would help to predict the success of reproductive treatments., Study Funding/competing Interest(s): This study was funded by The Netherlands Organisation for Scientific Research (918-15-667); National Health and Medical Research Council of Australia (APP1120356) and the National Council for Scientific Research (CONICET), Argentina, PIP grant 11220120100279CO. The authors have nothing to disclose., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Results from medical research from high-income countries may not apply to low- and middle-income countries. Some expatriate physicians combine clinical duties with research. We present global health research conducted by Dutch medical doctors in Global Health and Tropical Medicine in low- and middle-income countries and explore the value of their research. We included all research conducted in the last 30 years by medical doctors in Global Health and Tropical Medicine in a low- and middle-income country, resulting in a PhD thesis. Articles and co-authors were found through Medline. More than half of the 18 identified PhD theses concerned maternal health and obstetrics, and the majority of the research was conducted in low-income countries, mostly in rural hospitals. Over 70 local co-authors were involved. Different aspects of these studies are discussed.

Introduction: Periconception obesity is associated with a higher risk for adverse perinatal outcomes such as gestational diabetes mellitus, preeclampsia, large for gestational age, operative delivery and preterm birth. Lifestyle interventions during pregnancy have resulted in insufficient effects on reducing these perinatal complications. A few reasons for this disappointing effect can be suggested: (1) the time period during pregnancy for improvement of developmental circumstances is too short; (2) the periconception period in which complications originate is not included; and (3) lifestyle interventions may not have been sufficiently multidisciplinary and customised. A preconception lifestyle intervention might be more effective to reduce perinatal complications. Therefore, the aim of the Towards Prepared mums study is to evaluate the effect of a lifestyle intervention starting prior to conception on lifestyle behaviour change., Methods and Analysis: This protocol outlines a non-blinded, randomised controlled trial. One hundred and twelve women (18-40 years of age) with overweight or obesity (body mass index≥25.0 kg/m 2 ) who plan to conceive within 1 year will be randomised to either the intervention or care as usual group. The intervention group will receive a multidisciplinary, customised lifestyle intervention stimulating physical activity, a healthy diet and smoking cessation, if applicable. The lifestyle intervention and monitoring will take place until 12 months postpartum. The primary outcome is difference in weight in kg from baseline to 6 weeks postpartum. Secondary outcomes are gestational weight gain, postpartum weight retention, smoking cessation, dietary and physical activity habits. Furthermore, exploratory outcomes include body composition, cardiometabolic alterations, time to pregnancy, need for assisted reproductive technologies, perinatal complications of mother and child, and lung function of the child. Vaginal and oral swabs, samples of faeces, breast milk, placenta and cord blood will be stored for evaluation of microbial flora, epigenetic markers and breast milk composition. Furthermore, a cost-effectiveness analysis will take place., Ethics and Dissemination: Ethical approval was obtained from the Medical Ethical Committee of Maastricht University Medical Centre+ (NL52452.068.15/METC152026). Knowledge derived from this study will be made available by publications in international peer-reviewed scientific journals and will be presented at (inter)national scientific conferences. A dissemination plan for regional and national implementation of the intervention is developed., Trial Registration Number: ClinicalTrials.gov NCT02703753., Competing Interests: Competing interests: RPMS-T is initiator and developer of Smarter Pregnancy and does not have a commercial interest. The Department of Obstetrics and Gynaecology of the Erasmus MC, University Medical Centre in Rotterdam is owner of this mHealth coaching tool., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Worldwide, the caesarean section (CS) is the most performed type of surgery and numbers are still rising. The gentle CS has become a more common procedure as it allows the parents to experience birth. Early and continuous skin-to-skin contact between the mother and her newborn is pursued. Parents are not separated from their newborns and stay with their child in the operation theatre and recovery room. However, data are limited on the incidence of surgical site infections (SSI) after gentle CS. The aim of our study was to examine the risk of postoperative wound infections after gentle CS. Secondary outcomes included other maternal complications and neonatal outcomes., Study Design: In this multicenter prospective cohort study, all women who underwent an elective gentle CS between January 2015 and January 2017 were eligible. Demographics, per procedural data, maternal complications and neonatal outcomes were collected. The follow-up lasted until six weeks post partum., Results: Of the 243 performed CSs, two (0.8%) SSIs occurred; one superficial and one deep wound infection. One patient (0.4%) was readmitted for treatment of endometritis. In total, 20 (8.2%) maternal complications were identified. Median time to skin-to-skin contact was 3 minutes (IQR 2-4.25) with a median neonatal oxygen saturation 10 minutes after birth of 95% (IQR 92-98). Mean gestational age was 274 ± 4.1 days (39 + 1 weeks) and mean neonatal pH was 7.28 (±SD 0.07). All children had Apgar scores >7 at 5 minutes after birth. Neonatal admission occurred in 19 cases (7.8%) and neonatal readmission in 10 cases (4.1%)., Conclusion: The gentle CS seems to be a safe procedure for both mother and child and is not associated with an increased risk of surgical site infections or direct suboptimal neonatal outcomes. Therefore, more intensive mother-child interaction during CS is allowed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant., Objective: To assess the clinical course, treatment schedules, and effect of invasion and treatment on recurrence and survival in patients with VPD., Methods: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centers. Disease-free survival and 5-year disease-specific survival were estimated by using Kaplan-Meier curves., Results: Data on 113 patients whose VPD was diagnosed between 1991 and 2016 were analyzed; 77% had noninvasive VPD. Most of the women (65%) underwent a surgical procedure. Recurrences were reported in 40%. Of the women with noninvasive VPD, 8% developed invasion. There were no disease-specific deaths reported in the women with noninvasive VPD. The 5-year disease-specific survival rate was greater than 98% in noninvasive and microinvasive VPD, but significantly worse in invasive VPD (50% [P < .0005])., Limitations: The main limitations of this study are its retrospective character and the fact that original pathology samples were not available for reassessment., Conclusions: VPD is extremely rare, and the recurrence rates are high. Most patients have noninvasive VPD, which does not affect survival and should be considered a chronic disorder with limited invasive potential. In cases of invasive disease, survival decreases significantly., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Study Question: Do sexual functioning, sexual esteem, genital self-image and psychological and relational functioning in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome differ from a comparison group of women without the condition?, Summary Answer: In comparison to controls, women with MRKH with a non-surgically or surgically created neovagina did not differ in psychological and relational functioning but reported lower sexual esteem and more negative genital self-image, intercourse-related pain, clinically relevant sexual distress and sexual dysfunction, with sexual esteem levels strongly associated with sexual distress and sexual dysfunction., What Is Known Already: Studies on sexual functioning measured with standardized questionnaires in women with MRKH syndrome compared with women without the condition have yielded contradictory results. Factors associated with sexual functioning in this patient population have rarely been investigated., Study Design, Size, Duration: Between November 2015 and May 2017, 54 women with MRKH syndrome with a neovagina and 79 age-matched healthy women without the condition were enrolled in this case-control study., Participants/materials, Setting, Methods: All participants had to be at least 18-years old and had to live in a steady heterosexual relationship. Women with MRKH syndrome were asked to participate by their (former) gynecologists at three university hospitals and by MRKH peer support group. Controls were recruited via advertisement in local newspapers and social media. Standardized questionnaires were administered to assess sexual functioning, sexual esteem, genital self-image and psychological and relational functioning., Main Results and the Role of Chance: Women with MRKH syndrome with a surgically or non-surgically created neovagina reported significantly more pain during intercourse (P < 0.05, d = 0.5), but did not differ in overall sexual functioning from control women. More women with MRKH syndrome reported clinically relevant sexuality-related distress (P < 0.05, odds ratio (OR): 2.756, 95% CI 1.219-6.232) and suffered a sexual dysfunction (P < 0.05, OR: 2.654, 95% CI: 1.088-6.471) in comparison with controls. MRKH women scored significantly lower on the sexual esteem scale (SES) (P < 0.01, d = 0.5) and the female genital self-image scale (FGSIS) (P < 0.01, d = 0.6) than controls. No significant differences were found between the two groups regarding psychological distress, anxiety and depression, global self-esteem and relational dissatisfaction. Sexual esteem was significantly associated with the presence of clinically relevant sexual distress (ß = 0.455, P = 0.001) and suffering a sexual dysfunction (ß = 0.554, P = 0.001) and explained, respectively, 40% and 28% of the variance., Limitations, Reasons for Caution: Given the nature of the study focusing on sexual functioning, a potential selection bias cannot be excluded. It is possible that those women with the most severe sexual and/or psychological disturbances did or did not choose to participate in our study., Wider Implications of the Findings: The study results add new data to the very limited knowledge about psychosexual functioning of women with MRKH syndrome and are of importance for more adequate counseling and treatment of these women., Study Funding/competing Interest(s): The research was financially supported by the Dutch Scientific Society of Sexology (Nederlandse wetenschappelijke Vereniging Voor Seksuologie). The funding was unrestricted, and there was no involvement in the conduct of the research. There are no conflicts of interest to declare., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Oocyte donation (OD) enables women with reproductive failure to conceive. Compared with naturally conceived (NC) and in vitrofertilisation (IVF) pregnancies, OD pregnancies are associated with a higher risk of pregnancy complications. The allogeneic nature of the fetus in OD pregnancies possibly plays a role in the development of these complications. The objective of the current study is therefore to study the number and nature of human leucocyte antigen (HLA) mismatches between fetus and mother and its association with the development of hypertensive pregnancy complications., Methods and Analysis: In this prospective multicentre cohort study, 200 patients visiting one of the 11 participating fertility centres in the Netherlands to perform OD or embryo donation or surrogacy will be invited to participate. These patients will be included as the exposed group. In addition, 146 patients with a NC pregnancy and 146 patients who applied for non-donor IVF are included as non-exposed subjects. These groups are frequency matched on age and ethnicity and only singleton pregnancies will be included. The primary clinical outcome of the study is the development of hypertensive disease during pregnancy. Secondary outcomes are the severity of the pre-eclampsia, time to development of pre-eclampsia and development of other pregnancy complications. The association of high number of HLA mismatches (>5) between mother and fetus will be determined and related to clinical outcome and pregnancy complication., Ethics and Dissemination: This study received ethical approval from the medical ethics committee in the Leiden University Medical Centre, the Netherlands (P16.048, ABR NL56308.058.16). Study findings will be presented at (inter) national conferences and published in peer-reviewed journals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: A significant proportion of women with advanced-stage ovarian cancer receive no cancer-directed treatment and limited research has been devoted to this group. This population-based study aimed to gain insight into treatment patterns and trends in patients with advanced epithelial ovarian cancer in the Netherlands and the main reasons for deciding for no cancer-directed treatment., Methods: All patients diagnosed with advanced epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) classification IIB-IV, between 2008 and 2016 were identified from the Netherlands Cancer Registry. Trends in the number of patients receiving cancer-directed treatment were analyzed. Multivariable logistic regression analysis was used to identify factors associated with no cancer-directed treatment. The main reasons for no cancer-directed treatment were analyzed., Results: A total of 9303 patients were included, of whom 14% (n=1270) received no cancer-directed treatment while 67% (n=6218) received a combination of cytoreductive surgery and chemotherapy. Some 15% (n=1399) received chemotherapy only, and 4.5% (n=416) surgical resection or hormonal therapy only. The proportion of patients receiving no cancer-directed treatment was higher in 2014-2016 (16%, n=496/3175) compared with 2008-2010 (11%, n=349/3057, p<0.001). Associated factors with no cancer-directed treatment were higher age, FIGO stage IV, lower socioeconomic status, co-morbidity, and more recent years of diagnosis (p<0.001). Main reasons for no cancer-directed treatment were patient's choice (40%) and poor condition of the patient (29%)., Conclusions: The proportion of patients with advanced epithelial ovarian cancer not receiving cancer-directed treatment has increased in the last decade in the Netherlands. Patient's choice was the main reason for the decision to undergo no cancer-directed treatment, which indicates patient involvement in the decision-making process. The second most common reason for no cancer-directed treatment was poor condition of the patient, which might indicate careful selection of patients for treatment. Decision-making regarding treatment is well-considered, but more insight is needed, especially from the patient's perspective., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Women with Turner syndrome (TS) are at increased risk of aortic dissection, which is related to ascending aortic diameter. However, the relation between aortic diameter and outcome is not well determined. This study evaluates the prevalence of aortic dilatation, the growth rate of the aorta and the risk of aortic complications in adults with TS., Methods: Single centre, retrospective study of all women with TS followed with a strict protocol in an outpatient TS clinic. Aortic diameters were analysed using advanced imaging. The primary outcome was a combined endpoint of aortic-related mortality, aortic dissection and preventive aortic surgery. The secondary endpoint was aortic growth and prevalence of aortic dilatation, defined as an aortic size index >20 mm/m 2 at baseline., Results: At least one cardiac MR/CT was available in 268 women with TS, having median age of 28.7 (IQR: 21.3-39.7) years. Aortic dilatation was present in 22%. Linear regression identified independent factors associated with larger aortic diameters: age (coefficient=0.23; p<0.001), hypertension (coefficient=2.7; p<0.001), bicuspid aortic valve (coefficient=3.3; p<0.001), 45XO karyotype (coefficient=1.7; p=0.002), weight (coefficient=0.075; p<0.001) and growth hormone treatment (coefficient=1.4; p=0.044). During follow-up (6.8±3.2 years), five women (2%) reached the primary endpoint (two dissections, three aortic surgery). Women withmore than one scan (n=171; 1015 patient-years follow-up), the median aortic growth was 0.20 (IQR: 0.00-0.44) mm/year. In multivariate analysis, aortic growth was not associated with baseline aortic diameter or other variables., Conclusions: Aortic dilatation is common and known associations were confirmed in large adult TS cohort However, aortic dissection, related mortality and preventive aortic surgery are rare. Growth hormone treatment in childhood was associated with aortic dimensions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction and Hypothesis: A great variety of conservative and surgical procedures to correct vaginal vault prolapse have been reported. The aim of this study was to describe practice pattern variation-the difference in care that cannot be explained by the underlying medical condition-among Dutch gynecologists regarding treatment of vaginal vault prolapse., Methods: A clinical practice survey was conducted from March to April 2017. The questionnaire was developed to evaluate treatment of vaginal vault prolapse. All members of the Dutch Society for Urogynaecology were invited to participate in a web-based survey., Results: One hundred four Dutch gynecologists with special interest in urogynecology responded to the survey (response rate, 44%). As first-choice therapy for vaginal vault prolapse, 78% of the respondents chose pessary treatment, whereas sacrospinous fixation was the second most common therapy choice according to 64% of the respondents. Preferences on how to approach vaginal vault prolapse surgically are conflicting. Overall, the most performed surgery for vaginal vault prolapse is sacrospinous fixation, followed by laparoscopic and robotic sacrocolpopexy., Conclusions: Gynecologists in The Netherlands manage vaginal vault prolapse very differently. No standardized method could be determined for the treatment of vaginal vault prolapse in The Netherlands, and we observed practice pattern variations.

Research Question: To evaluate implementation of the key recommendations of the European Society of Human Reproduction and Embryology (ESHRE) guidelines on endometriosis, and to assess factors influencing diagnostic delay of endometriosis from Dutch gynaecologists' point of view., Design: Questionnaire study among gynaecologists from all hospitals in the Netherlands. The questionnaire consisted of 56 questions relating to implementation of the ESHRE guidelines, organization of endometriosis care and diagnostic delay., Results: Gynaecologists from 67 out of 85 hospitals completed the questionnaire. A total of 99-100% of respondents agree with, and 91-100% adhere to, the diagnosis-related recommendations in the guidelines. Diagnostic delay is estimated at 42 months. Main factors contributing to diagnostic delay according to gynaecologists are lack of knowledge and awareness of endometriosis in both patients and medical professionals, as well as limitations in diagnostics and late referral. Suggested interventions to reduce diagnostic delay are aimed at improving knowledge and awareness in both patients and medical professionals, as well as improving collaborations between medical professionals., Conclusions: Overall familiarity with, and use of, the 2014 ESHRE guidelines among Dutch gynaecologists is high. Dutch gynaecologists agree with the recommendations relating to diagnosis and adhere to them closely. Diagnostic delay, however, is still considerable; therefore, efforts to reduce diagnostic delay of endometriosis should be aimed at improving knowledge and awareness in both patients and medical professionals, as well as improving collaboration., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: Vulnerable clients (i.e. clients reporting psychopathology, psychosocial problems, or substance use, and/or features of deprivation) represent a challenge in perinatal care, both in term of care process and outcome. Adhering to a structured care process (i.e. structured Antenatal Risk Management [sARM]) has shown to benefit professionals in supporting vulnerable clients, but its effect on client experiences is yet to be determined. As better processes are assumed to benefit outcome, we investigated the relationship between vulnerable clients' experiences with antenatal care in perinatal units adhering to differing degrees of sARM., Methods: We combined data from two sources: on the client level antenatal collected survey data from which vulnerability status (Mind2Care instrument) and client experiences (ReproQ questionnaire) were derived, and on the unit level interview data from healthcare providers from which the unit degree of sARM was ascertained., Results: A total of N = 1.176 clients from N = 38 units were included in the study. Vulnerable clients with psychosocial problems reported more negative experiences than non-vulnerable clients. In high sARM units, vulnerable clients, regardless of type of problems, reported more negative experiences than non-vulnerable clients. In multiple regression analysis this effect disappeared and only vulnerability defined as psychosocial problems remained predictive for negative experiences., Conclusions: Vulnerable clients, specifically those with psychosocial problems, present a challenge in perinatal healthcare. Negative appraisal of care might be an unavoidable drawback of adhering to sARM. It also stresses the need for improving caregiver-client expectations and system side improvements., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: As competency-based education has gained currency in postgraduate medical education, it is acknowledged that trainees, having individual learning curves, acquire the desired competencies at different paces. To accommodate their different learning needs, time-variable curricula have been introduced making training no longer time-bound. This paradigm has many consequences and will, predictably, impact the organization of teaching hospitals. The purpose of this study was to determine the effects of time-variable postgraduate education on the organization of teaching hospital departments., Methods: We undertook exploratory case studies into the effects of time-variable training on teaching departments' organization. We held semi-structured interviews with clinical teachers and managers from various hospital departments., Results: The analysis yielded six effects: (1) time-variable training requires flexible and individual planning, (2) learners must be active and engaged, (3) accelerated learning sometimes comes at the expense of clinical expertise, (4) fast-track training for gifted learners jeopardizes the continuity of care, (5) time-variable training demands more of supervisors, and hence, they need protected time for supervision, and (6) hospital boards should support time-variable training., Conclusions: Implementing time-variable education affects various levels within healthcare organizations, including stakeholders not directly involved in medical education. These effects must be considered when implementing time-variable curricula.

Study Question: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)?, Summary Answer: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT., What Is Known Already: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited., Study Design, Size, Duration: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study., Participants/materials, Setting, Methods: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology., Main Results and the Role of Chance: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT., Limitations, Reasons for Caution: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses., Wider Implications of the Findings: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation., Study Funding/competing Interests: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests., Trial Registration Number: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: BRCA1/2 mutation carriers' choice between risk-reducing salpingo-oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making., Design: Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process., Setting and Participants: Pre-menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands., Main Outcome Measures: IPDAS quality criteria, relevance, usability, clarity., Results: The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step-by-step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process., Discussion and Conclusions: Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk-reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making., (© 2017 The Authors Health Expectations published by John Wiley & Sons Ltd.)

Background: Despite much debate, there is little evidence on consequences of consent procedures for residual tissue use. Here, we investigated these consequences for the availability of residual tissue for medical research, clinical practice, and patient informedness., Methods: We conducted a randomised clinical trial with three arms in six hospitals. Participants, patients from whom tissue had been removed for diagnosis or treatment, were randomised to one of three arms: informed consent, an opt-out procedure with active information provision (opt-out plus), and an opt-out procedure without active information provision. Participants received a questionnaire six weeks post-intervention; a subsample of respondents was interviewed. Health care providers completed a pre- and post-intervention questionnaire. We assessed percentage of residual tissue samples available for medical research, and patient and health care provider satisfaction and preference. Health care providers and outcome assessors could not be blinded., Results: We randomised 1,319 patients, 440 in the informed consent, 434 in the opt-out plus, and 445 in the opt-out arm; respectively 60.7%, 100%, and 99.8% of patients' tissue samples could be used for medical research. Of the questionnaire respondents (N = 224, 207, and 214 in the informed consent, opt-out plus, and opt-out arms), 71%, 69%, and 31%, respectively, indicated being (very) well informed. By questionnaire, the majority (53%) indicated a preference for informed consent, whereas by interview, most indicated a preference for opt-out plus (37%). Health care providers (N = 35) were more likely to be (very) satisfied with opt-out plus than with informed consent (p = 0.002) or opt-out (p = 0.039); the majority (66%) preferred opt-out plus., Conclusion: We conclude that opt-out with information (opt-out plus) is the best choice to balance the consequences for medical research, patients, and clinical practice, and is therefore the most optimal consent procedure for residual tissue use in Dutch hospitals., Trial Registration: Dutch Trial Register NTR2982.

Objective: To determine clinical predictors of escape red blood cell (RBC) transfusion in postpartum anaemic women, initially managed expectantly, and the additional predictive value of health-related quality of life (HRQoL) measures., Design: Secondary analysis of women after postpartum haemorrhage, either randomly allocated to, or opting for expectant management., Setting: Thirty-seven hospitals in the Netherlands., Population: A total of 261 randomised and 362 nonrandomised women., Methods: We developed prediction models to assess the need for RBC transfusion: one using clinical variables (model 1), and one extended with scores on the HRQoL-measures Multidimensional Fatigue Inventory (MFI) and EuroQol-5D (model 2). Model performance was assessed by discrimination and calibration. Models were internally validated with bootstrapping techniques to correct for overfitting., Main Outcome Measures: Escape RBC transfusion., Results: Seventy-five women (12%) received escape RBC transfusion. Independent predictors of escape RBC transfusion (model 1) were primiparity, multiple pregnancy, total blood loss during delivery and haemoglobin concentration postpartum. Maternal age, body mass index, ethnicity, education, medical indication of pregnancy, mode of delivery, preterm delivery, placental removal, perineal laceration, Apgar score and breastfeeding intention had no predictive value. Addition of HRQoL-scores (model 2), significantly improved the model's discriminative ability: c-statistics of model 1 and 2 were 0.65 (95% CI 0.58-0.72) and 0.72 (95% CI 0.65-0.79), respectively. The calibration of both models was good., Conclusions: In postpartum anaemic women, several clinical variables predict the need for escape RBC transfusion. Adding HRQoL-scores improves model performance. After external validation, the extended model may be an important tool for counselling and decision making in clinical practice., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objective: Despite an extensive screening programme in The Netherlands, some cases of cervical cancer are still diagnosed in late stages of disease. The aim of the present study was to investigate which elements in the diagnostic process of cervical cancer may be improved., Methods: This is a retrospective study of 120 patients with cervical cancer diagnosed between January 1st 2008 and June 1st 2010 at the University Medical Center Utrecht. Patient charts, referral information, and pathology results were analyzed., Results: 39.1% of cancer cases were screen or interval detected; the other 60.9% of patients had not been screened, either due to non-attendance or because they fell outside the age range for screening. The final diagnosis of cervical cancer was established by biopsy in 77 (64.2%) and by excision of the cervical transformation zone in 35 (29.2%) of the patients. Fifteen (43%) of these excisions could have been avoided if biopsies would have been taken at the first examination, and had shown invasive cancer., Conclusions: Cervical cancer screening aims at early detection of precursor lesions to decrease the incidence of cancer. This in-depth analysis suggests that improvement of quality of care is to be expected from correct recognition of cervical cancer by physicians and adjustments of the screening programme to reach younger women and non-responders., (Copyright © 2015 Elsevier Inc. All rights reserved.)