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Background In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. Methods This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. Discussion The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. Trial registration number The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Contains fulltext : 291177.pdf (Publisher’s version ) (Open Access) BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss. METHODS: All PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time. RESULTS: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%. CONCLUSIONS: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time.

Background Hypertensive disorders of pregnancy are associated with cardiovascular disease later in life. Given that hypertensive disorders of pregnancy often occur at a relatively young age, there might be an opportunity to use preventive measures to reduce the risk of early cardiovascular disease and mortality. The aim of this study was to assess the risk of cardiovascular mortality in women after a hypertensive disorder of pregnancy.Methods In this population-based cohort study, the Netherlands Perinatal Registry (PRN) and the national death registry at the Dutch Central Bureau for Statistics were linked. We analysed women in the Netherlands with a first birth during 1995-2015 to determine the association between cardiovascular mortality and hypertensive disorders of pregnancy (based on recorded diastolic blood pressure or proteinuria, or both). We analysed the association between the highest diastolic blood pressure measured in pregnancy and cardiovascular mortality and constructed survival curves to assess cardiovascular mortality after hypertensive disorders of pregnancy, specifically pre-eclampsia and gestational hypertension. To differentiate between the severity of hypertensive disorders of pregnancy, cardiovascular mortality was assessed in women with a combination of hypertensive disorders of pregnancy with preterm birth (gestational age < 37 weeks) and growth restriction (birthweight in the 10th percentile or less). All hazard ratios (HRs) were adjusted for maternal age.Findings Between Jan 1, 1995, and Dec 31, 2015, the PRN contained 2 462 931 deliveries and 1 625 246 women. In 1 243 890 women data on their first pregnancy were available and were included in this analysis after linkage, with a median follow-up time of 11(.)2 years (IQR 6(.)1-16(.)3). 259 177 (20(.)8%) women had hypertensive disorders of pregnancy, and of these 45 482 (3(.)7%) women had pre-eclampsia and 213 695 (17(.)2%) women had gestational hypertension; 984 713 (79(.)2%) women did not develop hypertension in their first pregnancy. Compared with women without hypertensive disorders of pregnancy, the risk of death from any cause was higher in women who had hypertensive disorders (HR 1middot30 [95% CI 1(.)23-1(.)37], p < 0(.)001), pre-eclampsia (1(.)65 [1(.)48-1(.)83]; p < 0(.)0001), and gestational hypertension (1(.)23 [1(.)16-1.30]; p < 0(.)0001). Those women with pre-eclampsia had a higher risk of cardiovascular mortality compared with those without any hypertensive disorders of pregnancy (adjusted HR 3middot39 [95% CI 2(.)67-4(.)29]), as did those with gestational hypertension (2(.)22 [1(.)91-2(.)57]). For women with a history of hypertensive disorders of pregnancy combined with preterm birth (gestational age < 37 weeks) and birthweight in the 10th percentile or less, the adjusted HR for cardiovascular mortality was 6middot43 (95% CI 4(.)36-9(.)47), compared with women without a hypertensive disorder of pregnancy. The highest diastolic blood pressure measured during pregnancy was the strongest risk factor for cardiovascular mortality (for 80-89 mm Hg: adjusted HR 1(.)47 [95% CI 1(.)00-2(.)17]; for 130 mm Hg and higher: 14(.)70 [7.31-29.52]).Interpretation Women with a history of hypertensive disorders of pregnancy have a risk of cardiovascular mortality that is 2-3 times higher than that of women with normal blood pressure during pregnancy. The highest measured diastolic blood pressure during pregnancy is an important predictor for cardiovascular mortality later in life; therefore, women who have hypertensive disorders of pregnancy should be given personalised cardiovascular follow-up plans to reduce their risk of cardiovascular mortality.Funding None.Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Supplementary Material 2: List of participating sites.

Supplementary Material 1: Trial registration data set.

Background & Aims: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss. Methods: All PSC patients living in a geographically defined area covering similar to 50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time. Results: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were (sic)12 169 and mean work productivity loss was 25%. Conclusions: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time.

Objective Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. Conclusions The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. (c) 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.