Clinical added value of MRI to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): study protocol for an international multicentre prospective diagnostic accuracy study.

BACKGROUND: Abdominal computed tomography (CT) is the standard imaging method for patients with suspected colorectal liver metastases (CRLM) in the diagnostic workup for surgery or thermal ablation. Diffusion-weighted and gadoxetic-acid-enhanced magnetic resonance imaging (MRI) of the liver is increasingly used to improve the detection rate and characterization of liver lesions. MRI is superior in detection and characterization of CRLM as compared to CT. However, it is unknown how MRI actually impacts patient management. The primary aim of the CAMINO study is to evaluate whether MRI has sufficient clinical added value to be routinely added to CT in the staging of CRLM. The secondary objective is to identify subgroups who benefit the most from additional MRI. METHODS: In this international multicentre prospective incremental diagnostic accuracy study, 298 patients with primary or recurrent CRLM scheduled for curative liver resection or thermal ablation based on CT staging will be enrolled from 17 centres across the Netherlands, Belgium, Norway, and Italy. All study participants will undergo CT and diffusion-weighted and gadoxetic-acid enhanced MRI prior to local therapy. The local multidisciplinary team will provide two local therapy plans: first, based on CT-staging and second, based on both CT and MRI. The primary outcome measure is the proportion of clinically significant CRLM (CS-CRLM) detected by MRI not visible on CT. CS-CRLM are defined as liver lesions leading to a change in local therapeutical management. If MRI detects new CRLM in segments which would have been resected in the original operative plan, these are not considered CS-CRLM. It is hypothesized that MRI will lead to the detection of CS-CRLM in ≥10% of patients which is considered the minimal clinically important difference. Furthermore, a prediction model will be developed using multivariable logistic regression modelling to evaluate the predictive value of patient, tumor and procedural variables on finding CS-CRLM on MRI. DISCUSSION: The CAMINO study will clarify the clinical added value of MRI to CT in patients with CRLM scheduled for local therapy. This study will provide the evidence required for the implementation of additional MRI in the routine work-up of patients with primary and recurrent CRLM for local therapy. TRIAL REGISTRATION: The CAMINO study was registered in the Netherlands National Trial Register under number NL8039 on September 20th 2019.

Planned Cesarean or planned vaginal delivery for twins: secondary analysis of randomized controlled trial.

OBJECTIVE: To evaluate whether there is a differential benefit of planned Cesarean delivery (CD) over planned vaginal delivery (VD) in women with a twin pregnancy and the first twin in cephalic presentation, depending on prespecified baseline maternal and pregnancy characteristics, and/or gestational age (GA) at delivery. METHODS: This was a secondary analysis of the Twin Birth Study, which included 2804 women with a twin pregnancy and the first twin (Twin A) in cephalic presentation between 32 + 0 and 38 + 6 weeks' gestation at 106 centers in 25 countries. Women were assigned randomly to either planned CD or planned VD. The main outcome measure was composite adverse perinatal outcome, defined as the occurrence of perinatal mortality or serious neonatal morbidity in at least one twin. The baseline maternal and pregnancy characteristics (markers) considered were maternal age, parity, history of CD, use of antenatal corticosteroids, estimated fetal weight (EFW) of Twin A, EFW of Twin B, > 25% difference in EFW between the twins, presentation of Twin B, chorionicity on ultrasound, method of conception, complications of pregnancy, ruptured membranes at randomization and GA at randomization. Separate logistic regression models were developed for each marker in order to model composite adverse perinatal outcome as a function of the specific marker, planned delivery mode and the interaction between these two terms. In addition, multivariable logistic regression analysis with backward variable elimination was performed separately in each arm of the trial. The association between planned mode of delivery and composite adverse perinatal outcome, according to GA at delivery, was assessed using logistic regression analysis. RESULTS: Of the 2804 women initially randomized, 1391 were included in each study arm. None of the studied baseline markers was associated with a differential benefit of planned CD over planned VD in the rate of composite adverse perinatal outcome. GA at delivery was associated differentially with composite adverse perinatal outcome in the treatment arms (P for interaction < 0.001). Among pregnancies delivered at 32 + 0 to 36 + 6 weeks, there was a trend towards a lower rate of composite adverse perinatal outcome in those in the planned-VD group compared with those in planned-CD group (29 (2.2%) vs 48 (3.6%) cases; odds ratio (OR) 0.62 (95% CI, 0.37-1.03)). In pregnancies delivered at or after 37 + 0 weeks, planned VD was associated with a significantly higher rate of composite adverse perinatal outcome, as compared with planned CD (23 (1.5%) vs 10 (0.7%) cases; OR, 2.25 (95% CI, 1.06-4.77)). CONCLUSION: The perinatal outcome of twin pregnancies with the first twin in cephalic presentation may differ depending on GA at delivery and planned mode of delivery. At 32-37 weeks, planned VD seems to be favorable, while, from around 37 weeks onwards, planned CD might be safer. The absolute risks of adverse perinatal outcomes at term are low and must be weighed against the increased maternal risks associated with planned CD. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Natural conception rates in couples with unexplained or mild male subfertility scheduled for fertility treatment: a secondary analysis of a randomized controlled trial.

STUDY QUESTION: What is the natural conception rate over the course of 12 months in couples with unexplained or mild male subfertility who are scheduled for fertility treatment and have a predicted unfavourable prognosis for natural conception? SUMMARY ANSWER: The natural conception rate over the course of 12 months in couples who were allocated to treatment was estimated to be 24.5% (95% CI: 20-29%). WHAT IS KNOWN ALREADY: After starting treatment, couples often perceive unsuccessful cycles as evidence of definitive failure even though they are still able to conceive naturally in between and after treatment. The magnitude of the natural conception rate for couples who chose to commence treatment is unknown, as is whether the calculated prognosis before commencing treatment is still applicable. STUDY DESIGN, SIZE, DURATION: We performed a secondary analysis of a randomized controlled trial including couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception. Couples were allocated to either three cycles IVF with single embryo transfer (SET), six cycles of IVF in a modified natural cycle (MNC) or six cycles of IUI with controlled ovarian hyperstimulation (IUI-COH). The detailed data collection in this trial allowed us to study the conception rates in periods that couples were not receiving treatment. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We split the dataset into periods during which couples were treated and periods during which they were not treated. Couples could conceive naturally in the periods before, in between and after treatment cycles. The outcome was ongoing pregnancy, thus natural conception rate refers to natural conception leading to ongoing pregnancy. We performed a Cox proportional hazards analysis with female age, duration of subfertility and a time-varying covariate with four categories: IVF-SET, IVF-MNC, IUI-COH and no treatment. We used this Cox model to estimate the natural conception rate over 12 months of no treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 602 included couples, there were 342 ongoing pregnancies, of which 77 (23%) resulted from natural conception. The estimated natural conception rate over 12 months was 24.5% (95% CI: 20-29%) on cohort level. Estimated rates for female age varying between 18 and 38 years and duration of subfertility between 1 and 3 years ranged from 22 to 35%. LIMITATIONS, REASONS FOR CAUTION: We considered couples at risk for natural conception when not receiving treatment, whereas they might not have had periovulatory sexual intercourse. As couples were scheduled for treatment, it is possible that these couples were less inclined to try to conceive naturally, potentially leading to an underestimation of their natural conception rate if they kept trying to conceive. WIDER IMPLICATIONS OF THE FINDINGS: Couples with unexplained subfertility who are about to start fertility treatment, still have about a one in four chance of ongoing pregnancy due to natural conception over 12 months. This information can add to the counselling of couples who commenced fertility treatment after failed cycles and to emphasize not to cease their natural attempts. STUDY FUNDING/COMPETING INTEREST(S): The INeS trial was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027), and a grant from Zorgverzekeraars Nederland, the Dutch association of health care insurers (09-003). The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. No other potential conflicts of interest reported. TRIAL REGISTRATION NUMBER: The INeS trial was registered at the Dutch trial registry (NTR 939).

Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcome: systematic review and meta-analysis.

OBJECTIVE: Doppler ultrasonographic assessment of the cerebroplacental ratio (CPR) and middle cerebral artery (MCA) is widely used as an adjunct to umbilical artery (UA) Doppler to identify fetuses at risk of adverse perinatal outcome. However, reported estimates of its accuracy vary considerably. The aim of this study was to review systematically the prognostic accuracies of CPR and MCA Doppler in predicting adverse perinatal outcome, and to compare these with UA Doppler, in order to identify whether CPR and MCA Doppler evaluation are of added value to UA Doppler. METHODS: PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, from inception to June 2016, for studies on the prognostic accuracy of UA Doppler compared with CPR and/or MCA Doppler in the prediction of adverse perinatal outcome in women with a singleton pregnancy of any risk profile. Risk of bias and concerns about applicability were assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool. Meta-analysis was performed for multiple adverse perinatal outcomes. Using hierarchal summary receiver-operating characteristics meta-regression models, the prognostic accuracy of CPR vs MCA Doppler was compared indirectly, and CPR and MCA Doppler vs UA Doppler compared directly. RESULTS: The search identified 4693 articles, of which 128 studies (involving 47 748 women) were included. Risk of bias or suboptimal reporting was detected in 120/128 studies (94%) and substantial heterogeneity was found, which limited subgroup analyses for fetal growth and gestational age. A large variation was observed in reported sensitivities and specificities, and in thresholds used. CPR outperformed UA Doppler in the prediction of composite adverse outcome (as defined in the included studies) (P < 0.001) and emergency delivery for fetal distress (P = 0.003), but was comparable to UA Doppler for the other outcomes. MCA Doppler performed significantly worse than did UA Doppler in the prediction of low Apgar score (P = 0.017) and emergency delivery for fetal distress (P = 0.034). CPR outperformed MCA Doppler in the prediction of composite adverse outcome (P < 0.001) and emergency delivery for fetal distress (P = 0.013). CONCLUSION: Calculating the CPR with MCA Doppler can add value to UA Doppler assessment in the prediction of adverse perinatal outcome in women with a singleton pregnancy. However, it is unclear to which subgroup of pregnant women this applies. The effectiveness of the CPR in guiding clinical management needs to be evaluated in clinical trials. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Cost-effectiveness of diagnostic testing strategies including cervical-length measurement and fibronectin testing in women with symptoms of preterm labor.

OBJECTIVE: To evaluate the cost-effectiveness of combining cervical-length (CL) measurement and fetal fibronectin (fFN) testing in women with symptoms of preterm labor between 24 and 34 weeks' gestation. METHODS: This was a model-based cost-effectiveness analysis evaluating seven test-treatment strategies based on CL measurement and/or fFN testing in women with symptoms of preterm labor from a societal perspective, in which neonatal outcomes and costs were weighted. Estimates of disease prevalence, test accuracy and costs were based on two recently performed nationwide cohort studies in The Netherlands. RESULTS: Strategies using fFN testing and CL measurement separately to predict preterm delivery are associated with higher costs and incidence of adverse neonatal outcomes compared with strategies that combine both tests. Additional fFN testing when CL is 15-30 mm was considered cost effective, leading to a cost saving of €3919 per woman when compared with a treat-all strategy, with a small deterioration in neonatal health outcomes, namely one additional perinatal death and 21 adverse outcomes per 10 000 women with signs of preterm labor (incremental cost-effectiveness ratios €39 million and €1.9 million, respectively). Implementing this strategy in The Netherlands, a country with about 180 000 deliveries annually, could lead to an annual cost saving of between €2.4 million and €7.6 million, with only a small deterioration in neonatal health outcomes. CONCLUSION: In women with symptoms of preterm labor at 24-34 weeks' gestation, performing additional fFN testing when CL is between 15 and 30 mm is a viable and cost-saving strategy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

IVF or IUI as first-line treatment in unexplained subfertility: the conundrum of treatment selection markers.

STUDY QUESTION: Are there treatment selection markers that could aid in identifying couples, with unexplained or mild male subfertility, who would have better chances of a healthy child with IVF with single embryo transfer (IVF-SET) than with IUI with ovarian stimulation (IUI-OS)? SUMMARY ANSWER: We did not find any treatment selection markers that were associated with better chances of a healthy child with IVF-SET instead of IUI-OS in couples with unexplained or mild male subfertility. WHAT IS KNOWN ALREADY: A recent trial, comparing IVF-SET to IUI-OS, found no evidence of a difference between live birth rates and multiple pregnancy rates. It was suggested that IUI-OS should remain the first-line treatment instead of IVF-SET in couples with unexplained or mild male subfertility and female age between 18 and 38 years. The question remains whether there are some couples that may have higher pregnancy chances if treated with IVF-SET instead of IUI. STUDY DESIGN, SIZE, DURATION: We performed our analyses on data from the INeS trial, where couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception were randomly allocated to IVF-SET, IVF in a modified natural cycle or IUI-OS. In view of the aim of this study, we only used data of the comparison between IVF-SET (201 couples) and IUI-OS (207 couples). PARTICIPANTS/MATERIALS, SETTING, METHODS: We pre-defined the following baseline characteristics as potential treatment selection markers: female age, ethnicity, smoking status, type of subfertility (primary/secondary), duration of subfertility, BMI, pre-wash total motile count and Hunault prediction score. For each potential treatment selection marker, we explored the association with the chances of a healthy child after IVF-SET and IUI-OS and tested if there was an interaction with treatment. Given the exploratory nature of our analysis, we used a P-value of 0.1. MAIN RESULTS AND THE ROLE OF CHANCE: None of the markers were associated with higher chances of a healthy child from IVF-SET compared to IUI-OS (P-value for interaction >0.10). LIMITATIONS, REASONS FOR CAUTION: Since this is the first large study that looked at potential treatment selection markers for IVF-SET compared to IUI-OS, we had no data on which to base a power calculation. The sample size was limited, making it difficult to detect any smaller associations. WIDER IMPLICATIONS OF THE FINDINGS: We could not identify couples with unexplained or mild male subfertility who would have had higher chances of a healthy child from immediate IVF-SET than from IUI-OS. As in the original trial IUI-OS had similar effectiveness and was less costly compared to IVF-SET, IUI-OS should remain the preferred first-line treatment in these couples. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from the Netherlands Organization for Health Research and Development, and a grant from the Netherlands' association of health care insurers. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered at the Dutch trial registry (NTR939).

Prediction of disease-free survival using relative change in FDG-uptake early during neoadjuvant chemoradiotherapy for potentially curable esophageal cancer: A prospective cohort study.

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been investigated as a tool for monitoring response to neoadjuvant chemo- and chemoradiotherapy (CT and CRT, respectively) and as a predictor for survival in patients with esophageal cancer. In contrast to patients who undergo neoadjuvant CT, it is not known whether patients who are clinically identified as responders after neoadjuvant CRT show better disease-free survival (DFS) than patients identified as nonresponders. The aim of the study was to determine the predictive value of FDG-uptake measured prior to and early during neoadjuvant CRT. Patients treated with neoadjuvant CRT between 2004 and 2009 within a randomized trial were included. FDG-uptake was measured at baseline and after 14 days of CRT. According to the PERCIST-criteria, patients were allocated to have metabolic response, stable disease, or progression. Patients were followed until recurrence of disease or death. The predictive value of FDG-PET was determined with univariable and multivariable analysis in patients who underwent potentially curative surgery. One-hundred and six patients were included in the analysis. Minimal follow-up for surviving patients was 60 months. No significant differences in DFS were found between patients with metabolic response, stable disease, or progression, with 5-year DFS rates of 66%, 53%, and 67%, respectively (P = 0.39). Relative change in FDG uptake after 14 days of CRT is not associated with DFS in patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy followed by surgery. These measurements should not be used for prognostication in this specific group of patients.

Is IVF-served two different ways-more cost-effective than IUI with controlled ovarian hyperstimulation?

STUDY QUESTION: What is the cost-effectiveness of in vitro fertilization (IVF) with conventional ovarian stimulation, single embryo transfer (SET) and subsequent cryocycles or IVF in a modified natural cycle (MNC) compared with intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) as a first-line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception?. SUMMARY ANSWER: Both IVF strategies are significantly more expensive when compared with IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH, the latter is the dominant strategy. Whether IVF-SET is cost-effective depends on society's willingness to pay for an additional healthy child. WHAT IS KNOWN ALREADY: IUI-COH and IVF, either after conventional ovarian stimulation or in a MNC, are used as first-line treatments for couples with unexplained or mild male subfertility. As IUI-COH is less invasive, this treatment is usually offered before proceeding to IVF. Yet, as conventional IVF with SET may lead to higher pregnancy rates in fewer cycles for a lower multiple pregnancy rate, some have argued to start with IVF instead of IUI-COH. In addition, IVF in the MNC is considered to be a more patient friendly and less costly form of IVF. STUDY DESIGN, SIZE, DURATION: We performed a cost-effectiveness analysis alongside a randomized noninferiority trial. Between January 2009 and February 2012, 602 couples with unexplained infertility and a poor prognosis on natural conception were allocated to three cycles of IVF-SET including frozen embryo transfers, six cycles of IVF-MNC or six cycles of IUI-COH. These couples were followed until 12 months after randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected data on resource use related to treatment, medication and pregnancy from the case report forms. We calculated unit costs from various sources. For each of the three strategies, we calculated the mean costs and effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated for IVF-SET compared with IUI-COH and for IVF-MNC compared with IUI-COH. Nonparametric bootstrap resampling was used to investigate the effect of uncertainty in our estimates. MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 healthy children (52%) born in the IVF-SET group, 83 (43%) the IVF-MNC group and 97 (47%) in the IUI-COH group. The mean costs per couple were €7187 for IVF-SET, €8206 for IVF-MNC and €5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences €2117; 95% CI: €1544-€2657 and €3136, 95% CI: €2519-€3754, respectively).The ICER for IVF-SET compared with IUI-COH was €43 375 for the birth of an additional healthy child. In the comparison of IVF-MNC to IUI-COH, the latter was the dominant strategy, i.e. more effective at lower costs. LIMITATIONS, REASONS FOR CAUTION: We only report on direct health care costs. The present analysis is limited to 12 months. WIDER IMPLICATIONS OF THE FINDINGS: Since we found no evidence in support of offering IVF as a first-line strategy in couples with unexplained and mild subfertility, IUI-COH should remain the treatment of first choice. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Netherlands Organization for Health Research and Development, (120620027) and a grant from Zorgverzekeraars Nederland, the Netherlands' association of health care insurers (09-003). TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.

Comparison of Imaging Strategies with Conditional versus Immediate Contrast-Enhanced Computed Tomography in Patients with Clinical Suspicion of Acute Appendicitis.

OBJECTIVES: To compare the diagnostic accuracy of conditional computed tomography (CT), i.e. CT when initial ultrasound findings are negative or inconclusive, and immediate CT for patients with suspected appendicitis. METHODS: Data were collected within a prospective diagnostic accuracy study on imaging in adults with acute abdominal pain. All patients underwent ultrasound and CT, read by different observers who were blinded from the other modality. Only patients with clinical suspicion of appendicitis were included. An expert panel assigned a final diagnosis to each patient after 6 months of follow-up (clinical reference standard). RESULTS: A total of 422 patients were included with final diagnosis appendicitis in 251 (60 %). For 199 patients (47 %), ultrasound findings were inconclusive or negative. Conditional CT imaging correctly identified 241 of 251 (96 %) appendicitis cases (95 %CI, 92 % to 98 %), versus 238 (95 %) with immediate CT (95 %CI, 91 % to 97 %). The specificity of conditional CT imaging was lower: 77 % (95 %CI, 70 % to 83 %) versus 87 % for immediate CT (95 %CI, 81 % to 91 %). CONCLUSION: A conditional CT strategy correctly identifies as many patients with appendicitis as an immediate CT strategy, and can halve the number of CTs needed. However, conditional CT imaging results in more false positives. KEY POINTS: • Conditional CT (CT after negative/inconclusive ultrasound findings) can be used for suspected appendicitis. • Half the number of CT examinations is needed with a conditional strategy. • Conditional CT correctly identifies as many patients with appendicitis as immediate CT. • Conditional imaging results in more false positive appendicitis cases.

Accuracy of MRI compared with ultrasound imaging and selective use of CT to discriminate simple from perforated appendicitis.

BACKGROUND: Discrimination between simple and perforated appendicitis in patients with suspected appendicitis may help to determine the therapy, timing of surgery and risk of complications. The aim of this study was to estimate the accuracy of magnetic resonance imaging (MRI) in distinguishing between simple and perforated appendicitis, and to compare MRI against ultrasound imaging with selected additional (conditional) use of computed tomography (CT). METHODS: Patients with clinically suspected appendicitis were identified prospectively at the emergency department of six hospitals. Consenting patients underwent MRI, but were managed based on findings at ultrasonography and conditional CT. Radiologists who evaluated the MRI were blinded to the results of ultrasound imaging and CT. The presence of perforated appendicitis was recorded after each evaluation. The final diagnosis was assigned by an expert panel based on perioperative data, histopathology and clinical follow-up after 3 months. RESULTS: MRI was performed in 223 of 230 included patients. Acute appendicitis was the final diagnosis in 118 of 230 patients, of whom 87 had simple and 31 perforated appendicitis. MRI correctly identified 17 of 30 patients with perforated appendicitis (sensitivity 57 (95 per cent confidence interval 39 to 73) per cent), whereas ultrasound imaging with conditional CT identified 15 of 31 (sensitivity 48 (32 to 65) per cent) (P = 0.517). All missed diagnoses of perforated appendicitis were identified as simple acute appendicitis with both imaging protocols. None of the MRI features for perforated appendicitis had a positive predictive value higher than 53 per cent. CONCLUSION: MRI is comparable to ultrasonography with conditional use of CT in identifying perforated appendicitis. However, both strategies incorrectly classify up to half of all patients with perforated appendicitis as having simple appendicitis. Triage of appendicitis based on imaging for conservative treatment is inaccurate and may be considered unsafe for decision-making. Presented to a scientific meeting of the Association of Surgeons of the Netherlands, Veldhoven, The Netherlands, May 2012; published in abstract form as Br J Surg 2012; 99(Suppl 7): S6.

A decision aid regarding treatment options for patients with an asymptomatic abdominal aortic aneurysm: a randomised clinical trial.

OBJECTIVE: Abdominal aortic aneurysm patients tend to be informed inconsistently and incompletely about their disorder and the treatment options open to them. The objective of this trial was to evaluate whether these patients are better informed and experience less decisional conflict regarding their treatment options after viewing a decision aid. DESIGN: A six-centre, randomised clinical trial comparing a decision aid plus regular information versus regular information from the surgeon. METHODS: Included patients had recently been diagnosed with an asymptomatic abdominal aortic aneurysm at least 4 cm in diameter. The decision aid consisted of a one-time viewing of an interactive CD-ROM elaborating on elective surgery versus watchful waiting. Generally, the decision aid advised patients with aneurysms less than 5.5 cm to agree to watchful waiting, for larger aneurysms the decision aid provided insight into the balance of benefit and harm of surgical and conservative approaches, taking into account age, co-morbidity and size of the aneurysm. The primary outcome was patient decisional conflict measured at 1 month follow-up (Decisional Conflict Scale). Secondary outcomes were patient knowledge, anxiety and satisfaction. RESULTS: In 178 aneurysm patients, decisional conflict scores did not differ significantly between the decision aid and the regular information groups (22 vs. 24 on the 0-100 Decisional Conflict Scale; p = .33). Patients in the decision aid group had significantly better knowledge (10.0 vs. 9.4 out of 13 points; p = .04), whereas anxiety levels (4.4 and 5.0 on a 0-21 scale; p = .73) and satisfaction scores (74 and 73 on a 0-100 scale; p = .81) were similar in both groups. CONCLUSION: In addition to regular patient-surgeon communication, a decision aid helps to share treatment decisions with abdominal aortic aneurysm patients by increasing their knowledge about the disorder and available treatment options without raising anxiety levels; however, it does not reduce decisional conflict, nor does it improve satisfaction.

Can we distinguish between infertility and subfertility when predicting natural conception in couples with an unfulfilled child wish?

STUDY QUESTION: Can mixture survival models help distinguish infertility from subfertility in couples with an unexplained unfulfilled child wish? SUMMARY ANSWER: Mixture models estimated that 47% of the couples were infertile; female age and previous pregnancy were significantly related to infertility, whereas duration of child wish was associated with a longer time to pregnancy for subfertile couples. WHAT IS KNOWN ALREADY: To differentiate between couples who require assisted conception and couples who still have good chances of natural, i.e. unassisted, conception, several prediction models of natural conception have been developed. Prognostic factors in these models are usually assessed by Cox proportional hazard models that cannot differentiate between couples with an unfulfilled child wish who are subfertile, i.e. have reduced ability to conceive naturally, and couples who are really infertile, i.e. are completely unable to conceive naturally. We evaluated whether a mixture survival model can make such a distinction. STUDY DESIGN, SIZE, DURATION: Consecutive couples presenting at the fertility clinics of 38 centres in the Netherlands between January 2002 and February 2004 joined a prospective cohort study. Of the 7860 couples in the cohort, 3917 couples met our inclusion criteria. The median follow-up was 219 days, with a maximum of 5 years. PARTICIPANTS, SETTING, METHODS: Couples had to present with an unexplained cause of an unfulfilled child wish. A mixture model was used to estimate the proportion of couples who were infertile and the time to pregnancy for the subfertile couples. MAIN RESULTS AND THE ROLE OF CHANCE: During the follow-up, 794 couples conceived naturally. The mixture model estimated that 47% [95% confidence interval (CI): 33-56%] of couples were infertile, despite the absence of objective factors indicating a cause for infertility. Of the evaluated prognostic factors, female age, duration of child wish, previous pregnancy, semen quality, BMI and cycle length, female age [odds ratio (OR): 1.11, 95% CI: 1.03-1.19] and previous pregnancy (0.22, 95% CI: 0.07-0.67) were significant predictors of infertility. Among subfertile couples, a longer duration of a child wish (FFR: 0.72, 95% CI: 0.61-0.85) was a significant prognostic factor for time to pregnancy. In the Cox models, all variables except BMI were significant predictors of time to pregnancy. LIMITATIONS, REASONS FOR CAUTION: The mixture model had limited power due to a low number of couples at the end of the follow-up period. Mixture model analyses on external, long-term follow-up data are necessary to validate our results. WIDER IMPLICATIONS OF THE FINDINGS: Mixture models could be a useful tool in selecting couples who require assisted reproductive technology because the effects of prognostic factors can be subdivided into effects on the fraction of infertile couples and effects on the time to pregnancy for subfertile couples, which is not possible in conventional models. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grant 945/12/002 from ZonMw, the Netherlands Organization for Health Research and Development, The Hague, the Netherlands.

Individualized decision-making in IVF: calculating the chances of pregnancy.

STUDY QUESTION: Are we able to develop a model to calculate the chances of pregnancy prior to the start of the first IVF cycle as well as after one or more failed cycles? SUMMARY ANSWER: Our prediction model enables the accurate individualized calculation of the probability of an ongoing pregnancy with IVF. WHAT IS KNOWN ALREADY: To improve counselling, patient selection and clinical decision-making in IVF, a number of prediction models have been developed. These models are of limited use as they were developed before current clinical and laboratory protocols were established. STUDY DESIGN, SIZE, DURATION: This was a cohort study. The development set included 2621 cycles in 1326 couples who had been treated with IVF or ICSI between January 2001 and July 2009. The validation set included additional data from 515 cycles in 440 couples treated between August 2009 and April 2011. The outcome of interest was an ongoing pregnancy after transfer of fresh or frozen-thawed embryos from the same stimulated IVF cycle. If a couple became pregnant after an IVF/ICSI cycle, the follow-up was at a gestational age of at least 11 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women treated with IVF or ICSI between January 2001 and April 2011 in a university hospital. IVF/ICSI cycles were excluded in the case of oocyte or embryo donation, surgically retrieved spermatozoa, patients positive for human immunodeficiency virus, modified natural IVF and cycles cancelled owing to poor ovarian stimulation, ovarian hyperstimulation syndrome or other unexpected medical or non-medical reasons. MAIN RESULTS AND THE ROLE OF CHANCE: Thirteen variables were included in the final prediction model. For all cycles, these were female age, duration of subfertility, previous ongoing pregnancy, male subfertility, diminished ovarian reserve, endometriosis, basal FSH and number of failed IVF cycles. After the first cycle: fertilization, number of embryos, mean morphological score per Day 3 embryo, presence of 8-cell embryos on Day 3 and presence of morulae on Day 3 were also included. In validation, the model had moderate discriminative capacity (c-statistic 0.68, 95% confidence interval: 0.63-0.73) but calibrated well, with a range from 0.01 to 0.56 in calculated probabilities. LIMITATIONS, REASONS FOR CAUTION: In our study, the outcome of interest was ongoing pregnancy. Live birth may have been a more appropriate outcome, although only 1-2% of all ongoing pregnancies result in late miscarriage or stillbirth. The model was based on data from a single centre. WIDER IMPLICATIONS OF THE FINDINGS: The IVF model presented here is the first to calculate the chances of an ongoing pregnancy with IVF, both for the first cycle and after any number of failed cycles. The generalizability of the model to other clinics has to be evaluated more extensively in future studies (geographical validation). Centres with higher or lower success rates could use the model, after recalibration, by adjusting the intercept to reflect the IVF success rates in their centre. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by the NutsOhra foundation (Grant 1004-179). The NutsOhra foundation had no role in the development of our study, in the collection, analysis and interpretation of data; in writing of the manuscript, and in the decision to submit the manuscript for publication. There were no competing interests.

Inter-clinic variation in the chances of natural conception of subfertile couples.

STUDY QUESTION: Are there differences between clinics in the chances of natural conception of couples? SUMMARY ANSWER: We found significant differences between clinics in the couples' natural conception chances, which could not be explained by differences in characteristics of the patients or the clinics. WHAT IS KNOWN ALREADY: In pooled data from multiple centers the synthesis prediction model for natural conception was found to be valid, yet the outcome of interest (i.e. natural conception) might differ between centers. Possible differences between clinics in natural conception rates, as well as the validity of the prediction model in each individual clinic are addressed in this paper. STUDY DESIGN, SIZE AND DURATION: A secondary data-analysis of a prospective cohort study among 3020 subfertile couples recruited in 38 clinics in the Netherlands between January 2002 and December 2004. Clinics with less than 20 couples were excluded from the analyses, resulting in 21 clinics with 2916 couples. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion of 2916 subfertile couples who underwent a basic fertility work-up. Couples were excluded who had a fertility disorder (one or two-sided tubal pathology, ovulation disorder, total motile sperm count <3 × 10(6)). Included couples were counseled for expectant management for at least six months or followed until the first day of treatment. Follow-up began at the completion of the fertility work-up. Couples lost to follow-up were censored at the last day of contact. Kaplan-Meier survival curves and a log-rank statistic were estimated. Crude and adjusted hazard ratios were determined, adjusted for patient characteristics and the type of clinic (university hospitals with an assisted conception unit (ACU), non-university hospitals with an ACU and non-university hospitals without an ACU). Hazard ratios were also ascertained with empirical Bayes (EB) estimates. Validation of the prediction model per clinic was performed through calibration. MAIN RESULTS AND THE ROLE OF CHANCE: We found significant differences between clinics in the chance of ongoing pregnancy (P < 0.001); even after adjustment for female age, duration of subfertility, percentage of progressive motile sperm, primary/secondary subfertility and post-coital test (P < 0.001). Adjusted hazard ratios and EB estimates ranged from 0.50 to 2.21 and 0.58 to 1.53, respectively. Among the 21 clinics, there were 4 university hospitals, 10 non-university hospitals with an ACU and 7 non-university hospitals without an ACU. In the multivariable analysis, the type of clinic was not significant (P = 0.11). Calibration gave an average intercept of -0.25 (95% range: -1.04-0.53) and average slope of 0.81 (95% range: 0.03-1.60). Six clinics had a negative intercept that differed significantly from zero and three clinics had a negative or positive slope that differed significantly from one. LIMITATIONS, REASONS FOR CAUTION: A more extensive model including more predictors could give less variation in the differences between the clinics. Variation in work-up protocol between clinics could also have played a role. In fertility prediction research the Cox proportional hazards regression is the most widely used statistical model, but as the underlying assumptions have rarely been evaluated, this model could lead to biased outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that the synthesis model to predict natural conception is useful overall in clinical practice but in a minority of clinics the model is not well calibrated. Updating the synthesis model to include a center-specific baseline chance might improve the synthesis model for certain clinics. STUDY FUNDING/COMPETING INTEREST(S): The study (on which this secondary data-analysis was based) was supported by grant 945/12/002 from ZonMW, the Netherlands Organization for Health Research and Development, The Hague, the Netherlands.

Time requirements and health effects of participation in colorectal cancer screening with colonoscopy or computed tomography colonography in a randomized controlled trial.

BACKGROUND AND STUDY AIMS: Time limitations and unwanted health effects may act as barriers to participation in colorectal cancer (CRC) screening. The aim of the study was to measure the time requirements and health effects of colonoscopy and computed tomography colonography (CTC) screening. PATIENTS AND METHODS: This was a prospective diary study in a consecutive sample within a randomized controlled CRC screening trial, comparing primary colonoscopy and CTC screening for average-risk individuals aged 50 - 74 years. The diary ended when all screening-related complaints had passed. RESULTS: The diary was returned by 75 % (241/322) of colonoscopy and 75 % (127/170) of CTC screenees. The median interval between leaving home and returning from the examination was longer for colonoscopy (4 hours and 18 minutes [4:18], interquartile range [IQR] 3:30 - 5:00) than for CTC (2:30 hours, IQR 2:06 - 3:00; P < 0.001). Similarly, the time to return to routine activities was longer after colonoscopy (3:54 hours, IQR 1:48 - 15:00) than after CTC (1:36 hours, IQR 0:54 - 4:42). The duration of screening-related symptoms after the examination was shorter for colonoscopy (11:00 hours, IQR 2:54 - 20:00) than for CTC (22:00 hours; IQR 5:30 - 47:00; P < 0.001). Abdominal complaints were reported more frequently after CTC. Anxiety, pain, and quality of life worsened during the screening process, with no differences between the two examinations. CONCLUSIONS: Compared with colonoscopy, CTC screening required less time and allowed screenees to return to their daily activities more quickly. In contrast, CTC was associated with a twofold longer duration of screening-related symptoms. Feelings of anxiety, pain, and quality of life scores were similar during colonoscopy and CTC screening. These results should be incorporated into cost-effectiveness analyses of CRC screening techniques.

Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine.

OBJECTIVE: We previously showed that maternal under-nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren. DESIGN: Historical cohort study. SETTING: Web-based questionnaire. POPULATION: The adult offspring (F2) of a cohort of men and women (F1) born around the time of the 1944-45 Dutch famine. METHODS: We approached the F2 adults through their parents. Participating F2 adults (n = 360, mean age 37 years) completed an online questionnaire. MAIN OUTCOME MEASURES: Weight, body mass index (BMI), and health in F2 adults, according to F1 prenatal famine exposure. RESULTS: Adult offspring (F2) of prenatally exposed F1 fathers had higher weights and BMIs than offspring of prenatally unexposed F1 fathers (+4.9 kg, P = 0.03; +1.6 kg/m(2), P = 0.006). No such effect was found for the F2 offspring of prenatally exposed F1 mothers. We observed no differences in adult health between the F2 generation groups. CONCLUSIONS: Offspring of prenatally undernourished fathers, but not mothers, were heavier and more obese than offspring of fathers and mothers who had not been undernourished prenatally. We found no evidence of transgenerational effects of grandmaternal under-nutrition during gestation on the health of this relatively young group, but the increased adiposity in the offspring of prenatally undernourished fathers may lead to increased chronic disease rates in the future.

Value of adding second-trimester uterine artery Doppler to patient characteristics in identification of nulliparous women at increased risk for pre-eclampsia: an individual patient data meta-analysis.

OBJECTIVE: To investigate the value of adding second-trimester uterine artery Doppler ultrasound to patient characteristics in the identification of nulliparous women at risk for pre-eclampsia. METHODS: For this individual patient data meta-analysis, studies published between January 1995 and December 2009 were identified in MEDLINE and EMBASE. Studies were eligible in which Doppler assessment of the uterine arteries had been performed among pregnant women and in which gestational age at ultrasound, Doppler ultrasound findings and data on the occurrence of pre-eclampsia were available. We invited corresponding authors to share their original datasets. Data were included of nulliparous women who had had a second-trimester uterine artery Doppler ultrasound examination. Shared data were checked for consistency, recoded to acquire uniformity and merged into a single dataset. We constructed random intercept logistic regression models for each of the patient and Doppler characteristics in isolation and for combinations. We compared goodness of fit, discrimination and calibration. RESULTS: We analyzed eight datasets, reporting on 6708 nulliparous women, of whom 302 (4.5%) developed pre-eclampsia. Doppler findings included higher, lower and mean pulsatility index (PI) and resistance index (RI) and any or bilateral notching. Of these, the best predictors were combinations of mean PI or RI and bilateral notching, with areas under the receiver-operating characteristics curve (AUC) of 0.75 (95% confidence interval (CI), 0.56-0.95) and 0.70 (95% CI, 0.66-0.74), respectively. Addition of Doppler findings to the patient characteristics blood pressure or body mass index (BMI) significantly improved discrimination. A model with blood pressure, PI and bilateral notching had an AUC of 0.85 (95% CI, 0.67-1.00). CONCLUSIONS: The addition of Doppler characteristics of mean PI or RI and bilateral notching to patient characteristics of blood pressure or BMI improves the identification of nulliparous women at risk for pre-eclampsia.

Treatment should be considered a competing risk when predicting natural conception in subfertile women.

BACKGROUND: Prediction of natural conception in subfertile couples can help to differentiate between couples who should have immediate treatment and couples who can aim for natural conception for some time. Natural conception rates are often estimated using standard techniques such as Kaplan-Meier or Cox proportional hazard models. These estimates can be biased by incorrect handling of data from women who start assisted reproductive technology therapy before the end of the follow-up period. This paper discusses the validity and the impact of the assumption of non-informative censoring as used in the Kaplan-Meier and Cox models. METHODS: In a cohort of 5360 subfertile couples with suspected tubal pathology, the probability of natural conception and the prognostic value of additional tests for tubal pathology were estimated using traditional methods and with a competing risks analysis. RESULTS: The estimated probability of natural conception within 3 years was almost 2-fold higher when assuming non-informative censoring compared with the competing risks model, 41 versus 22%. The prognostic value of tests was more conservative using the competing risks model than with the traditional methods, the fecundity rate ratio for Chlamydia antibody testing was 0.72 versus 0.67, for hysterosalpingography, 0.83 versus 0.71 and for diagnostic laparoscopy, 0.89 versus 0.74. CONCLUSIONS: Given the improbable validity of the non-informative censoring assumption, the predictions of natural conception and of the prognostic value of tests are likely to be overestimated by the traditional analytic methods. We suggest the use of competing risks models as an alternative, more conservative, form of analysis when predicting natural conception and evaluating prognostic fertility tests.

Health-related quality of life in women with newly diagnosed polycystic ovary syndrome randomized between clomifene citrate plus metformin or clomifene citrate plus placebo.

STUDY QUESTION: What is the health-related quality of life (HRQoL) in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with clomifene citrate (CC) combined with metformin compared with those using CC combined with placebo? SUMMARY ANSWER: Overall quality of life in women with PCOS treated with CC plus metformin was significantly lower than in women treated with CC plus placebo. WHAT IS KNOWN ALREADY: There are no data on HRQoL in adult women who receive ovulation induction with the purpose of conceiving. Women with PCOS have higher scores on depression and anxiety scales and lower QoL scores than women without PCOS. STUDY DESIGN, SIZE AND DURATION: This study was a secondary analysis of a multi-centre RCT completed between June 2001 and May 2004. The randomization was stratified per centre, and the centres received blinded, numbered containers with medication. There were172 women available for the HRQoL assessment: 85 were allocated to metformin and 87 were allocated to placebo. PARTICIPANTS, SETTING AND METHODS: The Rotterdam Symptom Checklist (RSCL), a standard self-administered questionnaire, was used to assess physical symptoms, psychological distress, activity levels and overall HRQoL. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention to treat analysis, we found differences between the treatment groups with respect to physical symptoms and overall HRQoL. Physical well-being was significantly impaired in women allocated to metformin but not in women allocated to placebo. The increase in physical symptoms in the metformin group was caused by side-effects typical of metformin, and was most pronounced at Week 1 (mean difference 12 [95% confidence interval (CI): 8-16] and still apparent at Week 16 [mean difference 7 (95% CI 2-12]. Overall well-being was significantly impaired in the metformin group compared with the placebo group [mean difference 13 (95% CI 6-20)]. LIMITATIONS AND REASONS FOR CAUTION: RSCL measurements were available only for three quarters of the participants. Although the number of missing questionnaires and the baseline measurements, were comparable between the treatment groups, some form of selection bias cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our finding that metformin was more burdensome than placebo, strengthens the recommendation that CC only and not CC plus metformin should be the drug of choice in this patient population. STUDY FUNDING/COMPETING INTEREST(S): None of the authors declared a conflict of interest. There was no study funding. TRIAL REGISTRATION NUMBER: ISRCTN55906981.

Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis.

BACKGROUND: Biomarkers have been proposed for identification of women at increased risk of developing pre-eclampsia. OBJECTIVES: To investigate the capacity of circulating placental growth factor (PlGF), vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG) to predict pre-eclampsia. SEARCH STRATEGY: Medline and Embase through October 2010 and reference lists of reviews, without constraints. SELECTION CRITERIA: We included original publications on testing of PlGF, VEGF, sFLT1 and sENG in serum or plasma of pregnant women at <30 weeks of gestation and before clinical onset of pre-eclampsia. DATA COLLECTION AND ANALYSIS: Two reviewers independently identified eligible studies, extracted descriptive and test accuracy data and assessed methodological quality. Summary estimates of discriminatory performance were obtained. MAIN RESULTS: We included 34 studies. Concentrations of PlGF (27 studies) and VEGF (three studies) were lower in women who developed pre-eclampsia: standardised mean differences (SMD) -0.56 (95% CI -0.77 to -0.35) and -1.25 (95% CI -2.73 to 0.23). Concentrations of sFLT1 (19 studies) and sENG (ten studies) were higher: SMD 0.48 (95% CI 0.21-0.75) and SMD 0.54 (95% CI 0.24-0.84). The summary diagnostic odds ratios were: PlGF 9.0 (95% CI 5.6-14.5), sFLT1 6.6 (95% CI 3.1-13.7), sENG 4.2 (95% CI 2.4-7.2), which correspond to sensitivities of 32%, 26% and 18%, respectively, for a 5% false-positive rate. AUTHOR'S CONCLUSIONS: PlGF, sFLT1 and sENG showed modest but significantly different concentrations before 30 weeks of gestation in women who developed pre-eclampsia. Test accuracies of all four markers, however, are too poor for accurate prediction of pre-eclampsia in clinical practice.