Early cost-effectiveness analysis of screening for preeclampsia in nulliparous women: A modelling approach in European high-income settings.

BACKGROUND: Preeclampsia causes substantial maternal and perinatal morbidity and mortality and significant societal economic impact. Effective screening would facilitate timely and appropriate prevention and management of preeclampsia. OBJECTIVES: To develop an early cost-effectiveness analysis to assess both costs and health outcomes of a new screening test for preeclampsia from a healthcare payer perspective, in the United Kingdom (UK), Ireland, the Netherlands and Sweden. METHODS: A decision tree over a 9-month time horizon was developed to explore the cost-effectiveness of the new screening test for preeclampsia compared to the current screening strategy. The new test strategy is being developed so that it can stratify healthy low risk nulliparous women early in pregnancy to either a high-risk group with a risk of 1 in 6 or more of developing preeclampsia, or a low-risk group with a risk of 1 in 100 or less. The model simulated 25 plausible scenarios in a hypothetical cohort of 100,000 pregnant women, in which the sensitivity and specificity of the new test were varied to set a benchmark for the minimum test performance that is needed for the test to become cost-effective. The input parameters and costs were mainly derived from published literature. The main outcome was incremental costs per preeclampsia case averted, expressed as an incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty. RESULTS: Base case results showed that the new test strategy would be more effective and less costly compared to the current situation in the UK. In the Netherlands, the majority of scenarios would be cost-effective from a threshold of €50,000 per preeclampsia case averted, while in Ireland and Sweden, the vast majority of scenarios would be considered cost-effective only when a threshold of €100,000 was used. In the best case analyses, ICERs were more favourable in all four participating countries. Aspirin effectiveness, prevalence of preeclampsia, accuracy of the new screening test and cost of regular antenatal care were identified as driving factors for the cost-effectiveness of screening for preeclampsia. CONCLUSION: The results indicate that the new screening test for preeclampsia has potential to be cost-effective. Further studies based on proven accuracy of the test will confirm whether the new screening test is a cost-effective additional option to the current situation.

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.

PARROT Ireland: Placental growth factor in Assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a Stepped Wedge Cluster Randomised Control Trial Research Study Protocol.

INTRODUCTION: Women presenting with suspected pre-eclampsia are currently triaged on the basis of hypertension and dipstick proteinuria. This may result in significant false positive and negative diagnoses resulting in increased morbidity or unnecessary intervention. Recent data suggest that placental growth factor testing may be a useful adjunct in the management of women presenting with preterm pre-eclampsia. The primary objective of this trial is to determine if the addition of placental growth factor testing to the current clinical assessment of women with suspected preterm pre-eclampsia, is beneficial for both mothers and babies. METHODS AND ANALYSIS: This is a multicentre, stepped wedge cluster, randomised trial aiming to recruit 4000 women presenting with symptoms suggestive of preterm pre-eclampsia between 20 and 36+6 weeks' gestation. The intervention of an unblinded point of care test, performed at enrolment, will quantify maternal levels of circulating plasma placental growth factor. The intervention will be rolled out sequentially, based on randomisation, in the seven largest maternity units on the island of Ireland. Primary outcome is a composite outcome of maternal morbidity (derived from the modified fullPIERS model). To ensure we are not reducing maternal morbidity at the expense of earlier delivery and worse neonatal outcomes, we have established a co-primary outcome which will examine the effect of the intervention on neonatal morbidity, assessed using a composite neonatal score. Secondary analyses will examine further clinical outcomes (such as mode of delivery, antenatal detection of growth restriction and use of antihypertensive agents) as well as a health economic analysis, of incorporation of placental growth factor testing into routine care. ETHICS AND DISSEMINATION: Ethical approval has been granted from each of the seven maternity hospitals involved in the trial. The results of the trial will be presented both nationally and internationally at conference and published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02881073.

Estimating the Cost of Preeclampsia in the Healthcare System: Cross-Sectional Study Using Data From SCOPE Study (Screening for Pregnancy End Points).

To estimate the cost of preeclampsia from the national health payer's perspective using secondary data from the SCOPE study (Screening for Pregnancy End Points). SCOPE is an international observational prospective study of healthy nulliparous women with singleton pregnancies. Using data from the Irish cohort recruited between November 2008 and February 2011, all women with preeclampsia and a 10% random sample of women without preeclampsia were selected. Additional health service use data were extracted from the consenting participants' medical records for maternity services which were not included in SCOPE. Unit costs were based on estimates from 3 existing Irish studies. Costs were extrapolated to a national level using a prevalence rate of 5% to 7% among nulliparous pregnancies. Within the cohort of 1774 women, 68 developed preeclampsia (3.8%) and 171 women were randomly selected as controls. Women with preeclampsia used higher levels of maternity services. The average cost of a pregnancy complicated by preeclampsia was €5243 per case compared with €2452 per case for an uncomplicated pregnancy. The national cost of preeclampsia is between €6.5 and €9.1 million per annum based on the 5% to 7% prevalence rate. Postpartum care was the largest contributor to these costs (€4.9-€6.9 million), followed by antepartum care (€0.9-€1.3 million) and peripartum care (€0.6-€0.7 million). Women with preeclampsia generate significantly higher maternity costs than women without preeclampsia. These cost estimates will allow policy-makers to efficiently allocate resources for this pregnancy-specific condition. Moreover, these estimates are useful for future research assessing the cost-effectiveness of preeclampsia screening and treatment.

Birth by caesarean section and school performance in Swedish adolescents- a population-based study.

BACKGROUND: Our objective was to assess the impact of obstetric mode of delivery, and in particular birth by Caesarean section (CS), on school performance in adolescents using a large, population-based cohort. METHODS: We extracted data from the Swedish Medical Birth Register and National School Register. We included all live singleton births in Sweden from 1982-1995 (n = 1,489,925). School grades were reported on a scale from 0 to 320, scores less than 160 (i.e. "pass") were considered to be "poor school performance." Mode of delivery was categorised as: unassisted vaginal delivery (VD), assisted VD, elective CS and emergency CS. We measured the association between mode of delivery and "poor school performance" using logistic regression. We then used quantile regression to assess the association between mode of delivery and school performance across the distribution of scores. We adjusted for maternal age, parity, small and large for gestational age, gestational age, maternal country of birth, maternal depression, non-affective disorder or bipolar disorder, parental income at time of birth, and parental social welfare at time of birth. We also conducted sensitivity analyses to investigate the association further. RESULTS: With logistic regression analysis, the adjusted odds ratio (aOR) of assisted VD and poor school performance, compared to unassisted VD, was 1.06 (95% CI: 1.03-1.08). For elective CS it was 1.06 (95% CI:1.03-1.09) and for emergency CS it was 1.12 (95% CI: 1.09-1.15). With quantile regression, assisted VD showed little difference in scores, when compared to unassisted VD, at any point across the distribution. Elective CS was associated with a 1-3 point decrease in scores, and emergency CS was associated with a 2-5 point decrease in scores. CONCLUSION: A slight association was found between birth by CS and school performance. However, the effect was quite small and given the complex nature of the relationship, should be interpreted with caution.

Assessment of glycogen phosphorylase isoenzyme BB as a biomarker for pre-eclampsia and small for gestational age.

BACKGROUND: Glycogen phosphorylase is a key enzyme in the regulation of glycogen metabolism and consists of three isoenzymes, including glycogen phosphorylase isoenzyme BB (GPBB). Pre-eclampsia, gestational hypertension, and small-for-gestational-age (SGA) infants are complications in about 15% of all nulliparous pregnancies. Biomarkers for these adverse pregnancy outcomes remain elusive. GPBB has been proposed as a potential biomarker for the detection of these adverse outcomes. We aimed to investigate this hypothesis. METHODS: Blood samples from women with pre-eclampsia or SGA were analysed from the time of disease presentation and from samples collected at 15 and 20 weeks' gestation. They were compared with control samples obtained from women recruited to the Screening for Pregnancy Endpoints (SCOPE) study. These control samples were from healthy women with uncomplicated pregnancies matched for age, ethnicity, parity, body-mass index, and gestational age. GPBB concentrations were measured with ELISA (Diacordon, Diagenics, Essen, Germany). FINDINGS: Significant differences in GPBB were observed between all three gestations (p=0·03). GPBB concentrations were higher in women with pre-eclampsia than in controls at the time of disease presentation (term pre-eclampsia n=14, median 22·2 ng/mL [IQR 15·1-39·8] vs 16·9 [10·4-19·1], p=0·04; preterm pre-eclampsia n=11, 23·1 [11·2-30·9] vs 17·2 [9·8-19·1], p=0·04) and at 20 weeks' gestation (n=39, 23·0 [15·6-31·4] vs 17·0 [13·4-23·6]; p=0·04). GPBB concentrations were also significantly higher in women with SGA than in controls at the time of disease detection (n=23, 22·7 [12·6-25·5] vs 17·0 [9·8-18·0]; p=0·03) but significantly less than in controls at 15 weeks' gestation before disease detection (n=25, 16·0 [12·1-23·2] vs 22·2 [17·0-28·9]; p=0·02). INTERPRETATION: We have shown that significant variation of GPBB concentrations occurs in normal pregnancy, pre-eclampsia, and SGA pregnancies. GPBB in healthy pregnancy lowers as pregnancy progresses from the first to the third trimester. GPBB might, therefore, be useful as a biomarker in early pregnancy and at the time of disease in the prediction of both preterm and term pre-eclampsia and SGA. FUNDING: National Institute for Health Research, SCOPE Study was funded by the Health Research Board. This work was performed in the Irish Centre for Fetal and Neonatal Translational Research and partly supported by Science Foundation Ireland.

A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED).

BACKGROUND: 5% of first time pregnancies are complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful screening test exists; consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROvED Consortium members have pioneered a personalised medicine approach to identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The key objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia. METHODS/DESIGN: We report the design of a multicentre, phase IIa clinical study aiming to recruit 5000 low risk primiparous women to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves maternal phlebotomy at 15 and 20 weeks' gestation, with optional testing and biobanking at 11 and 34 weeks. Blood samples will be analysed using two innovative, proprietary prototype platforms; one metabolomic based and one proteomic based, both of which outperform current biomarker based screening tests at comparable gestations. Analytical and clinical data will be collated and analysed via the Copenhagen Trials Unit. DISCUSSION: The IMPROvED study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If 'at risk' patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROvED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome. TRIAL REGISTRATION: Trial registration number NCT01891240The IMPROvED project is funded by the seventh framework programme for Research and Technological development of the EU. http://www.fp7-improved.eu/

Colorectal stents: do we have enough evidence?

BACKGROUND: The use of colonic stents has significantly evolved over the last few years. Emergency surgery for colonic obstructions is usually associated with significant mortality, morbidity and often stoma formation. Colonic stents provide an alternative way to relieve colonic obstruction, and hence avoiding the risks associated with emergency surgery. This literature review aims to summarize the important current evidence regarding colorectal stenting and show whether further evaluation of the procedure is required. RESULTS: The available large number of non-randomized studies suggests that Self-Expandable-Metal-Stents (SEMS) placement for acute colonic obstruction could be considered as safe and effective alternative to surgery in experienced hands either as a bridge to surgery or as a palliative measure. This evidence has led to SEMS being widely adopted. However, randomized evidence has begun to show the defects that are inherent in the low level evidence that has so far supported SEMS use and it may be that reports of randomized controlled trials may clarify the patient population where SEMS placement is appropriate. CONCLUSION: While we are still waiting for the outcome of the multicentre randomized controlled trials in the UK and Europe, clinicians must be aware of the current evidence limitations and apply SEMS use pragmatically.