Title: Screening programme for pre-eclampsia (SPREE)
Funder: Department of Health and Social Care

Abstract: BACKGROUND. Pre-eclampsia (PE), which affects about 2% of pregnancies, is a major cause of maternal and perinatal morbidity and mortality. PE can be subdivided into preterm-PE requiring delivery <37 weeks’ gestation and late-PE with delivery >37 weeks. Preterm-PE is associated with a higher incidence of adverse outcomes. There is evidence that the prevalence of PE can potentially be reduced by the prophylactic use of low-dose aspirin started before 16 weeks’ gestation and therefore there is a need for effective early detection of high-risk women that could benefit from aspirin therapy. HYPOTHESIS. We have developed a technique for PE screening, using a novel Bayes-based method, which is likely to be superior to the current method recommended by the National Institute for Health and Clinical Excellence (NICE) based on maternal characteristics and medical history (Mat-CH). Our method uses Bayes theorem to combine the prior information from Mat-CH with measurements of mean arterial pressure (MAP), uterine artery pulsatility index (Ut-PI), serum placental growth factor (PLGF) and serum pregnancy associated plasma protein-A (PAPP-A) at 11-13 weeks’ gestation (combined test). The estimated detection rate, for false positive rate of 10%, of the NICE method is about 40% for preterm-PE and 35% for all-PE and the respective values for our proposed combined test are about 75% and 55% and mini combined test (Mat-CH with MAP and PAPP-A) are 60% and 50%. DESIGN. Prospective cohort study in six NHS hospitals. The study will comprise of a multicentre study on the clinical evaluation of the new method and comparison of performance with current practice. This will require training healthcare providers for each component of screening in order to ensure quality. SETTING. Antenatal scan clinics in the UK NHS. POPULATION. Women with singleton pregnancies attending for their routine 11-13 weeks scan. OUTCOME. The primary outcome will be the false positive and true positive frequencies for screening using the Bayes-based method and for screening according to the NICE guidelines. SAMPLE SIZE. 16,000 singleton pregnancies. STATISTICAL ANALYSIS. The primary analysis will be a comparison of detection rates using the Bayes-based method with the NICE guidelines. McNemars test at the one sided 2.5% level will be applied. The analysis will be adjusted for the effects of aspirin treatment, because treatment biases the comparison of screening performance by reducing the incidence of PE in the treated group. We have investigated the properties of this analysis across a range of scenarios to assess effect of bias adjustments on the type I and type II error rates. In the most extreme case the sample size of 16,000 has 99% power demonstrating an increase in detection rate of all-PE from 35% to 50%. TIME TABLE. Protocol, months 1-2; Training, months 1-3; ethics and R&D approval, months 2-5; site initiation, months 5-6; patient recruitment, months 7-16; collection of pregnancy outcomes, months 12-25; analysis and writing of results, months 26-30. ECONOMIC BENEFITS. Effective screening for PE can lead to effective prevention of the condition and reduce the associated costs for the short-term and long-term management of women with PE and their children.

Lay abstract: Pre-eclampsia (PE) is a medical condition characterised by high blood pressure and the presence of protein in the urine of a pregnant woman. It develops in at least 2% of all pregnancies. The effects of PE can be serious both for the mother and the baby, especially when the disease is severe requiring delivery before 37 weeks’ gestation (preterm-PE) and there is associated slow growth of the fetus. There is some evidence that in women at high-risk of developing PE their risk may be reduced by taking low-dose aspirin every day throughout pregnancy, provided the treatment starts before 16 weeks. The National Institute for Health and Clinical Excellence (NICE) has issued guidelines recommending that the way to determine whether a woman is at high-risk of developing PE should depend on their characteristics and medical history (Mat-CH). However, this method of screening only identifies about 40% of the women that develop preterm-PE and 35% of all cases of PE. We have developed a new method of screening that combines the information from Mat-CH with the results from various tests to calculate the individual risk for developing PE. Extensive research in the last decade has led to the identification of 4 potentially useful tests: measurements of blood pressure, blood flow in the maternal blood vessels that supply the uterus and the levels of two placental proteins in the mother’s blood. These tests can be carried out at the time of the routine ultrasound examination at 11-13 weeks. There is some evidence that the new test can identify 75% of the women that develop preterm-PE and 55% of all-PE. If future research identifies additional new markers which can improve the performance of screening, these can easily be incorporated into our new method. The proposed study will test the usefulness of our new method against that currently recommended by NICE. It will evaluate how our proposed screening for PE performs in several NHS sites. We will provide training to all healthcare providers involved in how to record medical history, obtain and record the measurements of study tests, and obtain pregnancy outcome data. In the participating hospitals, all women attending for their routine 11-13 weeks scan will be invited by a dedicated researcher or midwife to take part in the screening study for PE. In women who agree to take part, we will record their Mat-CH, measure their blood pressure, blood flow to the uterus and the level of two proteins in their blood. All data will be recorded in our secure user-friendly software that can be used in all hospitals to calculate the risk of PE. The software will allow continuous monitoring of the quality of obtaining and recording measurements. A total of 16,000 pregnancies will be recruited and the study will be coordinated by the University College London Comprehensive Clinical Trials Unit. Our team has extensive experience in the development of a screening method for PE and has successfully completed several large multicentre studies in many pregnancy complications. PPI input has been sought and has contributed to the development of the application and will input into the study from funding through to reporting of the findings. Key strategies have been defined to ensure appropriate dissemination of project information and results to project team members, scientific and clinical community and the general public.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH