Preeclampsia (PE) is an important cause of maternal and perinatal mortality and morbidity. The risk of adverse outcome is much higher when the disease is severe and of early onset requiring delivery before 37 weeks' gestation (preterm PE) than at term. A major challenge in modern obstetrics is early identification of pregnancies at high-risk of preterm PE and undertaking of the necessary measures to improve placentation and reduce the prevalence of the disease.
Prediction of preterm preeclampsia
Extensive research in the last 20 years has identified a series of early biophysical and biochemical markers of impaired placentation Akolekar et al, 2011). A combination of maternal demographic characteristics, including medical and obstetric history, uterine artery pulsatility index (PI), mean arterial pressure (MAP) and maternal serum pregnancy associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at 11-13 weeks' gestation can identify a high proportion of pregnancies at high-risk for preterm PE (Akolekar et al, 2011 (2012).
Prevention of preterm preeclampsia
The prophylactic use of low-dose aspirin for prevention of PE has been an important research question in obstetrics for the last three decades. More than 50 trials have been carried out throughout the world and a meta-analysis of these studies reported that the administration of low-dose aspirin in high-risk pregnancies is associated with a decrease in the rate of PE by approximately 10% (Askie et al, 2007).
Recent meta-analysis of randomized studies reported that low-dose aspirin started at or before 16 weeks was associated with a 50% reduction in the overall risk for PE and an 80% reduction in preterm PE (Bujold et al 2010, Roberge et al, 2012). However, the small number and small size of individual trials preclude definitive conclusions to be drawn and the results need to be examined in a prospective major randomised trial. In such trial the dose of aspirin to be used should be 150mg because with lower dosage a high proportion of the population are non responders (Caron et al, 2009, Rey and Rivard, 2011).
Safety of low-dose aspirin
First-trimester use of low-dose aspirin is not associated with increase in risk for fetal abnormalities (Slone et al, 1976; Klebanoff and Berendes, 1988; Werler et al, 1989; Norgard et al, 2005). Although approximately 10% of women receiving Aspirin develop gastro-intestinal symptoms there is no evidence of increase in any type of maternal bleeding or placental abruption (Sibai et al, 1993; Caritis et al., 1998; Rotchell et al, 1998, Bujold et al, 2010). Similarly, there is no association between daily consumption of low-dose Aspirin during the third-trimester and antenatal closure of the ductus arteriosus, intraventricular hemorrhage or neonatal bleeding (Di Sessa et al, 1994; Schiessl et al, 2005; Wyatt-Ashmead, 2011,Duley et al, 2007).
This will be a multicentre trial in the UK and other countries in the European Union. There will be screening for preterm PE at 11-13 weeks' gestation by a combination of maternal medical history and characteristics, maternal serum PAPP-A, and PlGF, MAP and uterine artery PI.Women who are deemed to be at high-risk for preterm PE (about 10% of the population) will be offered the opportunity to participate in the aspirin vs. placebo trial. Participants will be randomized to one tablet per night of either aspirin 150 mg or matching placebo tablet and treatment will continue until 36-37 weeks.
Objectives: To examine if the prophylactic use of low-dose aspirin from the first-trimester of pregnancy in women at increased risk for preterm preeclampsia can reduce the incidence of the disease. Secondary objectives include the effect of aspirin on the incidence of early PE (delivery <34 weeks) and total PE, birthweight below the 3rd, 5th and 10th percentile, stillbirth or neonatal death, neonatal intensive care unit admission, composite measure of neonatal mortality and morbidity, placental abruption, spontaneous preterm delivery <34 weeks and <37 weeks.
Sample size: We need to recruit 33,680 pregnancies to the screening study to identify 3,368 high-risk pregnancies. If 50% (1,684) of these agree to participate in the randomized study and aspirin reduces the rate of preterm PE by 50%, this will be significant with a power of 90%.
Governance: The trial will be conducted in compliance with the protocol, the Declaration of Helsinki (1996), the principles of Good Clinical Practice and applicable regulatory requirements. The study will be reviewed and approved by the National Research Ethics Committee, Medicine and Healthcare products Regulatory Agency and applicable Hospital Trusts. The University College London Clinical Trials Unit will manage the sponsors' responsibilities and Quality Assurance to ensure compliance with the Clinical Trial Regulations.