Aspirin versus metformin in pregnancies at high risk of preterm pre-eclampsia in China (AVERT): protocol for a multicentre, double-blind, 3-arm randomised controlled trial

Abstract

Introduction: Pre-eclampsia (PE) affects about 5% of Chinese pregnant women and is a major cause of maternal and perinatal morbidity and mortality. The first trimester screening model developed by the Fetal Medicine Foundation, which uses the Bayes theorem to combine maternal characteristics and medical history together with measurements of biomarkers, has been proven to be effective and has superior screening performance to that of the traditional risk factor-based approach for the prediction of PE. Prophylactic use of low-dose aspirin in women at risk for PE has resulted in a lower incidence of preterm-PE. However, there is no consensus on the preferred aspirin dosage for the prevention of preterm-PE. Evidence has also suggested that metformin has the potential benefit in preventing PE in pregnant women who are at high risk of the disorder.

Method and analysis: We present a protocol (V.2.0, date 17 March 2022) for the AVERT trial, which is a multicentre, double-blinded, 3-arm randomised controlled trial (RCT) that uses an effective PE screening programme to explore the optimal dosage of aspirin and the role of metformin for the prevention of PE among high-risk pregnant women in China. We intend to recruit 66 000 singleton pregnancies without treatment of low-dose aspirin and metformin at 11-13 weeks' gestation and all eligible women attending for their first trimester routine scan will be invited to undergo screening for preterm-PE by the combination of maternal factors, mean arterial pressure and placental growth factor. Women found to be at high risk of developing preterm-PE will be invited to take part in the RCT. This study will compare the incidence of preterm-PE with delivery at <37 weeks' gestation, as the primary outcome, of three different interventional groups: (1) aspirin 75 mg daily, (2) aspirin 150 mg daily and (3) aspirin 75 mg with metformin 1.5 g daily. 957 participants per treatment group are required to detect a significant difference of 59% in the reduction of the incidence of preterm-PE with 80% power and type I error of 5%. Pregnancy and neonatal outcomes will be collected and analysed.

Ethics and dissemination: Ethical approval for the study was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC Ref. No. 2021.406) in Hong Kong and the Ethics Committee of each participating hospital in Mainland China. The study is registered at ClinicalTrials.gov. The results of the AVERT trial will be disseminated at international academic conferences and published in high-impact factor journals.

Trial registration number: NCT05580523.