Cost-effectiveness of the sFlt-1/PlGF ratio and telemonitoring in managing suspected pre-eclampsia: protocol for the PREPARE II randomised controlled trial

Introduction The soluble FMS-like tyrosine kinase-1 and placental growth factor (sFlt-1/PlGF) ratio has demonstrated impressive predictive test characteristics in women with suspected pre-eclampsia. However, it remains a matter of debate whether the introduction of this novel test can indeed translate to a reduction in pre-eclampsia-related hospital admissions, outpatient visits and can consequently lower overall healthcare costs. The PREPARE II study aims to investigate whether the sFlt-1/PlGF ratio, along with digital self-monitoring, can reduce pre-eclampsia-related healthcare utilisation in the first week following the test for women with suspected pre-eclampsia. Methods and analysis This is a randomised controlled trial across six centres which includes women (≥16 years old) between 20 and 37 weeks of gestation with suspected pre-eclampsia due to one or more identified symptoms. For power calculation, we assumed that the sFlt-1/PlGF ratio including a telemonitoring strategy leads to a de-escalation of care by cumulatively reducing the frequency of pre-eclampsia-related hospital admissions and/or outpatient visits in the first week from 50% in the control group to 35% in the intervention group. Considering a loss to follow-up of 5%, a sample size of approximately 470 women is required with 235 women per arm (α=5%; power=90%). The intervention is an algorithm based on the urine protein/creatinine ratio (PCr)+sFlt-1/PlGF ratio, along with a telemonitoring strategy. The algorithm incorporates a PCr cut-off of 30 (mg/mmol) and a sFlt-1/PlGF ratio cut-off of 38 for risk classification. Subsequent clinical follow-up recommendations are stratified based on this classification: low risk entails no additional follow-up, returning to routine antenatal care; intermediate risk includes telemonitoring; high risk necessitates immediate admission. The primary outcome is the occurrence of pre-eclampsia-related healthcare utilisation in the first week after testing. Secondary outcomes are maternal/perinatal adverse events, total healthcare usage, pre-eclampsia diagnosis, quality of life and productivity losses. A cost-effectiveness analysis from a societal perspective will be performed. Ethics and dissemination Ethical approval was obtained from the Medical Ethics Committee of Leiden University Medical Centre (METC LDD) on 21 July 2025 (reference NL-009295). The results will be disseminated through peer-reviewed publications and presentations at international conferences. Trial registration NL88527.058.24.