Algorithm-Based Timing of Delivery Using the sFlt-1/PlGF Ratio in Early-Onset Severe Preeclampsia. (MAP 2 Study : Management Based on Angiogenic Markers in Preeclampsia 2 Study )

Multicenter Randomized Trial of an sFlt-1/PlGF Ratio-Based Algorithm for Timing of Delivery in Early-Onset Severe Preeclampsia: The MAP 2 Study

Preeclampsia is a serious pregnancy complication caused by abnormal placental development and function. It can lead to high blood pressure and damage to organs such as the liver, kidneys, brain, or cardiovascular system. In these cases, the only definitive treatment is delivery. However, deciding when to deliver is challenging: delaying delivery increases risks for both mother and baby, while delivering too early increases complications related to prematurity.

This study aims to evaluate whether a blood test measuring the sFlt-1/PlGF ratio an angiogenic marker that reflects placental function and predicts complications more accurately than traditional clinical criteria can help determine the optimal timing of delivery in women with severe preeclampsia between 30 weeks and 33 weeks plus 6 days of gestation. It is a multicenter, randomized controlled clinical trial conducted in 11 referral hospitals in Spain and will include 386 singleton pregnancies.

Participants will be randomly assigned to one of two groups. In the control group, standard expectant management will be followed, aiming to continue the pregnancy until 34 weeks if maternal and fetal conditions remain stable, and the sFlt-1/PlGF results will be masked. In the study group, delivery timing will be guided by the sFlt-1/PlGF ratio: if the ratio is greater than 655, delivery will be planned from 30 weeks onward; if greater than 110, delivery will be planned from 34 weeks; and if 110 or lower, pregnancy may continue until 37 weeks.

The study has two primary outcomes. The first is a composite of severe maternal complications, including neurological, hepatic, renal, respiratory, or cardiovascular dysfunction, severe hypertension, placental abruption, or fetal death. The second is a composite of neonatal complications, including admission to the neonatal intensive care unit or neonatal death.

The goal is to demonstrate that using angiogenic markers reduces maternal complications without significantly increasing neonatal complications. If successful, this approach could support more individualized management of early-onset severe preeclampsia, improving maternal safety while carefully balancing the risks of prematurity for the newborn.

This is a multicenter, open-label, randomized controlled clinical trial designed to evaluate whether incorporating maternal angiogenic markers into clinical decision-making improves outcomes in early-onset severe preeclampsia. The study will include 386 singleton pregnancies diagnosed with preeclampsia with severe features according to ACOG criteria between 30+0 and 33+6 weeks of gestation across 11 tertiary referral centers in Spain. At inclusion, the maternal plasma sFlt-1/PlGF ratio will be measured in all participants. Women will then be randomly assigned (1:1) to either standard expectant management (control group) or angiogenic marker-guided management (intervention group) using a centralized REDCap randomization system that will generate the allocation sequence in blocks of 10, stratified by participating center. In the control group, clinical management will follow current standard practice, with planned delivery at 34 weeks if maternal and fetal conditions remain stable, and sFlt-1/PlGF results will be masked to treating clinicians. In the intervention group, timing of delivery will be guided by predefined sFlt-1/PlGF thresholds: >655 from 30+0 weeks, >110 from 34+0 weeks, and ≤110 allowing expectant management up to 37 weeks, provided no other obstetric indication for delivery arises. The primary objective is to evaluate whether the use of an algorithm based on the sFlt-1/PlGF ratio to guide the timing of delivery in women with early-onset severe preeclampsia with severe features improves maternal and neonatal outcomes compared with standard management. Secondary objectives include evaluating the predictive value of baseline and longitudinal sFlt-1/PlGF measurements, assessing the association between angiogenic marker abnormalities and disease progression, determining their relationship with placental dysfunction assessed by Doppler and histopathological examination, and evaluating the impact of the algorithm on maternal and neonatal healthcare resource utilization. Analyses will follow the intention-to-treat principle and will account for the multicenter design of the study.

Inclusion criteria :

• Women aged 18 or older
• Singleton pregnancies
• Diagnosed with severe preeclampsia per 2020 ACOG criteria, between 30.0 and 33.6 weeks by first-trimester ultrasound.

Exclusion criteria :

• Major fetal malformations
• Confirmed genetic syndromes.