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 )

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое sFlt-1/PlGF ratio-guided management algorithm
  Management will be optimized based on angiogenic factor results. The sFlt-1/PlGF ratio will be determined at 30.0 weeks or at diagnosis between 30.0 and 33.6 weeks of gestation, and weekly measurements will be repeated. Based on predefined thresholds, delivery will be planned as follows: if sFlt-1/PlGF \>655, planned delivery will occur after fetal lung maturation if gestational age is \<35 weeks; if sFlt-1/PlGF \<655 and ≥110, planned delivery will occur after 34 weeks (with prior lung maturati
• Другое Usual Care
  The control arm will receive usual care for severe preeclampsia according to each center's clinical protocols. The sFlt-1/PIGF ratio will be determined at 30 weeks or diagnosis between 30 and 33.6 weeks of gestation, and weekly measurements will be repeated, but the ratio will not be available to the clinician or researchers

Первичные конечные точки

• Composite adverse maternal and fetal outcomes [Срок оценки: From randomization until delivery or completion of maternal follow-up, assessed up to 40 days postpartum.]
• The neonatal composite outcome [Срок оценки: From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first).]

Вторичные конечные точки (12)

• Maternal risk prediction using the fullPIERS model [Срок оценки: From randomization until delivery, assessed up to 37 completed weeks of gestation]
• Maternal length of hospitalization [Срок оценки: From randomization until maternal hospital discharge, assessed up to 40 days postpartum.]
• Intrauterine growth restriction [Срок оценки: From date of randomization until the last scan before delivery or fetal death, assessed up to 37 completed weeks of gestation.]
• Postnatal small for gestational age [Срок оценки: At delivery]
• Gestational age at delivery [Срок оценки: At the time of delivery]
• Proportion of participants undergoing cesarean delivery [Срок оценки: At delivery]
• Neonatal morbidity according to the Morbidity Assessment Index for Newborns (MAIN) [Срок оценки: From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first).]
• Neonatal complications [Срок оценки: From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first).]
• Days of admission in the neonatal high-dependency care unit [Срок оценки: From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first)]
• Days of neonatal admission to the intensive care unit [Срок оценки: From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first).]
• Uterine artery pulsatility index [Срок оценки: From date of randomization until the last scan before delivery or fetal death, assessed up to 37 completed weeks of gestation.]
• Middle cerebral artery pulsatility index [Срок оценки: From date of randomization until the last scan before delivery or fetal death, assessed up to 37 completed weeks of gestation.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• Major fetal malformations
• Confirmed genetic syndromes.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Испания · 1 центр

• c/ Sabino Arana, 1. 08028 Barcelona — Barcelona

Публикации

• Peguero A, Fernandez-Blanco L, Mazarico E, Benitez L, Gonzalez A, Youssef L, Crispi F, Hernandez S, Figueras F. Added prognostic value of longitudinal changes of angiogenic factors in early-onset severe pre-eclampsia: a prospective cohort study. BJOG. 2021 Jan;128(2):158-165. doi: 10.1111/1471-0528.16383. Epub 2020 Jul 21. PMID 32593222
• Peguero A, Herraiz I, Perales A, Melchor JC, Melchor I, Marcos B, Villalain C, Martinez-Portilla R, Mazarico E, Meler E, Hernandez S, Matas I, Del Rio M, Galindo A, Figueras F. Placental growth factor testing in the management of late preterm preeclampsia without severe features: a multicenter, randomized, controlled trial. Am J Obstet Gynecol. 2021 Sep;225(3):308.e1-308.e14. doi: 10.1016/j.ajog.2 PMID 33823150
• Iams JD, Romero R, Culhane JF, Goldenberg RL. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet. 2008 Jan 12;371(9607):164-75. doi: 10.1016/S0140-6736(08)60108-7. PMID 18191687
• Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol. 2013 Dec;209(6):544.e1-544.e12. doi: 10.1016/j.ajog.2013.08.019. Epub 2013 Aug 22. PMID 23973398
• Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ, Lim KH, Wenger JB, Thadhani R, Karumanchi SA. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012 Feb 21;125(7):911-9. doi: 10.1161/CIRCULATIONAHA.111.054361. Epub 2012 Jan 18. PMID 22261192
• Soundararajan R, Suresh SC, Mueller A, Heimberger S, Avula S, Sathyanarayana C, Mahesh S, Madhuprakash S, Rana S. Real life outpatient biomarker use in management of hypertensive pregnancies in third trimester in a low resource SeTting: ROBUST study. Pregnancy Hypertens. 2021 Mar;23:97-103. doi: 10.1016/j.preghy.2020.11.010. Epub 2020 Dec 3. PMID 33307400
• Lopes Perdigao J, Chinthala S, Mueller A, Minhas R, Ramadan H, Nasim R, Naseem H, Young D, Shahul S, Chan SL, Yeo KJ, Rana S. Angiogenic Factor Estimation as a Warning Sign of Preeclampsia-Related Peripartum Morbidity Among Hospitalized Patients. Hypertension. 2019 Apr;73(4):868-877. doi: 10.1161/HYPERTENSIONAHA.118.12205. PMID 30798660
• Sibiude J, Guibourdenche J, Dionne MD, Le Ray C, Anselem O, Serreau R, Goffinet F, Tsatsaris V. Placental growth factor for the prediction of adverse outcomes in patients with suspected preeclampsia or intrauterine growth restriction. PLoS One. 2012;7(11):e50208. doi: 10.1371/journal.pone.0050208. Epub 2012 Nov 28. PMID 23209675

Идентификаторы

NCT: NCT07665112 · PI25/00371 · PI25/00371

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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