Severe Preeclampsia
Conditions
Keywords
Angiogenic biomarkers, sFlt-1/PlGF ratio
Brief summary
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.
Detailed description
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.
Interventions
OTHERsFlt-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 maturation if gestational age is \<35 weeks); and if sFlt-1/PlGF \<110, planned delivery will occur at 37 weeks. If immediate delivery criteria are met, delivery will be recommended regardless of the ratio.
OTHERUsual 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
Sponsors
Hospital Clinic of Barcelona
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Instituto de investigación Hospital 12 de Octubre
Hospital de Sant Pau
Fundació Sant Joan de Déu
Hospital Universitario La Paz
Hospital Materno-Infantil de Canarias. Las Palmas de Gran Canaria. Spain
Hospital Son Llatzer
Hospital Clinico Universitario San Cecilio
Hospital Universitario Virgen de la Arrixaca
Fundacion Para La Investigacion Hospital La Fe
Hospital Vall d'Hebron
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Multicenter, randomized, open-label, controlled trial of superiority conducted across 11 national reference university hospitals in Spain, with two parallel groups . Participants will be recruited at diagnosis or at 30 weeks' gestation if preeclampsia was previously identified. Participants will be randomized to one of the two study arms in a 1:1 ratio to the intervention group or the control group using the online service (REDCap) that will generate the randomized sequence in blocks of 10 stratified by participating center. The allocation will be sequestered internally by a Clinical Trials Unit. The management of patients will follow the standard practices of the participating center and include the administration of corticosteroids for fetal lung maturation, magnesium sulfate for eclampsia prophylaxis, and clinical laboratory monitoring according to established protocols.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite adverse maternal and fetal outcomes | From randomization until delivery or completion of maternal follow-up, assessed up to 40 days postpartum. | Dichotomous outcome: occurrence of ≥1 maternal or fetal complication from randomization to delivery. Complications included: (1) central nervous system dysfunction (eclampsia, Glasgow Coma Scale \<13, stroke, reversible ischaemic neurological deficit, or cortical blindness); (2) hepatic dysfunction (INR \>1.2 without disseminated intravascular coagulation, MELD score \>10, or hepatic hematoma/rupture); (3) renal dysfunction (dialysis, serum creatinine \>1.5 mg/dL, urine output \<0.5 mL/kg/h over 12 h per RIFLE criteria, or need for furosemide); (4) respiratory dysfunction (pulmonary edema, mechanical ventilation, oxygen \>50% for \>1 h, or severe respiratory distress with dyspnoea, crackles, and SaO₂ \<90%); (5) cardiovascular dysfunction (inotropes, left ventricular failure, myocardial infarction, or transfusion \>4 units); (6) resistant hypertension (≥3 drugs at maximal doses or controlled with ≥4); (7) placental abruption; and (8) stillbirth (≥22 weeks, WHO). |
| The neonatal composite outcome | From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first). | Dichotomous outcome: Occurrence of ≥1 neonatal complication, defined as neonatal death before 28 days of life or admission to a neonatal intensive care unit or high-dependency unit according to British Association of Perinatal Medicine criteria, between birth and 28 days of life. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maternal risk prediction using the fullPIERS model | From randomization until delivery, assessed up to 37 completed weeks of gestation | The fullPIERS model is a validated prediction scoring for preeclampsia that incorporates gestational age (weeks), chest pain or dyspnea, oxygen saturation (%), platelet count (×10⁹/L), serum creatinine (mg/dL or µmol/L), and aspartate transaminase (AST, U/L) to estimate the risk of severe maternal complications, primarily within 48 hours after assessment. |
| Maternal length of hospitalization | From randomization until maternal hospital discharge, assessed up to 40 days postpartum. | Duration of maternal hospitalization, defined as the number of days from randomization to hospital discharge. This is a continuous variable. |
| Intrauterine growth restriction | From date of randomization until the last scan before delivery or fetal death, assessed up to 37 completed weeks of gestation. | Occurrence of prenatal fetal growth restriction (FGR), defined as an antenatal estimated fetal weight \<10th percentile for gestational age on ultrasound, assessed as a dichotomous outcome (yes/no) |
| Postnatal small for gestational age | At delivery | Occurrence of small for gestational age (SGA), defined as birthweight \<10th percentile for gestational age and sex, analyzed as a binary outcome |
| Gestational age at delivery | At the time of delivery | Gestational age at delivery (in weeks): |
| Proportion of participants undergoing cesarean delivery | At delivery | Cesarean delivery will be defined as any surgical delivery of the fetus. The outcome will be analyzed as a dichotomous variable and reported as the proportion of participants undergoing cesarean delivery . |
| Neonatal morbidity according to the Morbidity Assessment Index for Newborns (MAIN) | From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first). | Neonatal morbidity will be assessed using the Morbidity Assessment Index for Newborns (MAIN), a validated composite score based on 47 weighted clinical and laboratory indicators. Scores range from 0 (no morbidity) upward, with higher scores indicating greater neonatal morbidity and worse neonatal health status. Scores of 0-150 represented minimal/no morbidity, 151-500 mild morbidity, 501-800 moderate morbidity, and \>800 severe morbidity . |
| Neonatal complications | From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first). | Neonatal complications will include metabolic acidosis (umbilical artery pH \<7.00 and base excess \<-16), Apgar score \<7 at 5 minutes, bronchopulmonary dysplasia, necrotizing enterocolitis stage 2 or 3 according to Bell's classification, Grade III intraventricular haemorrhage (IVH) and periventricular haemorrhagic infarction (PHI), according to the contemporary classification proposed by Parodi (28), periventricular leukomalacia, retinopathy stage 3-5, hypoxic-ischemic encephalopathy (defined by Apgar score \<5 at 10 minutes, umbilical artery pH \<7.00, or base excess \>-16 at 60 minutes, associated with neurological signs), neonatal renal insufficiency (creatinine \>1.5 mg/dL), and the need for inotropic agents. |
| Days of admission in the neonatal high-dependency care unit | From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first) | Number of days admitted in the high-dependency care unit |
| Days of neonatal admission to the intensive care unit | From delivery up to neonatal discharge from hospital or neonatal death or 28 days of life (whichever comes first). | Lenght of neonatal stay from admission to discharge from NICU |
| Uterine artery pulsatility index | From date of randomization until the last scan before delivery or fetal death, assessed up to 37 completed weeks of gestation. | Mean uterine artery pulsatility index measured by Doppler ultrasound. |
| Middle cerebral artery pulsatility index | 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 measured by fetal Doppler ultrasound. |
| Umbilical artery pulsatility index | From date of randomization until the last scan before delivery or fetal death, assessed up to 37 completed weeks of gestation. | Umbilical artery pulsatility index measured by Doppler ultrasound. |
| Placental dysfunction (histological assessment) | At delivery | Placental dysfunction assessed by histopathological examination according to the Amsterdam consensus classification, including features of maternal vascular malperfusion and fetal vascular malperfusion |
Countries
Spain
Contacts
CONTACTCesar Gil Armas, MD
PRINCIPAL_INVESTIGATORFrancesc Figueras Retuerta, PhD
Hospital Clinic of Barcelona
Outcome results
None listed