sFlt1/PlGF and Planned Delivery to Prevent Preeclampsia at Term. (PE37)

Protocol of the PE37 Study: A Multicenter Randomized Trial of Screening With sFlt1/PlGF and Planned Delivery to Prevent Preeclampsia at Term

• Preeclampsia (PE) affects ~5% of pregnancies. Although improved obstetrical care has significantly diminished associated maternal mortality, PE remains a leading cause of maternal morbidity and mortality in the world.
• Term PE accounts for 70% of all PE and a large proportion of maternal-fetal morbidity related with this condition. Prediction and prevention of term PE remains unsolved.
• Previously proposed approaches are based on combined screening and/or prophylactic drugs, but these policies are unlikely to be implementable in many world settings.
• Recent evidence shows that sFlt1-PlGF ratio at 35-37w predicts term PE with 80% detection rate.
• Likewise, recent studies demonstrate that induction of labor (IOL) from 37w is safe.
• The investigators hypothesize that a single-step universal screening for term PE based on sFlt1/PlGF ratio at 35-37w followed by IOL from 37w would reduce the prevalence of term PE without increasing cesarean section rates or adverse neonatal outcomes.
• The investigators propose a randomized clinical trial to evaluate the impact of a screening of term PE with sFlt-1/PlGF ratio in asymptomatic nulliparous women at 35-37w. Women will be assigned to revealed (sFlt-1/PlGF known to clinicians) versus concealed (unknown) arms. A cutoff of >90th centile will be used to define high risk of PE and offer IOL from 37w.
• If successful, the results of this trial will provide evidence to support a simple universal screening strategy reducing the prevalence of term PE, which could be applicable in most healthcare settings and have enormous implications on perinatal outcomes and public health policies worldwide.

Study Overview

• Status: Recruiting
• Conditions: Preeclampsia; Intrauterine Growth Restriction; Perinatal Death; Maternal Hypertension; Neonatal Outcome
• Intervention / Treatment: Diagnostic test: sFlt1/PlGF screening in maternal blood at 35 to 36.6 weeks of gestation

Detailed Description

Finding an effective prediction and prevention for term PE remains an unsolved challenge. From previous recent evidence it seems clear that prediction very close to term may achieve a high detection rate, but there is no evidence as to which strategy might be effective in preventing PE in high-risk women. The investigators postulate that a solution that would be applicable in most settings worldwide would require a simplified, pragmatic, approach. The rationale of this proposal is that PE could be reduced with a single-step lab test screening followed by induction of labor (IOL).

A single-step lab measure to detect PE. Combined algorithms using angiogenic factors with Doppler ultrasound and maternal features seem to achieve the highest performance in detecting pre-clinical PE. However, the need to train staff and change pregnancy care protocols renders difficult generalization in high-resource and even more low-resource settings. On the contrary, single lab tests can be more easily incorporated into the mainstream clinical practice and provide a widespread solution for high-resource settings and specially sub-optimal healthcare systems heavily affected by the consequences of term PE. Angiogenic factors are the obvious candidate for these purposes. The sFlt1/PlGF ratio at 35-36w predicts term PE with a DR of 82% and is a standardized lab test nowadays, realizable by ELISA with widely available automated lab platforms. Normal values in late pregnancy have been reported and are fairly similar among different populations. As preliminary research for this study, the investigators have confirmed that the gestational-age adjusted normal values of sFlt1/PlGF matched quite remarkably those previously published in different populations across Europe. A one-step screening with sFlt1/PlGF would select a 5-10% of the population with the highest risk for PE.

IOL at 37 weeks as an intervention in women at high-risk for PE. Previous trials based on statins have failed to show a reduction of PE in high-risk women. IOL at 37 weeks is an alternative to avoid PE in those high-risk women. IOL has consistently been demonstrated to be safe ( ) and does not affect long-term maternal quality of life ( ). Both the HYPITAT and the DIGITAT randomized trials showed that IOL did not increase caesarean rates or adverse neonatal outcomes ( ). A recent large randomized trial in the US has shown that even in low-risk women, universal IOL decreased cesarean section rates and was well accepted ( ). While in low-risk pregnancies labour induction has been found to be beneficial from 39 weeks (ARRIVE study), in women with placental-related conditions such as hypertension (HYPITAT) or small-for-gestational age (DIGITAT) it is 37+ weeks when the trade-off between neonatal and maternal benefits makes induction recommendable.

Therefore, the investigators hypothesize that a single-step universal screening for term PE based on sFlt1/PlGF ratio at 35-36.6 w followed by IOL at 37w in those women found to be at high risk might represent a feasible and reproducible strategy, applicable worldwide, to reduce the prevalence of term PE without increasing cesarean section rates or adverse neonatal outcomes.

Individual participant data, study protocol, statistical analysis plan and informed consent form will be available with publication by email addresses after approval of a proposal with a signed data access agreement

• Study Type: Interventional
• Enrollment (Estimated): 9132
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Elisa Llurba, MD; PhD; Phone Number: 0034687743699; Email: ellurba@santpau.cat

Study Locations

• Belgium
  • Liège, Belgium
    • Recruiting
    • CHU Liège
    • Contact: Frederic Chantraine
• Czechia
  • Prague, Czechia
    • Recruiting
    • Institute for the Care of Mother and Child
    • Contact: Ladislav Kofta
• India
  • Delhi
    • New Delhi, Delhi, India, 110002
      • Recruiting
      • Maulana Azad Medical College (MAMC)
      • Contact: Sangeeta Gupta, MD; Email: drsangeetamamc@gmail.com
    • New Delhi, Delhi, India, 110029
      • Recruiting
      • All India Institute of Medical Sciences (AIIMS) Ansari Nagar
      • Contact: Aparna Sharma, MD; Email: kaparnasharma@gmail.com
    • New Delhi, Delhi, India, 110029
      • Suspended
      • Vardhman Mahavir Medical College (VMMC)
• Poland
  • Warsaw, Poland
    • Recruiting
    • Centre of Postgraduate Medical Education, Obstetrics and Gynecology and Perinatal Medicine
    • Contact: Anna Kajdy
• Spain
  • Barcelona, Spain
    • Recruiting
    • Hospital del Mar
    • Contact: Toni Payà
  • Barcelona, Spain
    • Recruiting
    • Hospital Sant Joan de Déu
    • Contact: Francesc Figueras; Email: ffiguera@clinic.cat
  • Barcelona, Spain
    • Recruiting
    • Hospital de La Santa Creu i Sant Pau
    • Contact: Elisa Llurba; Email: ellurba@santpau.cat
  • Barcelona, Spain
    • Recruiting
    • Hospital Maternitat del Clínic
    • Contact: Francesc Figueras; Email: ffiguera@clinic.cat
  • Madrid, Spain
    • Not yet recruiting
    • Hospital La Paz
    • Contact: José Luis Bartha
  • Palma De Mallorca, Spain
    • Recruiting
    • Hospital Son Llatzer
    • Contact: Albert Tubau
  • Valencia, Spain
    • Recruiting
    • Hospital la Fe
    • Contact: Alfredo Perales
  • Zaragoza, Spain
    • Suspended
    • Hospital Lozano Blesa
  • Barcelona
    • Badalona, Barcelona, Spain
      • Recruiting
      • Hospital Germans Trias i Pujol
      • Contact: Mina Comas, PhD; Email: minacomas.germanstrias@gencat.cat
  • Islas Canarias
    • Las Palmas De Gran Canaria, Islas Canarias, Spain
      • Not yet recruiting
      • Complejo Hospitalario Universitario Insular Materno Infantil
      • Contact: Leonor Valle; Email: leonorvalle@yahoo.es
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Active, not recruiting
      • Virgen de la Arrixaca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Nulliparous women
• Singleton pregnancies
• >18 years old
• 35.0-36.6 weeks of gestation
• Maternal written consent form

Exclusion Criteria:

• Fetuses/neonates with major malformations or genetic anomalies that could modify the timing of delivery or has an impact on obstetric outcome
• Suspected fetal growth restriction (estimated fetal weight <3 centile or between the 3rd and 10th centile together with abnormal Doppler in the mean uterine artery Doppler pulsatility index, or in umbilical artery pulsatility index or in the middle cerebral artery or in the cerebral umbilical index (CPR))
• Participation in another interventional study that could modify the timing of delivery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Non-intervention or non-reveal group; Non-intervention or non-reveal (result unknown) group: routine follow-up and spontaneous delivery
Experimental: Intervention group or reveal group; A ratio cutoff of >p90th will be used to define low and elevated risk of developing a placental complications of pregnancy and therefore induction of labour will be offered from 37th weeks of gestation	Diagnostic test: sFlt1/PlGF screening in maternal blood at 35 to 36.6 weeks of gestation; A ratio cutoff of >p90th will be used to define low and elevated risk of developing a placental complications of pregnancy and therefore induction of labour will be offered from 37th weeks of gestation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of term Preeclampsia development	Number of participants with term preeclampsia/total number participants.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal morbidity rate	Composite including any of the following: (i) HELLP syndrome; (ii) Central nervous system dysfunction (eclampsia, Glasgow Coma Score <13, stroke, reversible ischemic neurological deficit or cortical blindness); (iii) hepatic dysfunction; (iv) renal dysfunction; (v) respiratory dysfunction; (vi) cardiovascular dysfunction; (vii) placental abruption; or, (viii) a requirement for transfusion of blood products according to the total deliveries.	6 weeks
Maternal Hospital stay	Days of admission	6 weeks
Caesarean section rate	number of c-section / total deliveries	4 weeks
Neonatal hospital stay	Days	18 weeks
Maternal experience	Satisfaction score (PSS, STAI, WHO and Labor Agentry scale).	12 weeks
Incurred costs	Calculated costs	6 weeks
Number of participants with Cardiovascular risk	Maternal blood pressure and endothelial function 6-months postpartum/ participants	6 months post-delivery
Perinatal complications rate	Presence of placental abruptio, severe fetal growth restriction (defined as birth weight <3rd centile), perinatal mortality, an Apgar score at 5-minute below 7.0, an umbilical artery pH below 7.10, need for respiratory support within 72 hours after birth neonatal intraventricular haemorrhage grade III/IV, necrotizing enterocolitis, sepsis, or hypoxic ischemic encephalopathy/total deliveries.	18 weeks

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Collaborators: Fundacion Clinic per a la Recerca Biomédica

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 8, 2021
• First Submitted That Met QC Criteria: February 19, 2021
• First Posted (Actual): February 23, 2021

Study Record Updates

• Last Update Posted (Estimated): December 21, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Preeclampsia, angiogenic factors, perinatal death, induction of labour
• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Death; Hypertension, Pregnancy-Induced; Growth Disorders; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Pre-Eclampsia; Fetal Growth Retardation; Perinatal Death
• Other Study ID Numbers: PE37

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No