Clinical trial NCT04766866: sFlt1/PlGF and Planned Delivery to Prevent Preeclampsia at Term.
Official title: Protocol of the PE37 Study: A Multicenter Randomized Trial of Screening With sFlt1/PlGF and Planned Delivery to Prevent Preeclampsia at Term
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Preeclampsia
Intrauterine Growth Restriction
Maternal Hypertension
Neonatal Outcome
Perinatal Death
Keywords: Preeclampsia, angiogenic factors, perinatal death, induction of labour
Lead sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
Sponsor class: OTHER
Collaborators: name: Fundacion Clinic per a la Recerca Biomédica
First posted: 2021-02-23
Enrollment: 9132
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, open-label randomized study with parallel groups.
Primary purpose: PREVENTION

Brief summary: * 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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Rate of term Preeclampsia development
timeFrame: 4 weeks
Secondary outcomes:
measure: Maternal morbidity rate
timeFrame: 6 weeks
measure: Maternal Hospital stay
timeFrame: 6 weeks
measure: Caesarean section rate
timeFrame: 4 weeks
measure: Perinatal complications rate
timeFrame: 18 weeks
measure: Neonatal hospital stay
timeFrame: 18 weeks
measure: Maternal experience
timeFrame: 12 weeks
measure: Incurred costs
timeFrame: 6 weeks
measure: Number of participants with Cardiovascular risk
timeFrame: 6 months post-delivery
Other outcomes:
Locations:
city: Liège
country: Belgium
facility: CHU Liège
city: Bogotá
country: Colombia
facility: Clinica del Prado SAS
city: Prague
country: Czechia
facility: Institute for the Care of Mother and Child
city: Quito
country: Ecuador
facility: Medicina Fetal Quito
city: New Delhi
country: India
facility: Maulana Azad Medical College (MAMC)
state: Delhi
city: New Delhi
country: India
facility: All India Institute of Medical Sciences (AIIMS) Ansari Nagar
state: Delhi
city: New Delhi
country: India
facility: Vardhman Mahavir Medical College (VMMC)
state: Delhi
city: Ciudad de mexico
country: Mexico
facility: Hospital Gineco-Obstetricia nº4
city: Panamá
country: Panama
facility: Hospital Santo Tomas
city: Warsaw
country: Poland
facility: Centre of Postgraduate Medical Education, Obstetrics and Gynecology and Perinatal Medicine
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona
city: Las Palmas De Gran Canaria
country: Spain
facility: Complejo Hospitalario Universitario Insular Materno Infantil
state: Islas Canarias
city: El Palmar
country: Spain
facility: Virgen de la Arrixaca
state: Murcia
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Maternitat del Clínic
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu
city: Madrid
country: Spain
facility: Hospital La Paz
city: Palma De Mallorca
country: Spain
facility: Hospital Son Llatzer
city: Valencia
country: Spain
facility: Hospital la Fe
city: Zaragoza
country: Spain
facility: Hospital Lozano Blesa
Study officials:
References: