Management of Early-onset Fetal Growth Restriction: Angiogenic Factors Versus Feto-placental Doppler (earlyGRAFD)

June 3, 2024 updated by: Hospital Universitari Vall d'Hebron Research Institute

Management of Early-onset Fetal Growth Restriction: Angiogenic Factors Versus Feto-placental Doppler (Early GRAFD)

This is a multicentre, open-label, randomized controlled trial. A total of 340 singleton pregnancies with an EFW ≤10th percentile between 26+0 and 31+6 weeks will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, different soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) cutoffs will be incorporated to the current protocol to adjust the frequency of ultrasounds and to plan elective delivery.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

340

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Pregnant women of at least 18 years old
  • Singleton pregnancy
  • Ultrasonographic EFW ≤10th percentile between 26+0 and 31+6 weeks of gestation
  • Gestational age confirmed by fetal crown-rump length measurement during the first trimester scan (from 11+0 to 13+6 weeks of gestation) or by in vitro fertilization dates.

Exclusion Criteria:

  • Major fetal malformations or genetic disorders
  • Fetal death
  • Refusal to give informed consent
  • Stage IV FGR

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Control

Small fetuses will be classified into 5 severity stages and managed as follows:

  • SGA: Estimated fetal weight (EFW) between p3 and p10 with normal Dopplers. Ultrasound/2 weeks, elective vaginal delivery at ≥39-40 weeks.
  • Stage I: EFW ≤p3 p or EFW p3-10 + UA PI >p95 and/or UtA PI >p95, and, at ≥32 weeks, CPR and/or MCA PI <p5, in 2 occasions >12 hours apart. Ultrasound weekly, elective vaginal delivery at ≥37 weeks.
  • Stage II: AEDF UA in 2 occasions >12 hours apart. Ultrasound every 48-72h, elective Cesarean delivery at ≥34 weeks.
  • Stage III: DV PI > p95 (or absent DV "a" wave) or reversed end-diastolic UA >50% of cycles, in both cases in two occasions > 6 hours apart. Ultrasound every 24-48h, elective Cesarean delivery at ≥30 weeks.
  • Stage IV: reversed DV "a" wave in two occasions > 6 hours apart. Elective Cesarean delivery at ≥26 weeks.
Experimental: Study

Doppler protocol (as in controls) + sFlt-1/PlGF ratio cutoffs will be incorporated as follows:

  • <38: Ultrasound biweekly in stage I FGR and every four weeks in SGA. In both cases delivery at ≥39-40 weeks.
  • 38-110: In stage I FGR and SGA ultrasound weekly. Delivery at ≥37 weeks.
  • >110: In stage I FGR and SGA ultrasound weekly. Delivery at ≥36 weeks.
  • >110 and concurrent preeclampsia: In stage I FGR and SGA ultrasound every 48h-72h. Delivery at ≥34 weeks.
  • >201: Ultrasound every 48-72h, delivery at ≥34+0 weeks. If concurrent preeclampsia, delivery at ≥32+0 weeks.
  • >655: Ultrasound every 48-72h, delivery at ≥32+0 weeks. If concurrent preeclampsia, delivery at ≥30+0 weeks.
  • >1000: In cases with concurrent PE, delivery at ≥29+0 weeks.
Diagnostic test: soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)
soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) will be incorporated to the management of early-onset small fetuses (estimated fetal weight ≤10th percentile)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fetal and Neonatal complications
Time Frame: During pregnancy and up to 28 days after delivery
stillbirth, neonatal death, artery cord pH ≤7.0, respiratory distress syndrome, required invasive ventilatory support, grade III or IV intraventricular hemorrhage, neonatal sepsis, necrotizing enterocolitis, neonatal seizures, pneumonia, meningitis, broncopulmonary dysplasia, hypoxic ischemic encephalopathy, Apgar score <7 at 5 minutes, or elective delivery at <28 weeks of gestation.
During pregnancy and up to 28 days after delivery
Composite adverse maternal outcome
Time Frame: During pregnancy and up to 28 days after delivery
Progression to PE with severity features; progression to hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (LDH >600 IU/L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevated more than twice the upper limit of normal, and the platelet count less than 100 X 109/L); eclampsia, stroke, hepatic hematoma or rupture; oliguria (urine output of <400 mL during 24 hours, or need for treatment with furosemide to maintain urine output at >400 mL for 24 hours); cardiovascular dysfunction (need for inotropic support, left ventricle failure, or myocardial infarction); placental abruption; maternal death; maternal admission to intensive care unit >48 hours, and/or requirement for blood transfusion.
During pregnancy and up to 28 days after delivery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maternal perceived stress
Time Frame: At inclusion and 4 weeks later
Mean and sd or median and IQR of the score obtained in the perceived stress scale in each group
At inclusion and 4 weeks later
Other perinatal outcomes
Time Frame: During pregnancy and up to 28 days after delivery
transient tachypnea, non-invasive ventilatory support, hypoglycemia, neonatal jaundice (treated with phototherapy), rate of elective deliveries < 30 weeks, <34 weeks and < 37 weeks for FGR and/or PE, birthweight <3 rd and <10th percentiles, mode of delivery (vaginal, instrumental vaginal delivery and Cesarean), rate of Cesarean delivery for abnormal CTG, median maternal stay in ICU, median neonatal stay in N-ICU, maternal corticosteroids (single dose, complete course), prenatal magnesium sulfate (at least 4h) for preterm delivery.
During pregnancy and up to 28 days after delivery
Number of ultrasounds per participant
Time Frame: During pregnancy (before and after 37 weeks)
Mean and sd or median and IQR in each group
During pregnancy (before and after 37 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital Universitari Vall d'Hebron Research Institute

Collaborators

Instituto de Salud Carlos III
Roche Diagnostics GmbH

Investigators

  • Principal Investigator: Manel Mendoza, MD, PhD, Vall d'Hebron Institut de Recerca (VHIR)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

June 3, 2024

Primary Completion (Estimated)

September 1, 2026

Study Completion (Estimated)

December 30, 2026

Study Registration Dates

First Submitted

February 13, 2022

First Submitted That Met QC Criteria

March 9, 2022

First Posted (Actual)

March 17, 2022

Study Record Updates

Last Update Posted (Estimated)

June 4, 2024

Last Update Submitted That Met QC Criteria

June 3, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PR(AMI)113/2022

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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