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

Management of Fetal Growth Restriction at Term: Angiogenic Factors Versus Feto-placental Doppler (GRAFD Trial)

Open randomized non-inferiority controlled trial to examine the use of angiogenic factors (instead of feto-placental Doppler) for fetal growth restriction at term to reduce the rate of labor inductions, without worsening perinatal outcomes.

Study Overview

• Status: Completed
• Conditions: Fetal Growth Retardation
• Intervention / Treatment: Procedure: Management based on sFlt-1/PlGF values

Detailed Description

Pregnant women with estimated fetal weight (EFW) < 10th centile between 36+0 and 37+6 weeks of gestation (WG) will receive complete ultrasonographic assessment consisting of feto-placental Doppler, amniotic fluid measurement and biophysical profile assessment. The cases not meeting any exclusion criteria will be offered to participate in this trial. After giving their informed consent a blood sample will be drawn in all of them and they will undergo randomization into two arms.

1. Intervention arm: In women allocated to the intervention group, the soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) result will be revealed to the investigators that will act according to the results of sFlt/PlGF:

   • Fetuses with sFlt-1/PlGF ≥38, elective delivery will be recommended at ≥37 weeks.
   • Fetuses with sFlt-1/PlGF <38, weekly follow up will be recommended until delivery (at ≥40 weeks).

2. Control arm: In women allocated to the control group, the sFlt-1/PlGF result will be blinded to caregivers. Routine Doppler-based clinical care will be used to counsel women. Following the Doppler classification:

   • Fetuses with EFW below the 3rd centile or below the 10th centile accompanied by any impaired fetoplacental Doppler, elective delivery will be recommended at at ≥37 weeks.
   • Fetuses with EFW above the 3rd centile without any fetoplacental Doppler abnormality, elective delivery will be recommended at at ≥40 weeks.

In both arms, fetuses will receive weekly follow-up from randomization to delivery consisting on feto-placental Doppler sFlt-1/PlGF and CTG. If any of the following is present at any time, earlier delivery will be recommended:

• sFlt-1/PlGF ≥38 (only in the intervention group),
• absent or reverse end-diastolic flow at the umbilical artery Doppler or DV PI>95th centile
• non-reassuring CTG
• preeclampsia
• diminished fetal movements
• biophysical profile ≤ 6 or oligohydramnios (deepest pocket <2 cm).

• Study Type: Interventional
• Enrollment (Actual): 1088
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Manel Mendoza, PhD; Phone Number: 3085 0034934893000; Email: mmendoza@vhebron.net

Study Locations

• Spain
  • A Coruña, Spain
    • Hospital Universitario de A Coruna
  • Alicante, Spain
    • Hospital General de Alicante
  • Badalona, Spain
    • Hospital Germans Trias i Pujol
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Cabueñes, Spain
    • Hospital Universitario de Cabueñes
  • Cadiz, Spain
    • Hospital Universitario Puerta Del Mar
  • Elche, Spain
    • Hospital General Universitario de Elche
  • Getafe, Spain
    • Hospital Universitario de Getafe
  • Girona, Spain
    • Hospital Universitari Doctor Josep Trueta
  • Manresa, Spain
    • Hospital Sant Joan de Déu de Manresa
  • Murcia, Spain
    • Hospital Clínico Universitario Virgen de la Arrixaca
  • Palma De Mallorca, Spain
    • Hospital Son Llatzer
  • Sabadell, Spain
    • Consorci Corporació Sanitària Parc Taulí de Sabadell
  • Santa Cruz De Tenerife, Spain
    • Hospital Universitario Nuestra Señora de Candelaria
  • Sevilla, Spain
    • Hospital Universitario Virgen de Valme
  • Tarragona, Spain
    • Hospital Universitari Joan Xxiii
  • Terrassa, Spain
    • Hospital Universitari Mutua Terrassa
  • Terrassa, Spain
    • Hospital de Terrassa
  • Torrejón De Ardoz, Spain
    • Hospital Universitario de Torrejon
  • Zaragoza, Spain
    • Hospital Clinico Universitario Lozano Blesa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Pregnant women ≥ 16 years of age.
2. Singleton pregnancy.
3. Ultrasonographic estimated fetal weight <10th centile.
4. Gestational age between 36+0 and 37+6 weeks.

Exclusion Criteria:

1. Major fetal malformations or genetic disorders.
2. Fetal death.
3. Absent or reverse end-diastolic flow in umbilical artery Doppler or DV PI>95th centile.
4. Non-reassuring cardiotocography (CTG).
5. Preeclampsia.
6. Diminished fetal movements.
7. Biophysical profile ≤ 6.
8. Oligohydramnios
9. Refusal to give informed consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control Group; Clinical practice: Management by Doppler and CTG findings. In women allocated to the control group, the sFlt-1/PlGF result will be blinded to caregivers. Routine Doppler-based clinical care will be used to counsel women. Following the Doppler classification: Fetuses with an EFW below the 3rd centile or below the 10th centile accompanied by any impaired fetoplacental Doppler, elective delivery will be recommended immediately (within 24h) at ≥37 weeks.; Fetuses with an EFW above the 3rd centile without any fetoplacental Doppler abnormality, elective delivery will be recommended at at ≥40 weeks.
Experimental: Intervention Group; Management based on sFlt-1/PlGF values	Procedure: Management based on sFlt-1/PlGF values; In women allocated to the intervention group, the sFlt-1/PlGF result will be revealed to the investigators that will act according to the results of sFlt/PlGF: Fetuses with sFlt-1/PlGF ≥38, elective delivery will be recommended immediately (within 24h) at ≥37 weeks.; Fetuses with sFlt-1/PlGF <38 weekly follow up will be recommended and delivery at ≥40 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse perinatal outcomes	Cesarean delivery for non-reassuring fetal status or neonatal acidosis (artery cord potential of hydrogen (pH) <7.15 + base excess > -12 milliequivalent/L)	4-6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of elective delivery	Percentage of women that required an elective delivery	4-6 weeks
Rate of Cesarean delivery	Percentage of women that required a Cesarean delivery	4-6 weeks
Rate of Induction of labor	Percentage of women that required an induction of labor	4-6 weeks
Rate of neonatal admission in intensive care unit	Percentage of newborns that required admission in intensive care	4-6 weeks
Time of neonatal admission in intensive care unit	Days in in intensive care of newborns that required admission	4-6 weeks
Rate of preeclampsia	Percentage of women that developed preeclampsia	4-6 weeks
Rate of neonatal complications	Percentage of newborns with adverse outcomes (composite)	4-10 weeks
Rate of maternal complications	Percentage of women with adverse outcomes (composite)	4-6 weeks
Rate of perinatal complications	Percentage of perinatal adverse outcomes (composite)	4-6 weeks
Rate of total deliveries at <37, <38, <39 and <40 weeks of gestation	Percentage of women that delivered at <37, <38, <39 and <40 weeks of gestation	4-6 weeks
Rate of elective deliveries at <37, <38, <39 and <40 weeks of gestation	Percentage of women that delivered electively at <37, <38, <39 and <40 weeks of gestation	4-6 weeks
Rate of newborns with birthweight <2000 and <2500 grams	Percentage of women that delivered a newborn with a birthweight <2000 and <2500 grams	4-6 weeks

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Investigators: Principal Investigator: Manel Mendoza, PhD, Vall d'Hebron Institut de Recerca

Publications and helpful links

General Publications

• Garcia-Manau P, Mendoza M, Bonacina E, Martin-Alonso R, Martin L, Palacios A, Sanchez ML, Lesmes C, Hurtado I, Perez E, Tubau A, Ibanez P, Alcoz M, Valino N, Moreno E, Borrero C, Garcia E, Lopez-Quesada E, Diaz S, Broullon JR, Teixidor M, Chulilla C, Gil MM, Lopez M, Candela-Hidalgo A, Salinas-Amoros A, Moreno A, Morra F, Vaquerizo O, Soriano B, Fabre M, Gomez-Valencia E, Cuina A, Alayon N, Sainz JA, Vives A, Esteve E, Ocana V, Lopez MA, Maroto A, Carreras E. The Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) Trial to Avoid Adverse Perinatal Outcomes: Protocol for a Multicenter, Open-Label, Randomized Controlled Trial. JMIR Res Protoc. 2022 Oct 11;11(10):e37452. doi: 10.2196/37452.

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2020
• Primary Completion (Actual): December 18, 2022
• Study Completion (Actual): December 18, 2022

Study Registration Dates

• First Submitted: August 4, 2020
• First Submitted That Met QC Criteria: August 4, 2020
• First Posted (Actual): August 6, 2020

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Growth Disorders; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Fetal Growth Retardation
• Other Study ID Numbers: PR(AMI)527/2019

Drug and device information, study documents

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