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

Sponsor

Hospital Universitari Vall d'Hebron Research Institute (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05284474

Collaborator

(none)

598

Enrollment

Locations

Arms

Anticipated Duration (Months)

24.9

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicentre, open-label, randomized controlled trial. A total of 598 singleton pregnancies with an EFW ≤10th percentile at <32+0 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.

Condition or Disease	Intervention/Treatment	Phase
Fetal Growth Retardation Preeclampsia Placenta Diseases	Diagnostic Test: soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

598 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Jan 30, 2025

Arms and Interventions

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. Fetal lung maturation at ≥ 33 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. Fetal lung maturation at ≥ 28 weeks. Stage IV: reversed DV "a" wave in two occasions > 6 hours apart. Elective Cesarean delivery at ≥26 weeks. Fetal lung maturation at ≥ 25+5 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 three weeks in SGA. In both cases delivery at ≥39-40 weeks. 38-85: In stage I FGR and SGA ultrasound weekly. Delivery at ≥37 weeks. >85: In stage I FGR and SGA ultrasound every 72h-96h. Delivery at ≥37 weeks. >110: In stage I FGR and SGA ultrasound every 48h-72h. Delivery at ≥36 weeks. If concurrent preeclampsia, delivery at ≥34+0 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 ≥28+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)

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. Fetal lung maturation at ≥ 33 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. Fetal lung maturation at ≥ 28 weeks. Stage IV: reversed DV "a" wave in two occasions > 6 hours apart. Elective Cesarean delivery at ≥26 weeks. Fetal lung maturation at ≥ 25+5 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 three weeks in SGA. In both cases delivery at ≥39-40 weeks. 38-85: In stage I FGR and SGA ultrasound weekly. Delivery at ≥37 weeks. >85: In stage I FGR and SGA ultrasound every 72h-96h. Delivery at ≥37 weeks. >110: In stage I FGR and SGA ultrasound every 48h-72h. Delivery at ≥36 weeks. If concurrent preeclampsia, delivery at ≥34+0 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 ≥28+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)

Outcome Measures

Primary Outcome Measures

Rate of severe perinatal complications [During pregnancy and up to 28 days after delivery]
Preeclampsia with severity features, placental abruption, eclampsia, stillbirth, neonatal death, umbilical artery pH ≤7.0
Composite adverse maternal outcome [During pregnancy and up to 28 days after delivery]
Percentage of pregnancies with HELLP syndrome, severe PE, eclampsia, stroke, hepatic hematoma or rupture, oliguria, need for furosemide, cardiovascular dysfunction (inotropic support, myocardial infarction, left ventricle failure), placental abruption, maternal admission to intensive care unit >48h, and/or requirement for blood transfusion in each group.
Number of ultrasounds per participant [During pregnancy]
Mean and sd or median and IQR in each group
Rate of elective deliveries <30 weeks [During pregnancy]
Percentage of deliveries indicated for FGR and/or PE <30 weeks
Rate of elective deliveries <34 weeks [During pregnancy]
Percentage of deliveries indicated for FGR and/or PE <34 weeks

Secondary Outcome Measures

Maternal perceived stress [During pregnancy]
Mean and sd or median and IQR of the score obtained in the perceived stress scale in each group
Rate of elective deliveries <37 weeks [During pregnancy]
Percentage of deliveries indicated for FGR and/or PE <37 weeks
Composite adverse neonatal outcome [During pregnancy and up to 28 days after delivery]
Percentage of neonates with Apgar score <7, umbilical artery pH ≤7.0, respiratory distress syndrome, transient tachypnea, required ventilatory support, grade III or IV intraventricular hemorrhage, neonatal sepsis, hypoglucemia, necrotizing enterocolitis, neonatal jaundice treated with phototherapy, neonatal seizures, pneumonia, meningitis and/or neonatal death.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Pregnant women of at least 18 years old
Singleton pregnancy
Ultrasonographic EFW ≤10th percentile between 24+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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Complejo Hospitalario Universitario de A Coruña	A Coruña	Spain
2	Hospital Universitario General de Alicante	Alicante	Spain
3	Hospital Universitari Germans Trias i Pujol	Badalona	Spain
4	Vall d'hebron Barcelona Hospital Campus	Barcelona	Spain	08035
5	Hospital de la Santa Creu i Sant Pau	Barcelona	Spain
6	Hospital Universitari Dexeus	Barcelona	Spain
7	Hospital Universitario Puerta del Mar	Cadiz	Spain
8	Hospital General Universitario de Elche	Elche	Spain
9	Hospital Universitario de Getafe	Getafe	Spain
10	Hospital Universitario de Cabueñes	Gijón	Spain
11	Hospital Universitari de Girona Doctor Josep Trueta	Girona	Spain
12	Hospital Universitario San Cecilio	Granada	Spain
13	Hospital Universitario de Jerez de la Frontera	Jerez De La Frontera	Spain
14	Hospital Universitari Arnau de Vilanova	Lleida	Spain
15	Hospital Universitari Son Espases	Palma De Mallorca	Spain
16	Hospital Universitari Son Llàtzer	Palma De Mallorca	Spain
17	Corporació Sanitària Parc Taulí	Sabadell	Spain
18	Hospital Universitario de Canarias	Santa Cruz De Tenerife	Spain
19	Hospital Universitario Virgen de Valme	Sevilla	Spain
20	Hospital Universitario Joan XXIII de Tarragona	Tarragona	Spain
21	Consorci Sanitari de Terrassa	Terrassa	Spain
22	Hospital Universitari Mútua Terrassa	Terrassa	Spain
23	Hospital Universitario de Torrejón	Torrejón De Ardoz	Spain
24	Hospital Clínico Universitario Lozano Blesa	Zaragoza	Spain