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

Study Overview
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Brief Summary
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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.

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

Conditions
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Fetal Growth Retardation, Preeclampsia, Placenta Diseases

Intervention / Treatment
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* Diagnostic Test: soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>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<br>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)<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of severe perinatal complications | Preeclampsia with severity features, placental abruption, eclampsia, stillbirth, neonatal death, umbilical artery pH ≤7.0 | During pregnancy and up to 28 days after delivery | 
| Composite adverse maternal outcome | 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. | During pregnancy and up to 28 days after delivery | 
| Number of ultrasounds per participant | Mean and sd or median and IQR in each group | During pregnancy | 
| Rate of elective deliveries <30 weeks | Percentage of deliveries indicated for FGR and/or PE <30 weeks | During pregnancy | 
| Rate of elective deliveries <34 weeks | Percentage of deliveries indicated for FGR and/or PE <34 weeks | During pregnancy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal perceived stress | Mean and sd or median and IQR of the score obtained in the perceived stress scale in each group | During pregnancy | 
| Rate of elective deliveries <37 weeks | Percentage of deliveries indicated for FGR and/or PE <37 weeks | During pregnancy | 
| Composite adverse neonatal outcome | 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. | During pregnancy and up to 28 days after delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PlGF, fetal growth restriction, small for gestational age, sFlt-1, Doppler