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

Study Overview
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Brief Summary
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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.

Detailed Description
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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. 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). 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).

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

Conditions
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Fetal Growth Retardation

Intervention / Treatment
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* Procedure: Management based on sFlt-1/PlGF values


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women ≥ 16 years of age. Singleton pregnancy. Ultrasonographic estimated fetal weight <10th centile. Gestational age between 36+0 and 37+6 weeks. Exclusion Criteria: Major fetal malformations or genetic disorders. Fetal death. Absent or reverse end-diastolic flow in umbilical artery Doppler or DV PI>95th centile. Non-reassuring cardiotocography (CTG). Preeclampsia. Diminished fetal movements. Biophysical profile ≤ 6. Oligohydramnios Refusal to give informed consent.

Ages Eligible for Study
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Minimum Age: 16 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control Group<br>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<br>Management based on sFlt-1/PlGF values | Procedure: Management based on sFlt-1/PlGF values<br>* 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.<br>|

What is the study measuring?
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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 |