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.

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).

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.

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.

Cesarean delivery for non-reassuring fetal status or neonatal acidosis (artery cord potential of hydrogen (pH) <7.15 + base excess > -12 milliequivalent/L)

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.

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.