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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.
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:
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:
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control Group | No Intervention | 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:
| |
| Intervention Group | Experimental | Management based on sFlt-1/PlGF values |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Management based on sFlt-1/PlGF values | Procedure | 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:
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
pregnant women
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| Name | Affiliation | Role |
|---|---|---|
| Manel Mendoza, PhD | Vall d'hebron Institut de Recerca | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Universitario de A Coruña | A Coruña | Spain | ||||
| Hospital General de Alicante |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39775039 | Derived | Garcia-Manau P, Bonacina E, Martin-Alonso R, Martin L, Palacios A, Sanchez-Camps 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, Ferrer-Costa R, Gil MM, Lopez M, Ramos-Forner GM, Blanco JE, Moreno A, Lazaro-Rodriguez M, Vaquerizo O, Soriano B, Fabre M, Gomez-Valencia E, Cuina A, Alayon N, Sainz-Bueno JA, Vives A, Esteve E, Ocana V, Lopez MA, Maroto A, Carreras E, Mendoza M. Angiogenic factors versus fetomaternal Doppler for fetal growth restriction at term: an open-label, randomized controlled trial. Nat Med. 2025 Mar;31(3):1008-1015. doi: 10.1038/s41591-024-03421-9. Epub 2025 Jan 7. | |
| 36222789 |
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|
| 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 |
| Alicante |
| Spain |
| Hospital Germans Trias i Pujol | Badalona | Spain |
| Hospital Universitari Vall d'hebron | Barcelona | Spain |
| Hospital Universitario de Cabueñes | Cabueñes | Spain |
| Hospital Universitario Puerta del Mar | Cadiz | Spain |
| Hospital General Universitario de Elche | Elche | Spain |
| Hospital Universitario de Getafe | Getafe | Spain |
| Hospital Universitari Doctor Josep Trueta | Girona | Spain |
| Hospital Sant Joan de Deu de Manresa | Manresa | Spain |
| Hospital Clínico Universitario Virgen de la Arrixaca | Murcia | Spain |
| Hospital Son Llàtzer | Palma de Mallorca | Spain |
| Consorci Corporació Sanitària Parc Taulí de Sabadell | Sabadell | Spain |
| Hospital Universitario Nuestra Señora de Candelaria | Santa Cruz de Tenerife | Spain |
| Hospital Universitario Virgen de Valme | Seville | Spain |
| Hospital Universitari Joan XXIII | Tarragona | Spain |
| Hospital de Terrassa | Terrassa | Spain |
| Hospital Universitari Mútua Terrassa | Terrassa | Spain |
| Hospital Universitario de Torrejon | Torrejón de Ardoz | Spain |
| Hospital Clinico Universitario Lozano Blesa | Zaragoza | Spain |
| Derived |
| 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. |
| ID | Term |
|---|---|
| D005317 | Fetal Growth Retardation |
| ID | Term |
|---|---|
| D005315 | Fetal Diseases |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006130 | Growth Disorders |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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