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
Authors: Garcia-Manau Pablo , Mendoza Manel , Bonacina Erika , Martin-Alonso Raquel , Martin Lourdes , Palacios Ana , Sanchez Maria Luisa , Lesmes Cristina , Hurtado Ivan , Perez Esther , Tubau Albert , Ibañez Patricia , Alcoz Marina , Valiño Nuria , Moreno Elena , Borrero Carlota , Garcia Esperanza , Lopez-Quesada Eva , Diaz Sonia , Broullon Jose Roman , Teixidor Mireia , Chulilla Carolina , Gil Maria M , Lopez Monica , Candela-Hidalgo Amparo , Salinas-Amoros Andrea , Moreno Anna , Morra Francesca , Vaquerizo Oscar , Soriano Beatriz , Fabre Marta , Gomez-Valencia Elena , Cuiña Ana , Alayon Nicolas , Sainz Jose Antonio , Vives Angels , Esteve Esther , Ocaña Vanesa , López Miguel Ángel , Maroto Anna , Carreras Elena 
Published: September 2022

Background
Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term.

Objective
The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes.

Methods
This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days 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, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs.

Results
Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023.

Conclusions
The angiogenic factor–based protocol may reduce the number of pregnancies classified as having fetal growth restriction without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities.

Trial Registration
ClinicalTrials.gov NCT04502823; https://clinicaltrials.gov/ct2/show/NCT04502823

International Registered Report Identifier (IRRID)
DERR1-10.2196/37452