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Small fetuses, with estimated fetal weight (EFW) below the tenth percentile, are classified as fetal growth restriction (FGR) or small for gestational age (SGA) based on prenatal ultrasound. FGR fetuses have a greater risk of stillbirth and perinatal complications and may benefit from serial ultrasound scans to guide early delivery. Abnormal serum angiogenic factors, such as the soluble fms-like tyrosine kinase-1 (sFlt-1):placental growth factor (PlGF) ratio, have shown potential to more accurately distinguish FGR from SGA, with fewer false positives. This randomized controlled trial compared a management protocol based on the sFlt-1:PlGF with EFW and Doppler ultrasound in avoiding adverse perinatal outcomes in small fetuses after 36 weeks of gestation. A total of 1,088 pregnant women with singleton pregnancies were randomized to either the Doppler-based (control) or the sFlt-1:PlGF-based (intervention) protocol. The primary outcome, neonatal acidosis or Cesarean delivery as a result of abnormal cardiotocography, was assessed in 1,013 participants. The incidence was 10.5% in the intervention group and 10.0% in the control group (absolute difference, 0.53 (-3.21 to 4.26)), with the upper limit of the confidence interval <8.5%, confirming noninferiority. Thus, the sFlt-1:PlGF was noninferior to EFW and Doppler ultrasound in avoiding neonatal acidosis or Cesarean delivery owing to nonreassuring fetal status in small fetuses after 36 weeks (ClinicalTrials.gov registration: NCT04502823 )., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest and declare that all have received reagents from Roche Diagnostics for the submitted work. M.M. and A.P. declared receipt of lecture fees and fees from Roche Diagnostics. M.M. declared receipt of consulting fees from Roche Diagnostics. M.M.G. declared receipt of travel support for attending conferences from Thermo Fisher and Perkin Elmer. M.M.G. declared receipt of lecture fees from Thermo Fisher. M.M., E.B., E.G., E.L.-Q., J.R.B., P.G.-M. and A.V. declared receipt of travel support for attending conferences from Roche Diagnostics. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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., (©Pablo Garcia-Manau, Manel Mendoza, Erika Bonacina, Raquel Martin-Alonso, Lourdes Martin, Ana Palacios, Maria Luisa Sanchez, Cristina Lesmes, Ivan Hurtado, Esther Perez, Albert Tubau, Patricia Ibañez, Marina Alcoz, Nuria Valiño, Elena Moreno, Carlota Borrero, Esperanza Garcia, Eva Lopez-Quesada, Sonia Diaz, Jose Roman Broullon, Mireia Teixidor, Carolina Chulilla, Maria M Gil, Monica Lopez, Amparo Candela-Hidalgo, Andrea Salinas-Amoros, Anna Moreno, Francesca Morra, Oscar Vaquerizo, Beatriz Soriano, Marta Fabre, Elena Gomez-Valencia, Ana Cuiña, Nicolas Alayon, Jose Antonio Sainz, Angels Vives, Esther Esteve, Vanesa Ocaña, Miguel Ángel López, Anna Maroto, Elena Carreras. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.10.2022.)