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

Background and Objectives: Third-trimester screening is widely used to identify small for gestational age (SGA) and fetal growth restriction (FGR), but optimal models and timing remain under investigation. This study aimed to assess the performance of combined maternal factors and biomarkers, including ultrasound estimated fetal weight (EFW), Doppler indices, mean arterial pressure (MAP), and angiogenic biomarkers, for predicting SGA neonates after a routine 35–36 weeks’ scan in an unselected population. Materials and Methods: We conducted a retrospective cohort study in three Spanish centers offering universal third-trimester ultrasound. Logistic regression analyses were carried out to predict birthweight < 10th and <5th percentile using maternal characteristics and medical history, EFW, MAP, Doppler indices, and the angiogenic biomarkers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Using a 10-fold cross-validation, we estimated the area under the receiver operating characteristic curve (AUC), detection rates (DRs), false-positive rates (FPRs), and their corresponding screen-positive rates (SPRs). External validation was performed using an independent cohort. Results: Among 3992 pregnancies, the DR of ultrasound alone for birthweight <10th percentile was 47.9% (95% CI: 44.0 to 51.9), with an FPR of 7.3%. Adding maternal factors increased DR to 57.0% (95% CI: 53.0 to 60.9) at 10% FPR and to 83.0% (95% CI: 79.9 to 85.9) at 30% FPR. Similarly, the DR of ultrasound alone for birthweight < 5th percentile was 48.4% (95% CI: 43.1 to 53.6), with an FPR of 4.5%. Adding maternal factors increased DR to 65.7 (95% CI: 60.5 to 70.5) at 10% FPR and to 88.2 (95% CI: 84.4 to 91.3) at 30% FPR. The inclusion of MAP, Doppler, and biomarkers provided marginal additional gains, particularly for 80%, an SPR of approximately 40% was required. Performance improved when focusing on neonates born before 38 weeks, with a DR of 77.5 (95% CI: 68.6 to 84.9) at 10% FPR for SGA < 10th percentile. However, less than 40% of screen-positive women remained undelivered by 40 weeks, limiting the number requiring further surveillance. Conclusions: A third-trimester screening at 35–36 weeks using maternal characteristics and EFW identifies most SGA neonates, particularly those delivering before 38 weeks. Even including other biomarkers, an SPR of about 40% should be necessary to achieve a high DR. However, less than 40% of the women would remain undelivered before a subsequent follow-up is required.

Background: Third-trimester screening is widely used to identify small-for-gestational-age (SGA) and fetal growth restriction (FGR), but optimal models and timing remain under investigation. This study aimed to assess the performance of combined maternal factors and biomarkers, including ultrasound estimated fetal weight (EFW), Doppler indices, mean arterial pressure (MAP), and angiogenic bi-omarkers, for predicting SGA neonates after a routine 35–36 week scan in an unselect-ed population. Methods: We conducted a retrospective cohort study in three Spanish centers offering universal third-trimester ultrasound. Logistic regression analyses were carried out to predict birthweight < 10th and < 5th percentile using maternal characteris-tics and medical history, EFW, MAP, Doppler indices, and the angiogenic biomarkers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Using a 10-fold cross-validation we estimated the area under the receiver operating character-istic curve (AUC), detection rates (DR), false-positive rates (FPR) and their corre-sponding screen-positive rates (SPR). External validation was performed using an in-dependent cohort. Results: Among 3,992 pregnancies, the DR of ultrasound alone for birthweight < 10th percentile was 47.9% (95% CI: 44.0 to 51.9), with an FPR of 7.3%. Adding maternal factors increased DR to 57.0% (95% CI: 53.0 to 60.9) at 10% FPR and to 83.0% (95% CI: 79.9 to 85.9) at 30% FPR. Similarly, the DR of ultrasound alone for birthweight < 5th percentile was 48.4% (95% CI: 43.1 to 53.6), with an FPR of 4.5%. Add-ing maternal factors increased DR to 65.7 (95% CI: 60.5 to 70.5) at 10% FPR and to 88.2 (95% CI: 84.4 to 91.3) at 30% FPR. The inclusion of MAP, Doppler and biomarkers pro-vided marginal additional gains, particularly for < 5th percentile prediction. To achieve a DR >80%, an SPR of approximately 40% was required. Performance improved when focusing on neonates born before 38 weeks, with a DR of 77.5 (95% CI: 68.6 to 84.9) at 10% FPR for SGA < 10th percentile. However, less than 40% of screen-positive women remained undelivered by 40 weeks, limiting the number requiring further surveillance. Conclusions: A third-trimester screening at 35-36 weeks using maternal characteristics and EFW identifies most SGA neonates, particularly those delivering before 38 weeks. Even including other biomarkers, an SPR of about 40% should be necessary to achieve a high DR. However, less than 40% of the women would remain undelivered before a subsequent follow-up is required.