Angiogenic factors alone or in combination with ultrasound Doppler criteria for risk classification among late‐onset small fetuses with or without pre‐eclampsia
Authors: Youssef L. , Crispi F. , Paolucci S. , Miranda J. , Lobmaier S. , Crovetto F. , Figueras F. , Gratacos E. 
Published: January 2025

ABSTRACTObjectiveTo investigate the prognostic value of maternal angiogenic factors in late‐onset small fetuses, alone or in combination with the ultrasound and Doppler parameters currently used for the classification of low‐risk small‐for‐gestational‐age (SGA) fetuses or high‐risk fetal growth restriction (FGR), overall and according to the presence or absence of pre‐eclampsia.MethodsThis was a prospective cohort study of women with a singleton pregnancy with a diagnosis of late‐onset fetal smallness (defined as birth weight < 10th centile) and a gestational age of ≥ 34 weeks at delivery. Ultrasound assessment of estimated fetal weight (EFW) and Doppler assessment of uterine artery pulsatility index (UtA‐PI) and cerebroplacental ratio (CPR) were performed every 1–2 weeks. Biochemical analysis of the angiogenic factors placental growth factor (PlGF) and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) in maternal peripheral venous blood samples was performed using enzyme‐linked immunosorbent assay within 1–2 weeks after diagnosis of SGA or FGR. The primary outcome was adverse perinatal outcome, defined as a composite of emergency Cesarean section for non‐reassuring fetal status, metabolic acidosis (umbilical artery pH < 7.0), neonatal unit admission and/or perinatal death. The predictive value of EFW < 3rd centile, Doppler parameters (UtA‐PI > 95th centile and CPR < 5th centile) and sFlt‐1/PlGF ratio > 95th centile, alone or in combination, was assessed using logistic regression analysis in the overall population and stratified by presence or absence of pre‐eclampsia developing at any time before delivery.ResultsAmong the 602 included cases, 91 (15.1%) developed pre‐eclampsia and 511 (84.9%) did not. In the overall study population, all parameters were associated independently with adverse perinatal outcome: EFW < 3rd centile (adjusted odds ratio (aOR), 2.58 (95% CI, 1.67–4.00)), UtA‐PI > 95th centile (aOR, 1.92 (95% CI, 1.25–2.94)), CPR < 5th centile (aOR, 2.35 (95% CI, 1.46–3.78)) and sFlt‐1/PlGF ratio > 95th centile (aOR, 1.71 (95% CI, 1.09–2.69)). Only sFlt‐1/PlGF ratio > 95th centile was associated independently with adverse perinatal outcome in cases with pre‐eclampsia, whereas in those without pre‐eclampsia, only EFW < 3rd centile and CPR < 5th centile were associated independently with adverse perinatal outcome. In the overall population, the detection rate (DR) and false‐positive rate for adverse perinatal outcome were, respectively: 39.8% (95% CI, 31.7–47.9%) and 16.9% (95% CI, 10.7–23.1%) for sFlt‐1/PlGF ratio > 95th centile alone; 86.8% (95% CI, 83.4–90.2%) and 61.9% (95% CI, 57.1–66.7%) for a combined model of EFW < 3rd centile, UtA‐PI > 95th centile and CPR < 5th centile; 81.3% (95% CI, 77.3–85.3%) and 52.3% (95% CI, 47.1–57.5%) for a combined model of EFW < 3rd centile and sFlt‐1/PlGF ratio > 95th centile; and 88.5% (95% CI, 85.4–91.6%) and 64.5% (95% CI, 59.8–69.2%) for a combined model including all the abovementioned observed parameters.ConclusionssFlt‐1/PlGF ratio alone had a low predictive value for adverse perinatal outcome, but when combined with EFW, its predictive performance was similar to that of EFW combined with Doppler parameters. Combining sFlt‐1/PlGF ratio with EFW and Doppler criteria achieved the highest DR for adverse perinatal outcome, and additionally, might help to identify imminent pre‐eclampsia in pregnancies complicated by fetal smallness. These findings support the use of angiogenic factors as an additional criterion to those currently used for identifying high‐risk FGR among late‐onset small fetuses, but do not support their use as a standalone biomarker. © 2025 International Society of Ultrasound in Obstetrics and Gynecology.