Placental insufficiency markers to assess the risk of non-chromosomal genetic conditions in early-onset fetal growth restriction.

To assess the value of placental insufficiency markers for estimating the risk of genetic anomalies in fetuses with isolated early-onset fetal growth restriction (FGR), defined as an estimated fetal weight ≤ 3rd percentile diagnosed ≤ 28 + 6 weeks' gestation. We performed a retrospective analysis of data collected prospectively from cases that attended Vall d'Hebron University Hospital, Barcelona, Spain, between February 2016 and December 2022. Singleton pregnancies diagnosed with isolated early-onset FGR between 20 + 0 and 28 + 6 weeks' gestation were eligible for inclusion. Cases in which a pathogenic or likely pathogenic fetal genetic abnormality was detected by chromosomal microarray (CMA) or whole-exome sequencing (WES) were identified. Cases were stratified by soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio (< 38 vs ≥ 38), PlGF level (< 100 vs ≥ 100 pg/mL), mean uterine artery (UtA) pulsatility index (PI) (< 95th vs ≥ 95th percentile) and fetal Doppler (normal vs abnormal) at the time of FGR diagnosis. Abnormal fetal Doppler was defined as a PI > 95th percentile in the umbilical artery or ductus venosus, or a middle cerebral artery PI or cerebroplacental ratio < 5th percentile. The prevalence of genetic anomalies in each subgroup was compared with that of the overall cohort. Additionally, combinations of markers of placental insufficiency were investigated to determine whether specific combinations could improve the ability to identify cases at risk of genetic anomaly. In the total cohort of 238 cases of isolated early-onset FGR, seven (2.9%) cases of genetic anomaly were detected. Of these, 2/7 (28.6%) were detected by prenatal or postnatal CMA and 5/7 (71.4%) by postnatal WES. Fetal Doppler alone and UtA-PI alone did not identify subgroups with a significantly different prevalence of genetic abnormality compared with the overall cohort. In contrast, a sFlt-1/PlGF ratio < 38 and PlGF level ≥ 100 pg/mL defined subgroups with a significantly higher prevalence of genetic abnormality, while no genetic anomalies were found in cases with a sFlt-1/PlGF ratio ≥ 38 or PlGF level < 45 pg/mL. Furthermore, smaller subgroups combining markers of placental insufficiency identified cases at significantly higher or lower risk of FGR-related genetic anomaly. Placental insufficiency markers, particularly the sFlt-1/PlGF ratio and PlGF level, may enable refined risk stratification of genetic anomalies in cases of isolated early-onset FGR, which could be used to provide individualized prenatal counseling and to optimize the use of WES. Furthermore, combining markers of placental insufficiency, such as UtA-PI and fetal Doppler, may improve risk stratification, potentially defining smaller subgroups with a higher prevalence of genetic anomalies, for which WES may provide greater diagnostic yield. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.