Angiogenic factor levels across severity stages of fetal smallness with or without associated pre-eclampsia

Angiogenic factors are elevated in fetal growth restriction (FGR), but their clinical value for assessing the severity of FGR and the potential influence of coexisting pre-eclampsia has scarcely been investigated. In this study, our aim was to investigate the profile of maternal angiogenic factors across severity stages of fetal smallness compared with controls, analyzed overall and stratified by the presence or absence of pre-eclampsia, and to investigate whether values of these angiogenic factors, such as placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and the sFlt-1/PlGF ratio, are helpful in determining the severity stage of fetal smallness.

This was a prospective cohort study of women with a singleton pregnancy diagnosed with fetal smallness (defined as birth weight < 10^th centile) (n = 604) between October 2010 and December 2017, compared with a control group of pregnant women with an appropriate-for-gestational-age (AGA) singleton fetus (defined as birth weight ≥ 10^th centile) (n = 424). At diagnosis, ultrasound was performed to assess estimated fetal weight (EFW) and Doppler pulsatility indices (PI) of the uterine artery (UtA), umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV), and these parameters were monitored regularly until delivery. Cerebroplacental ratio (CPR) was calculated as MCA-PI/UA-PI. Small fetuses were classified as: small-for-gestational age (SGA) if EFW ≥ 3^rd and < 10^th centile, with normal Doppler parameters; FGR Stage I if either EFW < 3^rd centile, persistent MCA-PI < 5^th centile, UA-PI > 95^th centile, CPR < 5^th centile or UtA-PI > 95^th centile; FGR Stage II if there was absent end-diastolic flow in the UA; FGR Stage III if there was reversed end-diastolic flow in the UA or DV-PI ≥ 95^th centile; or FGR Stage IV if there was non-reassuring cardiotocography or absent/reversed DV atrial flow. Maternal peripheral venous blood concentrations of PlGF and sFlt-1 were determined using enzyme-linked immunosorbent assay, and the sFlt-1/PlGF ratio was calculated. Linear trend of proportions was tested using the Mantel-Haenszel chi-square test.

Among AGA controls (n = 424), SGA (n = 192), FGR Stage I (n = 380), FGR Stage II (n = 16) and FGR Stages III-IV (n = 16) fetuses, the proportion of cases with a sFlt-1/PlGF ratio > 95^th centile was 12.7%, 7.8%, 30.8%, 43.8% and 62.5%, respectively (P = 0.0001), and the median multiples of the median (MoM) values for the sFlt-1/PlGF ratio were 0.55 (interquartile range (IQR), 0.19-2.00), 1.00 (IQR, 0.31-2.67), 3.03 (IQR, 0.91-8.20), 3.94 (IQR, 0.85-9.13) and 7.32 (IQR, 1.44-16.29), respectively (P = 0.24). Pre-eclampsia was diagnosed at any time between inclusion and delivery in 1.9% of controls, 3.6% of SGA, 21.1% of FGR Stage I, 37.5% of FGR Stage II and 50.0% of FGR Stages III-IV fetuses. Among all small fetuses with vs without pre-eclampsia, the proportion of pregnancies with sFlt-1/PlGF ratio > 95^th centile was 56.9% vs 15.4% (P < 0.001) and the median MoM of the sFlt-1/PlGF ratio was 8.11 (IQR, 3.83-27.09) vs 1.59 (IQR, 0.52-5.04) (P = 0.18).

Serum levels of angiogenic factors became more abnormal as the severity stage of fetal smallness increased. This association with severity was stronger in the presence of pre-eclampsia. However, absolute values of serum levels showed substantial overlap in both the presence and the absence of pre-eclampsia, making their use in determining the severity stage of fetal smallness challenging. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.