Placental biomarker and fetoplacental Doppler abnormalities are strongly associated with placental pathology in pregnancies with small-for-gestational-age fetus: prospective study

Abstract

Objective: Placental dysfunction can result in small-for-gestational age (SGA) or fetal growth restriction (FGR). The aim of this prospective cohort study was to assess the association of the cerebroplacental ratio (CPR) and other more conventional fetoplacental Doppler indices, circulating placental growth factor (PlGF) levels and soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio, with specific placental abnormalities in a large cohort of pregnancies with an SGA/FGR fetus.

Methods: This was a prospective cohort study of singleton pregnancies with a SGA/FGR fetus conducted at the Centre for Maternal and Fetal Medicine at the Mater Mother's Hospital, Queensland, Australia. Multivariable logistic regression with adjustment for pre-eclampsia was used to evaluate the effect of CPR < 5^th centile, umbilical artery Doppler abnormality (defined as umbilical artery (UA) pulsatility index (PI) > 95^th centile, or absent or reversed end-diastolic flow), mean uterine artery (UtA) PI > 95^th centile and abnormal placental biomarkers (PlGF level < 100 ng/L and sFlt-1/PlGF ratio > 5.78 if gestational age < 28 weeks or > 38 if gestational age ≥ 28 weeks) on the following placental abnormalities, classified based on the Amsterdam Placental Workshop Group Consensus criteria: placental maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and delayed villous maturation (DVM).

Results: Among the 367 women included in this study, MVM was present in 159 (43.3%) placentae, FVM in 20 (5.4%), VUE in 49 (13.4%), DVM in 19 (5.2%) and CHI in six (1.6%). Compared to SGA controls with normal fetoplacental Doppler and placental biomarkers, CPR < 5^th centile (adjusted odds ratio (aOR), 3.17 (95% CI, 1.95-5.16); P < 0.001), abnormal UA Doppler (aOR, 2.97 (95% CI, 1.80-4.90); P < 0.001) and mean UtA-PI > 95^th centile (aOR, 5.42 (95% CI 2.75-10.70); P < 0.001) were associated with higher odds of placental abnormality. The odds of MVM specifically were significantly higher when CPR < 5^th centile (aOR, 2.47 (95% CI, 1.64-4.33); P < 0.001), abnormal UA Doppler (aOR, 3.13 (95% CI, 1.91-5.12); P < 0.001) or mean UtA-PI > 95^th centile (aOR, 4.01 (95% CI, 2.25-7.13); P < 0.001) was present. The odds of placental abnormality were also significantly higher if PlGF levels were < 100 ng/L (aOR, 3.66 (95% CI, 2.22-6.06); P < 0.001) or the sFlt-1/PlGF ratio was elevated (aOR, 3.74 (95% CI, 2.17-6.43); P < 0.001). The odds of MVM were also higher in women with PlGF < 100 ng/L (aOR, 2.89 (95% CI, 1.72-4.85); P < 0.001) and elevated sFlt-1/PlGF ratio (aOR, 3.15 (95% CI, 1.83-5.45); P < 0.001).

Conclusion: In pregnancies with SGA/FGR fetus, mean UtA-PI > 95^th centile, abnormal UA Doppler, CPR < 5^th centile, PlGF < 100 ng/L and elevated sFlt-1/PlGF ratio were all strongly associated with placental abnormality, particularly MVM. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Keywords: cerebroplacental ratio; fetal growth restriction; maternal vascular malperfusion; placental dysfunction; placental growth factor; placental pathology; pregnancy; small‐for‐gestational age; soluble fms‐like tyrosine kinase‐1; umbilical artery Doppler.

Figure 1

Flowchart summarizing study population and placental pathology. Thirty‐three placentae were without identifiable predominant pathology and therefore could not be classified. *Other pathology included ascending intrauterine infection, subchorionic or intraparenchymal hemorrhage, and villous hydrops of uncertain significance. AC, abdominal circumference; EFW, estimated fetal weight.

Figure 2

Incidence (per 100) of placental abnormality in pregnancies with small‐for‐gestational‐age fetus, stratified by normality () or abnormality () of fetoplacental Doppler parameters (cerebroplacental ratio (CPR), umbilical artery (UA) Doppler and mean uterine artery (UtA) pulsatility index (PI)) and placental biomarkers (placental growth factor (PlGF) and soluble fms‐like tyrosine kinase‐1 (sFlt‐1)/PlGF ratio). Plots show difference in incidence of: (a) maternal vascular malperfusion (MVM), (b) fetal vascular malperfusion (FVM), (c) villitis of unknown etiology (VUE), (d) delayed villous maturation (DVM) and (e) chronic histiocytic intervillositis (CHI). Abnormality of Doppler parameters defined as CPR < 5^th centile, abnormal UA Doppler (UA‐PI > 95^th centile or absent or reversed end‐diastolic flow) and mean UtA‐PI > 95^th centile. Abnormality of placental biomarkers defined as PlGF level < 100 ng/L and sFlt‐1/PlGF ratio > 5.78 for gestational age < 28 weeks and > 38 for gestational age ≥ 28 weeks.