Assessing Placental Dysfunction Subtypes in Pregnancies With a Low PlGF Centile

Abstract

Background: A low circulating placental growth factor (PlGF) concentration is considered a marker of placental dysfunction, the predominant cause of preeclampsia and fetal growth restriction. Besides iatrogenic delivery, there are no effective treatments, potentially due to its heterogeneity. We hypothesize that more than one subtype of placental dysfunction exists in pregnancies with a low circulating PlGF.

Methods: Matched placental villous and maternal plasma samples (low PlGF <5th, n=19; normal PlGF ≥5th centile, n=20) were collected from uncomplicated pregnancies and those complicated by one or a combination of preeclampsia, fetal growth restriction, or chronic hypertension. Transcriptomic and metabolomic data sets were obtained from villous samples and used to perform cluster-of-cluster analysis. Clinical outcomes were compared between clusters, as well as subsequent pathway analysis.

Results: Multi-'omic cluster-of-cluster analysis resulted in three molecular clusters. Cluster one predominantly consisted of those with a low PlGF (9/10); PlGF results in cluster two varied (low, n=8/20; normal, n=12/20), while cluster three mainly comprised of those with a normal PlGF result (n=7/9). Birthweight was significantly lower in cluster one, as well as an increased incidence of early-onset preeclampsia. However, pathways commonly associated with placental dysfunction were only identified in cluster two.

Conclusions: Multi-'omic analysis revealed two potential subtypes of placental dysfunction associated with a low circulating PlGF. These results support previous studies suggesting the existence of preeclampsia subtypes. Clinical outcome comparisons indicate cluster one as the severe subtype; however, pathway analysis contradicted this. Improved understanding of subtype etiology could enable a more personalized therapeutic approach for pregnancies complicated by placental dysfunction.

Keywords: cluster analysis; hypertension; placenta; preeclampsia.