Assessing Placental Dysfunction Subtypes in Pregnancies With a Low PlGF Centile

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 >1 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 1 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: Multiomic cluster-of-cluster analysis resulted in 3 molecular clusters. Cluster 1 predominantly consisted of those with a low PlGF (9/10); PlGF results in cluster 2 varied (low, n=8/20; normal, n=12/20), while cluster 3 mainly comprised of those with a normal PlGF result (n=7/9). Birthweight was significantly lower in cluster 1, as well as an increased incidence of early-onset preeclampsia. However, pathways commonly associated with placental dysfunction were only identified in cluster 2. CONCLUSIONS: Multiomic analysis revealed 2 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 1 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.