Assessing Placental Dysfunction Subtypes in Pregnancies With a Low PlGF Centile

Area of Science:

• Reproductive Biology
• Genomics and Proteomics
• Maternal-Fetal Medicine

Background:

• Low circulating placental growth factor (PlGF) is a marker for placental dysfunction, a primary cause of preeclampsia and fetal growth restriction.
• Current treatments are limited, and placental dysfunction's heterogeneity may hinder therapeutic development.
• This study hypothesizes the existence of multiple subtypes of placental dysfunction in pregnancies with low PlGF.

Purpose of the Study:

• To investigate the potential existence of distinct subtypes of placental dysfunction using multiomic analysis.
• To correlate molecular subtypes with clinical outcomes in pregnancies with low PlGF.
• To explore etiological differences between identified subtypes for personalized treatment strategies.

Main Methods:

• Collected matched placental villous and maternal plasma samples from uncomplicated and complicated pregnancies (preeclampsia, fetal growth restriction, chronic hypertension).
• Categorized samples based on circulating PlGF levels (low <5th centile vs. normal ≥5th centile).
• Performed multiomic (transcriptomic and metabolomic) cluster-of-cluster analysis and compared clinical outcomes and pathway analysis between molecular clusters.

Main Results:

• Multiomic analysis identified three molecular clusters.
• Cluster 1 was predominantly associated with low PlGF and showed significantly lower birthweight and increased early-onset preeclampsia.
• Pathway analysis revealed dysfunction-associated pathways primarily in cluster 2, not the clinically severe cluster 1, suggesting distinct etiological mechanisms.

Conclusions:

• Multiomic analysis suggests at least two potential subtypes of placental dysfunction associated with low circulating PlGF.
• Clinical outcomes suggest cluster 1 represents a severe subtype, but pathway analysis indicates different underlying mechanisms.
• Understanding subtype-specific etiology is crucial for developing personalized therapeutic approaches for placental dysfunction.