Poster Session 1 - R1
1Katherine Leavey, 1Isaac Gibbs, 2Samantha Benton, 3David Grynspan, 2,4Shannon Bainbridge, 1,5Brian Cox
1 Dept. of Physiology, University of Toronto, Toronto, ON, Canada; 2 Dept. of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; 3 Dept. of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada; 4 Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada; 5 Dept. of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada
Infants born small-for-gestational-age (SGA) due to a pathological placenta-based fetal growth restriction (FGR) can be difficult to separate from those that are simply constitutionally small. Additionally, even amongst pregnancies with evident placental pathology, considerable heterogeneity in adverse clinical outcomes and long-term consequences has been observed. In our prior study on preeclampsia (PE), another heterogeneous placenta-centric disorder of pregnancy, we found that by clustering placentas based on their gene expression profiles only, multiple subtypes of PE could be elucidated. We, therefore, applied a similar approach to test the hypothesis that subtypes of normotensive SGA placentas also exist, represent part of the spectrum of placental dysfunction often affiliated with PE, and can be dissociated into pathological FGR and non-pathological SGA. To accomplish this, a total of 20 normotensive SGA placentas (estimated fetal weight/birth weight <10th percentile for gestational age and sex) were purchased from a biobank and underwent genome-wide mRNA assessment and detailed histopathology scoring. These were then combined with a group of samples from our previously published PE cohort (N=77) to form an aggregate SGA-focused cohort (N=97) of normotensive average-for-gestational-age (AGA), normotensive SGA, and hypertensive SGA placentas. Gene expression data was subjected to unsupervised clustering, and each identified cluster was assessed for enriched clinical and histological features. Unsupervised clustering of the aggregate dataset revealed three transcriptional subtypes of normotensive SGA placentas: one with some signs of mild pathology, co-clustering with the healthy controls, another with more severe evidence of hypoxic damage and maternal vascular malperfusion lesions, and the third demonstrating an immune/inflammatory response and histological signs of maternal anti-fetal rejection. Furthermore, all three of these normotensive SGA subtypes co-clustered with a group of hypertensive SGA patients, displaying more severe clinical outcomes but very comparable transcriptional and histological placental profiles. Overall, this study provides evidence for at least two pathological placental etiologies of normotensive FGR, which show considerable similarity to our previously identified “canonical” and “immunological” PE placental subtypes. We also discovered a subtype of normotensive SGA placentas that may represent a mild form of pathological growth restriction, but could also be associated with some constitutionally small infants. Future work that focuses on the identification of etiology-driven biomarkers and therapeutic interventions for each subtype of SGA/FGR is warranted.