Towards an understanding of COVID-19-associated preeclampsia

SARS-CoV-2 infection during pregnancy has been associated with higher rates of preeclampsia (PE). While placental abnormalities resembling PE have been reported in COVID-19 pregnancies, the molecular mechanisms underlying the association remain unclear.

We conducted bulk RNA sequencing on placental tissues from four pregnancy groups: uneventful prepandemic (preCOVID-19), prepandemic PE (preCOVID-19 PE), COVID-19 without PE (COVID no PE), and COVID-19 complicated by PE or other hypertensive disorders (COVID PE). Differential expression was analyzed using Deseq2 likelihood ratio test (LRT), and gene set enrichment analysis identified dysregulated pathways.

Clustering of LRT-significant differentially expressed genes (DEGs) identified a set of 16 genes (defined by the false discovery rate adjusted p-value < 0.05) across the four pregnancy groups, showing stepwise expression changes-lowest in preCOVID-19 uneventful, followed by those in COVID-19 without PE, then preCOVID-19 PE, and highest in COVID PE. This cluster included genes associated with placental dysfunction, such as LAMA5 and BTNL9. While morphogenesis-related pathways were enriched across all pathological groups, immune activation pathways were predominantly enriched in COVID PE, moderately in preCOVID-19 PE, and absent in COVID no PE.

Our findings identify a COVID-19-associated placental signature that mirrors PE features and shows a progressive expression pattern defining a continuum of placental stress, with maternal SARS-CoV-2 infection potentially exacerbating underlying dysfunction.