ABSTRACT: Introduction: SARS-CoV-2 infection during pregnancy has been associated with an increased number or frequency of adverse pregnancy outcomes including preeclampsia (PE). Placental abnormalities that resemble features observed in PE have previously been reported in pregnancies affected by COVID-19 disease. However, the molecular mechanisms linking SARS-CoV-2 infection to placental dysfunction and PE-like presentations remain poorly understood. Methods: We performed bulk RNA sequencing on placental tissues from four groups: uneventful prepandemic pregnancies (preCOVID-19, n=10), prepandemic pregnancies with preeclampsia (PE, n=10), COVID-19 pregnancies without PE (COVID no HDP, n=28), and COVID-19 pregnancies with PE or other hypertensive disorders of pregnancy (HDP) (termed as COVID HDP, n=10). A likelihood ratio (LRT) test was applied to identify genes differentially expressed (DEGs) across groups. Gene set enrichment analysis (GSEA) was conducted to identify enriched pathways in pathological groups compared to preCOVID-19. Expression profiles were aligned with previously defined PE subtypes using a reported PE gene panel. Results: The LRT test identified a set of 16 genes that were differentially expressed (adjusted p-value <0.05) across the four groups, showing stepwise upregulation—lowest in preCOVID-19 uneventful pregnancies, followed by COVID-19 without HDP, then preCOVID-19 PE, and highest in COVID-19 HDP placentas. This cluster included genes linked to placental dysfunction such as LAMA5, BTNL9. COVID HDP and PE groups clustered together, sharing upregulation of FLT1, ENG, and others, while MORN3 and TAP1 were unique to COVID HDP. COVID no HDP formed a distinct cluster, marked by upregulation of SNX10 and MTF1 and downregulation of all the other genes of the panel. Morphogenesis related ontologies were enriched in all pathological groups. However, immune related pathways, such as T cell activation and cytokine signaling, were most strongly overrepresented in the COVID HDP group, followed by moderate enrichment in PE, and were absent in COVID no HDP group. Discussion: Our findings reveal a molecular signature in placenta affected by maternal COVID-19 disease pregnancies that mirrors and amplifies features observed in PE. The progressive expression pattern suggests a continuum of placental stress, with SARS-CoV-2 infection potentially exacerbating underlying dysfunction. These results provide insight into the origin of COVID-19 associated placental dysfunction and its overlap with established PE subtypes.
