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Abstract Objectives Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a ‘preeclampsia‐like syndrome’. However, the mechanisms underpinning SARS‐CoV‐2‐induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS‐CoV‐2 infection. Methods We utilised whole‐transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS‐CoV‐2 in the third trimester of their pregnancy (n = 7) and those collected prior to the start of the coronavirus disease 2019 (COVID‐19) pandemic (n = 9). Results Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified SARS‐CoV‐2 to promote signatures associated with hypoxia and placental dysfunction. Notably, genes associated with vasodilation (NOS3), oxidative stress (GDF15, CRH) and preeclampsia (FLT1, EGFR, KISS1, PAPPA2) were enriched with SARS‐CoV‐2. Pathways related to increased nutrient uptake, vascular tension, hypertension and inflammation were also enriched in SARS‐CoV‐2 samples compared to uninfected controls. Conclusions Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS‐CoV‐2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS‐CoV‐2 infection.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The virus primarily affects the lungs where it induces respiratory distress syndrome ranging from mild to acute, however, there is a growing body of evidence supporting its negative effects on other system organs that also carry the ACE2 receptor, such as the placenta. The majority of newborns delivered from SARS-CoV-2 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. There appears to be a higher incidence of pregnancy-related complications in SARS-CoV-2 positive mothers, such as miscarriage, restricted fetal growth, or still-birth. In this review, we discuss the pathobiology of COVID-19 maternal infection and the potential adverse effects associated with viral infection, and the possibility of transplacental transmission.