Multi-omics analysis of human placentas from first year of the COVID-19 pandemic reveals sex-dependant effects

The COVID-19 pandemic affected millions of pregnant persons, yet the consequences of maternal SARS-CoV-2 infection on the placental function and the fetal health remain poorly characterized. While inflammatory and structural alterations have been described in placentas from exposed pregnancies, the underlying molecular mechanisms are still unclear. The aim of this study was to evaluate transcriptomic alterations in placentas exposed to maternal SARS-CoV-2 infection (COVID+) compared to unexposed placentas (COVID-). We analyzed 67 placentas collected between March 2020 and June 2021 from singleton pregnancies with (n = 41) or without (n = 26) a history of maternal SARS-CoV-2 infection during pregnancy. Demographic, obstetric, placental, and fetal data were extracted from the medical records. SARS-CoV-2 RNA was not detected in any placental sample. Bulk RNA-sequencing was performed on villous biopsies preserved either frozen or in RNALater. Global transcriptomic analysis comparing COVID+ and COVID- placentas revealed an upregulation of genes involved in cytoskeleton organization. Stratified analysis by fetal sex identified a marked sex-specific response, with 43 differentially expressed genes (DEGs) in placenta from female fetuses (XX) in the COVID+ group compared to COVID-, whereas only one DEG was identified in placenta from male fetuses (XY). In XX COVID+ placentas, pathways related to cytoskeleton organization, pregnancy specific processes, and muscle development were altered. These results highlight a sex-specific dysregulation of placental gene expression following maternal SAR-CoV-2 infection, predominantly affecting placentas from female fetuses.