Association between SARS‐CoV‐2 infection during pregnancy and placental pathology assessed by histology and gene expression

Abstract Introduction Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection during pregnancy has been associated with varying degrees of placental inflammation but the underlying molecular mechanism is unknown. We utilized placental gene expression analysis to examine possible mechanistic differences between patients with SARS‐CoV‐2 infection during pregnancy and uninfected controls. Methods In this prospective dual‐site cohort study, placentas were biopsied at delivery in patients infected with SARS‐CoV‐2 at different trimesters of pregnancy (case group). Specimens collected prior to the SARS‐CoV‐2 pandemic were utilized as controls. We examined differences in placental pathology based on four categories (acute inflammation, chronic inflammation, fetal vascular malperfusion, and maternal vascular malperfusion) by trimester of SARS‐CoV‐2 infection. Placental biopsies from the chorionic villous layer underwent gene expression analysis. Transcripts with more than twofold abundance difference between cases and controls were considered differentially expressed. Those differentially expressed transcripts were submitted to bioinformatic analysis to identify underlying cellular drivers and transcriptional pathways. All models were adjusted for study site, age, parity, body mass index, race/ethnicity, and insurance status. Results Histology and gene expression were available for 886 historic control placentas. Seventy‐one cases infected with SARS‐CoV‐2 were enrolled—70 placentas were analyzed for histology and 68 for gene expression. There was a higher frequency of high‐grade pathology for patients infected in the first versus second/third trimester, 63.6% with any high‐grade pathology for first trimester infection versus 28.8% in second to third trimester infection, p = 0.038. The highest number of genes was identified as differentially expressed in the first trimester (2623 first, 804 second, 641 third). Bioinformatic analyses of gene expression identified differential expression of transcriptional pathways that facilitate macrophage activation, mesenchymal transitions, Type I interferon/innate antiviral signaling, and glucocorticoid receptor activity in first trimester infections, of interferon signaling and inflammatory activation (NF‐kB) in second trimester infections, and of macrophage activation and downregulation of epithelial gene transcripts in third trimester infections. Conclusion SARS‐CoV‐2 infection was associated with multiple alterations in placental gene regulation, with increasing number of genes and transcription pathways differentially expressed with infection earlier in pregnancy. Future research should clarify the impact of these factors and how they ultimately result in placental pathology and obstetric outcomes.