SARS-CoV-2 infection during pregnancy linked to gene expression changes and placental pathology

A prospective cohort study published in Pregnancy has found that SARS-CoV-2 infection during pregnancy, particularly in the first trimester, is associated with significant alterations in placental gene expression and higher rates of high-grade placental pathology.¹

The dual-site study was conducted at Prisma Health in South Carolina and Endeavor Health in Illinois. Researchers enrolled 71 pregnant individuals who tested positive for SARS-CoV-2 between June 2020 and June 2021 and compared their placentas with 886 historic control specimens collected before the COVID-19 pandemic.

Placental pathology was assessed histologically in 70 cases, and transcriptome-wide gene expression was evaluated in 68 placentas using RNA sequencing. The analysis focused on four major categories of placental injury: acute inflammation, chronic inflammation, maternal vascular malperfusion (MVM), and fetal vascular malperfusion (FVM).²

Infection timing was a key variable. First-trimester infections were associated with a higher frequency of high-grade pathology compared with second and third-trimester infections (63.6% vs 28.8%, P = .038). The study noted, “There was a higher frequency of high-grade pathology for patients infected in the first versus second/third trimester.”

Differential gene expression analysis revealed 2623 transcripts with more than twofold abundance changes in first-trimester infections, compared with 804 and 641 in the second and third trimesters, respectively. Bioinformatics analyses identified trimester-specific activation of transcription pathways involved in immune modulation, antiviral defense, and inflammation.

In first-trimester infections, bioinformatics analysis highlighted increased activity in transcription pathways linked to macrophage activation and mesenchymal transition. Specifically, the macrophage activation factor (MAF) pathway showed a statistically significant increase in activity (V$MAF_Q6 motif, fold difference 1.73, SE = 1.25, P = .02). However, no significant differences were found in interferon or inflammatory signaling pathways during the first trimester, possibly due to sample size limitations.

In second-trimester infections, interferon regulatory factors (IRF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways were activated. The study noted, “TELiS analyses of second-trimester infection suggested less interferon signaling, but additional inflammatory activation in comparison to controls.”

Third-trimester infections showed upregulation of IRF and STAT transcription factor pathways, consistent with innate antiviral signaling, and continued upregulation of MAF pathways. Glucocorticoid receptor activity, a known anti-inflammatory signal, was also elevated (V$GR_01 motif, fold difference = 1.82, SE = 1.23, P = .005).

“Gene pathways identified in this study can turn on many downstream targets—for example, NFκB acts as a master switch for inflammation and activates an inflammatory response among many types of cells,” the authors wrote. They hypothesized that changes in pathway activation may be transient but lead to long-term placental injury, as evidenced by abnormal histologic findings at delivery.

While the study did not assess perinatal outcomes directly, it reinforces prior research suggesting that first-trimester infections may have a more profound impact on placental health and function. “SARS-CoV-2 infection was associated with multiple alterations in placental gene regulation, with an increasing number of genes and transcription pathways differentially expressed with infection earlier in pregnancy,” the authors concluded.

Limitations of the study included a small sample size for first-trimester cases, absence of neonatal outcome data, and potential confounding factors. The authors acknowledged that “we cannot draw causal inferences about COVID’s impact on the placenta,” but emphasized that the findings support further investigation into how early SARS-CoV-2 infection may alter placental biology and potentially affect fetal development.

References:

1. Suresh S, Britt JL, Freedman A, et al. Association between SARS‐CoV‐2 infection during pregnancy and placental pathology assessed by histology and gene expression. 2025;1(4). doi:https://doi.org/10.1002/pmf2.70052
2. Freedman AA, Keenan-Devlin LS, Borders A, Miller GE, Ernst LM. Formulating a Meaningful and Comprehensive Placental Phenotypic Classification. Pediatric and Developmental Pathology. 2021;24(4):337-350. doi:https://doi.org/10.1177/10935266211008444