A large study of early pregnancy found little evidence that SARS-CoV-2 commonly infects placental tissue, but also showed that even limited virus presence can reshape immune signaling at the site where pregnancy begins.
Research: Despite limited detection of the virus in placental tissue, SARS-CoV-2 infection during the first trimester causes severe immune dysregulation at the maternal-fetal interface. Image credit: Kateryna Kon / Shutterstock
Recent research published in journals nature communications suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely undetectable in placental tissue during the first trimester, suggesting that efficient intrauterine infection is unlikely during early pregnancy despite causing significant cellular and immune changes in the placenta.
Analysis of 761 samples from early pregnancy revealed that while intrauterine infections in early pregnancy are rare, changes in the placenta are likely caused by antiviral responses that can affect trophoblast function.
The study also found that higher serum IgG antibody levels were inversely associated with tumor necrosis factor beta (TNF-β), suggesting that adaptive immunity may help regulate the inflammatory response and supporting the authors’ view of the potential value of preconception vaccination.
Background of COVID-19 pregnancy and placental risks
Coronavirus disease 2019 (COVID-19) is now transitioning into an endemic epidemic and remains a global health concern. Physiological changes make pregnant people especially susceptible to respiratory infections.
Studies have linked COVID-19 infection to adverse outcomes such as hospitalization, premature birth, and stillbirth. Although viral components have been detected in placental tissue, confirmed intrauterine infection appears to be rare and its timing remains unclear. Further studies are needed to clarify the impact of infection during early pregnancy and its impact on maternal and fetal immune dynamics.
First trimester placenta study design
About research. In this study, researchers investigated the impact of COVID-19 on the maternal-fetal interface during early pregnancy in individuals undergoing elective surgical abortion within 13 weeks of pregnancy. They obtained paired decidual and villous tissue samples from participants between January and September 2023.
The study period spanned two waves of COVID-19 infections, after the end of China’s strict COVID-19 containment policies, when it was thought unlikely that infections would go undetected early. To minimize confounding by past immunity, researchers excluded participants who had been vaccinated within the past six months or had a previous severe SARS-CoV-2 infection based on antibody half-life data.
The research team performed reverse transcription quantitative polymerase chain reaction (RT-qPCR) targeting the SARS-CoV-2 envelope (E), nucleocapsid (N), and ribonucleic acid-dependent ribonucleic acid polymerase (RdRp) genes. This analysis also measured host invasion genes, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2).
Fluorescence in situ hybridization (FISH) and immunofluorescence assay (IFA) confirmed the presence of very low levels of viral material, with no apparent active placental infection.
Histology compared decidual and villous tissue from SARS-CoV-2 positive and negative samples to assess host gene expression.
The researchers performed serological analysis using a chemiluminescent assay to measure anti-receptor binding domain (RBD) immunoglobulin G (IgG) and IgM levels. They also performed cytokine profiling and serum metabolomics to assess systemic immune responses.
To further characterize the molecular changes, the research team applied ribonucleic acid sequencing (RNA-seq) to selected decidua-villus pairs at both the tissue and single-cell levels. Subsequently, differential gene expression analysis (DEG), gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were performed.
Additionally, the researchers analyzed serum samples using ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS)-based metabolomics. Finally, they performed Pearson correlation analysis to investigate associations between antibody levels, inflammatory markers, cytokines, chemokines, and metabolites.
Placental immune dysregulation and reduced virus detection
Results Molecular analysis showed minimal presence of SARS-CoV-2 in early placental tissue, with only low levels of N gene signal detected in three samples and no evidence of E or RdRp genes, suggesting a fragmented or incomplete viral genome.
RNA-seq also failed to detect any viral transcripts, supporting a very low viral load. Histological evaluation showed no structural differences between virus-positive and -negative tissues. Genes for viral entry into host cells (TMPRSS2 and ACE2) were expressed, but their coexpression between cell types was limited, which may explain the rarity of placental transmission.
Serological analysis of 433 participants divided individuals into acute (IgM positive), convalescent (IgG positive), and uninfected groups. Acute infection was associated with elevation of proinflammatory cytokines such as interleukin-31 (IL-31) and growth-regulated oncogene alpha (GRO-α).
In contrast, convalescent samples showed increased anti-inflammatory IL-10 levels. Notably, IgG levels are inversely correlated with tumor necrosis factor beta (TNF-β), suggesting a protective role in immune regulation, whereas IgM levels correlate with multiple inflammatory markers and reflect an active immune response.
Although the systemic inflammatory profile was relatively suppressed, transcriptome analysis showed that local immune activation at the maternal-fetal interface was significant. RNA-seq analysis and immune deconvolution and single-cell profiling showed increased immune cell infiltration, upregulation of interferon-stimulated genes (ISGs), and increased M2-like macrophage population.
Additionally, disruption of cell-to-cell signaling, particularly involving the wingless-associated integration site (WNT) and transforming growth factor beta (TGF-β) pathways, and downregulation of angiogenesis-related genes were observed. The authors suggest that these changes can impair trophoblast function and placental development, potentially contributing to adverse pregnancy outcomes despite the limited presence of the virus.
Preconception vaccination and its effects on pregnancy
The results of this study suggest that SARS-CoV-2 was rarely detected in placental tissue during the first trimester, supporting the notion that intrauterine infections during early pregnancy are rare. However, maternal infection is associated with changes in placental immune activation and trophoblast function, which may affect pregnancy outcome.
The inverse correlation between IgG levels and TNF-β indicates a protective role for adaptive immunity, supporting the importance of vaccination before pregnancy, the authors said. Most cases were mild or asymptomatic, so the impact of severe cases may be underestimated.
The authors also note that the timing of infection is not precisely known and single-cell RNA sequencing was performed on only one set of tissues in each group. Further studies should investigate long-term outcomes, timing of infection, and larger and more diverse cohorts to better define maternal and fetal risks.
Reference magazines:
- Liu, XX, Shen, X., Cui, X. et al. (2026). SARS-CoV-2 infection during the first trimester of pregnancy causes severe immune dysregulation at the maternal-fetal interface, despite limited detection of the virus in placental tissue. Nature Communications. DOI: 10.1038/s41467-026-71770-9, https://www.nature.com/articles/s41467-026-71770-9
