# COVID-19 vaccination and miscarriage risk: RNA-seq and bioinformatics analysis at the maternal-foetal interface

## TL;DR

This study investigates whether the COVID-19 vaccine affects gene expression at the maternal-foetal interface and finds no increased risk of miscarriage.

## Contribution

The study provides novel RNA-seq evidence on the impact of the COVID-19 vaccine on gene expression at the maternal-foetal interface.

## Key findings

- The vaccine modulated gene expression, up-regulating complement activation and down-regulating graft-vs-host response pathways.
- Three genes (FOS, FOSB, LY96) associated with miscarriage were up-regulated during infection but suppressed by the vaccine.
- The vaccine inhibited miscarriage-related pathways like the tumour necrosis factor signalling pathway.

## Abstract

Vaccine hesitancy persists because definitive evidence regarding the underexplored safety of COVID-19 vaccines in pregnancy is still lacking, particularly concerning their effects on the maternal-foetal interface (MFI) and potential links to miscarriage. We aimed to verify whether COVID-19 vaccines modulate gene expression at the MFI, thereby influencing recurrent miscarriage.

We conducted an RNA sequencing analysis on decidual tissues from six pairs of early pregnancy participants, both vaccinated and unvaccinated. We extracted the data sets associated with COVID-19 placenta (GSE181238) and recurrent miscarriage (GSE22490) from the Gene Expression Omnibus database for further bioinformatic analysis, focussing on the expression, function, and distribution of core genes at the MFI.

Compared to the control group, 879 differentially expressed genes (P < 0.05; fold changes >1.5; false discovery rate <0.05) were identified in the vaccinated group. Complement activation and cell adhesion pathways were up-regulated, while the graft-vs-host response was down-regulated. The vaccine down-regulated some genes overexpressed in recurrent miscarriage cases. Three significant genes – FOS, FOSB, and LY96 – associated with miscarriage were identified; these genes are up-regulated during infection but suppressed by the vaccine. Functional enrichment analysis revealed the vaccine's immune activity, similar to but weaker than COVID-19 infection, and it inhibited certain miscarriage-related pathways, such as the tumour necrosis factor signalling pathway. Gene set variation analysis suggested a positive influence of the vaccine on immune tolerance at MFI.

This study indicates that the COVID-19 vaccine may exert nonnegative effects on the maternal-foetal immune micro-environment and is unlikely to increase the risk of miscarriage.