Pregnancy is a finely tuned immunological process requiring maternal tolerance of the semi-allogeneic fetus while maintaining defense against pathogens (Weng et al., 2023). The immune system dynamically shifts across gestation—initially adopting a pro-inflammatory state to aid implantation, transitioning to an anti-inflammatory profile for fetal growth, and reverting to inflammation at labor onset. Implantation involves trophoblast invasion into the decidua, forming the placenta. This process relies on immune regulation at the maternal-fetal interface, primarily involving decidual immune cells such as NK cells (∼70 %), macrophages (20–25 %), dendritic cells (1.7 %), and T cells (3–10 %), with few B cells and neutrophils (Muzzio et al., 2014, Presicce et al., 2020). Their absence or dysregulation is linked to pregnancy loss, preterm birth, and preeclampsia (Brien et al., 2017; Romero et al., 2014).

The maternal-fetal interface, composed of trophoblasts and decidual tissue, is an immunologically unique site that balances fetal tolerance and pathogen defense. However, this tolerance can increase susceptibility to viruses like influenza, Zika, or cytomegalovirus (CMV). Pattern recognition receptors (PRRs)—such as RIG-I-like receptors (RLRs), Toll-like receptors (TLRs), and DNA sensors—play critical roles in detecting viral nucleic acids and initiating antiviral responses through type I interferon (IFN-α/β) production and interferon-stimulated genes (ISG) expression (Tesser et al., 2025).

Trophoblasts express these PRRs and contribute directly to antiviral defense. For instance, type III IFNs (IFN-λs), produced by trophoblasts, limit Zika virus spread to neighbouring cells (Bayer et al., 2016). These cytokines, encoded by IFNL1–3 in humans and IFNL 2–3 in mice, act at epithelial barriers (Manivasagam and Klein, 2021). Yet, excessive PRR activation can cause harmful inflammation, disrupt placental structure, and result in fetal damage, as seen in Zika infection models. Such responses may also shape fetal immune and neurodevelopment (Yockey and Iwasaki, 2018).

Among cytosolic PRRs, RIG-I and MDA5 are key sensors of viral RNA and major inducers of type I IFNs (Yoneyama et al., 2015, Kato et al., 2008). Both are expressed in placental cells like syncytiotrophoblasts and cytotrophoblasts (Bryant et al., 2017), where they likely contribute to antiviral defense against RNA viruses including ZIKV and dengue (Chazal et al., 2018). While their precise roles remain under investigation, RIG-I-like receptor signaling appears essential for balancing protection and immune tolerance during pregnancy. The objective of this review is to provide a comprehensive overview of the RLR signaling pathway, with a particular focus on its expression and regulatory mechanisms during pregnancy. The review further explores the consequences of RLR pathway dysregulation in the context of pregnancy complications and highlights the emerging therapeutic and diagnostic potential of targeting this pathway to mitigate adverse maternal and fetal outcomes.