Pregnancy challenges the maternal immune system to balance defense against pathogens and tolerance to the semi-allogeneic fetus. This balance is achieved through shifts in T lymphocyte responses across gestation (Jafarpour et al., 2020). In normal pregnancies, the first trimester presents a proinflammatory profile, with cytokines like IFN-γ, TNF-ɑ, and IL-2, critical for implantation and placentation. In the second trimester, an anti-inflammatory milieu predominates, with IL-4, IL-5, IL-6, IL-10, and IL-13 supporting fetal growth. The third trimester again shifts to a proinflammatory state to enable parturition (Graham et al., 2021).

Maternal exposure to adversities can disrupt this immunological balance, and altered cytokine profiles have been linked to placental, immune, and nervous system development (Woods et al., 2023). Such imbalance has been associated with adverse outcomes like spontaneous abortion, prematurity, and altered neurodevelopment, increasing the risk for neurodevelopmental disorders (Paraschivescu et al., 2020, Hall et al., 2023).

Our group recently demonstrated that maternal immunological markers, alongside psychosocial stress, predict neurodevelopmental trajectories in the first two years of life. Two principal components (PCs) captured cytokine coordination: PC1 (IL-13, IL-10, IL-8, IL-6, IL-4) was associated with improved cognitive outcomes, while PC2 (IFN-γ, IL-17a, TNF-α, IL-1β) predicted poorer cognitive, language, and motor development (Euclydes et al., 2024). The mechanisms underlying these associations are complex, with the placenta acting as a central mediator between maternal and fetal environments (Howerton and Bale, 2012). One key form of maternal-fetal communication occurs through exosomes (Salomon et al., 2014, Saadeldin et al., 2015), extracellular vesicles (30–100 nm) derived from endocytosis, with a bi-lipid membrane (György et al., 2011).

Placental exosomes, produced by the syncytiotrophoblast and released into maternal circulation from week six onward, increase throughout pregnancy (Sarker et al., 2014). Although their release mechanisms and roles under environmental stressors remain unclear (Bai et al., 2021), alterations in their levels have been linked to high maternal BMI (Elfeky et al., 2017), glucose levels (Salomon et al., 2016), and hypoxia (Pillay et al., 2016). Exosomes are believed to support maternal immune tolerance by inducing T-cell apoptosis and inhibiting NK cell cytotoxicity (Bai et al., 2021). They also influence cytokine regulation, promoting monocyte migration and differentiation into macrophages, and stimulating the secretion of cytokines and chemokines such as IL-1β, IL-6, serpin-E1, TNF-α, and colony-stimulating factors that aid trophoblast development (Maligianni et al., 2022). Additionally, exosomes may contribute to cytokine clearance via encapsulation mechanisms following immune stimulation (Dimik et al., 2023).

Despite growing evidence of placental exosomes as biomarkers of pregnancy adversities and modulators of maternal cytokines, studies examining their simultaneous relationship with infant neurodevelopment are scarce. In this study, we examined the association between third-trimester maternal cytokines, the PLAP+ /CD63 + exosome ratio, and neurodevelopmental outcomes at 12 months. Based on our previous findings (Euclydes et al., 2024) and other reports (Chudnovets et al., 2020), we hypothesize that maternal cytokine networks and placental exosomes jointly influence early childhood neurodevelopment.