Journal of Pregnancy and Child Health
Open Access

Pregnancy is a complex physiological state in which the immune system must balance the defense against pathogens with the tolerance of the developing fetus, which is genetically distinct from the mother. The maternal immune system undergoes significant adaptations to ensure that the fetus is protected from infections while preventing immune rejection. However, excessive or dysregulated maternal immune activation, often characterized by elevated levels of interleukins and other inflammatory cytokines, has been linked to a range of adverse pregnancy outcomes, including preterm birth, preeclampsia, fetal growth restriction, and neurodevelopmental disorders such as autism spectrum disorder. Inflammatory cytokines, particularly interleukins (ILs), play a central role in regulating immune responses during pregnancy. The effects of maternal immune activation on fetal development are profound, influencing both short-term outcomes, such as preterm labor, and long-term outcomes, such as neurodevelopmental and metabolic disorders in offspring. This review explores the role of interleukins and inflammatory cytokines in maternal immune activation during pregnancy and examines their impact on fetal development [1].

Maternal Immune System Adaptations during Pregnancy

During pregnancy, the maternal immune system must maintain a delicate balance between immune tolerance and immune activation. The fetus is an allograft, containing paternal antigens that could potentially be recognized by the maternal immune system as foreign. To prevent immune rejection, the maternal immune system undergoes changes to promote tolerance, particularly during the first trimester. This is mediated by various immune cells, including regulatory T cells (Tregs), which help maintain immune homeostasis and suppress inflammatory responses. However, during later stages of pregnancy, the maternal immune system is also primed to respond to infections and other external threats. Despite the protective adaptations, excessive maternal immune activation can lead to inflammatory responses that disrupt normal pregnancy progression. Cytokines, which are small proteins involved in cell signaling, are central to immune regulation. Interleukins, a subgroup of cytokines, are particularly important during pregnancy, as they regulate both the immune response and fetal development. Dysregulation of interleukin levels can lead to pathological inflammation, affecting both maternal and fetal health [2].

Interleukins and Their Role in Maternal Immune Activation

Interleukins are a broad class of cytokines that play pivotal roles in the immune response. They are produced by various immune cells, including T cells, macrophages, and dendritic cells, and mediate a wide range of biological processes, such as inflammation, immune cell activation, and tissue remodeling. In the context of pregnancy, interleukins regulate the maternal immune response to ensure proper placental implantation, fetal development, and protection from infections. Among the many interleukins, several are particularly significant in the context of maternal immune activation and fetal development. IL-6, IL-1β, IL-8, and IL-17 are commonly elevated in situations of maternal immune activation and are known to influence both maternal and fetal health outcomes [3].

IL-6 and Inflammatory Cytokines in Pregnancy

IL-6 is one of the most studied inflammatory cytokines during pregnancy. It plays a crucial role in immune regulation, acute-phase responses, and inflammation. Elevated levels of IL-6 during pregnancy have been associated with a range of adverse outcomes, including preterm birth, preeclampsia, and fetal growth restriction. IL-6 induces the production of other pro-inflammatory cytokines and acute-phase proteins, thus amplifying the inflammatory response. Maternal IL-6 levels are typically elevated in response to infections, but they can also be increased in conditions such as maternal obesity, psychological stress, and environmental exposures, all of which have been linked to adverse pregnancy outcomes. IL-6 activates several pathways that affect both the maternal and fetal compartments. In the placenta, IL-6 can induce the expression of adhesion molecules, increase vascular permeability, and stimulate the release of prostaglandins, which play a role in labor initiation. These mechanisms may contribute to premature rupture of membranes and preterm labor [4]. Furthermore, IL-6 can cross the placenta and affect fetal development. Elevated IL-6 levels in the maternal bloodstream can alter the placental microenvironment, disrupting nutrient and oxygen exchange and impairing fetal growth. This disruption may lead to fetal growth restriction and developmental delays. Long-term effects on offspring health have also been observed, with increased IL-6 levels associated with metabolic disorders, neurodevelopmental disorders, and cardiovascular diseases later in life.

IL-1β and its Role in Inflammation and Fetal Development

IL-1β is another key inflammatory cytokine involved in maternal immune activation. It plays a central role in mediating inflammation and initiating labor. IL-1β is produced in response to infections and tissue damage, and its levels increase during pregnancy complications such as chorioamnionitis, an infection of the fetal membranes. The release of IL-1β triggers the production of prostaglandins, which are involved in the inflammatory response and are critical for the initiation of labor. Elevated IL-1β levels during pregnancy can lead to premature uterine contractions, premature rupture of membranes, and preterm birth. Additionally, IL-1β influences the expression of adhesion molecules and cytokines within the placenta, contributing to placental dysfunction and inadequate fetal perfusion. Studies have shown that higher levels of IL-1β are associated with fetal growth restriction and adverse neurodevelopmental outcomes in the offspring, such as cognitive impairments and behavioral disorders [5].

IL-8 and Chemotaxis in Pregnancy

IL-8 is a chemokine that plays a critical role in the recruitment of immune cells to sites of infection or inflammation. It is produced by various cell types, including endothelial cells, macrophages, and neutrophils. During pregnancy, IL-8 is involved in the regulation of immune cell migration and the response to infection or inflammatory stimuli. Increased IL-8 levels in maternal circulation are often associated with intrauterine infection and preterm labor. The overproduction of IL-8 leads to the accumulation of neutrophils in the uterine tissues, which can promote inflammation, uterine contractions, and early labor. Elevated IL-8 levels have also been linked to adverse fetal outcomes, including preterm birth and fetal growth restriction. In addition, IL-8 may have a direct effect on fetal development, as it can influence placental function and the ability of the placenta to supply the fetus with adequate nutrients and oxygen.

IL-17 and Immune Dysregulation in Pregnancy

IL-17 is a pro-inflammatory cytokine produced primarily by T-helper 17 (Th17) cells, and it plays a significant role in the immune response to infections and in autoimmune diseases. Dysregulation of IL-17 production during pregnancy has been associated with preterm birth, fetal growth restriction, and placental dysfunction. IL-17 has been shown to increase the production of other inflammatory cytokines, including IL-6 and IL-1β, leading to a heightened inflammatory response in the maternal-fetal interface. Increased IL-17 levels in maternal serum have been linked to adverse pregnancy outcomes, such as preeclampsia, intrauterine inflammation, and spontaneous preterm labor. Elevated IL-17 levels may also disrupt the balance of immune tolerance, leading to increased risk of immune-mediated pregnancy complications [6].

Impact of Maternal Immune Activation on Fetal Development

Maternal immune activation and the resulting cytokine dysregulation can have profound effects on fetal development. Early exposure to elevated levels of inflammatory cytokines such as IL-6, IL-1β, IL-8, and IL-17 has been shown to disrupt key processes in fetal development, including neurodevelopment, immune system development, and organogenesis. In particular, maternal immune activation during pregnancy has been associated with neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Cytokines such as IL-6 and IL-1β can influence neuronal differentiation, synaptogenesis, and brain structure, potentially altering neural circuits and impairing cognitive and behavioral function. Furthermore, maternal inflammation can affect the development of the fetal immune system, increasing the risk of immune dysregulation and susceptibility to infections later in life. In addition to neurodevelopmental effects, maternal immune activation can influence the metabolic programming of the fetus. Altered cytokine levels during pregnancy have been linked to an increased risk of metabolic disorders, including obesity, diabetes, and cardiovascular diseases, in offspring. This phenomenon, known as fetal programming, suggests that inflammatory signals during pregnancy may permanently alter the development of key organs and systems in the fetus, leading to long-term health consequences.

Conclusion

The role of interleukins and inflammatory cytokines in maternal immune activation is critical for the regulation of both immune responses and fetal development during pregnancy. Dysregulation of these cytokines can lead to excessive inflammation, with profound effects on pregnancy outcomes and fetal health. Elevated levels of interleukins such as IL-6, IL-1β, IL-8, and IL-17 have been implicated in a range of pregnancy complications, including preterm birth, fetal growth restriction, and neurodevelopmental disorders in offspring. Understanding the molecular mechanisms underlying maternal immune activation and its impact on fetal development is crucial for identifying new therapeutic strategies to prevent or mitigate adverse pregnancy outcomes. Further research is needed to explore the complex interactions between maternal inflammation, cytokine signaling, and fetal development, with the goal of improving maternal and neonatal health outcomes.