Pregnancy is often viewed as a semi-allograft situation because the fetus carries paternal antigens, which can create an immunological imbalance that contributes to complications during pregnancy [1]. In this context, the fetus triggers a secondary protective immune response. The mismatch between the mother's immune system and the fetal antigens can lead to various pregnancy-related challenges and even failure [2]. A pregnancy that succeeds is a consequence of appropriate embryo implantation, optimal decidualization, and placentation [3]. Each phase involves numerous molecular and physiological processes essential for attaining the balance crucial for pregnancy progression.

The signal transducer and activator of transcription (STAT) protein family comprises essential intracellular transcription factors that play a crucial role in various cellular processes [4]. STAT proteins are structured with an amino-terminal domain, a coiled-coil domain, a DNA-binding domain, an SH2 domain, and a carboxy-terminal transactivation domain [5]. STATs promote the swift activation of target genes in response to external stimuli like cytokines, interferons, growth factors, and other signals, directing this process through intracellular Janus kinases [6]. After the interaction and activation of a ligand with its receptor, Janus kinases phosphorylate tyrosine residues in the receptor's catalytic domain. This process results in the recruitment and phosphorylation of STAT proteins, which then form either homo- or heterodimers. These dimers translocate to the nucleus to regulate gene transcription [7]. STAT proteins play remarkable functions in affecting immune responses through their key involvement in cytokine signaling, affecting both innate and adaptive immune cell subsets. Therefore, due to the role of these molecules in regulating the immune system, the presence of STAT proteins is observed during key stages of pregnancy, including migration, implantation, decidualization, and placentation. For example, interferon tau (IFNτ, IFNT) is a type I interferon that has been found only in ruminants; however, human cells can also be affected by it [8]. IFNT binds to IFN-α receptors, which increases the phosphorylation of STAT1 and STAT2. This process regulates the expression of IRF-1 and the production of antiviral cytokines [9]. As a result, it can induce the production of anti-inflammatory factors and modulate the immune system in the mother's uterus. Research has shown that STAT1 regulates trophoblast differentiation, while STAT2 is involved in placental growth [10], [11], [12]. Both STAT1 and STAT2 play essential roles in the expression of genes that prevent maternal immune rejection and help modulate pregnancy. A healthy pregnancy seems to require a well-balanced immune response regulated by pregnancy hormones. Th17 cells play a role in regulating trophoblast proliferation and invasion by producing IL-17 through the activation of STAT3 and NF-κB pathways [13].

Different STAT molecules have distinct roles in regulating the expression of pregnancy-related genes. Activation of SRC kinase and phosphorylation of STAT5 are crucial for the decidual transformation of human endometrial stromal cells [14]. Additionally, the elevated expression of STAT5A in first-trimester villi regulates fetal DNA epigenetic mechanisms during development [15]. STAT5 subtype is crucial for uterine receptivity and decidualization, which are vital for successful implantation. Epigenetic patterns can affect the pregnancy process through different pathways involving STAT. Changes in STAT4 expression and promoter methylation significantly affect follicular development. By modulating kisspeptin-1 (KISS1) expression, alterations in STAT4 transcription increase granulosa cell (GC) apoptosis [16]. Finally, STAT6 regulates inflammatory cytokines during pregnancy, affecting Th2 immune responses and anti-inflammatory cytokines like IL-10 and IL-4 [17].

The various STAT subtypes work together to regulate a complex network of signaling pathways that are essential for a successful pregnancy, from implantation to labor. Maintaining a balanced expression of these subtypes is crucial for the health of both the mother and the developing fetus. However, there are increasing reports of abnormal STAT signaling and dysregulation of these proteins during pregnancy, which can lead to a range of pregnancy-related disorders. Gaining a better understanding of the functions of these molecules could provide valuable insights into pregnancy complications and potentially lead to therapeutic interventions. In this review, we first examine the regulatory functions of STATs across cells and the various factors that contribute to pregnancy maintenance or loss; then discuss the complications arising from dysregulated STAT signaling; and finally discuss therapies targeting STAT signaling pathways.