Decidual macrophages are maternal cells and protect human pregnancy throughout gestation by inhibiting the immune response by decidual NK, T lymphocytes, and other circulatory macrophages [6]. Thanks to their additional production of matrix metalloproteinases 9 and vascular endothelial growth factor, decidual macrophages are believed to play a role in the spiral artery remodeling [12]. Despite this role in spiral artery modification, the association between abnormal number or function of decidual macrophages and preeclampsia is controversial [7].

Placental macrophages, also called “Hofbauer cells,” are CD68⁺ fetal cells early detectable in pregnancy in the villous stroma. Since Hofbauer cells appear in the placental villi prior to the appearance of the fetal circulation, they may originate in the early stage of pregnancy from progenitor cells within the population of mesenchymal cells in the villous stroma; then, later in pregnancy, they may originate from penetration of embryonic bone marrow-derived monocytes into the villous stroma [3]. Generally, macrophages intervene in phagocytosis of apoptotic bodies and cellular debris as well as antigen presentation in response to inflammation and infectious insults; the specific role of placental macrophages has not been fully understood yet [13]. Their close contact with endothelial progenitor cells and primitive vessels suggests that Hofbauer cells intervene in early placental vascular genesis [14]. Moreover, the identification of proteins regulating branching morphogenesis localized to Hofbauer cells permits to hypothesize a role of placental macrophages in the development of the placental villous tree [15]. Alterations in the number and aspect of Hofbauer cells may be associated with complications of pregnancy such as fetal immune or nonimmune hydrops and fetal metabolic storage diseases such as GM1 gangliosidosis, glucuronidase deficiency, and type VII mucopolysaccharidosis [13]. Histological features of elevated concentration of Hofbauer cells have been related to adverse pregnancy outcome in association with villitis of unknown etiology or acute chorioamnionitis (see below) [13].

T regulatory cells (Treg) are a subset of T lymphocytes that act as strong suppressors of inflammatory immune response with a fundamental role in preventing destructive immune response and auto-inflammatory and autoimmune disease, warranting peripheral self-tolerance and immune homeostasis [20, 21]. Treg cells levels are high in maternal blood during the first and second trimesters of pregnancy and decline prior to delivery and postpartum [20]. Moreover, Treg cells physiologically accumulate in the maternal decidua. A deficiency in Treg cells number has been associated with recurrent miscarriage and preeclampsia [20]. Indeed, it is of interest to underline that there are two developmental pathways of Tregs: thymic (tTreg) and extrathymic or peripheral (pTreg). tTregs appear to suppress autoimmunity, whereas pTregs operate to downregulate responses to antigens, such as those from ingested food, symbiotic bacteria, and allergens. Genomic analysis allowed to hypothesize that pTregs emerged in eutherian (placental) mammals to protect from maternal–fetal conflict. As a matter of fact, conserved noncoding sequence 1 (CNS1), which is required for pTreg development, has been detected present in all placental mammals, whereas it is absent in non-placental mammals such as the wallaby, opossum, and platypus, as it is expected to be absent in non-mammals such as zebra fish. pTregs specifically sort out paternal antigens in the trophoblastic cells and suppress effector T cells in an active process to induce tolerance [22]. Figure 4.2 shows the quasi-perfect correspondence between wild-type pregnant mice and knocked-out ones as regards embryonic reabsorption and number of females that presents reabsorbed embryos [23].

These processes could develop into acute chorioamnionitis. In these cases, most of infecting agents originate in the cervicovaginal tract and gain access to the uterine cavity breaching the normal cervical barrier. Maternal neutrophils infiltrate the chorionic plate and membranous chorioamnion (Fig. 4.3) [27]. Normally, neutrophils are a population of inflammatory cells that do not infiltrate placental compartments. When an infective insult occurs, neutrophils can invade placental structures; they can derive both from the intervillous space and the venules of decidua capsularis. In case of acute chorioamnionitis, a maternal and/or a fetal inflammatory response should be distinguished. The stage (progression of the disease) and the grade (intensity of the disease) of the inflammatory response are summarized in Table 4.2. Acute chorioamnionitis has been associated with adverse pregnancy and neonatal outcome, in relation to prematurity due to preterm delivery and/or preterm premature rupture of the membrane [29]. Fetal inflammatory response is the main factor that affected fetal–neonatal well-being; fetal inflammatory response involves chorionic plate vessels and/or umbilical vein prior to the involving of umbilical arteries. The association between fetal inflammatory response and adverse neonatal condition and outcome takes place especially when umbilical arteries are involved. Neonatal sepsis could be a consequence of fetal inflammatory response but also neurological impairment may develop including cerebral palsy [30].