Macrophages are already present in the uterus before pregnancy and play a crucial role in all phases of the menstrual cycle (54). Part of the dMφs are derived from maternal blood monocytes and are recruited to the uterus shortly after conception, which occurs in direct response to semen-derived immune regulatory proteins like MCP-1. Also the embryo itself produces MCP-1 to attract monocytes to the uterus (55). Monocytes migrate towards the syncytiotrophoblast that invades the endometrial stroma during implantation. This migration is guided by trophoblast cells that excrete several signaling molecules (e.g. IL8, MCP1 and MIPα) (56–59). As mentioned in the introduction section, a short pro-inflammatory phase is needed during implantation as this helps trophoblast cells to gain space in the endometrium and prepares the endometrium for implantation of the embryo (57, 58, 60). In response to trophoblast signals, recruited macrophages express pro-inflammatory cytokines like IL6, IL8, TNFα and IFNγ (58). DMφs actively prevent apoptosis of invading trophoblast, for instance by secreting TGFβ which can inhibit NK cells from inducing trophoblast apoptosis, and IL6 and IL10 which can downregulate Fas mediated apoptosis (61, 62). DMφs also secrete G-CSF and IL33, which promote trophoblast proliferation, migration and invasion (63, 64). Conversely, several in vitro studies have shown that pro-inflammatory monocytes can restrict trophoblast invasiveness and increase trophoblast apoptosis (65–68). This suggests that the pro-inflammatory macrophage response needs to be balanced and carefully timed to prevent trophoblast damage.

In mice, it has been clearly demonstrated that macrophages have pro-inflammatory characteristics early in the implantation phase, followed by a mixed pro-inflammatory and immunomodulatory response once trophoblast further invades the uterine stroma and placental development continues (55). In humans, a similar shift in dMφs phenotype can be expected in the first trimester. Indeed, some studies in humans describe both anti- and pro-inflammatory characteristics in first trimester dMφs (69–72). For example, macrophage activation markers like HLA-DR, CD80 and CD86, involved in macrophage T-cell interactions, can be found on first trimester dMφs (69, 70). Others found dMφs displaying immunomodulatory phenotypical markers (CD163, CD206 and CD209) to be capable of secreting both anti- and pro-inflammatory cytokines (71, 72). However, the majority of studies indicate dMφs in humans to be predominantly anti-inflammatory and immunomodulatory. Distinct observations on the phenotype of dMφs are likely due to differences in the specific time point in the first trimester at which the experiments are performed. Studies report expression of anti-inflammatory markers (e.g. CD163, CD206 and CD209) and the secretion of anti-inflammatory cytokines (e.g. IL10, CCL12, CCL17 and CCL18) (69, 72–75). Gene expression profiling studies show that genes related to immunomodulation and tissue remodeling are activated in first trimester dMφs (76). This is further observed when studying the response of dMφs to placental signals. Multiple studies have cultured dMφs with placental explants or with decidua or trophoblast derived cytokines and demonstrate that polarizes dMφs towards a more anti-inflammatory phenotype (73, 74, 77, 78). It was even shown that HLA-G expressed on invading trophoblast can directly bind to leukocyte immunoglobulin-like receptors on dMφs to induce a more anti-inflammatory phenotype in dMφs (79–82).

Besides implantation, dMφs participate in SA remodeling (83). The migration of dMφs towards the SAs relies on crosstalk between trophoblast cells and SA endothelial cells (ECs). Several factors expressed by EVT (e.g. CXCL8 and IL6) stimulate the ECs to secrete CCL14 and CXCL6, causing dMφs to home to the walls of the SAs. At this site, dMφs secrete several cytokines (e.g. IL1β, IL6, IL8, IL10 and IFNγ) that are involved in remodeling of the SAs (84). DMφs cause disruption of the VSMC through the expression of several metalloproteinases (MMP) (85, 86) and induce apoptosis and phagocytosis of VSMCs (87, 88). The apoptotic cell bodies that are released into the maternal circulation during placental development are cleared by dMφs, which is accompanied by the release of anti-inflammatory cytokines (88). Furthermore, dMφs exert angiogenic properties via the production of VEGF and angiogenic growth factor (Ang) 1 and Ang2 (50, 89, 90). Similar to implantation of the embryo, remodeling of SAs seems to require a short inflammatory phase. In the SAs, this is characterized by foamy (lipid filled) macrophages in the intima of the vessel wall that resolve once SA remodeling is complete (90). It is important that this inflammatory response is transient as persistent inflammation can cause acute atherosis, marked by fibrinoid necrosis of the vessel wall, lymphocytic infiltration, and excessive accumulation of foamy macrophages, potentially resulting in MVM (84, 91). Besides alterations in dMφ activation, dysregulation in their numbers can cause defects in placental development. A macrophage surplus can lead to excessive apoptosis of EVT, limiting the invasion of trophoblast in the SAs and causing vessels to be (partly) unremodeled (88, 92). Mouse studies have shown that also reduced macrophage numbers can result in suboptimal implantation, hypocellularity of the decidua and a thickened VSMC layer in decidual maternal blood vessels, indicating impaired decidualization and incomplete remodeling of the uterine vasculature (93, 94).

Next to their role in placental development, first trimester dMφs are involved in maintaining a tolerogenic intrauterine environment. DMφs are located in close proximity to decidual Treg cells and can induce Treg cell expansion through binding of CD80 and CD86 on dMφs to cytotoxic T-lymphocyte antigen 4 (CTLA4) on Treg cells. At the same time, this interaction increases the activity of indoleamine 2,3-dioxygenase (IDO) in dMφs, an enzyme known to induce immune tolerance in various immune cell subsets. In pregnancy, IDO is involved in preventing a harmful maternal T cell response towards the fetus (95). Another mechanism of preventing a maternal inflammatory response is through interaction of programmed death (PD)1 on T cells with its ligand (PDL1) on dMφs leading to downregulation of the IFNγ production by maternal T cells (96).

From the studies on first trimester dMφs we can conclude that their numbers and phenotypical characteristics must be carefully regulated to promote trophoblast viability and invasiveness, processes that are important for implantation of the embryo and remodeling of the SAs. Both implantation and SA remodeling are facilitated by a short inflammatory dMφ response important for trophoblast invasiveness, followed by dMφs that predominantly express immunomodulatory characteristics to further support placental development and maternal-fetal tolerance.

During the second trimester of pregnancy, numbers of dMφs continue to expand to nearly half of the maternal immune cell population at mid-pregnancy (46). Most of these second trimester dMφs are positive for anti-inflammatory, immunoregulatory cell surface markers like CD163, CD206, and CD209 (46, 97). Interestingly, HLA-DR, CD80 and CD86, co-stimulatory molecules for T cell activation, are expressed on second trimester dMφs. These molecules also have the ability to weaken T cell responses by binding to CTLA-4 expressed on decidual T cells, indicating that the expression of co-stimulatory molecules on dMφs might not cause T cell activation in pregnancy (97). Indeed, it was shown that dMφs co-cultured with allogeneic T cells were unable to induce T cell proliferation or activation, and instead caused upregulation of Treg cells (98). One mechanism for promoting Treg cell activity was found to be through the production of cellular retinal dehydrogenase by dMφs that can synthesize retinoic acid, which regulates Treg cells (99). In addition, dMφs suppress cytotoxic NK and T cell activity through TIM3 and Galectin9 expression (46).

Third trimester dMφs are high in CD163 expression and relatively low in CD80, CD86 and HLA-DR (99, 100). In addition, genes encoding for a pro-inflammatory macrophage phenotype are silenced, while genes for a more regulatory, immunotolerant phenotype are activated (101). Similar to the first trimester, the decidua itself is key in promoting the immunoregulatory macrophage phenotype. Upregulation of CD163 and CD209 and downregulation of CD86 has been observed after conditioning monocytes with cell medium from term decidual tissue (102). In mice, pro-inflammatory immune responses can be downregulated by decidua derived progesterone through inhibition of toll like receptor (TLR) 4 and TLR9 triggered release of IL6 and nitric oxide (NO) by dMφs (103). Another mechanism proposed to induce maternal-fetal tolerance is through exposure of maternal macrophages to trophoblast debris. Phagocytosis of trophoblast cells from term human placental explants by maternal blood monocytes resulted in reduced expression of CD80, CD86, CD40, MCP1, and B7-H3 (involved in suppressing T cell activation), increased secretion of cytokines like IL1β, IL12p70 and IL8, and upregulation of IDO (104).

Near birth, the immunoregulatory role of dMφs changes as dMφs participate in the inflammatory response that triggers the spontaneous onset of labor. This is marked by an increased level of inflammatory cytokines like IL1ß, IL8 and IL6 during labor, as well as elevated numbers of dMφs with pro-inflammatory character (105, 106). One study even reported macrophages to increase up to four times in laboring women (107). In rats, it could be demonstrated that macrophages infiltrate the decidua prior to the onset of labor, further suggesting that dMφs directly initiate parturition (107). To summarize, the second and third trimester of pregnancy, before the spontaneous onset of labor, are focused at immunotolerance and the downregulation of potential pro-inflammatory responses, which safeguards maternal-fetal tolerance and improves placental functioning, allowing for optimal fetal growth. At term, dMφs start to display pro-inflammatory characteristics that promote the onset of labor.

In the first trimester, the large majority of HBCs are of the M2a (CD206⁺CD209⁺HLA-DR⁺CD163⁺) and M2c (CD206⁺CD209⁺HLA-DR^-CD163⁺) subtype which are involved in tissue repair and immunoregulation. These cells express arginase (Arg) I and Arg II, enzymes involved in M2 polarization (110, 111). M1 markers like CD80, CD86 or iNOS, an enzyme involved in the M1 polarization pathway, are not expressed (110). Findings on the expression of HLA on first trimester HBCs are conflicting. While the majority of studies report HBCs to be typically low in HLA in the first trimester (111, 115, 118–120), some have found clusters of M1-like or M2a/M2b HBCs that do express the classical HLA-DR (110, 115).

Several alternative subdivisions of HBC types have been suggested. For example, classification into a group with an anti-inflammatory profile (IL11, IL17, TGFβ and VEGF) that formed the vast majority of HBCs, and a pro-inflammatory group that constituted only 5% of the population (IL1β, IL6 and TNFα) (121). Another division based on the expression of CD74 (gamma chain of HLA class II) revealed a CD74⁺ HBC subset that expressed genes encoding for cytokine stimuli, inflammatory responses, antigen presentation and myeloid leukocyte activation. This subset was suggested to be involved in removal of cellular debris during early development of the placenta (122). Another mechanism for the removal of anti-fetal antibodies from the placenta is through the expression of three subtypes of the Fc receptors for IgG (FcγR), FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) on HBCs that can bind antigen-antibody complexes (123). These receptors are furthermore implicated in the transplacental transmission of maternal IgG antibodies into the fetal circulation, providing HBCs with a crucial role in immunological protection of the fetus (8, 123–125). HBCs are furthermore involved in the development of the villi and its vasculature. They are found in abundance within the mesenchymal villous stroma that later develops into immature intermediate villi and are found in close association with fetal capillaries (108, 126, 127). Culturing trophoblast cells with HBC supernatant lead to enhanced trophoblast growth and differentiation (128). HBCs are the primary cells expressing sprouty proteins, important for branching villous and vascular morphogenesis and growth factor signaling (129). Moreover, HBCs produce VEGF and its receptors, and several other factors like fibroblast growth factor 2 (FGF-2) and osteopontin (OPN) that promote placental growth and angiogenesis, and tissue inhibitor metalloproteinase 9 (TIMP-9) and MMP-9 that facilitate trophoblast invasion (111, 130–135). Moreover, HBCs exhibit phagocytic capacities and bactericidal functions by producing reactive oxygen species (ROS) and glucose-6-phosphate dehydrogenase (G6PD) (111, 136).

To conclude, the largest share of the first trimester HBC population is involved in immune regulation and supporting a tolerogenic environment by removing tissue debris and fetal antibodies. In addition, HBCs have an important role in the development of the villous architecture and the fetal vasculature.

During the second and third trimester, HBCs are found in all types of villi where they are located close to the fetal capillaries, although they are rarely seen in terminal villi (109, 115, 137–139). Almost no expression of M1 markers like CD40, CD11b and CD80 has been observed at term, while M2 markers like CD163, CD209, CD206, folate receptor (FR)-β are abundantly expressed (110, 115, 140). Genetic profiling of HBCs confirms this as M1 associated genes are silenced, and M2 related genes are activated (101).

In the third trimester, a notable shift in HBC phenotype is observed, characterized by a decrease in M2a and increase in M2c HBCs, which ultimately form the predominant subset (110, 115). M2c HBCs are engaged in anti-inflammatory reactions, tissue remodeling and immune suppression. M2b cells, mostly absent in the first and second trimester, emerge near term and constitute approximately one third of the HBC population (110, 115). They can be identified by CD86 expression, alongside the secretion of IL6 and TNFα. The M2b subset is stimulated by immune complexes and participates in antibody-mediated immunity (110, 115). Consistent with findings in the first trimester, studies report different results regarding HLA expression on HBCs. Either varying expression of HLA-DR between placentas, lack of HLA-DR expression or presence of HLA on the majority of HBCs have been reported (46, 110, 134, 140–143). One hypothesis proposed to explain these discrepancies is the mode of delivery, wherein placentas obtained after primary cesarean section exhibit lower HLA expression due to a lack of inflammatory responses that mark the onset of parturition (138). Alternatively, the presence of HLA on HBCs could indicate a matured third trimester subset that is capable of antigen presentation to T cells (142). This would be in line with the increase of M2b HBCs in the third trimester (110, 115).

Third trimester HBCs are involved in maintaining a state of immune tolerance. HBCs secrete IDO and IL10, which induce an anti-inflammatory phenotype in maternal immune cell subsets like macrophages and Tregs (73, 144). Mixed lymphocyte reactions show that third trimester HBCs inhibit the activation of lymphocytes, and the proliferation and production of cytotoxic cells (145). Limiting potentially harmful immune responses is also established through the expression of death-inducing TNF superfamily ligands and receptors that are implicated in autocrine programmed cell death, and therefore also involved in placental tissue remodeling processes (146). One study showed that third trimester HBCs might be more biased towards immune tolerance compared to HBCs earlier in pregnancy. It was demonstrated that first and second trimester HBCs could be polarized into M1-like cells with higher levels of inflammatory cytokine secretion (e.g. IL1β, IL12, IL6 and TNFα) using LPS, while HBCs at term kept an M1/M2 balance and did not upregulate M1 markers like CD80, CD86, TLR1 and TLR4 in response to LPS (110, 120). Although this response might be lower in the third trimester, studies consistently demonstrate that LPS stimulation can increase the number of HBCs and induce the secretion of inflammatory cytokines like TNFα, IL10, IL1α, IL1β, IL6 and IL12 (121, 139, 141). Term HBCs express low levels of NOS type II, which can implicate a surveilling function to detect pro-inflammatory events or maternal pathogens by being able to respond with a cytotoxic effect through NO secretion (147). DNA methylation studies of HBCs show enrichment of genes involved in immunological defense, inflammation, acute inflammatory response to stress, regulation of immune cell activation, complement activation, cell adhesion and angiogenesis (101).

Third trimester angiogenetic capacities of HBCs are mainly due to VEGF, which is produced at even higher levels in the third trimester compared to the first. VEGF producing HBCs are located near regions where Ang 1 and 2 is expressed within the mature intermediate and terminal villi (133, 134). Together with VEGF, HBCs secrete FGF2, which enhances endothelial branching and chemoattraction of fetal endothelial cells (115). HBCs furthermore contribute to the regulation of placental blood flow through thromboxane and prostaglandin E2, which are involved in vasoconstriction and vasodilatation respectively (148). HBC derived IL17 is likely involved in the upregulation of these angiogenic factors (149).

Taken together, second and third trimester HBCs have similar functionalities compared to the first trimester. From the aforementioned studies we can conclude that a more mature subset of HBCs emerges as pregnancy progresses, which is involved in immunosurveillance and downregulation of potential pro-inflammatory responses. HBCs furthermore continue to participate in the development of the placental vascularity throughout the second and third trimester.

Previously, we investigated decidual immune cell subsets in term pregnancies affected by FGR and showed a 50% increase in CD68⁺ dMφ numbers in FGR compared to healthy pregnancies, accompanied by decrease of the CD206⁺/CD68⁺ dMφ ratio, suggesting a reduction of anti-inflammatory dMφs in FGR (24). The majority of FGR placentas in our cohort showed signs of VUE and a combination of multiple placental lesions (MVM, FMV and VUE) (24). Contrary to our results, another study showed no differences for dMφ numbers, defined as CD14⁺, between FGR and healthy pregnancies at term. There was no assessment of placental pathology (154). Other studies do confirm our observations. Higher numbers of CD68⁺ dMφ with increased HLA-DR staining were detected in the extravillous areas of term placentas. FGR cases with chronic villitis and VUE were excluded in this cohort (155). Another study showed elevated numbers of CD68⁺ and CD163⁺ macrophages in the intervillous space of FGR pregnancies, likely to be maternal macrophages that migrated there. Placentas showed signs of immaturity of the chorionic villi with sclerosis, intervillous fibrinoid deposition and calcification, resulting in afunctional villous areas. In addition, preterm FGR cases (born before 37 weeks) showed impaired vascularization and villous hypoplasia (156). Another study comparing gene expression between term FGR and control placentas showed more expression of genes for total macrophages and M1-like macrophages in FGR cases, which correlated with NEURL1 and ODF3B gene expression, both involved in immune cell proliferation, activation and inflammation (157).

One study investigated both second and third trimester dMφs in FGR pregnancies. In the second trimester, an increased number of CD68⁺ macrophages was detected in the microlymphatic vessels between decidual cells, in contrast to healthy pregnancies where macrophages are found in the decidual stroma or transforming vessels. This finding was associated with impaired SA remodeling. In third trimester FGR placentas, CD68⁺ macrophages were identified in leukocyte clusters close to apoptotic EVTs. There was a lack of EVT invasion in the SA, along with thickened VSMC layer and intact endothelium, suggesting that a macrophage excess was involved in trophoblast cell death and subsequent impaired SA remodeling (28).

Furthermore, it appears that macrophages from FGR pregnancies have impaired angiogenic capacities. Maternal monocytes differentiated into M2-like macrophages that were cultured with placental mesenchymal stromal cells from FGR pregnancies showed inhibited tube formation in in vitro assays, suggesting that macrophages from FGR pregnancies can cause impaired remodeling of the uterine vasculature (158). Although limited, the existing literature points towards an increase in macrophages of a more inflammatory character in FGR, which may have detrimental effects on implantation and the development of the placental vasculature.

One study found CD68⁺ HBCs to be increased in FGR cases compared to healthy pregnancies, while HBCs positive for CD206 were reduced. Placentas with VUE were excluded and no other placental pathology data was available (155). On the contrary, also lower numbers of CD68⁺ and CD163⁺ HBCs have been found in the terminal villi of term and preterm FGR compared to healthy controls. The FGR placentas showed signs of villous immaturity and afunctional villous areas (159). This decrease in CD68⁺ HBCs has also been reported by another study. However, when A1 antichymotrypsine was used as a marker for HBCs, more HBCs were found in FGR (160). The authors suggest that A1 antichymotrypsine, a protein involved in the inhibition of natural killing and antibody-dependent cell-mediated cytotoxicity, is more specific for HBCs than CD68, which could explain the different results. They proposed that the increase in HBCs could be a compensatory mechanism to prevent a maternal immune response towards fetal alloantigens. The placental morphology and histopathology was not assessed in this study (160). The limited availability of studies and the use of different markers makes it difficult to draw conclusions on the role of HBCs in FGR.

Different mouse models have been used to mimic FGR and investigate placental immune cell subsets. However, it must be considered that placentation in mice varies from placentation in humans. Mice placentas have a distinct trophoblast cell type that is less invasive compared to humans, and the placental labyrinth structure differs from the more open intervillous space in human placentas (161). Two mouse models, one based on the deficiency of FcR-γ and another one on complement factor C5a receptor deficiency, exhibit high rates of spontaneous pregnancy loss and severe FGR in the surviving fetuses, alongside morphological signs of impaired placental vascularization. There was an increased infiltration of monocytes and neutrophils, along with a functional deficiency of VEGF (162). Another mouse model based on PBX1-deficient decidual NK cells resulted in unexplained recurrent pregnancy loss and FGR. The placentas of these mice showed higher infiltration of dMφs and neutrophils compared to the wild type at mid gestation. No differences in placental morphology was found between FGR and control pregnancies (163). Also mice undergoing BCG-trained immunity show a higher incidence of FGR, but contrary to other studies, show decreased placental macrophages in the second week of pregnancy (similar to second trimester in humans) compared to controls. However, these macrophages did show a tendency towards a more inflammatory profile. The authors hypothesize that a lack of macrophages causes placental developmental defects, such as impaired EVT infiltration and reduced SA remodeling, causing FGR. Unfortunately, this hypothesis was not substantiated with placental morphology assessment at mid pregnancy. At term, no differences in placental morphology were found for FGR pregnancies and numbers of placental macrophages did not differ from control mice (159). Another way to induce FGR in mice is the administration of uric acid, which was found to induce placental inflammation and an increase of CD68⁺ macrophages in the junctional and labyrinth zone. No changes in placental gross histopathology were seen (164). Imbred mice mating models also demonstrate FGR, with a 1.8-fold increase in F4/80⁺ macrophages, localized in the labyrinth and chorionic plate. At term, the macrophage number increased up to 11-fold. The placentas from FGR pregnancies were smaller, displayed signs of thrombosis and fibrosis and a reduced size of the placental labyrinth (165). Inflammation in mice has furthermore shown to impact fetal growth and placental macrophage levels in subsequent generations. First degree offspring of LPS treated female mice showed higher FGR rates compared to controls. Interestingly, their offspring (second generation) showed impaired fetal growth as well, together with higher levels of CD68⁺ macrophages and lower levels of CD163⁺ macrophages in the mesometrial triangle, junctional zone and labyrinth. Deficient trophoblast invasion and narrower SAs were observed and Doppler measurements confirmed inadequate SA perfusion (166). Another study used a mouse model based on maternal KIR2DL1 expression on NK cells and paternal HLA-C*050 expression on fetal trophoblast cells that lead to FGR with impaired remodeling of the SA and high resistance placental blood flow. FGR placentas were enriched in genes for macrophage recruitment and macrophages showed higher expression of genes involved in macrophage invasion under hypoxic conditions, dendritic cell maturation, antigen presentation and inflammation (167). To summarize, these mouse models reveal that FGR placentas can be characterized by elevated numbers of placental macrophages skewed towards a pro-inflammatory phenotype. These immunological alterations likely contribute to the observed disturbances in placental development and functioning.

Direct modulation of macrophage phenotype and functionality has not been investigated in the context of pregnancy complications. Potential strategies could be targeted at macrophage polarization, cytokine and chemokine secretion, or signaling pathways by which macrophages interact with other immune cells. Naturally, these macrophage modulators must be safe to use in pregnancy. Several studies have demonstrated that culturing macrophages with medium derived from placental tissue can induce favorable M2-like characteristics in placental macrophages (58, 73, 102). Therefore, investigating the specific placental mediators at play could be promising in finding potential macrophage regulatory therapies. For example, vitamin D is produced by the placenta and can affect macrophage polarization by binding to intracellular vitamin D receptors (VDR) present in macrophages (180). Within the placenta, it stimulates the interaction between placental macrophages and Treg cells and skews the balance towards a Th2 milieu (181). Vitamin D supplementation reduces IL1, IL6 and IL12 secretion by macrophages and downregulates TLR2 and TLR4 expression, while it enhances phagocytotic capacities (180). Similar results have been found for medroxyprogesterone, which could polarize monocytes into an M2 phenotype with downregulation of CD11c, IL1β and TNFα and upregulation of CD163 and IL10. Moreover, medroxyprogesterone could reverse M1 polarization and promoted decidualization and trophoblast invasion (182). For VEGF derived from decidual stromal cells, it has been established that it can upregulate M2 markers like CD206, CD163 and CCL17, and can reverse M1 polarization. It furthermore enhances macrophage migration (74). Another example is IL6 secreted by trophoblast, which activates the STAT-3 pathway and increases CD206, CCL18, IL10 and TGFβ in macrophages. Furthermore, these IL6 activated macrophages promoted trophoblast invasion and migration (77). Also hyaluronan can activate STAT-3 and -6 by binding to CD44 on dMφs. This downregulates M1-like receptors like CD80 and CD86, and upregulates CD163 and CD206 (78). In mice, human chorionic gonadotropin (hCG) administration has been shown to reduce the number of dMφs and induce M2 polarization (183).

A drug that could potentially downregulate the maternal inflammatory response in FGR is hydroxychloroquine, an antimalarial drug by origin. In pregnant women, hydroxychloroquine has been shown to ameliorate autoimmune diseases like systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), and it has been associated with lower PE and preterm birth rates, and an increased birth weight (184). Its immune modulatory effects include decreasing the production of prostaglandins and pro-inflammatory cytokines like TNFα, IFNγ and IL6, inhibiting MMPs and blocking TRL signaling pathways (185, 186). Furthermore, it impairs antigen processing in antigen presenting cells and reduces T cell activation (177). Hydroxychloroquine can have a direct anti-inflammatory effect on first trimester trophoblast tissue in pregnant women with APS and excessive placental inflammation and insufficiency (187). Another agent to might have favorable effects in FGR is curcumin. It has been established that it can promote trophoblast growth, and reduce oxidative stress and the secretion of pro-inflammatory cytokines (e.g. IL6, IL8) in the placental villi and fetal membranes (188, 189). In rats, it has been shown to improve defects in trophoblast invasion and SA remodeling, along with a decrease in NFkβ, IL6 and MCP1 (190). In a rat PE model, curcumin combined with aspirin resulted in a reduction in placental oxidative stress, with decreased sFlt-1 and pro-inflammatory cytokines, and increased PlGF expression (191). Although not investigated in FGR specifically, its mechanism of action might improve placental function in FGR as well.

Prior to exploring therapies that directly affect macrophages, acquiring a deeper understanding of the pathways through which dMφs and HBCs affect placental functioning in FGR and other immune-mediated pregnancy complications is crucial. Moreover, the use of potential macrophage modulating therapies requires adequate diagnostic tools to determine the pathophysiological mechanism in individual FGR cases and personalize the therapeutic approach accordingly.