The reviewed literature consistently indicates that SPMs, particularly LXA4 and its receptor FPR2/ALX, generally show an increase during normal pregnancy, compared with non-pregnant women. Nevertheless, their expression patterns exhibit some variability [17,18,19,20,21,22,23,24,25]. FPR2 expression in the human endometrium peaks during the menstrual and late secretory phases, the latter corresponding to the post-implantation period, but significantly declines during the proliferative and early secretory phases. Additionally, LXA4 levels were found to progressively increase throughout pregnancy, without a marked rise either before or after labor [26]. In fact, myometrial LXA4 levels show no significant differences between laboring and non-laboring women, despite increased FPR2 expression in labor [26]. Another study found elevated LXA4 levels at the onset of labor and a negative correlation with neutrophil presence in the tissue, suggesting its role in modulating inflammation during childbirth [19]. Notably, machine learning approaches highlight the predictive potential of SPM measurements for preterm birth. RvD1 has emerged as a strong predictor of spontaneous preterm birth, whereas preterm births associated with placental abnormalities have been associated to elevated levels of pro-inflammatory leukotrienes. Among eicosanoids, LOX and CYP450 metabolites showed the greatest accuracy in identifying overall and spontaneous preterm birth [27]. These findings reveal inconsistencies when comparing laboring and non-laboring women, suggesting that SPM regulation is dynamic throughout pregnancy, though their exact roles in labor remain uncertain. A potential explanation for these differences lies in the variable biological stress of labor, which triggers adrenaline release. This adrenaline response may drive an increased demand for SPMs to mitigate excessive inflammation during labor.

FPR2/ALX expression is highest early in pregnancy and declines as gestation progresses [28]. RvD1 tends to show a modest increase from the second trimester to the third and during labor [29,30,31]; however, there are discrepancies between studies. Higher RvD1 levels are noted in term deliveries compared to preterm births in both humans and animal models [29]. Increased 12-LOX and 15-LOX, but not 5-LOX, was associated with the increase of LXA4 in active labor [19]. MaR1 shows a slight decline throughout pregnancy [32], whereas not enough information was found regarding other SPMs in order to draw significant conclusions.

A major challenge in the current literature is the lack of standardization across studies, leading to inconsistencies in results. Variations in measurement units, detection methods, and sample sources further complicate comparisons. Blood samples are often used because of their accessibility, but they may not accurately reflect local placental conditions. Despite these limitations, an illustrative graph built upon standardized data collected from blood serum levels of LXA4 and RvD1 (Fig. 2A), showing a marked elevation in LXA4 levels from the first to second trimester and a physiological decrease between the second and third trimesters for both LXA4 and RvD1. Nonetheless, all studies unequivocally show a need for LXA4 and RvD1 production as pregnancy progresses.

SPM levels during pregnancy and pathological conditions. A Physiological trend of LXA4 and RvD1 levels across the three pregnancy trimestres. Data points represent mean concentrations in nM for each study. Distinct trends are observed for both mediators. B Mean differences in LXA4 levels (nM) compared to controls in their respetive studies, for pregnancies complicated by preeclampsia (PE) and fetal growth restriction (FGR). C Mean differences in RvD1 levels (nM) compared to controls for PE and FGR. Positive and negative differences are highlighted in the green and red areas, respectively

Pregnancy can be affected by complications such as PE, preterm labor, fetal growth restriction and spontaneous abortion. These conditions often involve disruptions in immune regulation, exacerbated inflammation, and impaired placental development. The involvement of dysregulated SPM levels in these pregnancy complications has been observed in numerous studies detailed in Table 1, which focuses exclusively on blood serum quantifications of LXA4 and RvD1, the most prominent SPMs studied in this field.

Spontaneous abortion, also known as miscarriage, refers to the unintended loss of a pregnancy before the 20 th week and can occur due to a range of causes, including genetic abnormalities, hormonal imbalances, immune dysfunction, or issues related with the uterine environment. The mechanisms behind spontaneous abortion remain complex and not fully understood. Research suggests that factors such as dysregulated inflammation and improper implantation and placental development may contribute to its occurrence.

Recent studies have associated spontaneous abortion with elevated expression of FPR2 in villous cytotrophoblasts [33] and increased levels of LOX enzymes in endometrial samples from cases of spontaneous abortion [34]. Additionally, both LXA4 and RvD1 were found to significantly inhibit endometrial stromal decidualization in cultured human cells, via the downregulation of canonical decidualization markers IGFBP-1 and PRL [34]. These findings suggest that irregular inflammatory environments, which disrupt decidualization, may contribute to pregnancy failure. However, the role of LXA4 extends beyond this, as it has also been linked to trophoblast properties and placentation processes. In an in vitro study, LXA4 was found to upregulate epithelial markers while downregulating mesenchymal markers such as vimentin and fibronectin, thereby promoting increased trophoblast invasiveness [35].This suggests that LXA4 may inhibit EMT in first-trimester EVTs by reducing E-cadherin and β-catenin expression, potentially exerting anti-nidation effects.

Animal studies further confirm the involvement of SPMs, such as LXA4, in pregnancy. A study by Xu et al. demonstrated that administration of LXA4 during the peri-implantation period in mice led to anti-nidation effects, ultimately preventing successful implantation and pregnancy [35]. In contrast, administering LXA4 after implantation improved birth rates by reducing miscarriages [35]. Another study found that LXA4 administration led to complete inhibition of implantation [36]. In an LPS-induced miscarriage model, RvD1 significantly reduced the stillbirth rate from 64 to 32% [37]. Additionally, mouse studies have linked LXA4 to downregulation of caspase-1 expression and activity, a key inflammasome component, in the placenta, and the reduction in caspase-1 activity was also associated with decreased trophoblast apoptosis [38]. Similar results were observed with DHA, which inhibited caspase-1 and cathepsin-S, reducing preterm birth rates and suggesting a role for resolvins in these processes [29].

A compelling interaction between glucocorticoids and SPMs, particularly LXA4, in miscarriage has been observed. In mouse models, co-treatment with dexamethasone and LXA4 or its analogs effectively reversed many of the adverse effects of dexamethasone alone. This included restoration of maternal and fetal weights, increased placental capillary volume and blood space size, and reduced placental apoptosis, thereby alleviating growth restriction [39]. Remarkably, LXA4 administration also decreased lipid peroxidation, even in untreated control mice, underscoring its antioxidative potential. Dexamethasone appears to negatively regulate LXA4 production by activating 5-LOX, increasing leukotriene synthesis, and suppressing 15-LOX expression. These changes significantly inhibit LXA4 production, exacerbating inflammation. However, LXA4 supplementation counteracts these effects, reducing inflammatory markers and restoring homeostasis [13, 39]. LXA4 also plays a pivotal role in cortisol regulation by upregulating 11β-HSD2, an enzyme responsible for cortisol inactivation. This effect has been observed in trophoblast cells in both human and mouse models [40, 41]. By mitigating excessive cortisol levels, LXA4 may help protect against glucocorticoid-induced complications during pregnancy. However, evidence suggests a complex interplay where LXA4 and glucocorticoids may mutually downregulate each other, a dynamic that warrants further investigation to better understand and optimize therapeutic applications.

Fetal growth restriction (FGR) is a critical healthcare challenge and a leading cause of late-pregnancy stillbirth, contributing significantly to neonatal mortality, prematurity, and long-term morbidity. In FGR cases, the placenta is often smaller and underdeveloped, showing marked morphological and functional abnormalities, including impaired trophoblast proliferation, increased apoptosis, and disrupted villous architecture with reduced branching of terminal villi. These placental deficiencies underscore improper placentation as a primary driver of FGR [42]. As such, of FGR as a strong predictor of perinatal death before 34 weeks [43].The impact of FGR extends beyond the neonatal period, as the offspring faces a heightened risk of cardiovascular, renal, and metabolic diseases, specifically hypertension and diabetes [44].

Reduced levels of LXA4 in the first trimester have been detected in women who later experienced either restricted or excessive fetal growth, suggesting a critical role for LXA4 in the regulation of fetal weight outcomes [45]. LXA4 was found to reverse the downregulation of cadherins, catenins, and cellular calcium levels in human umbilical vein endothelial cells (HUVECs), effectively preventing endothelial hyperpermeability. This effect was confirmed to be mediated through FPR2, as it was abolished by an FPR2 antagonist [46]. In trophoblast cell lines, silencing FPR2 significantly diminishes migratory and invasive potential. Downstream target genes such as STAT5B, SOCS3, and cadherins were identified as key mediators of FPR2’s role in trophoblast invasion and EMT [47]. However, conflicting results have emerged. For instance, one study reported that FPR2 suppression in trophoblast cells reduced apoptosis, activated the PI3 K/AKT pathway and impaired migration rates; however, it improved endothelial capillary-forming functions [33]. Another study found that FPR2 suppression increased endothelial permeability and reduced their tube formation [28]. In a first-trimester trophoblast model, LXA4 was shown to promote their migration [48]. This suggests that the effects of LXA4 and FPR2 signaling on trophoblasts and their interplay with endothelial cells may depend on yet unexplored context-specific factors (Fig. 2B).

Other SPMs are also implicated in FGR, specifically RvD1 (Fig. 2C). A recent study reported lower levels of RvD1 throughout pregnancy in women who later developed FGR. Mid-to-late pregnancy RvD1 levels demonstrated moderate predictive accuracy for FGR risk, particularly in older pregnant women, where advanced maternal age itself is a known risk factor [30]. In addition to SPM levels, research has highlighted a connection FPR2 signaling and negative pregnancy outcomes. For example, reduced FPR2 expression in the chorion has been observed in pregnancies involving small-for-gestational-age infants [47]. Conversely, upregulated FPR2 expression coupled with significantly lower levels of RvD1 has been associated with chorioamnionitis, a recognized cause of FGR [37]. FPR2 expression patterns are temporally regulated throughout pregnancy. In a mouse model, FPR2 mRNA levels are higher during the first trimester compared to term samples, with a marked decline as gestation progresses. Silencing FPR2 resulted in increased trophoblast proliferation, indicated by elevated choriogonadotropin expression. An apoptosis array revealed that FPR2 enhances the expression of apoptotic-related p53, caspase-8, and Bax, while anti-apoptotic Bcl2 levels remained unchanged. Additionally, silencing FPR2 in HUVECs reduced proliferation and impaired network formation, indicative of increased vascular permeability [28].

Taken together, the current evidence underscores the pivotal role of FPR2 in maintaining trophoblast and endothelial function in the placenta. Deregulated FPR2 expression and disruptions in SPM production, particularly LXA4, are likely to contribute to impaired placentation and FGR. As seen in spontaneous miscarriage, SPMs appear to have a dual and temporally regulated role in FGR. While conflicting findings exist regarding the beneficial or detrimental effects of increased SPMs, a physiological rise in SPMs post-implantation is essential to preserve endothelial integrity and support trophoblast proliferation. These complexities highlight the need for further investigation to clarify the precise mechanisms underlying FPR2 and SPM-mediated placental function.

Preeclampsia (PE) is a pregnancy disorder characterized by new-onset hypertension occurring after 20 weeks of gestation. PE affects 2–7% of all pregnancies [17] and remains a leading cause of maternal and fetal morbidity and mortality [49]. PE is often associated with an increased risk of conditions such as diabetes mellitus and metabolic syndrome later in life. The condition is driven by key pathological processes, including endothelial dysfunction, placental insufficiency, inflammation, oxidative stress, and heightened immune responses. Severe cases of PE can result in organ damage, particularly renal and vascular dysfunction, where inflammatory and angiogenic factors contribute to glomerular endotheliosis, a life-threatening complication [50].

Altered inflammation of maternal–fetal interface is a critical factor in the pathophysiology of PE with markedly elevated levels of pro-inflammatory factors and a shift from M2 macrophage phenotype to M1 phenotype in PE placentas [51, 52]. Given the inflammatory basis of PE, the role of SPMs in this disorder is unsurprising. Elevated levels of LXA4 have been reported in PE patients compared to gestation-matched controls (Fig. 2B), suggesting a compensatory response to excessive inflammation [17, 20, 22, 32]. A reduced LXA4/TNFα and LXA4/IL-1β ratio in PE patients suggests insufficient anti-inflammatory effects, likely due to exacerbated, chronic inflammation in these women [17]. However, other studies have reported decreased LXA4 levels in both serum and placental tissues of PE patients, with reduced expression of LOX enzymes, indicating impaired SPM production in PE [40, 41].

Findings regarding resolvins in PE are also contradictory. A 2020 study reported lower RvD1 levels in PE, accompanied by a reduced resolvin/leukotriene ratio, indicating a pro-inflammatory shift [32]. In contrast, another study found elevated plasma levels of RvD1 during early gestation (12–19 weeks), which decreased at later stages (30–34 weeks) in women who developed PE, compared to those who remained normotensive [53]. Elevated early gestational RvD1 levels were also observed in women who later developed preterm PE [31] (Fig. 2C). Furthermore, higher resolvin levels have been documented in PE patients with metabolic syndrome, characterized by hypertension, hyperglycemia, dyslipidemia, and abdominal obesity [49]. Although maresins are less studied in PE, reduced median levels in PE patients suggest impaired inflammation resolution [54].

SPMs mitigate inflammation by modulating key signaling pathways, including NF-κB pathway. Blocking LXA4 signaling in a PE mouse model exacerbated the symptoms, increasing blood pressure, proteinuria, and FGR [41]. Moreover, FPR2 negatively correlates with NF-κB expression, reinforcing its role in dampening inflammation [20], as further supported by another study [55]. In addition, a strong correlation between RvD1 levels and blood pressure in PE has been observed, indicating a role for SPMs in vascular regulation [49]. The detection of eicosanoid levels in a study allowed researchers to distinguish between PE patients with term and preterm births, with increased RvD1 levels seen in patients later diagnosed with preterm PE [31]. Lipid peroxidation markers, such as thiobarbituric acid reactive substance and 8-isoprostane, were significantly elevated in PE plasma, exacerbating endothelial inflammation. Treatment with LXA4 in PE plasma-conditioned HUVECs reduced PMN adhesion by up to 91%, demonstrating potent anti-inflammatory effects [18]. Currently, the only definitive treatment for PE is induced delivery, highlighting the urgent need for alternative therapies. The anti-inflammatory and vascular regulatory properties of SPMs position them as promising candidates for therapeutic exploration, warranting further investigation in clinical trials.

Overall, SPMs are potentially involved in several processes during early and late pregnancy, modulating stromal decidualization, trophoblast migration and proliferation, immune modulation as well as their contribution to placental development and vascular remodeling during the placentation phase. A dysregulation in SPM production can contribute to poor placentation, growth restriction or even spontaneous abortion (Fig. 3).

Specialized Pro-resolving Mediators (SPMs) in the implantation and placentation phases of pregnancy. In the implantation phase, SPMs downregulate stromal decidualization markers (IGFBP-1, PRL), migration and proliferation factors (MMP9, HCG, pPI3 K/pAKT), and epithelial-mesenchymal transition (EMT), while increasing markers such as E-cadherin, β-catenin, vimentin, fibronectin, and VEGF. During placentation, SPMs promote macrophage activation and recruitment, support the M2 phenotype by increasing IL-10 production, and inhibit the NF-κB pathway. Furthermore, SPMs enhance capillary formation and mitigate adverse processes such as caspase-1 activation, trophoblast apoptosis, lipid peroxidation, endothelial hyperpermeability, and endothelial-polymorphonuclear cell (PMN) adhesion. Red arrows indicate downregulation while green arrows indicate upregulation. The figure label represents the cell types involved, including endometrial stromal cells (ESCs), human umbilical vein endothelial cells (HUVECs), trophoblasts, macrophages, and PMNs