PE affects about 3% of all pregnancies and belongs to a group of diseases generically known as hypertensive disorders of pregnancy, together with chronic hypertension, gestational hypertension and chronic hypertension with superimposed PE (JA et al., 2011). High blood pressure is the main symptom of PE, but other symptons are frequent in this disease, such as proteinuria, edema, multiorgan failure, FGR and HELLP (Hemolysis, elevated liver enzymes, and low platelet count) syndrome and eclampsia. It has a fact that PE predisposes both the mother and the fetus to suffer cardiovascular diseases and other complications after birth (Jurewicz, 2018; Wallace et al., 2018). Clinically, the diagnosis of PE is established from a systolic and diastolic blood pressure ≥140 mm Hg and ≥90 mm Hg, respectively, measured at least two times 4 h apart; higher values (≥160 mm Hg and ≥110 mm Hg, respectively) are frequent (Karrar and Hong, 2022). PE has been classified into mild or severe PE, although it is widely accepted that PE symptons can get worse very rapidly, posing a severe health problem for both the fetus and the mother (Tranquilli, 2013). However, it is common to distinguish between early onset PE (EO-PE) and late onset PE (LO-PE) depending on whether the appearance of the first symptoms takes place before or after the 34th week of gestation (Redman, 2017). The etiopathogenesis of EO-PE is unknown, although the most widely accepted hypothesis considers it consequence of a failure in the placentation process associated with defective spiral artery remodeling and trophoblast invasion. This leads to a persistent hypoxia/ischemia state in the placental tissue and to an imbalance in the angiogenic process which eventually leads to abnormal trophoblast behavior, oxidative stress, vascular inflammation and endocrine alterations. Eventually, systemic endothelial injury may lead to multiorgan failure and systemic complications (Ortega et al., 2022b). LO-PE is more likely bound to maternal extrinsic factors and, although placental damage also exists, the pathophysiological signatures, the impact of PE for both the fetus and mother, clinical features and serum markers are significantly different (Raymond and Peterson, 2011).

The only definite cure for PE is delivery, although low-dose aspirin (LDA) can be used as a prophylactic measure for patients at high risk (Bujold et al., 2010; Rolnik et al., 2017; Ives et al., 2020). Main risk factors associated to PE includes genetic background (family history) or previous events of PE; preexisting medical conditions, like hypertension, antiphospholipid syndrome, or insulin-dependent diabetes; obesity; age (≥40 years old), assisted reproductive techniques; nulliparity and multiparity (Lisonkova and Joseph, 2013; Paré et al., 2014). In this context and, in the absence of effective therapies, early prediction of PE is critical for preventive therapy and to guarantee adequate patient surveillance (Wagner, 2004; Sibai, 2005; Sunjaya et al., 2019). Likewise, a detailed understanding of the pathophysiology of PE will help to find novel biomarkers with translational applications.

PEVs are potential mediators of PE pathogenesis and offer promising therapeutic applications from bench to bedside. According to different research works, the number of EVs and PEVs are higher in preeclamptic women compared to unaffected women, suggesting a putative pathophysiological role of these components (Knight et al., 1998; Salomon et al., 2017). Likewise, PEVs are larger in PE women (Tong et al., 2017). Additionally, different studies have shown that there are differences between EO-PE and LO-PE, as the number of placental microvesicles and pEXOs is higher in EO-PE compared to LO-PE. However, some studies have described that there are not changes in the levels of PLAP + EV between normotensive and LO-PE women, confirming the etiopathogenic differences between EO-PE and LO-PE (Goswamia et al., 2006; Orozco et al., 2009; Chen et al., 2012; Pillay et al., 2016). Regarding their content, lipidomic analysis have revealed that STBMs from PE women display enhanced levels of total phosphatidylserine whereas phosphatidylinositol, phosphatidic acid, and ganglioside mannoside 3 were significantly downregulated in comparison with normal pregnancies (Baig et al., 2013).

The changes in the EV profile can critically affect to different pathophysiological mechanisms of PE. For instance, it has been demonstrated that administration of PEVs in a mice model of PE induced proteinuria and hypertension in non-pregnant mice, disrupting endothelial activity and promoting vasoconstriction (Han et al., 2020). Interestingly, the clearance of these pathological PEVs prevented the induction of the preeclampsia-like phenotype, suggesting a causal role of these components in PE. Gill et al., (2019) reported a remarkable increase of neprilysin (NEP) in PEVs obtained from PE women, playing pathological roles in hypertension, heart failure, and amyloid deposition, involved in the development of PE. Focusing on the vascular alterations and damage observed in the course of this obstetric disease Tannetta et al. (Tannetta et al., 2013) defined that there are differences in physical and antigenic features of PEV between normal and preeclamptic preparations. For instance, they showed that pEXOs and placental microvesicles presented lower PLAP levels in their surface and larger quantities of biologically active endoglin (Eng) and Fms Related Receptor Tyrosine Kinase 1 (Flt-1). Both Flt-1 and Eng as well as their soluble forms (sEng/sfl1-1) are major contributors to the pathophysiology of PE by reducing the bioavailability of the proangiogenic markers vascular endothelial growth factor (VEGF) and placental derived growth factor (PlGF) (Gilbert et al., 2008). SNAs appears to be a major source of sFlt-1 in PE, being associated with increased syncytial knots formation and shedding of these EV into maternal circulation and lungs and contributing to the systemic vascular injury observed (Rajakumar et al., 2012; Buurma et al., 2013). Besides, it has been described that macrovesicles from preeclamptic but not from normal placenta induced endothelial activation, suggesting a potential pathophysiological role EV in the endothelial injury systemically (Shen et al., 2014). Microparticles released by STBs seems to contain lower amounts of Tissue Factor Pathway Inhibitor (TFPI) enhancing the bioavailability of Tissue Factor (TF) and its procoagulant activity observed in women with gestational vascular complications (Aharon et al., 2009). Simultaneously, STBMs from PE women show higher levels of TF, consistently with the altered hemostasis reported in these patients (Gardiner et al., 2011). Also, PEVs from patients with PE contains higher levels of mucin-1, a glycoprotein which impairs EVT invasion via β1-integrin signaling (Shyu et al., 2011; Tannetta et al., 2017). Proteomic studies have evidenced decreased integrins in STBMs from PE women, related to reduced trophoblast invasion and defective placental vascularization (Baig et al., 2014). pEXOs can also present syncytin-1 and -2 in their membrane, two proteins involved in STB formation and critically downregulated in women with PE (Vargas et al., 2011). However, syncytin 2 is reduced in pEXOs from preeclamptic placenta when compared with normal women and there is a decreased internalization of exosomes released by trophoblast cells deficient in syncytin-1 and -2 (Vargas et al., 2014).

As above mentioned, an exacerbated inflammatory response and ischemia/hypoxia are important pathophysiological mechanisms in PE. Exosomes from EVT cultured in vitro under low oxygen tension increase TNFα expression in human umbilical vein endothelial cells (HUVECs), inhibiting their migration (Truong et al., 2017). Likewise, low oxygen tension was also associated with a differential miRNA signature in exosomal derived from EVT, all of them associated with cell migration and cytokine production (Truong et al., 2017). Shen et al., (2018) found that placenta-associated serum exosomal miR-155, which was upregulated in patients with PE, decreased nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) expression in primary HUVECs. Similarly, it has been reported (Ospina-Prieto et al., 2016) that increased levels of exosomal miR-141 derived from placental trophoblast in patients with PE could induce T cell proliferation. Kovacs et al. (Kovács et al., 2018) found that EV from PE women induce an aberrant response in macrophages, affecting chemotaxis, cell adhesion and migration in vitro. These authors described increased CD47 levels (“do not eat me” signal) and decreased external phosphatidylserine levels (“eat me” signal) along with a decreased uptake of these EVs. A possible explanation is partially described in other article (Wang et al., 2019), where the authors showed that miR‐548c‐5p expression was lower in serum exosomes and placental mononuclear cells in PE patients compared to non-pathological pregnancies. This down‐regulation is associated with an increased secretion of inflammatory cytokines (IL‐12 and TNF‐α) and nuclear translocation of NF‐κB, leading to an aberrant macrophage response. In addition to macrophages, neutrophils are also tightly modulated by PEVs. Indeed, in vitro studies have shown that PEVs can dramatically increase the production of superoxides by donor neutrophils and stimulate the production of neutrophil extracellular traps (NETs), reducing maternal blood flow in preeclamptic placentas (Tong and Chamley, 2015). Reduced levels of gelsolin reported in women with PE can be associated with an aberrant shedding of EVs while treating placental explants with preeclamptic sera enhanced expression of the proinflammatory marker High Mobility Group Box 1 (HMGB1) detected in SNAs, according to previous works (Zhang et al., 2020). Moreover, microvesicles derived from preeclamptic placenta exacerbated in vitro the response of PBMCs to LPS, supporting a proinflammatory action of these EVs in PE (Holder et al., 2012). Additional works have reported a reduced presence of the Placental Protein 13 (PP13) in PEV of PE women, suggesting that this dysregulation can be involved in the immunopathological mechanisms observed (Sammar et al., 2018).

The diagnostic value of PEVs has also been tested. For example, Salomon et al. (Salomon et al., 2017) found that in asymptomatic women who lately developed PE, the concentration of total exosomes and pEXOs was higher than in controls. Similarly, hsa-miR-486-1-5p, and hsa-miR-486-2-5p miRNAs contained in the exosomes are elevated in PE compared with normal pregnancies, suggesting their potential application for the early PE biomarkers. Other authors (Biró et al., 2017) observed circulating exosomal total-miRNA and hsa-miR-210 levels were significantly elevated in PE women in comparison with normotensive women and patients diagnosed with other hypertensive disorders of pregnancy (chronic and gestational hypertension), suggesting a promising role for differential diagnosis. Some studies have described that apoptotic microparticles derived from trophoblast in PE women revealed a significant increase of circular DNA in comparison to normal pregnancies, which can be used for both early genetic diagnosis and monitoring of pathological pregnancies (Orozco et al., 2008). As summarized in Figure 2, the amount and content of PEVs is involved in the pathogenesis of PE, modulating several processes, such as the immune response, the angiogenic balance and other mechanisms related with this disease.

GDM represents the most common medical complication of pregnancy The incidence and prevalence of this condition is increasing due to improved clinical diagnosis and screening programs (Alfadhli, 2015). The main risk factors for GDM are obesity, sedentary lifestyle, multiparity, family history of type 2 diabetes mellitus (T2DM), past history of GDM or delivery of a macrosomic baby, advanced maternal age, ethnicity and polycystic ovarian syndrome (Lin et al., 2016; Yaping et al., 2022). The main symptom associated with GDM is the appearance of chronic hyperglycemia during pregnancy without a previous diagnosis of diabetes (Diabetes Care, 2018). From a pathophysiological perspective, GDM is the result of pancreatic β-cell dysfunction on a background of chronic insulin resistance during pregnancy. In a healthy pregnancy, peripheral insulin sensitivity increases in early pregnancy, promoting the glucose uptake by adipose tissues for late pregnancy. Throughout the pregnancy, the pancreas undergoes a compensatory response with hyperplasia and hypertrophy to meet the energetic demands of this period. This leads to a decreased peripheral insulin sensitivity and increased blood glucose levels to be exchanged through the placenta and used by the fetus. After delivery, β-cell function, glucose levels and insulin sensitivity are restored (Catalano et al., 1991; Di Cianni et al., 2003). However, in GDM there is an ineffective compensatory response of the pancreas, that combined with reduced insulin sensitivity results in a marked hyperglycemia. It has been hypothesized that GDM women may have slightly impaired the peripheral insulin sensitivity before pregnancy and after delivery, insulin sensitivity, β-cell function and glucose levels can be either restored or might remain impaired on a pathway toward GDM in future pregnancy or T2DM (Plows et al., 2018). During the course of this complex disorder, there are several organs directly involved such as the brain, gut, liver, muscles and adipose tissue. In addition to the pancreas, the placenta is the most important organ involved in the pathogenesis of GDM. More specifically, the release of several hormones produced by the placenta (mainly lactogen, but also growth hormone, prolactin, corticotropin-releasing hormone and progesterone) promote insulin resistance and hyperglycemia (Rodriguez and Mahdy, 2022).

GDM is associated to multiple complications during pregnancy, increasing the incidence of hypertensive disorders of pregnancy like preeclampsia, polyhydramnios, excessive fetal growth, maternal and neonatal morbidities, including cesarean, neonatal hypoglycemia, hypocalcemia and respiratory stress syndrome, amongst others (Metzger et al., 2008). Long-term complications include increased risk of diabetes and cardiovascular disease in the mothers and obesity and diabetes for the children (Ashwal and HodGestational, 2015). According to the International Association Diabetes Pregnancy Study Groups (IADPSG) (Metzger et al., 2010), detection and diagnosis of GDM is usually performed by an oral glucose tolerance test (OGTT), considering the following criteria: 1) Measure of fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), or random plasma glucose on all or only high-risk women; 2) If results not diagnostic of overt diabetes, GDM is clinically diagnosed when (FPG) ≥92 mg/dl and <126 mg/d; 3) if FPG is < 92 mg/dl, a 2-h 75-g OGTT should be performed at 24–28 weeks’ gestation after overnight fast, being diagnosed as GDM if FPG ≥92 mg/dl or 1 h plasma glucose ≥180 or 2-h plasma glucose ≥153. Changes in diet and physical activity are the primary treatments for GDM, but pharmacotherapy, usually insulin, is required when normoglycemia is not achieved. Oral hypoglycemic agents, principally metformin and glibenclamide (glyburide), can also be used (McIntyre et al., 2019).

PEVs have been studied as well in the context of GDM pathogenesis. As mentioned before, glucose can stimulate the production and release of PEVs independently from oxygen tension (Rice et al., 2015). It has been reported GDM patients with 2.2-fold, 1.5-fold and 1.8-fold increased levels of PEVs with respect to normoglycemic pregnant women during the first, second and third trimester, respectively (Salomon et al., 2016). The possible role of differences in proteins in PEVs isolated from GDM has been analyzed. Proteomic analysis of PEVs isolated at the time of GDM diagnosis showed differential expression of Calcium/calmodulin-dependent Protein Kinase II beta (CAMK2β) and Pappalysin-1 (PAPP-A), which are capable of influencing insulin signaling and glucose metabolic pathways (Jayabalan et al., 2019a). It has been reported that Dipeptidyl peptidase-4 (DPPIV) in GDM patients serum compared with normoglycemic pregnant women show greater DPPIV activity and a 8-fold increase of DDPIV-bound PEV (Kandzija et al., 2019). Importantly, DDPIV is characterized by breaking down glucagon-like peptide-1 (GLP-1), a critical regulatory molecule on glucose-dependent insulin secretion.

PEV-associated miRNAs have been studied as well in the context of GDM. Nair et al. (Nair et al., 2021a) described significative changes between normoglycemic and GDM women in 101 EV-associated miRNAs, suggesting an adaptative response to this pathological condition. Likewise, it has been described a significant increase in early pregnancy (6–15 weeks) in the expression of several EV-miRNAs and PEV-miRNAs such as miR‒122-5p, miR‒132-3p; miR‒1323; miR‒136-5p; miR‒182-3p; miR‒210-3p; miR‒29a-3p; miR‒29b-3p; miR‒342-3p, and miR-520h (Gillet et al., 2019). Similarly, PEVs seems to carry a set of miRNAs which modulates skeletal muscle insulin sensitivity. Consequently, PEVs isolated from women with GDM reduced insulin-mediated migration and glucose uptake in primary skeletal muscle cells from healthy individuals. Conversely, PEVs from normoglycemic women increased insulin-mediated migration and glucose uptake in primary muscle cells obtained from GDM patients (Nair et al., 2018). In vivo models also showed that PEV isolated from GDM women could induce impaired glucose tolerance and changes in the miRNA profile and insulin signaling in skeletal muscle tissues, specially through the phosphorylation of IRS-1 and Akt (James-Allan et al., 2020). Besides, when compared to normoglycemic PEVs, glucose stimulated insulin secretion from pancreatic islets were reduced.

There is a strong association of increased body mass index (BMI) values in early pregnancy (BMI>25) with GDM development (Zhang et al., 2022). Previous studies have described a positive correlation between BMI and total number of blood EV during pregnancy. However, the higher BMI is, the less is the number of PEVs to the total amount of EVs (Elfeky et al., 2017). Likewise, EVs from women with a BMI >25 display a proinflammatory profile, with an increased release of IL-6, IL-8 and TNF-α from endothelial cells (Salomon et al., 2016; Elfeky et al., 2017). Previous studies have found that PEVs can stimulate the release of different proinflammatory cytokines by endothelial cells (Rice et al., 2015). In turn, EVs derived from the endothelium can promote significant pathophysiological changes related to GDM in the placenta (Sáez et al., 2018a; Sáez et al., 2018b) demonstrating the interaction that exist between PEVs and the endothelium. On the other hand, EVs produced by adipose tissue promote placental changes during GDM. In this sense, these EVs appears to be directly correlated with birthweight Z score, modulating different products and events like Sirtuin, oxidative phosphorylation, and mammalian target of rapamycin (mTOR) signaling pathway (Jayabalan et al., 2019b). Figure 3 summarizes the influence of PEVs in GDM. However, the effect of PEVs and EVs released by other tissues in GDM pathophysiology is far from being fully elucidated. The use of these PEVs as prognostic, predictive or diagnostic biomarkers as well as potential therapeutic targets is a promising field of study, with potential effects in the clinical management of these patients (Nair et al., 2021b).

Complications in maternal-fetal communication can lead to one of the most worrying pathologies in pregnancy, which is FGR. Traditionally, FGR describes a condition in which fetus is smaller (below the 10th percentile) than expected based on gestational age (SGA). However, as not every fetus has the same growth potential, so the definition has been expanded, and now it refers to those SGA fetuses due to a pathologic cause and consequently are at risk of adverse events (Easter et al., 2017). Current consensus requests weight <third percentile or three out of the following criteria: birth weight <10th percentile, head circumference <10th percentile, length <10th percentile, prenatal diagnosis of FGR, and the presence of any pregnancy complication (Beune et al., 2018). To diagnose FGR accurately, umbilical artery Doppler assessment must be abnormal and percentile limits are 10, 5 or 3 compared to a population of reference. Then subjacent causes must be detected. In developed countries, the frequency of FGR increases with the age of the mother and often is the consequence of preexisting preeclampsia but in developing countries malnutrition and infectious diseases are relevant factors (Easter et al., 2017). Other factors involved are maternal hypertension, diabetes mellitus, autoimmune diseases, smoking, or drug and alcohol abuse. Among the factors linked to the fetus chromosomal abnormalities (trisomy 13, 18, and 21), mutations at insulin-like growth factor or multiple gestation are the most relevant (Condrat et al., 2021). Inadequate placentation is also important. In all these cases, pathological extracellular vesicle trafficking at the feto-maternal crosstalk has been suggested by several authors.

In those cases of FGR underlying preeclampsia, the surface area available for feto-maternal traffic is decreased due to deficient remodeling of uterine spiral arteries and villous damage, reducing the exchange of oxygen and nutrients. Some prognostic biomarkers used in preeclampsia have been employed in FGR as well. Low levels of angiogenic molecules like PIGF or altered serum levels of PAPP-A in the first trimester are considered in clinical practice for prenatal screening. Low circulating levels of anabolic hormones IGF-1 and its binding proteins explain nutrient privation and reduced growth potential. Finally, circulating EGF Like Domain Multiple 7 (EGFL7) has been used to classify isolated FGR and preeclampsia at different gestational stages (Ortega et al., 2022b).

Predictive biomarkers for clinic practice are not available at the moment. Future studies will focus on the characterization of placenta and fetal-derived EVs and their cargoes to find predictive biomarkers (Buca et al., 2020). Prospective cohort studies studying placenta-derived exosomes in maternal and fetal circulation for fetuses with FGR or SGA have been published. In a study, the authors reported reduced [PLAP^+ve:total exosomes] ratios in FGR compared to controls and SGA cases (Miranda et al., 2018). Likewise, EVs derived from umbilical cord as well as the expression levels of miR-150 either in tissue or in EV were decreased in a pig model of FGR. Upregulation of this miRNA promoted proliferation, cell migration and tube formation by HUVEC cells, promoting a pro-angiogenic effect (Luo et al., 2018). These results support the existence of a pathogenic feto-maternal communication and uteroplacental vascular insufficiency. Hromadnikova et al., (2019) in a retrospective case control study, selected C19MC miRNAs exosomes from early gestation stages, observing a down-regulation of miR-520a-5p in first trimester of women suffering preeclampsia and gestational hypertension who later developed FGR. These authors described this miRNA as a novel biomarker for the onset of FGR due to its abundance in placenta and reduced expression levels in other tissues. Similarly, Rodosthenous et al., (2017) noticed that the level of various EV-associated miRNAs in the second trimester of pregnancy were correlated with fetal growth, describing sex-specific associations. However, future studies are needed to unravel the role of EVs and PEVs in FGR.

Chorioamnionitis (infection of the membranes and chorion of the placenta) represents a common complication of pregnancy associated with significant perinatal, maternal and long-term adverse consequences (Tita and Andrews, 2010). Chorioamnionitis can be acute, subacute or chronic, showing different clinical characteristics and complications (Fowler and SimonChorioamnionitis, 2022). Chorioamnionitis is classified in two main categories: Histologic (based on microscopic evidence of inflammation of the membranes) and clinical (based on medical manifestations of local and systemic inflammation such as fever, abdominal pain or leukocytosis (>15,000 cells/mm³) (Menon et al., 2010). There are plenty etiological agents that may cause chorioamnionitis. The most frequent cause of chorioamnionitis are ascending bacteria from the vagina and cervix, appearing as a polymicrobial infection secondary complication of prolonged rupture of the membranes (Czikk et al., 2011). Other less common agents include viruses, fungi and even parasites like Plasmodium falciparum (Czikk et al., 2011; Singoei et al., 2021). Previous works have noticed an important role of PEVs in chorioamnionitis. As above mentioned, PEVs seem to have an impact in resistance pathways of viral infection. For instance, PEVs are able to inhibit viral replication, or they may content some antiviral agents like interferon (IFNλ1), although they can also favor viral spread, acting as a secure vehicle for them and promoting immune evasion (Condrat et al., 2021). Otherwise, PEVs also play a pivotal role in bacterial infections. Kaletka et al. (Zeldovich et al., 2013) studied trophoblastic EVs afer being infected by Listeria monocytogenes. Interestingly they found that these PEVs were immunostimulatory, activating macrophages to a proinflammatory state, but also making them more vulnerable to being infected by this bacteria. Thus, both effects are likely observed in PEVs regarding infections: Inducing an immune response but also, promoting the spread of the pathogens. Similarly, Bergamelli et al., (2021) demonstrated that infection with human cytomegalovirus (CMV) affected in vitro the expression level of several surface markers in PEVs, defining an altered profile of these components due to this infection. Although these changes can be useful for defending against the infection, a very recent article has demonstrated that PEVs from infected CMV potentiate infection in in naive recipient cells of fetal origin, including human neural stem cells (Bergamelli et al., 2022). Besides, the authors proposed PEVs as central players of viral dissemination to the fetal brain due to congenital CMV infection and this statement is supported by Gall et al., (2022) who recognized the critical role of PEVs in different neuroinflammatory processes and the development of perinatal brain injury in the setting of chorioamnionitis by propagating and sustaining the inflammatory cascade. On the other hand, Moro et al., (2016) studied placental MVs and their miRNA content in pregnant women with Human Immunodeficiency virus (HIV) and Plasmodium falciparum infection. Interestingly, they show that HIV-infected mothers exhibited higher concentrations of total and trophoblast microparticles, which induced a higher expression of MHCII and lower production of MCP1. On the other hand, placental malaria was characterized by an upregulated miR-517c, which might have a pathogenic role on the adverse outcomes during pregnancy and malaria infection. Overall, the role of PEVs in chorioamnionitis and infections show promising but still reduced results, and due to the relevance of placenta in these conditions, further efforts would be of great aid in this field.

PTB (characterized by labor prior to 37 completed weeks of pregnancy) affects approximately 15 million infants yearly, representing an important cause of neonatal morbidity and mortality (Blencowe et al., 2013). The etiopathogenesis of this condition remains to be fully described, but different risk factors such as high blood pressure, diabetes, obesity, underweight, psychological stress, history of previous preterm labor, exacerbated inflammation during pregnancy and tobacco smoking are implicated in the development of premature birth (Stewart and Graham, 2010; Condrat et al., 2021). PTB has been associated with higher number of EVs (Menon and Shahin, 2021) and in vivo models have shown that these EV could induce preterm labor due to the presence of increased inflammatory mediators (Sheller-Miller et al., 2019). Proteomic studies have identified 72 proteins that might play a crucial role in preterm labor, being associated with critical inflammatory and metabolic signals (Menon et al., 2019a). Similarly, Cantonwine et al., (2016) described that from a total of 62 proteins contained in circulating EVs qualified for diagnosis alpha-2-macroglobulin (α2M), human endogenous medium-reiteration-frequency-family-34 ORF (HEMO), and mannose binding lectin 2 (MBL2), displayed a specificity of 83% with median area under the curve (AUC) of 0.89, which could be use as predictive biomarkers of spontaneous PTB if validated in future studies. Simultaneously, Menon et al., (2019b) described up to 173 miRNAs importantly altered in serum exosomes of women with PTB. However, they could not describe the precise origin of these exosomes. Likewise, a possible role of bacterial exosomes derived from Ureaplasma and Veillonellaceae are more abundant in the urine of women with PTB (Yoo et al., 2016) suggesting the complex background of EVs in PTB.

Although less studied PEVs have also been identified as critical mechanisms involved in the onset and progression of labor, having been suggested as potential biomarkers for preterm delivery (Salomon et al., 2018). The amount of PEVs in PTB has not been explored; however, there is a clinical case in which a dramatic increase of PLAP (10.5-fold), which can be present in PEVs, was associated with PTB (Ferianec and Linhartova, 2011). Fallen et al. (Fallen et al., 2018) identified a set of circulating and EV-associated miRNAs with potential pathophysiological effects in the placenta associated to PTB. Due to the multiple roles of the placenta during pregnancy and labor, we encourage for specific studies that focus on PEV in PTB, as this might be used as promising biomarkers in this research area. In Figure 4, the main implications of PEVs described until date is summarized.