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The Fas/Fas ligand (FASL) system and Elabela-apelin receptor signaling pathways are implicated in the pathophysiology of preeclampsia. The aim of the current study was to investigate whether a model combining the measurement of sFas and Elabela in the maternal circulation may serve as a clinical biomarker for early- and/or late-onset preeclampsia more effectively than measures of each biomarker individually. Blood samples were collected from 214 women in the following groups: (1) normal pregnancy sampled <34 weeks of gestation (n = 56); (2) patients who developed early-onset preeclampsia (n = 54); (3) normal pregnancy sampled ≥34 weeks of gestation (n = 52); (4) patients who developed late-onset preeclampsia (n = 52). Maternal circulating soluble Fas and Elabela concentrations were determined using sensitive and validated immunoassays. Two sample t-tests, multivariate logistic regression, and receiver operating characteristic curves were used for analyses. (1) Women with early-onset preeclampsia, and those with late-onset preeclampsia with placental lesions of maternal vascular malperfusion, had increased concentrations of sFas compared to their gestational age-matched normal controls; (2) women with late-onset preeclampsia, but not those with early-onset preeclampsia, had increased concentrations of Elabela compared to their gestational age-matched counterparts; and (3) an increase in both Elabela and sFas concentrations was more strongly associated with late-onset preeclampsia than early-onset preeclampsia relative to models including either of the markers alone. A combined model of maternal sFas and Elabela concentrations provides a stronger association with late-onset preeclampsia than either protein alone. This finding demonstrates the possibility to improve the classification of late-onset preeclampsia by combining the results of both molecular biomarkers. [ABSTRACT FROM AUTHOR]

Objective: Preterm labor and birth are strongly associated with sterile intra-amniotic inflammation, a clinical condition that is proposed to be initiated by danger signals, or alarmins. The aim of this study was to investigate whether the intra-amniotic administration of the alarmin heat shock protein 70 (HSP70) induces preterm labor/birth and adverse neonatal outcomes.Methods: Pregnant mice received an intra-amniotic injection of 200 ng (n = 8), 400 ng (n = 6), 500 ng (n = 10), or 1 µg of HSP70 (n = 6). Control mice were injected with saline (n = 10). Following injection, the rates of preterm labor/birth and neonatal mortality were recorded. Neonatal weights at weeks 1, 2, and 3 were also recorded.Results: The intra-amniotic injection of 400 ng [late preterm birth 16.7 ± 16.7% (1/6)], 500 ng [early and late preterm birth 10 ± 10% (1/10) each], or 1 µg [early preterm birth 16.7 ± 16.7% (1/6)] of HSP70 induced low rates of preterm/birth. However, the intra-amniotic injection of 500 ng or 1 µg of HSP70 induced significantly higher rates of neonatal mortality compared to controls [saline 14.2% (10/74), 200 ng 9.8% (6/61), 400 ng 17.9% (9/45), 500 ng 28.8% (23/78), and 1 µg 21.4% (13/49)]. Neonates born to dams injected with 200, 500 ng, or 1 µg HSP70 were leaner than controls (p ≤ .05).Conclusion: Intra-amniotic administration of the alarmin HSP70 did not induce high rates of preterm labor/birth; yet, it did indeed result in adverse neonatal outcomes. [ABSTRACT FROM AUTHOR]

Objective: Pyroptosis is an inflammatory form of programmed cell death that is mediated by the activation of the inflammasome and depends on the pore-forming function of gasdermin D. Therefore, the detection of gasdermin D represents in vivo evidence of pyroptosis. We recently showed that there is intra-amniotic inflammasome activation in spontaneous labor at term; however, evidence of pyroptosis is lacking. The objectives of this study were to investigate (1) whether gasdermin D is detectable in the amniotic fluid of women who delivered at term; (2) whether amniotic fluid gasdermin D concentrations are associated with the process of spontaneous labor at term; and (3) whether gasdermin D is expressed in the chorioamniotic membranes from these patients.Methods: This retrospective cross-sectional study included amniotic fluid samples from 41 women who underwent spontaneous labor at term (n = 17) or delivered at term without labor (n = 24). As a readout of pyroptosis, gasdermin D was determined in amniotic fluid samples using a specific and sensitive ELISA kit. The 90th percentile of amniotic fluid gasdermin D concentrations was calculated among women without spontaneous labor at term (reference group). The association between high amniotic fluid gasdermin D concentrations (≥90th percentile in the reference group) and spontaneous labor at term was tested using the Fisher's exact test. A p value <.05 was considered significant. Multiplex immunofluorescence staining and phenoptics (multispectral imaging) were performed to determine gasdermin D expression in the chorioamniotic membranes and to colocalize this protein with the inflammasome-related molecules caspase-1 and interleukin-1β.Results: (1) Gasdermin D is present in the amniotic fluid of women who delivered at term; (2) the 90th percentile of amniotic fluid gasdermin D concentrations in women who delivered at term without spontaneous labor was 3.4 ng/mL; (3) the proportion of women with amniotic fluid gasdermin D concentrations above the threshold was higher in those who underwent term labor than in those who delivered at term without labor; (4) amniotic fluid concentrations of gasdermin D > 3.4 ng/mL were significantly associated with the presence of spontaneous labor in women who delivered at term (odds ratio 6.0, p-value .048); and (5) the protein expression of gasdermin D is increased in the chorioamniotic membranes of women who underwent spontaneous labor at term and is colocalized with caspase-1 and IL-1β.Conclusions: Gasdermin D is increased in the amniotic fluid and chorioamniotic membranes of women who underwent spontaneous labor at term compared to those without labor. These data provide evidence implicating pyroptosis in the mechanisms that lead to the sterile inflammatory process of term parturition. [ABSTRACT FROM AUTHOR]

Objective: ELABELA is a newly discovered peptide hormone that appears to be implicated in the mechanisms leading to preeclampsia, independently of angiogenic factors. The aim of the current study was to investigate whether women with early- or late-onset preeclampsia have altered ELABELA plasma concentrations compared to gestational-age-matched normal pregnant women.Methods: This retrospective cross-sectional study focused on the maternal plasma samples collected from 232 women with a singleton pregnancy who were allocated into the following groups: (1) early-onset preeclampsia (<34 weeks of gestation, N = 56); (2) late-onset preeclampsia (≥34 weeks of gestation, N = 57); and (3) gestational-age-matched controls with a normal pregnancy [(<34 weeks of gestation, N = 59); (≥34 weeks of gestation, N = 60)]. ELABELA plasma concentrations were determined using a validated enzyme immunoassay.Results: (1) ELABELA plasma concentrations are higher in patients with late-onset preeclampsia compared with those from gestational-age-matched controls with a normal pregnancy [median: 7.99 ng/mL (IQR, 5.3-13.95 ng/mL) versus median: 4.17 ng/mL (IQR, 3-11.19 ng/mL), p =.001]; (2) ELABELA plasma concentrations in patients with early-onset preeclampsia do not differ from those of normal pregnant women [median: 6.09 ng/mL (IQR, 2.8-10.66 ng/mL) versus median: 4.02 ng/mL (IQR, 3.26-7.49), p = .32]; and (3) ELABELA plasma concentrations are higher in patients with late-onset preeclampsia compared to those with early-onset preeclampsia [median: 7.99 ng/mL (IQR, 5.3-13.95 ng/mL) versus median: 6.09 ng/mL (IQR, 2.8-10.66 ng/mL), p = .01].Conclusion: ELABELA plasma concentrations are higher in patients with late-onset preeclampsia than in those with a normal pregnancy. However, women with early-onset preeclampsia have similar ELABELA plasma concentrations to those with a normal pregnancy. These findings provide insight into the ELABELA axis during the human syndrome of preeclampsia. In addition, these data support the concept that different pathophysiologic mechanisms are implicated in early- and late-onset preeclampsia. [ABSTRACT FROM AUTHOR]

Objective: Upon inflammasome activation, the adaptor protein of the inflammasome ASC (apoptosis-associated speck-like protein containing a CARD) forms intracellular specks, which can be released into the extracellular space. The objectives of this study were to investigate whether (1) extracellular ASC is present in the amniotic fluid of women who delivered at term; (2) amniotic fluid ASC concentrations are greater in women who underwent spontaneous labor at term than in those who delivered at term in the absence of labor; and (3) amniotic epithelial and mesenchymal cells can form intracellular ASC specks in vitro. Methods: This retrospective cross-sectional study included amniotic fluid samples from 41 women who delivered at term in the absence of labor (n = 24) or underwent spontaneous labor at term (n = 17). Amniotic epithelial and mesenchymal cells were also isolated from the chorioamniotic membranes obtained from a separate group of women who delivered at term (n = 3), in which ASC speck formation was assessed by confocal microscopy. Monocytes from healthy individuals were used as positive controls for ASC speck formation (n = 3). Results: (1) The adaptor protein of the inflammasome ASC is detectable in the amniotic fluid of women who delivered at term; (2) amniotic fluid ASC concentration was higher in women who underwent spontaneous labor at term than in those who delivered at term without labor; and (3) amniotic epithelial and mesenchymal cells are capable of forming ASC specks and/or filaments in vitro. Conclusion: Amniotic fluid ASC concentrations are increased in women who undergo spontaneous labor at term. Amniotic epithelial and mesenchymal cells are capable of forming ASC specks, suggesting that these cells are a source of extracellular ASC in the amniotic fluid. These findings provide in vivo evidence that there is inflammasome activation in the amniotic cavity during the physiological process of labor at term. [ABSTRACT FROM AUTHOR]

Introduction: A bioassay based on the detection of beta-glucan, a constituent of the cell wall of fungi, has been successfully used to diagnose fungal infections in a variety of biological fluids but not yet in the amniotic fluid.Objective: To determine the diagnostic performance of a beta-glucan bioassay in the detection of Candida species in the amniotic fluid of women who either did or did not have an intrauterine contraceptive device (IUD) in place during an episode of spontaneous preterm parturition.Methods: The study population comprised women who had a singleton pregnancy without congenital or chromosomal abnormalities, who experienced preterm labor or preterm prelabor rupture of the fetal membranes, and who underwent a transabdominal amniocentesis for clinical indications. Samples of amniotic fluid were cultured for aerobic and anaerobic bacteria, genital mycoplasmas, and Candida species, and assayed for beta-glucan, using the (1→3)-beta-d-glucan-specific Limulus amebocyte lysate test (beta-glucan assay) in all cases. Amniotic fluid interleukin (IL)-6 assay results were also available for all cases. The beta-glucan assay takes about 1 hour to run: a concentration >80 pg/mL was considered positive for fungi. Sterile intra-amniotic inflammation of the amniotic cavity was defined by the presence of an amniotic fluid IL-6 concentration ≥2.6 ng/mL and a negative amniotic fluid culture.Results: (1) One hundred ninety-seven (197) women met the study criteria, of whom 58 (29.4%) had an IUD in place; (2) 20 (10.2%) women had a culture of proven intra-amniotic Candida species-related infection, 19 of whom had a positive beta-glucan assay [sensitivity, 95% (19/20; 95% confidence interval (CI): 75.1-99.9%)]; and (3) the specificity of the beta-glucan assay was 75.1% [133/177; 95% CI: 68.1-99.9%]. It was affected by the presence of nonfungal intra-amniotic infections and an IUD, but not by the presence of sterile intra-amniotic inflammation, and there was a significant interaction between the presence of an IUD and nonfungal intra-amniotic infections (estimated for the interaction effect = 2.1923, p value =.026). The assay's specificity was reduced when nonfungal intra-amniotic infections were diagnosed but only in women who did not have an IUD. Among women without an IUD, the assay's specificity was 91.4% (117/128); it was 93% (106/114) for those without intra-amniotic infection, and 78.6% (11/14) for those with a nonfungal intra-amniotic infection; the difference was not significant (p = .09). Among women with an IUD, the assay's specificity was 32.7% (16/49); 42.9% (9/21) for those with a nonfungal intra-amniotic infection; and 25% (7/28) for those without intra-amniotic infection; and the difference was significant (p = .03).Conclusions: The beta-glucan assay is a sensitive, rapid, point-of-care test used to diagnose intra-amniotic Candida species-related infection, and it has a high specificity in pregnant women who did not have an IUD in place. [ABSTRACT FROM AUTHOR]