The prediction of early preeclampsia

To identify maternal plasma protein markers for early preeclampsia (delivery <34 weeks of gestation) and to determine whether the prediction performance is affected by disease severity and presence of placental lesions consistent with maternal vascular malperfusion (MVM) among cases.This longitudinal case-control study included 90 patients with a normal pregnancy and 33 patients with early preeclampsia. Two to six maternal plasma samples were collected throughout gestation from each woman. The abundance of 1,125 proteins was measured using high-affinity aptamer-based proteomic assays, and data were modeled using linear mixed-effects models. After data transformation into multiples of the mean values for gestational age, parsimonious linear discriminant analysis risk models were fit for each gestational-age interval (8-16, 16.1-22, 22.1-28, 28.1-32 weeks). Proteomic profiles of early preeclampsia cases were also compared to those of a combined set of controls and late preeclampsia cases (n = 76) reported previously. Prediction performance was estimated via bootstrap.We found that 1) multi-protein models at 16.1-22 weeks of gestation predicted early preeclampsia with a sensitivity of 71% at a false-positive rate (FPR) of 10%. High abundance of matrix metalloproteinase-7 and glycoprotein IIbIIIa complex were the most reliable predictors at this gestational age; 2) at 22.1-28 weeks of gestation, lower abundance of placental growth factor (PlGF) and vascular endothelial growth factor A, isoform 121 (VEGF-121), as well as elevated sialic acid binding immunoglobulin-like lectin 6 (siglec-6) and activin-A, were the best predictors of the subsequent development of early preeclampsia (81% sensitivity, FPR = 10%); 3) at 28.1-32 weeks of gestation, the sensitivity of multi-protein models was 85% (FPR = 10%) with the best predictors being activated leukocyte cell adhesion molecule, siglec-6, and VEGF-121; 4) the increase in siglec-6, activin-A, and VEGF-121 at 22.1-28 weeks of gestation differentiated women who subsequently developed early preeclampsia from those who had a normal pregnancy or developed late preeclampsia (sensitivity 77%, FPR = 10%); 5) the sensitivity of risk models was higher for early preeclampsia with placental MVM lesions than for the entire early preeclampsia group (90% versus 71% at 16.1-22 weeks; 87% versus 81% at 22.1-28 weeks; and 90% versus 85% at 28.1-32 weeks, all FPR = 10%); and 6) the sensitivity of prediction models was higher for severe early preeclampsia than for the entire early preeclampsia group (84% versus 71% at 16.1-22 weeks).We have presented herein a catalogue of proteome changes in maternal plasma proteome that precede the diagnosis of preeclampsia and can distinguish among early and late phenotypes. The sensitivity of maternal plasma protein models for early preeclampsia is higher in women with underlying vascular placental disease and in those with a severe phenotype

The vaginal immunoproteome for the prediction of spontaneous preterm birth: A retrospective longitudinal study

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB. METHODS: Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations. RESULTS: Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (\u3c34 weeks) sPTB. CONCLUSIONS: The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes. FUNDING: This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research

Bacteria in the amniotic fluid without inflammation: Early colonization vs. contamination

Objectives: Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation. Methods: A retrospective cross-sectional study included 360 patients with preterm labor and intact membranes who underwent transabdominal amniocentesis for evaluation of the microbial state of the amniotic cavity as well as intra-amniotic inflammation. Cultivation techniques were used to isolate microorganisms, and broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was utilized to detect the nucleic acids of bacteria, viruses, and fungi. Results: Patients whose amniotic fluid samples evinced microorganisms but did not indicate inflammation had a similar perinatal outcome to those without microorganisms or inflammation [amniocentesis-to-delivery interval (p=0.31), spontaneous preterm birth before 34 weeks (p=0.83), acute placental inflammatory lesions (p=1), and composite neonatal morbidity (p=0.8)]. Conclusions: The isolation of microorganisms from a sample of amniotic fluid in the absence of intra-amniotic inflammation is indicative of a benign condition, which most likely represents contamination of the specimen during the collection procedure or laboratory processing rather than early colonization or infection

COVID-19 is associated with early emergence of preeclampsia: results from a large regional collaborative

Objective: To examine the relationship between COVID-19 and preeclampsia (PreE) in a large, diverse population. Study Design: The COVID-19 in Pregnancy and The Newborn: State of Michigan Collaborative established a database of pregnant patients admitted to 14 institutions in Southern Michigan. Patients with COVID-19 (cases) were matched to 2 or 3 non-COVID patients (controls) on the same unit within 30 days of each case. Relative Risks (RR) were calculated using robust Poisson regression models with adjustment for covariates. Chi-squared test for trend was used to assess the increase in risk with the severity of disease. Results: 369 cases and 1,090 controls were delivered between March - October 2020. An increased risk of PreE (RR=1.8), driven almost entirely by an increase in preterm PreE (pretermPreE) (RR=2.85) was observed in COVID pregnancies (Table 1), with a dose-response relationship with symptomatology and severity (Table 2). The associations between COVID-19 disease and PreE or pretermPreE were independent of other risk factors, as demonstrated by the minimal changes in RR after adjustment for confounders (Table 1). However, African American (AA) COVID patients experienced pretermPreE 1.9 times more than COVID patients of other races (10.1 vs 5.3), an increase not observed in control patients. The strength of the association for COVID with PreE was comparable to the association of PreE with chronic hypertension and nulliparity (data not shown). Increasing symptoms and severity of COVID-19 were associated with an increased risk for PreE with placental lesions, even after adjustment for relevant covariates (Tables 1 & 2). Non-PreE COVID patients had an increased trend of placental lesions compared to non-COVID patients, reaching significance for intravillous thrombin. Conclusion: COVID-19 is significantly associated with early emergence of PreE, independent of known risk factors other than AA race. Our study shows that among patients predisposed to PreE, COVID-19 impacts PreE severity in that it leads to pretermPreE. Further studies on COVID-19 and PreE, with a focus on racial disparities, is warranted

Racial Disparities and Risk for COVID-19 Among Pregnant Patients: Results from the Michigan Statewide Collaborative

Objective: Previous studies have looked at COVID-19 outcomes in pregnancy and racial disparities among patients with COVID-19, but few have studied racial disparities among pregnant patients with COVID-19. Our goal in this study is to analyze the relationship between race and disparate COVID-19 risk in pregnancy. Study Design: A retrospective cohort analysis was performed on data collected as part of the COVID-19 in Pregnancy and The Newborn: State of Michigan Collaborative, a database of pregnant patients admitted to 14 institutions in Southern Michigan. Cases were defined as patients with a positive SARS-CoV-2 test result. Controls, those with suspicion of COVID-19 prior to universal screening or a negative PCR test, were matched to cases on the same unit within 30 days of each case. For this analysis, the two primary groups of interest were non-Hispanic Black (Black) vs. non-Hispanic White (White) patients. Potential covariates were age, body mass index (BMI), chronic hypertension, diabetes, asthma, substance use, and smoking; the dependent variable was COVID/non-COVID in a robust Poisson regression model. In addition, 18 symptoms and disease severity (mild/moderate/severe) were compared between the Black and White groups using the same statistical method. Results: Of 1,131 gravidas, 42.9%(n=485) were Black. These patients were at two-fold greater risk for COVID-19 compared with their White counterparts [35.9% vs. 18.3%, RR=1.96(1.6-2.4)]. After adjusting for obesity and diabetes, the risk of COVID-19 in Black patients remained higher compared to the risk among White patients (aRR=2.46 [1.87-3.24]). There were no differences in symptoms nor severity of disease presentation between the groups. Conclusion: In our population, Black patients are more likely to be diagnosed with COVID-19 infection during pregnancy. This finding is not explained by a range of covariates. Other factors, such as social determinants of health, may be important to understand this disparity and warrant further examination

Maternal SARS-COV-2 infection and prematurity: the Southern Michigan COVID-19 collaborative

OBJECTIVE: COVID-19 has been reported to increase the risk of prematurity, however, due to the frequent absence of unaffected controls as well as inadequate accounting for confounders in many studies, the question requires further investigation. We sought to determine the impact of COVID-19 disease on preterm birth (PTB) overall, as well as related subcategories such as early prematurity, spontaneous, medically indicated preterm birth, and preterm labor (PTL). We assessed the impact of confounders such as COVID-19 risk factors, a-priori risk factors for PTB, symptomatology, and disease severity on rates of prematurity. METHODS: This was a retrospective cohort study of pregnant women from March 2020 till October 1st, 2020. The study included patients from 14 obstetric centers in Michigan, USA. Cases were defined as women diagnosed with COVID-19 at any point during their pregnancy. Cases were matched with uninfected women who delivered in the same unit, within 30 d of the delivery of the index case. Outcomes of interest were frequencies of prematurity overall and subcategories of preterm birth (early, spontaneous/medically indicated, preterm labor, and premature preterm rupture of membranes) in cases compared to controls. The impact of modifiers of these outcomes was documented with extensive control for potential confounders. A p value \u3c.05 was used to infer significance. RESULTS: The rate of prematurity was 8.9% in controls, 9.4% in asymptomatic cases, 26.5% in symptomatic COVID-19 cases, and 58.8% among cases admitted to the ICU. Gestational age at delivery was noted to decrease with disease severity. Cases were at an increased risk of prematurity overall [adjusted relative risk (aRR) = 1.62 (1.2-2.18)] and of early prematurity (\u3c34 weeks) [aRR = 1.8 (1.02-3.16)] when compared to controls. Medically indicated prematurity related to preeclampsia [aRR = 2.46 (1.47-4.12)] or other indications [aRR = 2.32 (1.12-4.79)], were the primary drivers of overall prematurity risk. Symptomatic cases were at an increased risk of preterm labor [aRR = 1.74 (1.04-2.8)] and spontaneous preterm birth due to premature preterm rupture of membranes [aRR = 2.2(1.05-4.55)] when compared to controls and asymptomatic cases combined. The gestational age at delivery followed a dose-response relation with disease severity, as more severe cases tended to deliver earlier (Wilcoxon p \u3c .05). CONCLUSIONS: COVID-19 is an independent risk factor for preterm birth. The increased preterm birth rate in COVID-19 was primarily driven by medically indicated delivery, with preeclampsia as the principal risk factor. Symptomatic status and disease severity were significant drivers of preterm birth

Preterm labor is characterized by a high abundance of amniotic fluid prostaglandins in patients with intra-amniotic infection or sterile intra-amniotic inflammation

Objective: To distinguish between prostaglandin and prostamide concentrations in the amniotic fluid of women who had an episode of preterm labor with intact membranes through the utilisation of liquid chromatography-tandem mass spectrometry. Study design: Liquid chromatography-tandem mass spectrometry analysis of amniotic fluid of women with preterm labor and (1) subsequent delivery at term (2) preterm delivery without intra-amniotic inflammation; (3) preterm delivery with sterile intra-amniotic inflammation (interleukin (IL)-6>2.6 ng/mL without detectable microorganisms); and (4) preterm delivery with intra-amniotic infection [IL-6>2.6 ng/mL with detectable microorganisms]. Results: (1) amniotic fluid concentrations of PGE2, PGF2α, and PGFM were higher in patients with intra-amniotic infection than in those without intra-amniotic inflammation; (2) PGE2 and PGF2α concentrations were also greater in patients with intra-amniotic infection than in those with sterile intra-amniotic inflammation; (3) patients with sterile intra-amniotic inflammation had higher amniotic fluid concentrations of PGE2 and PGFM than those without intra-amniotic inflammation who delivered at term; (4) PGFM concentrations were also greater in women with sterile intra-amniotic inflammation than in those without intra-amniotic inflammation who delivered preterm; (5) amniotic fluid concentrations of prostamides (PGE2-EA and PGF2α-EA) were not different among patients with preterm labor; (6) amniotic fluid concentrations of prostaglandins, but no prostamides, were higher in cases with intra-amniotic inflammation; and (7) the PGE2:PGE2-EA and PGF2α:PGF2α-EA ratios were higher in patients with intra-amniotic infection compared to those without inflammation. Conclusions: Mass spectrometric analysis of amniotic fluid indicated that amniotic fluid concentrations of prostaglandins, but no prostamides, were higher in women with preterm labor and intra-amniotic infection than in other patients with an episode of preterm labor. Yet, women with intra-amniotic infection had greater amniotic fluid concentrations of PGE2 and PGF2α than those with sterile intra-amniotic inflammation, suggesting that these two clinical conditions may be differentiated by using mass spectrometric analysis of amniotic fluid.</p

Preterm labor is characterized by a high abundance of amniotic fluid prostaglandins in patients with intra-amniotic infection or sterile intra-amniotic inflammation

To distinguish between prostaglandin and prostamide concentrations in the amniotic fluid of women who had an episode of preterm labor with intact membranes through the utilisation of liquid chromatography-tandem mass spectrometry. Liquid chromatography-tandem mass spectrometry analysis of amniotic fluid of women with preterm labor and (1) subsequent delivery at term (2) preterm delivery without intra-amniotic inflammation; (3) preterm delivery with sterile intra-amniotic inflammation (interleukin (IL)-6>2.6 ng/mL without detectable microorganisms); and (4) preterm delivery with intra-amniotic infection [IL-6>2.6 ng/mL with detectable microorganisms]. (1) amniotic fluid concentrations of PGE, PGF, and PGFM were higher in patients with intra-amniotic infection than in those without intra-amniotic inflammation; (2) PGE and PGF concentrations were also greater in patients with intra-amniotic infection than in those with sterile intra-amniotic inflammation; (3) patients with sterile intra-amniotic inflammation had higher amniotic fluid concentrations of PGE and PGFM than those without intra-amniotic inflammation who delivered at term; (4) PGFM concentrations were also greater in women with sterile intra-amniotic inflammation than in those without intra-amniotic inflammation who delivered preterm; (5) amniotic fluid concentrations of prostamides (PGE-EA and PGF-EA) were not different among patients with preterm labor; (6) amniotic fluid concentrations of prostaglandins, but no prostamides, were higher in cases with intra-amniotic inflammation; and (7) the PGE:PGE-EA and PGF:PGF-EA ratios were higher in patients with intra-amniotic infection compared to those without inflammation. Mass spectrometric analysis of amniotic fluid indicated that amniotic fluid concentrations of prostaglandins, but no prostamides, were higher in women with preterm labor and intra-amniotic infection than in other patients with an episode of preterm labor. Yet, women with intra-amniotic infection had greater amniotic fluid concentrations of PGE and PGF than those with sterile intra-amniotic inflammation, suggesting that these two clinical conditions may be differentiated by using mass spectrometric analysis of amniotic fluid

Gasdermin D: Evidence of pyroptosis in spontaneous preterm labor with sterile intraâ amniotic inflammation or intraâ amniotic infection

ProblemPyroptosis, inflammatory programmed cell death, is initiated through the inflammasome and relies on the poreâ forming actions of the effector molecule gasdermin D. Herein, we investigated whether gasdermin D is detectable in women with spontaneous preterm labor and sterile intraâ amniotic inflammation or intraâ amniotic infection.Method of studyAmniotic fluid samples (n = 124) from women with spontaneous preterm labor were subdivided into the following groups: (a) those who delivered at term (n = 32); and those who delivered preterm (b) without intraâ amniotic inflammation (n = 41), (c) with sterile intraâ amniotic inflammation (n = 32), or (d) with intraâ amniotic infection (n = 19), based on amniotic fluid ILâ 6 concentrations and the microbiological status of amniotic fluid (culture and PCR/ESIâ MS). Gasdermin D concentrations were measured using an ELISA kit. Multiplex immunofluorescence staining was also performed to determine the expression of gasdermin D, caspaseâ 1, and interleukinâ 1β in the chorioamniotic membranes. Flow cytometry was used to detect pyroptosis (active caspaseâ 1) in decidual cells from women with preterm labor and birth. Results(a) Gasdermin D was detected in the amniotic fluid and chorioamniotic membranes from women who underwent spontaneous preterm labor/birth with either sterile intraâ amniotic inflammation or intraâ amniotic infection, but was rarely detected in those without intraâ amniotic inflammation. (b) Amniotic fluid concentrations of gasdermin D were higher in women with intraâ amniotic infection than in those with sterile intraâ amniotic inflammation, and its expression in the chorioamniotic membranes was associated with caspaseâ 1 and ILâ 1β (inflammasome mediators). (c) Decidual stromal cells and leukocytes isolated from women with preterm labor and birth are capable of undergoing pyroptosis given their expression of active caspaseâ 1.ConclusionPyroptosis can occur in the context of sterile intraâ amniotic inflammation and intraâ amniotic infection in patients with spontaneous preterm labor and birthPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152726/1/aji13184.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152726/2/aji13184_am.pd