Adi Laurentiu Tarca

Chronic placental inflammation (CPI), an umbrella term encompassing chronic chorioamnionitis, chronic villitis, and chronic deciduitis, is associated with preterm birth (PTB), yet its cellular and molecular determinants across gestation remain poorly defined. Here, we constructed an integrated multiomic atlas of CPI by profiling placental and extraplacental tissues from preterm and term pregnancies using imaging mass cytometry, single-cell RNA sequencing, spatial transcriptomics, and T cell receptor (TCR) repertoire mining. CPI emerged as a gestational age–dependent immune continuum rather than a uniform inflammatory state. Preterm CPI was characterized by infiltration of cytotoxic CD8 ⁺ T cells, activated macrophages, and natural killer (NK) cells in the extraplacental membranes. In contrast, term CPI exhibited spatially confined immune niches enriched for homeostatic myeloid cells and regulatory T cells. Multiomic integration revealed active contributions from the developing fetal immune system in preterm CPI, including macrophages, T cells, and mast cells that reshaped maternal-fetal immune cross-talk. Cell-cell–communication analyses uncovered proinflammatory signaling states in preterm CPI and resolution-phase pathways in term CPI, whereas TCR repertoire profiling identified memory clonotypes with viral epitope similarity, consistent with antigen-agnostic activation. Overall, this atlas defines the cellular, spatial, and transcriptional architecture of CPI and provides a framework for translational biomarker discovery and therapeutic intervention development.

1. DNA methylation is an epigenetic modification involved primarily in gene expression regulation, embryonic development, and cellular differentiation [1,2]. Its dysregulation has been linked to va...

BACKGROUND: Preeclampsia is classified as either a more severe early onset or a more prevalent late-onset form. Lower PlGF (placental growth factor) and increased sFlt-1 (fms-like tyrosine kinase-1) in maternal circulation are promising biomarkers, yet they lack specificity for preeclampsia. METHODS: We quantified ≈7000 proteins in 673 samples collected from 89 patients with late-onset preeclampsia and 91 controls at T1 (15–22), T2 (22–30), and T3 (30–42) weeks. Elastic net and random forest models were fitted and evaluated by cross-validation. Differential abundance analysis followed by functional profiling, was used to identify and interpret protein changes. RESULTS: An increase in protein differential abundance in late-onset preeclampsia was observed with advancing gestation, reaching 806 proteins at T3 related to angiogenesis, cell adhesion, and extracellular matrix remodeling. FAAH2 (fatty acid amide hydrolase 2), SIGLEC6 (sialic acid-binding Ig-like lectin-6), IL17RC (interleukin-17 receptor C), HTRA1 (serine protease), sFlt-1, and 47 other proteins dysregulated at T3 were validated in a reanalysis of a ≈5000 protein Norwegian data set. Random forest models with 20 proteins showed high accuracy at T3 (area under the curve [AUC], 0.83 [0.77–0.89], sensitivity 59%) even in cases not yet diagnosed at sampling (n=31, AUC, 0.80 [0.71–0.90], sensitivity 58%), outperforming sFlt-1 and PlGF. Moderate accuracy was obtained at T1 (AUC, 0.63 [0.54–0.72], sensitivity 33%) and T2 (AUC, 0.59 [0.50–0.68], sensitivity 17%). Combining maternal characteristics and obstetric history with proteomics data increased accuracy at T1 (AUC, 0.68 [0.59–0.77], sensitivity 28%), T2 (AUC, 0.68 [0.60–0.77], sensitivity 31%), and T3 (AUC, 0.87 [0.81–0.92], sensitivity 69%). CONCLUSIONS: The findings confirm the involvement of abnormal trophoblast invasion, angiogenesis, and extracellular matrix remodeling in late-onset preeclampsia, while highlighting new protein alterations consistent across diverse cohorts.

Background Although a short cervix in the mid-trimester of pregnancy is one of the strongest predictors of preterm birth (i.e., parturition before 37 completed weeks), there is limited understanding of how the dynamics of cervical remodeling (i.e., changes in cervical length) leading up to labor and delivery can inform obstetrical risk. Methods In this study, latent growth curve analysis was applied to serial cervical length measurements across pregnancy (median per subject = 6; IQR = 3–8) to quantify characteristics of cervical change in a cohort of 5111 singleton pregnancies carried by Black American women. Results A conditional mediation model including nine common maternal risk factors of spontaneous preterm birth as exogenous predictors accounts for 26.5% of the variability in gestational duration. The collective evidence supports the conclusion that the effect of common maternal characteristics on spontaneous preterm birth is mediated through cervical length change. Specifically, previous preterm birth, pre-pregnancy BMI, parity, and previous abortion are shown to have unique influences on preterm birth risk that likely operate, in part, through linear changes in the cervix across pregnancy. Conclusions This study provides an account of the intermediary role of cervical dynamics in associations between known maternal risk factors and gestational age at delivery. Although these findings may not be generalizable to all populations, they have the potential to enhance screening efforts for women who are disproportionately affected by health disparities related to preterm birth.

Sonographic cervical length is a powerful predictor of maternal risk for spontaneous preterm birth (sPTB). Twin and family studies have established a maternal genetic heritability for sPTB ranging from 13 to 20%, however, there is no corresponding estimate for the heritability of mid-trimester cervical length, or an understanding of how genetic factors contribute to cervical changes across pregnancy. This study was based on a prospective longitudinal cohort of (N = 5,160) Black/African American women who underwent serial sonographic examination of the uterine cervix during pregnancy and were genotyped via next-generation low-pass whole genome sequencing. Bivariate genetic correlations estimated using genome-wide complex trait analysis (GCTA) indicated that a large proportion of the genes influencing cervical change across pregnancy also influenced gestational duration. SNP-level associations were observed near genes involved in the progesterone, estrogen, and insulin signaling pathways. These results suggest that a large proportion of genetic loci for preterm birth exert their influence through the process of cervical remodeling. Polygenic profiling of maternal genetic liability to cervical shortening could aid in the development of clinical risk assessment tools to identify high-risk women who may benefit from more frequent cervical length screening and earlier interventions to prevent preterm delivery.

Problem: Preeclampsia is a heterogeneous syndrome of diverse etiologies and molecular pathways leading to distinct clinical subtypes. Herein, we aimed to characterize the extracellular vesicle (EV)‐associated and soluble fractions of the maternal plasma proteome in patients with preeclampsia and to assess their value for disease prediction.Method of Study: This case–control study included 24 women with term preeclampsia, 23 women with preterm preeclampsia, and 94 healthy pregnant controls. Blood samples were collected from cases on average 7 weeks before the diagnosis of preeclampsia and were matched to control samples. Soluble and EV fractions were separated from maternal plasma; EVs were confirmed by cryo‐EM, NanoSight, and flow cytometry; and 82 proteins were analyzed with bead‐based, multiplexed immunoassays. Quantile regression analysis and random forest models were implemented to evaluate protein concentration differences and their predictive accuracy. Preeclampsia subgroups defined by molecular profiles were identified by hierarchical cluster analysis. Significance was set at p < 0.05 or false discovery rate‐adjusted q < 0.1.Results: In preterm preeclampsia, PlGF, PTX3, and VEGFR‐1 displayed differential abundance in both soluble and EV fractions, whereas angiogenin, CD40L, endoglin, galectin‐1, IL‐27, CCL19, and TIMP1 were changed only in the soluble fraction (q < 0.1). The direction of changes in the EV fraction was consistent with that in the soluble fraction for nine proteins. In term preeclampsia, CCL3 had increased abundance in both fractions (q < 0.1). The combined EV and soluble fraction proteomic profiles predicted preterm and term preeclampsia with an AUC of 78% (95% CI, 66%–90%) and 68% (95% CI, 56%–80%), respectively. Three clusters of preeclampsia featuring distinct clinical characteristics and placental pathology were identified based on combined protein data.Conclusions: Our findings reveal distinct alterations of the maternal EV‐associated and soluble plasma proteome in preterm and term preeclampsia and identify molecular subgroups of patients with distinct clinical and placental histopathologic features.

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 (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.