Homeostatic Macrophages Prevent Preterm Birth and Improve Neonatal Outcomes by Mitigating In Utero Sterile Inflammation in Mice.

Preterm birth (PTB), often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Most PTB cases involve intra-amniotic inflammation without detectable microorganisms, termed in utero sterile inflammation, for which there is no established treatment. In this study, we propose homeostatic macrophages to prevent PTB and adverse neonatal outcomes caused by in utero sterile inflammation.

Proteomic Profiles of Maternal Plasma Extracellular Vesicles for Prediction of Preeclampsia.

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.

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.

Predicting Spontaneous Preterm Birth Using the Immunome.

Throughout pregnancy, the maternal peripheral circulation contains valuable information reflecting pregnancy progression, detectable as tightly regulated immune dynamics. Local immune processes at the maternal-fetal interface and other reproductive and non-reproductive tissues are likely to be the pacemakers for this peripheral immune "clock." This cellular immune status of pregnancy can be leveraged for the early risk assessment and prediction of spontaneous preterm birth (sPTB).

Immunophenotyping of Leukocytes in Amniotic Fluid.

Immunophenotyping allows for the deep characterization of leukocytes present in biological samples. Here, we describe a complete procedure for the immunophenotyping of amniotic fluid, which can provide information into the immune processes taking place in the amniotic cavity. The protocol describes amniotic fluid cell count determination, processing, and the use of viability, extracellular antibody, and intracellular/intranuclear antibody staining prior to flow cytometer acquisition.

Dissociation of Placental Tissues for Single-Cell Techniques.

The dissociation of whole tissue into single-cell suspensions is a critical step for techniques focused on profiling of individual cells. Here, we describe a protocol for the preparation of high-quality single-cell suspensions from human placental tissues: the basal plate (BP), placental villi (PV), and chorioamniotic membranes (CAM). This protocol also provides guidance for the cryopreservation and recovery of single-cell suspensions for later use.

Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.

Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia.

A mitochondrial regulator protein, MNRR1, is elevated in the maternal blood of women with preeclampsia.

Objective: Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative stress and an anti-angiogenic state play a crucial role. Mitochondria are a major source of cellular reactive oxygen species.

Deciphering maternal-fetal cross-talk in the human placenta during parturition using single-cell RNA sequencing.

Labor is a complex physiological process requiring a well-orchestrated dialogue between the mother and fetus. However, the cellular contributions and communications that facilitate maternal-fetal cross-talk in labor have not been fully elucidated. Here, single-cell RNA sequencing (scRNA-seq) was applied to decipher maternal-fetal signaling in the human placenta during term labor.

Microbiome preterm birth DREAM challenge: Crowdsourcing machine learning approaches to advance preterm birth research.

Every year, 11% of infants are born preterm with significant health consequences, with the vaginal microbiome a risk factor for preterm birth. We crowdsource models to predict (1) preterm birth (PTB; <37 weeks) or (2) early preterm birth (ePTB; <32 weeks) from 9 vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from public raw data via phylogenetic harmonization. The predictive models are validated on two independent unpublished datasets representing 331 samples from 148 pregnant individuals.

Host-microbiome interactions in distinct subsets of preterm labor and birth.

Preterm birth, the leading cause of perinatal morbidity, often follows premature labor, a syndrome whose prevention remains a challenge. To better understand the relationship between premature labor and host-microbiome interactions, we conducted a mechanistic investigation using three preterm birth models. We report that intra-amniotic delivery of LPS triggers inflammatory responses in the amniotic cavity and cervico-vaginal microenvironment, causing vaginal microbiome changes and signs of active labor.

Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes.

Background: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.

Methods: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α.

Immune-featured decidual stromal cells: pregnancy's multitasking superstars.

Pregnancy poses an immunological challenge, since the mother's immune system must adapt to tolerate the developing embryo until birth. The mechanisms governing this maternal-fetal dialogue have traditionally centered on the immune system. Yang et al.

Preeclampsia at term: evidence of disease heterogeneity based on the profile of circulating cytokines and angiogenic factors.

Background: Intravascular inflammation and an antiangiogenic state have been implicated in the pathophysiology of preeclampsia. On the basis of the profiles of their angiogenic/antiangiogenic factors, women with preeclampsia at term may be classified into 2 subgroups with different characteristics and prevalence of adverse outcomes. This study was undertaken to examine whether these 2 subgroups of preeclampsia at term also show differences in their profiles of intravascular inflammation.

Immunosequencing and Profiling of T Cells at the Maternal-Fetal Interface of Women with Preterm Labor and Chronic Chorioamnionitis.

T cells are implicated in the pathophysiology of preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Specifically, maternal decidual T cells infiltrate the chorioamniotic membranes in chronic chorioamnionitis (CCA), a placental lesion considered to reflect maternal anti-fetal rejection, leading to preterm labor and birth. However, the phenotype and TCR repertoire of decidual T cells in women with preterm labor and CCA have not been investigated.

The MNRR1 activator nitazoxanide abrogates lipopolysaccharide-induced preterm birth in mice.

Intra-amniotic inflammation leading to preterm birth is one of the leading causes of neonatal morbidity and mortality. We recently reported that the mitochondrial levels of MNRR1 (Mitochondrial Nuclear Retrograde, Regulator 1; also called CHCHD2, AAG10, or PARK22), an important bi-organellar regulator of cellular function, are reduced in the context of inflammation and that genetic and pharmacological increases in MNRR1 levels can counter the inflammatory profile. Herein, we show that nitazoxanide, a clinically approved drug, is an activator of MNRR1 and abrogates preterm birth in a well-characterized murine model caused by intra-amniotic lipopolysaccharide (LPS) injection.

The Vaginal Microbiota of Pregnant Women Varies with Gestational Age, Maternal Age, and Parity.

The composition of the vaginal microbiota is heavily influenced by pregnancy and may factor into pregnancy complications, including spontaneous preterm birth. However, results among studies have been inconsistent due, in part, to variation in sample sizes and ethnicity. Thus, an association between the vaginal microbiota and preterm labor continues to be debated.

Thymic stromal lymphopoietin participates in the host response to intra-amniotic inflammation leading to preterm labor and birth.

The aim of this study was to establish the role of thymic stromal lymphopoietin (TSLP) in the intra-amniotic host response of women with spontaneous preterm labor (sPTL) and birth. Amniotic fluid and chorioamniotic membranes (CAM) were collected from women with sPTL who delivered at term (n = 30) or preterm without intra-amniotic inflammation (n = 34), with sterile intra-amniotic inflammation (SIAI, n = 27), or with intra-amniotic infection (IAI, n = 17). Amnion epithelial cells (AEC), Ureaplasma parvum, and Sneathia spp.

Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein.

Objective: Mitochondrial dysfunction was observed in acute systemic inflammatory conditions such as sepsis and might be involved in sepsis-induced multi-organ failure. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2), also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1), a bi-organellar protein located in the mitochondria and the nucleus, is implicated in cell respiration, survival, and response to tissue hypoxia. Recently, the reduction of the cellular CHCHD2/MNRR1 protein, as part of mitochondrial dysfunction, has been shown to play a role in the amplification of inflammatory cytokines in a murine model of lipopolysaccharide-induced systemic inflammation.

Further Evidence that an Episode of Premature Labor Is a Pathologic State: Involvement of the Insulin-Like Growth Factor System.

Introduction: Approximately 47% of women with an episode of preterm labor deliver at term; however, their infants are at greater risk of being small for gestational age and for neurodevelopmental disorders. In these cases, a pathologic insult may disrupt the homeostatic responses sustaining pregnancy. We tested the hypothesis of an involvement of components of the insulin-like growth factor (IGF) system.

Differential immunophenotype of circulating monocytes from pregnant women in response to viral ligands.

Background: Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading viruses; however, whether pregnancy alters monocyte responses is still under investigation. Herein, we undertook a comprehensive in vitro study of peripheral monocytes to characterize the differences in phenotype and interferon release driven by viral ligands between pregnant and non-pregnant women.

Microbiome Preterm Birth DREAM Challenge: Crowdsourcing Machine Learning Approaches to Advance Preterm Birth Research.

Globally, every year about 11% of infants are born preterm, defined as a birth prior to 37 weeks of gestation, with significant and lingering health consequences. Multiple studies have related the vaginal microbiome to preterm birth. We present a crowdsourcing approach to predict: (a) preterm or (b) early preterm birth from 9 publicly available vaginal microbiome studies representing 3,578 samples from 1,268 pregnant individuals, aggregated from raw sequences via an open-source tool, MaLiAmPi.

Evidence for the participation of CHCHD2/MNRR1, a mitochondrial protein, in spontaneous labor at term and in preterm labor with intra-amniotic infection.

Objective: Intra-amniotic inflammation (IAI), associated with either microbe (infection) or danger signals (sterile), plays a major role in the pathophysiology of preterm labor and delivery. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2) [also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1)], a mitochondrial protein involved in oxidative phosphorylation and cell survival, is capable of sensing tissue hypoxia and inflammatory signaling. The ability to maintain an appropriate energy balance at the cellular level while adapting to environmental stress is essential for the survival of an organism.