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. First, a single-cell atlas of the human placenta was established, demonstrating that maternal and fetal cell types underwent changes in transcriptomic activity during labor. Cell types most affected by labor were fetal stromal and maternal decidual cells in the chorioamniotic membranes (CAMs) and maternal and fetal myeloid cells in the placenta. Cell-cell interaction analyses showed that CAM and placental cell types participated in labor-driven maternal and fetal signaling, including the collagen, C-X-C motif ligand (CXCL), tumor necrosis factor (TNF), galectin, and interleukin-6 (IL-6) pathways. Integration of scRNA-seq data with publicly available bulk transcriptomic data showed that placenta-derived scRNA-seq signatures could be monitored in the maternal circulation throughout gestation and in labor. Moreover, comparative analysis revealed that placenta-derived signatures in term labor were mirrored by those in spontaneous preterm labor and birth. Furthermore, we demonstrated that early in gestation, labor-specific, placenta-derived signatures could be detected in the circulation of women destined to undergo spontaneous preterm birth, with either intact or prelabor ruptured membranes. Collectively, our findings provide insight into the maternal-fetal cross-talk of human parturition and suggest that placenta-derived single-cell signatures can aid in the development of noninvasive biomarkers for the prediction of preterm birth.

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. OBJECTIVE: This study aimed to determine the plasma profiles of cytokines and chemokines in women with preeclampsia at term who had a normal or an abnormal angiogenic profile. STUDY DESIGN: A nested case-control study was conducted to include women classified into 3 groups: women with an uncomplicated pregnancy (n=213) and women with preeclampsia at term with a normal (n=55) or an abnormal (n=41) angiogenic profile. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 multiple of the median <10th percentile for gestational age. Concentrations of cytokines were measured by multiplex immunoassays. RESULTS: Women with preeclampsia at term and an abnormal angiogenic profile showed evidence of the greatest intravascular inflammation among the study groups. These women had higher plasma concentrations of 5 cytokines (interleukin-6, interleukin-8, interleukin-12/interleukin-23p40, interleukin-15, and interleukin-16) and 7 chemokines (eotaxin, eotaxin-3, interferon-γ inducible protein-10, monocyte chemotactic protein-4, macrophage inflammatory protein-1ß, macrophage-derived chemokine, and thymus and activation-regulated chemokine compared to women with an uncomplicated pregnancy. By contrast, women with preeclampsia at term and a normal angiogenic profile, compared to women with an uncomplicated pregnancy, had only a higher plasma concentration of monocyte chemotactic protein-4. A correlation between severity of the antiangiogenic state, blood pressure, and plasma concentrations of a subset of cytokines was observed. CONCLUSION: Term preeclampsia can be classified into 2 clusters. One is characterized by an antiangiogenic state coupled with an excessive inflammatory process, whereas the other has neither of these features. These findings further support the heterogeneity of preeclampsia at term and may explain the distinct clinical outcomes.

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. In this study, we used phenotyping, TCR sequencing, and functional assays to elucidate the molecular characteristics and Ag specificity of T cells infiltrating the chorioamniotic membranes in women with CCA who underwent term or preterm labor. Phenotyping indicated distinct enrichment of human decidual effector memory T cell subsets in cases of preterm labor with CCA without altered regulatory T cell proportions. TCR sequencing revealed that the T cell repertoire of CCA is characterized by increased TCR richness and decreased clonal expansion in women with preterm labor. We identified 15 clones associated with CCA and compared these against established TCR databases, reporting that infiltrating T cells may possess specificity for maternal and fetal Ags, but not common viral Ags. Functional assays demonstrated that choriodecidual T cells can respond to maternal and fetal Ags. Collectively, our findings provide, to our knowledge, novel insight into the complex processes underlying chronic placental inflammation and further support a role for effector T cells in the mechanisms of disease for preterm labor and birth. Moreover, this work further strengthens the contribution of adaptive immunity to the syndromic nature of preterm labor and birth.

Clinical chorioamnionitis at term X: microbiology, clinical signs, placental pathology, and neonatal bacteremia - implications for clinical care.

OBJECTIVES: Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5-12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. The objectives of this study were to determine the (1) amniotic fluid microbiology using cultivation and molecular microbiologic techniques; (2) diagnostic accuracy of the clinical criteria used to identify patients with intra-amniotic infection; (3) relationship between acute inflammatory lesions of the placenta (maternal and fetal inflammatory responses) and amniotic fluid microbiology and inflammatory markers; and (4) frequency of neonatal bacteremia. METHODS: This retrospective cross-sectional study included 43 women with the diagnosis of clinical chorioamnionitis at term. The presence of microorganisms in the amniotic cavity was determined through the analysis of amniotic fluid samples by cultivation for aerobes, anaerobes, and genital mycoplasmas. A broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry was also used to detect bacteria, select viruses, and fungi. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin-6 (IL-6) concentration ≥2.6 ng/mL. RESULTS: (1) Intra-amniotic infection (defined as the combination of microorganisms detected in amniotic fluid and an elevated IL-6 concentration) was present in 63% (27/43) of cases; (2) the most common microorganisms found in the amniotic fluid samples were Ureaplasma species, followed by Gardnerella vaginalis; (3) sterile intra-amniotic inflammation (elevated IL-6 in amniotic fluid but without detectable microorganisms) was present in 5% (2/43) of cases; (4) 26% of patients with the diagnosis of clinical chorioamnionitis had no evidence of intra-amniotic infection or intra-amniotic inflammation; (5) intra-amniotic infection was more common when the membranes were ruptured than when they were intact (78% [21/27] vs. 38% [6/16]; p=0.01); (6) the traditional criteria for the diagnosis of clinical chorioamnionitis had poor diagnostic performance in identifying proven intra-amniotic infection (overall accuracy, 40-58%); (7) neonatal bacteremia was diagnosed in 4.9% (2/41) of cases; and (8) a fetal inflammatory response defined as the presence of severe acute funisitis was observed in 33% (9/27) of cases. CONCLUSIONS: Clinical chorioamnionitis at term, a syndrome that can result from intra-amniotic infection, was diagnosed in approximately 63% of cases and sterile intra-amniotic inflammation in 5% of cases. However, a substantial number of patients had no evidence of intra-amniotic infection or intra-amniotic inflammation. Evidence of the fetal inflammatory response syndrome was frequently present, but microorganisms were detected in only 4.9% of cases based on cultures of aerobic and anaerobic bacteria in neonatal blood.

Intertwin time interval: how it affects the immediate neonatal outcome of the second twin.

OBJECTIVE: Customarily 30 minutes is used as the upper limit of intertwin birth times. This study was conducted to define factors that influence the immediate neonatal outcome of the second twin and to assess whether a valid cutoff time is evident. STUDY DESIGN: We evaluated all live born viable vaginal twin deliveries (144) between November 1997 and December 2003. The relationship between intertwin birth time and neonatal outcome was then evaluated continuously and in 15 to 30-minute intervals. RESULTS: In multivariate analysis, only intertwin birth time predicted umbilical cord pH. Arterial/venous pH decreased linearly at a rate of 0.00063 and 0.00081 U/min. Venous pH was significantly lower in later 15-minute intervals compared with earlier ones (P = .002), and in patients delivering before or after a 30-minute cutoff (7.31 vs 7.26, P = .012). CONCLUSION: Our study confirmed that longer intertwin birth time is associated with a continuous slow decline in umbilical cord pH. However, the small differences in pH were not large enough to impact clinical management.