Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm.

Human parturition at term and preterm is an inflammatory process synchronously executed by both fetomaternal tissues to transition them from a quiescent state t an active state of labor to ensure delivery. The initiators of the inflammatory signaling mechanism can be both maternal and fetal. The placental (fetal)-maternal immune and endocrine mediated homeostatic imbalances and inflammation are well reported. However, the fetal inflammatory response (FIR) theories initiated by the fetal membranes (amniochorion) at the choriodecidual interface are not well established. Although immune cell migration, activation, and production of proparturition cytokines to the fetal membranes are reported, cellular level events that can generate a unique set of inflammation are not well discussed. This review discusses derangements to fetal membrane cells (physiologically and pathologically at term and preterm, respectively) in response to both endogenous and exogenous factors to generate inflammatory signals. In addition, the mechanisms of inflammatory signal propagation (fetal signaling of parturition) and how these signals cause immune imbalances at the choriodecidual interface are discussed. In addition to maternal inflammation, this review projects FIR as an additional mediator of inflammatory overload required to promote parturition.

Preterm labor with and without chorioamnionitis is associated with activation of myometrial inflammatory networks: a comprehensive transcriptomic analysis.

BACKGROUND: The onset of preterm labor is associated with inflammation. Previous studies suggested that this is distinct from the inflammation observed during term labor. Our previous work on 44 genes differentially expressed in myometria in term labor demonstrated a different pattern of gene expression from that observed in preterm laboring and nonlaboring myometria. We found increased expression of inflammatory genes in preterm labor associated with chorioamnionitis, but in the absence of chorioamnionitis observed no difference in gene expression in preterm myometria regardless of laboring status, suggesting that preterm labor is associated with different myometrial genes or signals originating from outside the myometrium. Given that a small subset of genes were assessed, this study aimed to use RNA sequencing and bioinformatics to assess the myometrial transcriptome during preterm labor in the presence and absence of chorioamnionitis. OBJECTIVE: This study aimed to comprehensively determine protein-coding transcriptomic differences between preterm nonlaboring and preterm laboring myometria with and without chorioamnionitis. STUDY DESIGN: Myometria were collected at cesarean delivery from preterm patients not in labor (n=16) and preterm patients in labor with chorioamnionitis (n=8) or without chorioamnionitis (n=6). Extracted RNA from myometrial tissue was prepared and sequenced using Illumina NovaSeq. Gene expression was quantified by mapping the sequence reads to the human reference genome (hg38). Differential gene expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were used to comprehensively interrogate transcriptomic differences and their associated biology. RESULTS: Differential gene expression analysis comparing preterm patients in labor with chorioamnionitis with preterm patients not in labor identified 931 differentially expressed genes, whereas comparing preterm patients in labor without chorioamnionitis with preterm patients not in labor identified no statistically significant gene expression changes. In contrast, gene set enrichment analysis and weighted gene coexpression network analysis demonstrated that preterm labor with and without chorioamnionitis was associated with enrichment of pathways involved in activation of the innate immune system and inflammation, and activation of G protein-coupled receptors. Key genes identified included chemotactic CYP4F3, CXCL8, DOCK2, and IRF1 in preterm labor with chorioamnionitis and CYP4F3, FCAR, CHUK, and IL13RA2 in preterm labor without chorioamnionitis. There was marked overlap in the pathways enriched in both preterm labor subtypes. CONCLUSION: Differential gene expression analysis demonstrated that myometria from preterm patients in labor without chorioamnionitis and preterm patients not in labor were transcriptionally similar, whereas the presence of chorioamnionitis was associated with marked gene changes. In contrast, comprehensive bioinformatic analysis indicated that preterm labor with or without chorioamnionitis was associated with innate immune activation. All causes of preterm labor were associated with activation of the innate immune system, but this was more marked in the presence of chorioamnionitis. These data suggest that anti-inflammatory therapy may be relevant in managing preterm labor of all etiologies.

Golgi Reassembly Stacking Protein 2 Modulates Myometrial Contractility during Labor by Affecting ATP Production.

The mechanism of maintaining myometrial contractions during labor remains unclear. Autophagy has been reported to be activated in laboring myometrium, along with the high expression of Golgi reassembly stacking protein 2 (GORASP2), a protein capable of regulating autophagy activation. This study aimed to investigate the role and mechanism of GORASP2 in uterine contractions during labor. Western blot confirmed the increased expression of GORASP2 in laboring myometrium. Furthermore, the knockdown of GORASP2 in primary human myometrial smooth muscle cells (hMSMCs) using siRNA resulted in reduced cell contractility. This phenomenon was independent of the contraction-associated protein and autophagy. Differential mRNAs were analyzed using RNA sequencing. Subsequently, KEGG pathway analysis identified that GORASP2 knockdown suppressed several energy metabolism pathways. Furthermore, reduced ATP levels and aerobic respiration impairment were observed in measuring the oxygen consumption rate (OCR). These findings suggest that GORASP2 is up-regulated in the myometrium during labor and modulates myometrial contractility mainly by maintaining ATP production.

Preterm labor is a distinct process from term labor following computational analysis of human myometrium.

BACKGROUND: The onset of the term human parturition involves myometrial gene expression changes to transform the uterus from a quiescent to a contractile phenotype. It is uncertain whether the same changes occur in the uterus during preterm labor. OBJECTIVE: This study aimed to compare the myometrial gene expression between term and preterm labor and to determine whether the presence of acute clinical chorioamnionitis or twin gestation affects these signatures. STUDY DESIGN: Myometrial specimens were collected during cesarean delivery from the following 7 different groups of patients: term not in labor (n=31), term labor (n=13), preterm not in labor (n=21), preterm labor with acute clinical chorioamnionitis (n=6), preterm labor with no acute clinical chorioamnionitis (n=9), twin preterm not in labor (n=8), and twin preterm labor with no acute clinical chorioamnionitis (n=5). RNA was extracted, reverse transcribed and quantitative polymerase chain reactions were performed on 44 candidate genes (with evidence for differential expression in human term labor) using the Fluidigm platform. Computational analysis was performed using 2-class unpaired Wilcoxon tests and principal component analysis. RESULTS: Computational analysis revealed that gene expression in the preterm myometrium, irrespective of whether in labor or not in labor, clustered tightly and is clearly different from the term labor and term not-in-labor groups. This was true for both singleton and twin pregnancies. Principal component analysis showed that 57% of the variation was explained by 3 principal components. These 44 genes interact in themes of prostaglandin activity and inflammatory signaling known to be important during term labor, but are not a full representation of the myometrium transcriptional activity. CONCLUSION: The myometrial contractions associated with preterm labor are associated with a pattern of gene expression that is distinct from term labor. Therefore, preterm labor may be initiated by a different myometrial process or processes outside the myometrium.

The role of corticoliberin concentration levels and placental CRH receptors 1 and 2 in the prolongation of pregnancy.

OBJECTIVE: To examine the changes in CRH concentrations in the blood serum of pregnant women and in the placenta of patients after the 41st week of gestation, and to determine its influence on the effectiveness of inducing labor and its progress. MATERIALS AND METHODS: The study group comprised pregnant patients who did not deliver until the 41 week of gestation (n = 114). The control group was divided into two subgroups: patients in whom delivery started spontaneously before the 41st week of gestation (n = 24) and pregnant patients in whom delivery started spontaneously after the 41st week of gestation (n = 23). Blood serum and placenta were obtained from the patients. Corticoliberin originating from blood serum was assessed with the use of ELISA Kit. Parts of the placenta were stained with monoclonal antibodies for the presence of corticoliberin, corticoliberin receptors 1 and 2. RESULTS: No statistically significant differences were found with regard to corticoliberin concentrations in the blood or during a qualitative assessment of the number of CRH R1 in the placenta between the research groups. However, corticoliberin receptor 2 had a statistically higher expression rate in the control group in which the delivery started spontaneously before the 41st week of gestation. CONCLUSION: In post-term pregnancy, the up-regulation of CRH R2 receptor is disturbed with no change in CRH R1 expression, which complicates the initiation of labor despite correct corticoliberin levels in both blood serum and the placenta. Pregnancy duration over 41 weeks and the effectiveness of preinducing or inducing labor do not depend on corticoliberin concentrations.

Transcription factors regulated by cAMP in smooth muscle of the myometrium at human parturition.

Cyclic adenosine monophosphate (cAMP) contributes to maintenance of a quiescent (relaxed) state in the myometrium (i.e. uterine smooth muscle) during pregnancy, which most commonly has been attributed to activation of protein kinase A (PKA). PKA-mediated phosphorylation of cytosolic contractile apparatus components in myometrial smooth muscle cells (mSMCs) are known to promote relaxation. Additionally, PKA also regulates nuclear transcription factor (TF) activity to control expression of genes important to the labour process; these are mostly involved in actin-myosin interactions, cell-to-cell connectivity and inflammation, all of which influence mSMC transition from a quiescent to a contractile (pro-labour) phenotype. This review focuses on the evidence that cAMP modulates the activity of TFs linked to pro-labour gene expression, predominantly cAMP response element (CRE) binding TFs, nuclear factor κB (NF-κB), activator protein 1 (AP-1) family and progesterone receptors (PRs). This review also considers the more recently described exchange protein directly activated by cAMP (EPAC) that may oppose the pro-quiescent effects of PKA, as well as explores findings from other cell types that have the potential to be of novel relevance to cAMP action on TF function in the myometrium.

Maternal Myometrium Metabolomic Profiles in Labor: Preliminary Results.

INTRODUCTION: Parturition involves multiple complex metabolic processes that supply essential metabolites to facilitate fetal delivery. Little is known about the dynamic metabolic responses during labor. OBJECTIVE: To profile the changes of myometrial metabolites between nonlabor and labor. METHODS: The study involved 30 women in nonlabor and 30 in labor who underwent cesarean section. The characteristics of myometrial metabolite changes during parturition were explored through untargeted metabolomic analysis. Data were analyzed by multivariate and univariate statistical analysis. RESULTS: Partial least squares-discriminant analysis plots significantly differentiated between the groups. In total, 392 metabolites were significantly distinct between the groups, among which lipid molecules were predominant. A 75% increase in fatty acids, 67% increase in fatty acid carnitines, 66% increase in glycerophospholipids, 83% increase in mono- and diacylglycerols, and 67% decrease in triacyclglycerols were observed in the patients during labor. Most glucose, amino acid, and steroid hormone metabolism also slightly increased in labor. CONCLUSIONS: An increase in lipolysis, fatty acid oxidation, amino acid catabolism, and steroid hormone metabolism was observed during parturition. The change of lipolysis and fatty acid oxidation is the most significant.

Peptidomics analysis of myometrium tissues in term labor compared with term nonlabor.

Preterm birth (PTB) is a major cause of neonatal mortality, with a poorly understood etiology. The regular contraction of the myometrium was considered as contributing to the etiology of the onset of labor, especially PTB. Thus, studying the mechanism of myometrium contraction is very important for understanding the initiation of labor and also for preventing PTB. Using liquid chromatography-mass spectrometry, we found 322 significantly differential peptides in myometrium tissues between term nonlabor and term labor groups (absolute fold change ≥ 2 and P < .05). We next analyzed length, molecular weights, isoelectric point, and cleavage site of all the different peptides. We, next, analyzed the functions of different peptides through their precursor proteins by Gene Ontology, enrichment and canonical pathway analysis. The results indicated that the extracellular matrix (ECM) played a major role in biological process, the cellular component, and molecular function categories, and revealed that ECM remodeling played a vital role in myometrial contraction. In addition, some known signaling, such as corticotropin-releasing hormone signaling and calcium signaling were proven to be involved in this process. Ingenuity Pathways Analysis upstream regulator analysis suggested that some of the known molecules, which reportedly were very important in labor onset, were included, for example, nuclear factor κB, tubulin, and phosphoinositide 3-kinase. We also identified 23 peptides derived from the precursor protein TITIN, of which 21 peptides sequences from TITIN were located in functional domains. These results suggested that peptides play an important role in labor onset and provide further insight into PTB therapy.

Decrease in SHP-1 enhances myometrium remodeling via FAK activation leading to labor.

Preterm birth is one of the most common complications during human pregnancy and is associated with a dramatic switch within the uterus from quiescence to contractility. However, the mechanisms underlying uterine remodeling are largely unknown. Protein kinases and phosphatases play critical roles in regulating the phosphorylation of proteins involved in the smooth muscle cell functions. In the present study, we found that Src-homology phosphatase type-1 (SHP-1, PTPN6) was significantly decreased in human myometrium in labor compared with that not in labor. Timed-pregnant mice injected intraperitoneally with the specific SHP-1 inhibitor protein tyrosine phosphatase inhibitor I (PTPI-1) manifested significantly preterm labor, with enriched plasmalemmal dense plaques between myometrial cells and increased phosphorylation at Tyr397 and Tyr576/577 sites of focal adhesion kinase (FAK) in myometrial cells, which remained to the time of labor, whereas the phosphorylation levels of ERK1/2 and phosphatidylinositol 3 kinase (PI3K) showed a rapid increase upon PTPI-1 injection but fell back to normal at the time of labor. The Tyr576/577 in FAK played an important role in the interaction between FAK and SHP-1. Knockdown of SHP-1 dramatically increased the spontaneous contraction of human uterine smooth muscle cells (HUSMCs), which was reversed by coinfection of a FAK-knockdown lentivirus. PGF2α downregulated SHP-1 via PLCß-PKC-NF-κB or PI3K-NF-κB pathways, suggesting the regenerative downregulation of SHP-1 enhances the uterine remodeling and plasticity by activating FAK and subsequent focal adhesion pathway, which eventually facilitates myometrium contraction and leads to labor. The study sheds new light on understanding of mechanisms that underlie the initiation of labor, and interventions for modulation of SHP-1 may provide a potential strategy for preventing preterm birth.

Are There Epigenetic Oxytocin-Mediated Effects on the Mother and Infant during Physiological Childbirth?

INTRODUCTION: Studies have shown that long-term positive behavioural and physiological changes are induced in connection with vaginal, physiological birth, and skin-to-skin contact after birth in mothers and babies. Some of these effects are consistent with the effect profile of oxytocin. This scoping review explores whether epigenetic changes of the oxytocin gene and of the oxytocin receptor gene (OTR) are involved in these effects. METHODS: We searched Pubmed, Medline, BioMed Central, Cochrane Library, OVID, and Web of Science for evidence of epigenetic changes in connection with childbirth in humans, with a particular focus on the oxytocin system. RESULTS: There were no published studies identified that were related to epigenetic changes of oxytocin and its receptor in connection with labour, birth, and skin-to-skin contact after birth in mothers and babies. However, some studies were identified that showed polymorphisms of the oxytocin receptor influenced the progress of labour. We also identified studies in which the level of global methylation was measured in vaginal birth and caesarean section, with conflicting results. Some studies identified differences in the level of methylation of single genes linked to various effects, for example, immune response, metabolism, and inflammation. In some of these cases, the level of methylation was associated with the duration of labour or mode of birth. We also identified some studies that demonstrated long-term effects of mode of birth and of skin-to-skin contact linked to changes in oxytocin function. CONCLUSION: There were no studies identified that showed epigenetic changes of the oxytocin system in connection with physiological birth. The lack of evidence, so far, regarding epigenetic changes did not exclude future demonstrations of such effects, as there was a definite role of oxytocin in creating long-term effects during the perinatal period. Such studies may not have been performed. Alternatively, the oxytocin linked effects might be indirectly mediated via other receptors and signalling systems. We conclude that there is a significant lack of research examining long-term changes of oxytocin function and long-term oxytocin mediated adaptive effects induced during physiological birth and skin-to-skin contact after birth in mothers and their infants.

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term.

Prior to and during the process of human labor, maternal circulating leukocytes infiltrate the maternal-fetal interface (choriodecidua) and become activated resembling choriodecidual leukocytes. Since, there is no evidence comparing maternal circulating and choriodecidual leukocytes, herein, we characterized their transcriptome and explored the biological processes enriched in choriodecidual leukocytes. From women undergoing spontaneous term labor we isolated circulating and choriodecidual leukocytes, performed microarray analysis (n = 5) and qRT-PCR validation (n = 9) and interaction network analysis with up-regulated genes. We found 270 genes up-regulated and only 17 genes down-regulated in choriodecidual leukocytes compared to maternal circulating leukocytes. The most up-regulated genes were CCL18, GPNMB, SEPP1, FN1, RNASE1, SPP1, C1QC, and PLTP. The biological processes enriched in choriodecidual leukocytes were cell migration and regulation of immune response, chemotaxis, and humoral immune responses. Our results show striking differences between the transcriptome of choriodecidual and maternal circulating leukocytes. Choriodecidual leukocytes are enriched in immune mediators implicated in the spontaneous process of labor at term.

Cooperative effects of sequential PGF2α and IL-1ß on IL-6 and COX-2 expression in human myometrial cells†.

The change from the state of pregnancy to the state of parturition, which we call uterine transitioning, requires the actions of inflammatory mediators and results in an activated uterus capable of performing the physiology of labor. Interleukin (IL)-1ß and prostaglandin (PG)F2α are two key mediators implicated in preparing the uterus for labor by regulating the expression of uterine activation proteins (UAPs) and proinflammatory cytokines and chemokines. To investigate this process, primary human myometrial smooth muscle cells (HMSMC) isolated from the lower segment of women undergoing elective cesarean sections at term (not in labor) were used to test the inflammatory cytokine and UAP outputs induced by PGF2α and IL-1ß alone or in sequential combinations. PGF2α and IL-1ß regulate mRNA abundance of the PGF2α receptor FP, the IL-1 receptor system, interleukin 6, and other UAPs (OXTR, COX2), driving positive feedback interactions to further amplify their own proinflammatory effects. Sequential stimulation of HMSMC by PGF2α and IL-1ß in either order results in amplified upregulation of IL-6 and COX-2 mRNA and protein, compared to their effects individually. These profound increases were unique to myometrium and not observed with stimulation of human fetal membrane explants. These results suggest that PGF2α and IL-1ß act cooperatively upstream in the birth cascade to maximize amplification of IL-6 and COX-2, to build inflammatory load and thereby promote uterine transition. Targeting PGF2α or IL-1ß, their actions, or intermediates (e.g. IL-6) would be an effective therapeutic intervention for preterm birth prevention or delay.

GIT2 deficiency attenuates inflammation-induced expression of pro-labor mediators in human amnion and myometrial cells†.

Untimely activation of the inflammatory response by sterile or infective insults in uterine tissues can result in preterm birth. Pro-inflammatory cytokines and pathogenic activation of toll-like receptors (TLRs) initiate a biochemical cascade of events leading to myometrial activation and contractility, cervical dilatation, and rupture of the chorioamniotic membranes. GIT2 is a signaling protein known to play a role in innate and adaptive immunity; however, its role in the inflammatory pathways of human labor is not known. In this article, we report that GIT2 expression is lower in human myometrium and fetal membranes with term labor, and in preterm amnion with histological chorioamnionitis. GIT2 knockdown by siRNA in primary myometrial and amnion cells exhibited reduced expression of pro-inflammatory cytokines and chemokines in response to inflammatory challenge by cytokines or TLR ligands. In addition, the pro-inflammatory cytokines IL1B and TNF could not induce the expression of extracellular matrix degrading enzymes in GIT2-deficient amnion cells. Myometrial activation in response to pro-inflammatory cytokines was also significantly suppressed in GIT2-deficient cells as evidenced by decreased prostaglandin release and expression of contraction-associated proteins. Further to this, collagen gel assays demonstrated that TNF had a reduced ability to induce myometrial contractility in situ in GIT2-deficient myometrial cells compared to control-transfected cells. In summary, the loss of GIT2 diminishes the effects inflammatory mediators have in promoting myometrial contraction and fetal membrane rupture in vitro, suggesting that GIT2 could be a possible target for preterm birth therapies.

Interplay of transcriptional signaling by progesterone, cyclic AMP, and inflammation in myometrial cells: implications for the control of human parturition.

Parturition involves cellular signaling changes driven by the complex interplay between progesterone (P4), inflammation, and the cyclic adenosine monophosphate (cAMP) pathway. To characterize this interplay, we performed comprehensive transcriptomic studies utilizing eight treatment combinations on myometrial cell lines and tissue samples from pregnant women. We performed genome-wide RNA-sequencing on the hTERT-HM${}^{A/B}$ cell line treated with all combinations of P4, forskolin (FSK) (induces cAMP), and interleukin-1$\beta$ (IL-1$\beta$). We then performed gene set enrichment and regulatory network analyses to identify pathways commonly, differentially, or synergistically regulated by these treatments. Finally, we used tissue similarity index (TSI) to characterize the correspondence between cell lines and tissue phenotypes. We observed that in addition to their individual anti-inflammatory effects, P4 and cAMP synergistically blocked specific inflammatory pathways/regulators including STAT3/6, CEBPA/B, and OCT1/7, but not NF$\kappa$B. TSI analysis indicated that FSK + P4- and IL-1$\beta$-treated cells exhibit transcriptional signatures highly similar to non-laboring and laboring term myometrium, respectively. Our results identify potential therapeutic targets to prevent preterm birth and show that the hTERT-HM${}^{A/B}$ cell line provides an accurate transcriptional model for term myometrial tissue.

Novel anti-inflammatory actions of TIPE2 in human primary amnion and myometrial cells.

Inflammation plays a pivotal role in the terminal process of human labor and delivery, including myometrial contractions and membrane rupture. TNF-alpha-induced protein 8-like-2 (TIPE2) is a novel inflammation regulator; however, there are no studies on the role of TIPE2 in human labor. We report that in myometrium, there is decreased TIPE2 mRNA expression during late gestation which was further decreased in labor. In fetal membranes, TIPE2 mRNA expression was decreased with both term and preterm labor compared to no labor samples. Knockdown of TIPE2 by siRNA in primary myometrium and amnion cells was associated with an augmentation of IL1B and TNF-induced expression of pro-inflammatory cytokines and chemokines; expression of contraction-associated proteins and secretion of the uterotonic prostaglandin PGF2α and expression of extracellular matrix degrading enzymes. In TIPE2-deficient myometrial cells treated with inhibitors of NF-κB or ERK1/2, the secretion of pro-labor mediators was reduced back to control levels. In conclusion, these in vitro experiments indicate that loss of TIPE2 exacerbates the inflammatory response.

Physiological and psychological stress responses to labor and delivery as expressed by salivary cortisol: a prospective study.

BACKGROUND: Labor is considered a stressful event, yet no study has described the course of stress measured by cortisol during labor and postpartum. OBJECTIVE: The objective of the study was to describe the patterns of physiological and psychological stress during labor as measured by salivary cortisol concentrations and stress questionnaires and their correlation to obstetric and neonatal outcomes. STUDY DESIGN: This prospective, observational study included 167 women with low-risk, singleton, term deliveries at a tertiary academic center. Physiological stress was evaluated by salivary cortisol measurements and emotional stress by questionnaire (stress scale ranging from 0 to 10) during the latent phase, active phase, and full dilation stages of labor as well as 2 minutes, 2 hours, and 24 hours after delivery. Cord blood cortisol and pH were also obtained. Modes of delivery, complications during labor and delivery, and early neonatal outcomes were evaluated. RESULTS: Salivary cortisol concentrations increased gradually from latent phase to active phase. The maximum increase was observed within 2 minutes of the delivery (from an average of 1.06 µg/dL to 1.67 µg/dL; 57% increase). Within 2 hours after delivery, cortisol decreased and reached a nongravid concentration after 24 hours (0.16 µg/dL). Cortisol concentrations during labor and up to 2 hours postpartum were above the average concentration of nongravid women (0.5 µg/dL). Women with epidural anesthesia had lower cortisol concentrations at complete dilation (P = .026) and 2 hours postpartum (P = .016) compared with women without epidural. Psychological stress peaked during latent and full dilation phases (mean 4.56 and 4.29, respectively). Maximum decrease from 4.29 to 2.04 (52%) occurred immediately postpartum. Cord cortisol was higher among women delivered by vacuum extraction compared with spontaneous vaginal delivery (17 ± 2 vs 11 ± 3.8, P = .03). CONCLUSION: This study reveals the course of cortisol concentrations during labor for low-risk pregnancies, with maximum increase immediately postpartum. Subjective stress levels decreased over the course of labor. Salivary cortisol portrays stress during labor and may be used as a reference to evaluate complicated pregnancies and to evaluate the role of cortisol during these deliveries.

Assessment of Placental Cortisol Pathway Gene Expression in Term Pregnant Women with Anxiety.

INTRODUCTION: The aim of this study was to expand on this field of work by examining, within a cohort of pregnant women with diagnosed clinical anxiety, the mRNA expression of a panel of genes associated with the cortisol pathway and comparing them to controls. METHODS: Placental samples were obtained from 24 pregnant women, 12 with a diagnosed anxiety disorder and 12 with no psychiatric history, within 30 min of delivery. Differential expression analysis of 85 genes known to be involved in glucocorticoid synthesis, metabolism or signalling was conducted for the: (1) full sample, (2) those at term without labour (5 cases, 7 controls) and (3) those at term with labour (7 cases, 5 controls). Correlation analyses between gene expression and measures of anxiety and depressive symptom severity were also conducted. RESULTS: No robust difference in placental gene expression between pregnant women with and without anxiety disorder was found nor did we detect robust differences by labour status. However, correlational analyses putatively showed a decrease in PER1 expression was associated with an increase in anxiety symptom severity, explaining up to 32% of the variance in anxiety symptom severity. DISCUSSION: Overall, the strongest correlation was found between a decrease in placental PER1 expression and increased anxiety scores. Labour status was found to have a profound effect on mRNA expression. The placental samples obtained from women following labour produced greater numbers of significant differences in mRNA species expression suggesting that in long-standing anxiety the placenta may respond differently under conditions of chronic stress.

Role of leucocyte caspase-1 activity in epidural-related maternal fever: a single-centre, observational, mechanistic cohort study.

BACKGROUND: Epidural-related maternal fever (ERMF) has been reported in ∼26% of labouring women. The underlying mechanisms remain unclear. We hypothesised that ERMF is promoted by bupivacaine disrupting cytokine production/release from mononuclear leucocytes [mononuclear fraction (MNF)]. We examined whether bupivacaine (i) reduces caspase-1 activity and release of the anti-pyrogenic cytokine interleukin (IL)-1 receptor antagonist (IL-1ra), and (ii) is pro-inflammatory through mitochondrial injury/IL-1ß. METHODS: In labouring women, blood samples were obtained before/after epidural analgesia was implemented. Maternal temperature was recorded hourly for the first 4 h of epidural analgesia. Time-matched samples/temperatures were obtained from labouring women without epidural analgesia, pregnant non-labouring, and non-pregnant women. The primary clinical outcome was change in maternal temperature over 4 h after the onset of siting epidural catheter/enrolment. The secondary clinical outcome was development of ERMF (temperature ≥ 38°C). The effect of bupivacaine/saline on apoptosis, caspase-1 activity, intracellular IL-1ra, and plasma IL-1ra/IL-1ß ratio was quantified in MNF from labouring women or THP-1 monocytes (using flow cytometry, respirometry, or enzyme-linked immunosorbent assay). RESULTS: Maternal temperature increased by 0.06°C h-1 [95% confidence interval (CI): 0.03-0.09; P=0.003; n=38] after labour epidural placement. ERMF only occurred in women receiving epidural analgesia (five of 38; 13.2%). Bupivacaine did not alter MNF or THP-1 apoptosis compared with saline control, but reduced caspase-1 activity by 11% (95% CI: 5-17; n=10) in MNF from women in established labour. Bupivacaine increased intracellular MNF IL-1ra by 25% (95% CI: 10-41; P<0.001; n=10) compared with saline-control. Epidural analgesia reduced plasma IL-1ra/IL-1ß ratio (mean reduction: 14; 95% CI: 7-30; n=30) compared with women without epidural analgesia. CONCLUSIONS: Impaired release of anti-pyrogenic IL-1ra might explain ERMF mechanistically. Immunomodulation by bupivacaine during labour could promote ERMF.

Epigenetic regulation of progesterone receptors and the onset of labour.

Progesterone plays a crucial role in maintaining pregnancy by promoting myometrial quiescence. The withdrawal of progesterone action signals the end of pregnancy and, in most mammalian species, this is achieved by a rapid fall in progesterone concentrations. However, in humans circulating progesterone concentrations remain high up to and during labour. Efforts to understand this phenomenon led to the 'functional progesterone withdrawal' hypothesis, whereby the pro-gestation actions of progesterone are withdrawn, despite circulating concentrations remaining elevated. The exact mechanism of functional progesterone withdrawal is still unclear and in recent years has been the focus of intense research. Emerging evidence now indicates that epigenetic regulation of progesterone receptor isoform expression may be the crucial mechanism by which functional progesterone withdrawal is achieved, effectively precipitating human labour despite high concentrations of circulating progesterone. This review examines current evidence that epigenetic mechanisms play a role in determining whether the pro-gestation or pro-contractile isoform of the progesterone receptor is expressed in the pregnant human uterus. We explore the mechanism by which these epigenetic modifications are achieved and, importantly, how these underlying epigenetic mechanisms are influenced by known regulators of uterine physiology, such as prostaglandins and oestrogens, in order to phenotypically transform the pregnant uterus and initiate labour.

Assessment of gastric emptying of maltodextrin, coffee with milk and orange juice during labour at term using point of care ultrasound: a non-inferiority randomised clinical trial.

Labouring women have been shown to have slower gastric emptying than non-pregnant subjects, and this argument is sometimes used to recommend fasting guidelines such as nil-by-mouth during labour. We performed a parallel group, randomised non-inferiority trial, comparing gastric emptying of 450 ml isocalorically-adjusted maltodextrin, coffee with milk or pulp-free orange juice, with 18 women in each group. The women were initially fasted for 2 h for clear fluids, 6 h for a light meal and 8 h for a high fat or high protein meal. We performed gastric ultrasound in the semirecumbent-right lateral decubitus position. Gastric antral area was measured at baseline and at 5 min, 30 min, 60 min, 90 min and 120 min. Gastric emptying of maltodextrin was significantly faster than coffee with milk (p < 0.001) and orange juice (p < 0.001). There was no statistically significant difference between pulp-free orange juice and coffee with milk (p = 0.97). The estimated gastric residual volume was lower than baseline from 90 min after drinking maltodextrin. In labouring women, maltodextrin is cleared from the stomach faster than coffee with milk and orange juice. Gastric emptying depends on other factors besides the caloric load and volume of the drink.