Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset.

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 × 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 × 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.

Myometrial cytokines and their role in the onset of labour.

Human labour is an inflammatory event, physiologically driven by an interaction between hormonal and mechanical factors and pathologically associated with infection, bleeding and excessive uterine stretch. The initiation and communicators of inflammation is still not completely understood; however, a key role for cytokines has been implicated. We summarise the current understanding of the nature and role of cytokines, chemokines and hormones and their involvement in signalling within the myometrium particularly during labour.

Cell-Free Fetal DNA, Telomeres, and the Spontaneous Onset of Parturition.

Multiple previous reports have provided compelling support for the premise that spontaneous parturition is mediated by activation of inflammation-related signaling pathways leading to increased secretion of cytokines and chemokines, the influx of neutrophils and macrophages into the pregnant uterus, increased production of uterine activation proteins (eg, connexin-43, cyclo-oxygenase-2, oxytocin receptors, etc), activation of matrix metalloproteinases, and the release of uterotonins leading to cervical ripening, membrane rupture, and myometrial contractions. The missing link has been the fetal/placental signal that triggers these proinflammatory events in the absence of microbial invasion and intrauterine infection. This article reviews the biomedical literature regarding the increase in cell-free fetal DNA (cffDNA), which is released during apoptosis in the placenta and fetal membranes at term, the ability of apoptosis modified vertebrate DNA to stimulate toll-like receptor-9 (TLR9) leading to increased release of cytokines and chemokines, and the potential "fail-safe" role for the anti-inflammatory cytokine IL-10. This article also reviews the literature supporting the key role that telomere loss plays in regard to increasing the ability of vertebrate (including placental) DNA to stimulate TLR9, and in regard to signaling the onset of apoptosis in the placenta and fetal membranes, thereby providing a biologic clock that determines the length of gestation and the timing for the onset of parturition. In summary, this literature review provides a strong rationale for future research to test the hypothesis that telomere loss and increased cffDNA levels trigger the proinflammatory events leading to the spontaneous onset of parturition in mammals: the "cffDNA/telomere hypothesis."

Transcriptomic profiling of human choriodecidua during term labor: inflammation as a key driver of labor.

PROBLEM: Inflammation is a driver of labor in myometrium and cervix; however, the involvement of decidua is poorly defined. We have reported decidual leukocyte infiltration prior to and during labor; the regulators of these inflammatory processes are unknown. METHOD OF STUDY: Choriodecidua RNA obtained after term labor or elective cesarean delivery was applied to Affymetrix GeneChips. Pathway analysis and gene validation were performed. RESULTS: Extensive inflammatory activation was identified in choriodecidua following labor, predominantly upregulation of genes regulating leukocyte trafficking and cytokine signalling. Genes governing cell fate, tissue remodelling, and translation were also altered. Upregulation of candidate genes (ICAM1, CXCR4, CD44, TLR4, SOCS3, BCL2A, and IDO) was confirmed. NFκB, STAT1&3, HMGB1, and miRNA-21, miRNA-46, miRNA-141, and miRNA-200 were predicted upstream regulators. CONCLUSION: This study confirms inflammatory processes are major players in labor events in choriodecidua, as in other gestational tissues. Suppressing uterine inflammation is likely to be critical for arresting premature labor.

Prevention of preterm labour via the modulation of inflammatory pathways.

Pregnancy is characterized by a complex interplay of inflammatory events regulated by both the innate and acquired immune systems. Similarly, parturition can be viewed as the activation of "pro-labour" inflammatory pathways, which drive cervical ripening and myometrial activation. Premature activation of these pathways, for example, by infection, can lead to preterm labour and birth. Nuclear factor κß is a key modulator of these pathways and functions by regulating the expression of prostaglandins, chemokines and pro-inflammatory cytokines involved in both term and preterm labour. Future design of therapeutics that target key mediators of inflammation and immune activation would therefore be a rational approach for preventing preterm labour and immune-mediated neonatal brain damage.

TLRs, macrophages, and NK cells: our understandings of their functions in uterus and ovary.

Inflammation involves multiple changes in many aspects of immune system. Interactions between immune system and female reproductive system strongly impact fertility and reproductive health in general. Many normal events of female reproduction system including ovulation, menstruation, implantation and labor onset are considered as inflammatory process. Emerging evidence reveals that three components of immune system that are critical to initiate and resolve inflammation, Toll-like receptors (TLRs), macrophages, and natural killer (NK) cells, play important roles not only to provide protection against infections by exogenous pathogens but also to regulate essential functions of uterus and ovary. This review will briefly summarize our understanding of the functions of TLRs, macrophages and NK cells in uterus and ovary.

Spontaneous labor onset: is it immunologically mediated?

OBJECTIVE: The investigators tested the hypothesis that maternal-fetal immune interactions could be important in initiating spontaneous labor onset by examining if labor was delayed when fetuses share maternal HLA antigen types. STUDY DESIGN: HLA antigen types A, B, and DR in 200 Danish mother-infant pairs delivering in 42-44 weeks (postterm) were compared with 195 mother-infant pairs delivering in 37-40 weeks (term). RESULTS: Sharing of HLA A and B antigens was more common than expected in postterm deliveries. Odds ratios were 1.54 (95% confidence interval [CI], 1.01-2.35) and 1.75 (95% CI, 0.87-3.52), respectively (risk per shared antigen: 1.40 [95% CI, 1.04-1.90] per unit increase). Adding stringent birth-length criteria for postmaturity (92 cases; 168 controls) strengthened risks associated with antigen sharing to 1.57 (95% CI, 0.90-2.74) and 2.60 (95% CI, 1.15-5.88), respectively (risk per shared antigen: 1.60 (95% CI, 1.10-2.32). CONCLUSION: Postterm-delivered infants had more HLA A and B antigens in common with their mothers, suggesting that recognition of HLA antigen differences by adaptive immunity may have a role in triggering labor onset.

Allergic women have reduced sHLA-G plasma levels at delivery.

PROBLEM: HLA-G antigen maintains a tolerogenic condition at the foeto-maternal interface, counteracts inflammation in autoimmune diseases and soluble HLA-G (sHLA-G) levels decrease in allergic-asthmatics. Taking into consideration these findings, we analyzed if sHLA-G and interleukin-10 (IL-10) could be influenced by pregnancy and labour in allergic and non-allergic women. METHOD OF STUDY: sHLA-G isoforms and IL-10 levels were determined in the plasma samples of 43 women (15 non-allergic, 28 allergic) during third trimester, at delivery and 2 years after pregnancy by immunoenzymatic assays. RESULTS: A significant increase in sHLA-G and IL-10 levels was documented at delivery in both allergic and non-allergic women. Allergic women showed lower sHLA-G concentrations. sHLA-G1 was evidenced as the predominant plasma isoform. CONCLUSION: The data showed increased sHLA-G and IL-10 concentrations at delivery, regardless of the allergic status. The sHLA-G1 isoform is mainly responsible for the increased sHLA-G levels at delivery.

The role of nuclear factor kappa B in human labour.

Preterm birth remains the leading cause of perinatal mortality and morbidity, largely as a result of a poor understanding of the precise mechanisms controlling labour onset in humans. Inflammation has long been recognised as a key feature of both preterm and term labour, with an influx of inflammatory cells into the uterus and elevated levels of pro-inflammatory cytokines observed during parturition. Nuclear factor kappa B (NF-kappaB) is a transcription factor family classically associated with inflammation. Accumulating evidence points to a role for NF-kappaB in the physiology and pathophysiology of labour. NF-kappaB activity increases with labour onset and is central to multiple prolabour pathways. Premature or aberrant activation of NF-kappaB may thus contribute to preterm labour. The current understanding of NF-kappaB in the context of human labour is discussed here.

Increasing quantity of maternal immunoglobulin G in trophoblastic tissue before the onset of normal labor.

While levels of maternal immunoglobulin G (IgG) increase in the fetal circulation during the third trimester, actual trophoblastic concentrations have not been extensively studied. To investigate this process, placentas from 71 patients with gestational ages between 26 and 42 weeks were examined by means of a peroxidase-antiperoxidase immunostaining technique specific for IgG. Linear regression revealed a significant increase in antibody with advancing gestational age (r = 0.36, p less than 0.01). In addition, placentas from patients in spontaneous term labor revealed a significantly higher antibody level when compared with those of patients at term delivered electively before the onset of labor (mean +/- SEM 2.6 +/- 0.2 vs 1.7 +/- 0.3, p less than 0.02). Patients in premature labor failed to demonstrate this increase in antibody staining. One possible explanation for these findings is an enhanced recognition of the fetal trophoblastic tissue by the maternal immune system at term. It also suggests immunologic factors may play an important role in the initiation of normal labor.

[Preliminary study of immune function of erythrocytes in normal and high-risk pregnant and post-partum women].

The rosette rates of erythrocytes C3b receptor (C3bR) and immune complex (IC) in normal and high-risk pregnant women were measured. The results showed that the rate of C3bR in normal gravidae was significantly higher than that in patients with pregnancy induced hypertensive syndrome (P less than 0.05). The rosette rate of IC in cases of premature rupture of membranes was significantly higher than that in normal pregnant women (P less than 0.01). In this paper, the rosette rates of C3bR and IC in normal gravidae, puerperas, neonates and control adults were compared and discussed.

Infection and labor. III. Interleukin-1: a signal for the onset of parturition.

The regulatory signals responsible for the increased biosynthesis of prostaglandins during parturition have not been established. Because interleukin-1 is capable of stimulating prostaglandin production by intrauterine tissues and is an inflammatory mediator, we propose that interleukin-1 may act as a signal for the onset of human labor in the setting of intrauterine infection. The purpose of these studies was to determine interleukin-1 activity in amniotic fluid and to establish its relationship with the onset of term and preterm labor. Amniotic fluid from 182 patients was assayed for interleukin-1 activity. Cell-associated interleukin-1 activity was detected in fluid obtained in the third trimester but not in fluid obtained in the second trimester of pregnancy, suggesting a maturational event in interleukin-1 production. The factor responsible for interleukin-1 activity had biochemical characteristics of interleukin-1 alpha (estimated molecular weight of 14 kilodaltons, isoelectric point = 4.9), and its activity was blocked with an anti-interleukin-1 alpha antisera. Women in spontaneous labor at term were likely to have fluid phase interleukin-1 activity in amniotic fluid than women who were not in labor at term. Preterm labor in the setting of intraamniotic infections was associated with significant interleukin-1 activity in amniotic fluid. This bioactivity was predominantly attributable to interleukin-1 beta. A strong correlation between interleukin-1 and amniotic fluid concentrations of prostaglandin E2 and prostaglandin F2 alpha was found in women in preterm labor. These findings support the hypothesis that interleukin-1 may play a role in the initiation of preterm labor associated with intraamniotic infection.