A Peripheral Immune Signature of Labor Induction

Abstract

Approximately 1 in 4 pregnant women in the United States undergo labor induction. The onset and establishment of labor, particularly induced labor, is a complex and dynamic process influenced by multiple endocrine, inflammatory, and mechanical factors as well as obstetric and pharmacological interventions. The duration from labor induction to the onset of active labor remains unpredictable. Moreover, prolonged labor is associated with severe complications for the mother and her offspring, most importantly chorioamnionitis, uterine atony, and postpartum hemorrhage. While maternal immune system adaptations that are critical for the maintenance of a healthy pregnancy have been previously characterized, the role of the immune system during the establishment of labor is poorly understood. Understanding maternal immune adaptations during labor initiation can have important ramifications for predicting successful labor induction and labor complications in both induced and spontaneous types of labor. The aim of this study was to characterize labor-associated maternal immune system dynamics from labor induction to the start of active labor. Serial blood samples from fifteen participants were collected immediately prior to labor induction (baseline) and during the latent phase until the start of active labor. Using high-dimensional mass cytometry, a total of 1,059 single-cell immune features were extracted from each sample. A multivariate machine-learning method was employed to characterize the dynamic changes of the maternal immune system after labor induction until the establishment of active labor. A cross-validated linear sparse regression model (least absolute shrinkage and selection operator, LASSO) predicted the minutes since induction of labor with high accuracy (R = 0.86, p = 6.7e-15, RMSE = 277 min). Immune features most informative for the model included STAT5 signaling in central memory CD8+ T cells and pro-inflammatory STAT3 signaling responses across multiple adaptive and innate immune cell subsets. Our study reports a peripheral immune signature of labor induction, and provides important insights into biological mechanisms that may ultimately predict labor induction success as well as complications, thereby facilitating clinical decision-making to improve maternal and fetal well-being.

Monocytes and macrophages in pregnancy: The good, the bad, and the ugly*

“…49 The immune profiles of peripheral blood samples collected between induction and active labor paired with mass cytometry and computational algorithms identified maternal immune signatures able to predict time since labor induction. 49 Active labor is characterized by signs of heightened inflammation in maternal circulation, including STAT3 signaling in classical monocytes. 49 Ultimately, trajectories of these models over time revealed that delays in STAT3 and STAT5 signaling pathways are associated with subsequent labor complications.…”

“…49 Active labor is characterized by signs of heightened inflammation in maternal circulation, including STAT3 signaling in classical monocytes. 49 Ultimately, trajectories of these models over time revealed that delays in STAT3 and STAT5 signaling pathways are associated with subsequent labor complications. STAT3 signals the support of cell migration to fetal membranes during labor by interfering with the responsiveness of progesterone.…”

“…51 IL-6 is also important for the stimulation of monocyte and T cell migration to the decidual membranes at the maternal-fetal interface, promoting inflammation and parturition. 49 Concentrations of metabolic hormones, such as leptin and insulin, and several adipokines, such as adipsin and adiponectin, increase in circulation during a healthy pregnancy. 45 Mechanistic studies revealed that leptin utilizes IL-6, via STAT3 and NFκβ pathways, to increase inflammatory cytokine levels and activation markers.…”

Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in the maternal circulation

“…Here, we focused on the maternal monocyte and neutrophil responses to endotoxin, given that these are the primary cellular components of the peripheral blood. Yet, given the proposed involvement of systemic adaptive cellular immunity throughout pregnancy [ 79 – 82 ], future studies should evaluate how peripheral T-cell and B-cell responses differ between pregnant and non-pregnant women.…”

Stress and Its Consequences—Biological Strain

“…Of course, there are likely to be many causative pathways that lead to one final common pathway for preterm parturition as a result of racism. Interestingly, although normal parturition involves inflammation, it is highly programmed with a transition point a little less than one month before the onset of labor, characterized by a shift in gene expression and cell signaling from a disposition of tolerance to one of rejection -labor [13,14]. This biochemical shift is evidence of a transcriptomic or immune clock of pregnancy that can be strained or dysregulated by physical or psychological stressors [11,27,28,29].…”