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

Abstract

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.

Understanding Host-Pathogen Interactions in Acute Chorioamnionitis Through the Use of Animal Models

“…New strategies should focus on better prediction of chorioamnionitis and may include the use of omics ( Ngo et al., 2018 ). Integrated trajectories of maternal metabolome, proteome, and immunome could define and characterize the patients at risk ( Pique-Regi et al., 2019 ; Stelzer et al., 2021 ). Treatment strategies may include the modulation of maternal immune responses such as the use of extracellular vesicles (exosomes) or peptides ( Spinelli et al., 2020 ).…”

Inflammatory Amplification: A Central Tenet of Uterine Transition for Labor

“…The authors identified a distinct molecular shift that occurred 2-4 weeks before delivery where pregnancy maintenance transitioned to pre-labor biology. The molecular shift involved metabolomic, proteomic, and immunologic systems and occurred with similar accuracy in both term and preterm women ( Stelzer et al., 2021 ).…”

A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement

“…Both applying approaches developed for other conditions to sepsis and ARDS and developing novel approaches will be necessary. Potential areas for advancement include methods to identify patients who benefit by incorporating combinations of clinical and molecular markers across multiple omics platforms (combining deep phenotyping with HTE identification), as has recently been explored in other non–critical care disorders ( 40 , 41 ), to modify treatment approaches in response to the rapid changes in the host immune response over time, and to use causal modeling when RCT data are sparse and only results of observational studies are available ( 42 ) ( Table 3 ).…”