Metabolites from midtrimester plasma of pregnant patients at high risk for preterm birth

Abstract

Background: There is an increased awareness regarding the association between exposure to environmental contaminants and adverse pregnancy outcomes including preterm birth. Whether an individual's metabolic profile can be utilized during pregnancy to differentiate the subset of patients who are ultimately destined to delivered preterm remains uncertain but could have MEANINGFUL clinical implications.

Objective: We sought to objectively quantify metabolomic profiles of patients at high risk of preterm birth by evaluating midtrimester maternal plasma and to measure whether endogenous metabolites and exogenous environmental substances differ among those who ultimately deliver preterm compared with those who deliver at term.

Study design: This was a case-control analysis from a prospective cohort of patients carrying a singleton, nonanomalous gestation who were at high risk of spontaneous preterm birth. Subjects with a plasma blood sample drawn at <28 weeks' gestation and no evidence of preterm labor at the time of enrollment were included. Metabolites were extracted from frozen samples, and metabolomic analysis was performed using liquid chromatography/mass spectrometry. The primary outcome was preterm birth at 16.0 to 36.9 weeks' gestation.

Results: A total of 42 patients met the inclusion criteria. Of these, 25 (59.5%) delivered preterm at <37 weeks' gestation, at a median of 30.14 weeks' gestation (interquartile range, 28.14-34.14). A total of 812 molecular features differed between preterm birth cases and term controls with a minimum fold change of 1.2 and P<.05. Of these, 570 of 812 (70.1%) were found in higher abundances in preterm birth cases; the other 242 of 812 (29.9%) were in higher abundance in term birth controls. The identity of the small molecule/compound represented by the molecular features differing statistically between preterm birth cases and term controls was identified as ranging from those involved with endogenous metabolic pathways (including lipid catabolism, steroids, and steroid-related molecules) to exogenous exposures (including avocadyne, diosgenin, polycyclic aromatic hydrocarbons, acetaminophen metabolites, aspartame, and caffeine). Random forest analyses evaluating the relative contribution of each of the top 30 compounds in differentiating preterm birth and term controls accurately classified 21 of 25 preterm birth cases (84%).

Conclusion: Both endogenous metabolites and exogenous exposures differ in maternal plasma in the midtrimester among patients who ultimately delivered preterm compared with those who deliver at term.

Keywords: endogenous metabolic pathways; environmental exposures; exogenous exposures; metabolomics; preterm birth.

FIGURE 1. Total ion chromatogram metabolomic cloud plot

Showing 812 ion features differing in preterm birth cases and term birth controls (fold change, ≥1.2; P<.05). Mass-to-charge ratios (y-axis) are plotted over chromatographic retention time (x-axis). The radius of each circle indicates the relative scale of fold change comparing the 2 groups.

FIGURE 2. Partial least squares discriminant analysis results summary

Demonstrating differentiation of preterm birth cases and term controls. Each dot represents 1 subject.

FIGURE 3. Random forest variable importance plot with top 30 compounds (y-axis)

Contributing most to the accuracy of the random forest prediction model.

FIGURE 4. MetaMapp network

As an integrated view of significant group-differentiating compounds as clustered in biochemical and chemical contexts.