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 deliver preterm remains uncertain but could have significant clinical implications.

Objective:

‍We sought to objectively quantify metabolomic profiles of patients at high risk for preterm birth by evaluating mid-trimester maternal plasma, and to measure whether endogenous metabolites and exogenous environmental substances differ among those who ultimately deliver preterm compared to those who deliver at term.

Study design:

‍This was a case-control analysis from a prospective cohort of patients carrying a singleton, non-anomalous gestation who were at high risk for spontaneous preterm birth. Subjects with a plasma blood sample drawn <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 16.0-36.9 weeks’ gestation.

Results:

‍42 patients met inclusion criteria. Of these, 25 (59.5%) delivered preterm <37 weeks’ gestation, at a median 30.14 [interquartile range 28.14 – 34.14] weeks’ gestation. Eight-hundred and twelve molecular features differed between preterm birth cases and term controls with a minimum fold change of 1.2 and p-value <0.05. Of these, 570/812 (70.1%) were found in higher abundances in preterm birth cases; the other 242/812 (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 were 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 21/25 (84%) of preterm birth cases.

Conclusion:

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