Abstract
Term preeclampsia (tPE), ≥37 weeks, is the most common form of PE and the most difficult to predict. Little is known about its pathogenesis. This study aims to elucidate the pathogenesis and assess early prediction of tPE using serial integrated metabolomic and proteomic systems biology approaches. Serial first- (11–14 weeks) and third-trimester (30–34 weeks) serum samples were analyzed using targeted metabolomic (1H NMR and DI-LC-MS/MS) and proteomic (MALDI-TOF/TOF-MS) platforms. We analyzed 35 tPE cases and 63 controls. Serial first- (sphingomyelin C18:1 and urea) and third-trimester (hexose and citrate) metabolite screening predicted tPE with an area under the receiver operating characteristic curve (AUC) (95% CI) = 0.817 (0.732–0.902) and a sensitivity of 81.6% and specificity of 71.0%. Serial first [TATA box binding protein-associated factor (TBP)] and third-trimester [Testis-expressed sequence 15 protein (TEX15)] protein biomarkers highly accurately predicted tPE with an AUC (95% CI) of 0.987 (0.961–1.000), sensitivity 100% and specificity 98.4%. Integrated pathway over-representation analysis combining metabolomic and proteomic data revealed significant alterations in signal transduction, G protein coupled receptors, serotonin and glycosaminoglycan metabolisms among others. This is the first report of serial integrated and combined metabolomic and proteomic analysis of tPE. High predictive accuracy and potentially important pathogenic information were achieved.
Highlights
Preeclampsia (PE) is a common obstetric disorder seen in 3–5% of pregnancies in developed countries[1]
For the first trimester: glucose, putrescine, PCaaC40:6, urea and dimethyl sulfone and for the third trimester: serotonin, t4-OH-proline, hexose, acetic acid and dimethyl sulfone were significantly altered in Term PE (tPE) after controlling for multiple comparisons (p-value < 0.05)
Late-onset PE, the majority of which are tPE cases is associated with micro-vascular disorders such as hypertension, diabetes and obesity decades after the obstetric manifestations[23]
Summary
Preeclampsia (PE) is a common obstetric disorder seen in 3–5% of pregnancies in developed countries[1]. Substantial evidence exists, based on placental histology[2], maternal demographic characteristics[3], biochemical[4] and uterine artery Doppler[5] data, suggesting that PE might be two distinct disorders These include an early-onset variety requiring delivery at
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