Effective Aspirin Treatment of Women at Risk for Preeclampsia Delays the Metabolic Clock of Gestation

Abstract

Preeclampsia, characterized by the onset of hypertension with significant proteinuria after 20 weeks’ gestation, is one of the leading causes of maternal and perinatal morbidity and mortality. Prophylactic low-dose aspirin treatment reduces the rate of preterm preeclampsia in high-risk women, but a significant proportion still develops preeclampsia. The mechanism of the prophylactic response is unknown. Here, the untargeted metabolomics analysis of 144 plasma samples from high-risk pregnant women before (11–13 weeks) and after (20–23 weeks) aspirin/placebo treatment elucidated metabolic effects of aspirin and metabolic differences potentially associated with the variation of the treatment response. We demonstrated that aspirin treatment resulted in a strong drug-associated metabolomics signature and that the preeclamptic or nonpreeclamptic outcome in response to treatment was significantly associated with the level of internal aspirin exposure ascertained from metabolomics data ( t test, P =0.0083). Comparing women with and without preeclampsia after aspirin treatment, differences in 73 metabolites were detected, some of which involve pathways whose regulation is of importance in pregnancy and placental functions, such as glycerophospholipids metabolism, polyunsaturated fatty acid metabolism, and steroid hormone biosynthesis. To further examine the hypothesis that aspirin delays gestational age advancement and thus the onset of preeclampsia, we constructed a metabolic clock on pretreatment and placebo-treated samples that estimated gestational age with high accuracy and found that aspirin significantly decelerated metabolic gestational age by 1.27 weeks (95% CI, 0.66–1.88 weeks), and partially reversed one-fourth of the metabolites changed over gestational age advancement, suggesting that aspirin treatment slowed down the metabolic clock of gestation.

Reply

“…Very recently, a study utilizing untargeted metabolomic analysis of plasma samples of aspirin/placebo-treated ASPRE trial participants has demonstrated that aspirin decreases significantly the metabolic clock-estimated gestational age. In addition, aspirin treatment partially reversed a wide range of metabolic changes over gestation, lending further support to our hypothesis that the benefit of aspirin treatment in preventing pre-eclampsia is mediated through decelerating the metabolic clock of gestation 6 .…”

ASPRE trial: effects of aspirin on mean arterial blood pressure and uterine artery pulsatility index trajectories in pregnancy

“…Although aspirin is highly effective in preventing preterm pre-eclampsia and appears to defer disease onset by delaying placental aging 5,6 , the precise mechanism by which the disease is prevented remains poorly understood. Initial studies in the 1980s were triggered by evidence of increased placental thromboxane and reduced prostacyclin levels in pre-eclamptic pregnancies, and by the then-recent discovery that aspirin selectively inhibits thromboxane synthesis without affecting prostacyclin production 24 .…”

“…However, while appropriate treatment of high-risk women with aspirin initiated in the first trimester is associated with a significant reduction in preterm pre-eclampsia risk, the exact mechanism by which aspirin prevents pre-eclampsia remains unclear. It has been shown that aspirin delays placental aging and disease onset 5,6 , and other theories include improvement in trophoblastic invasion, endothelial stabilization and reduction in inflammation [7][8][9] , but large human studies to support such theories are lacking. The effect of aspirin on biomarkers of pre-eclampsia is also poorly understood, and its knowledge may provide insights into the mechanism of action of the drug.…”

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis

“…Metabolomic analyses were conducted by Metabolon, Inc. using ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS), as previously described [57]. Briefly, samples were analyzed through four different methods: (1) acidic positive ion conditions, chromatographically optimized for more hydrophilic compounds, (2) acidic positive ion conditions optimized for more hydrophobic compounds, (3) basic negative ion optimized conditions using a separate dedicated C18 column, and (4) negative ionization following elution from a HILIC column.…”