TY - JOUR
T1 - Effective Aspirin Treatment of Women at Risk for Preeclampsia Delays the Metabolic Clock of Gestation
AU - Li, Xiqi
AU - Milosavljevic, Aleksandar
AU - Elsea, Sarah H.
AU - Wang, Chi Chiu
AU - Scaglia, Fernando
AU - Syngelaki, Argyro
AU - Nicolaides, Kypros H.
AU - Poon, Liona C.
N1 - Publisher Copyright:
© 2021 American Heart Association, Inc.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - aspirin
KW - gestational age
KW - metabolomics
KW - preeclampsia
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U2 - 10.1161/HYPERTENSIONAHA.121.17448
DO - 10.1161/HYPERTENSIONAHA.121.17448
M3 - Article
C2 - 34225470
AN - SCOPUS:85116069710
SN - 0194-911X
VL - 78
SP - 1398
EP - 1410
JO - Hypertension
JF - Hypertension
IS - 5
ER -