Low-dose aspirin, which selectively inhibits thromboxane synthesis, is now standard of care for the prevention of preeclampsia in at risk women, but some women still develop preeclampsia despite an aspirin regimen. To explore the “aspirin failures,” we undertook a comprehensive evaluation of placental lipids to determine if abnormalities in non-aspirin sensitive lipids might help explain why some women on low-dose aspirin develop preeclampsia. We studied placentas from women with normal pregnancies and women with preeclampsia. Placental villous explants were cultured and media analyzed by mass spectrometry for aspirin-sensitive and non-aspirin-sensitive lipids. In women who developed severe preeclampsia and delivered preterm, there were significant elevations in non-aspirin-sensitive lipids with biologic actions that could cause preeclampsia. There were significant increases in 15- and 20-hydroxyeicosatetraenoic acids and sphingolipids: d-e-C18:0 ceramide, d-e-C18:0 sphingomyelin, d-e-sphingosine-1-phosphate, and d-e-sphinganine-1-phosphate. With regard to lipids sensitive to aspirin, there was no difference in placental production of thromboxane or prostacyclin, but prostaglandins were lower. There was no difference for isoprostanes, but surprisingly, anti-inflammatory omega 3 and 6 PUFAs were increased. In total, 10 of 30 eicosanoids and 5 of 42 sphingolipids were abnormal in women with severe early onset preeclampsia. Lipid changes in women with mild preeclampsia who delivered at term were of lesser magnitude with few significant differences. The placenta produces many aspirin-sensitive and non-aspirin-sensitive lipids. Abnormalities in eicosanoids and sphingolipids not sensitive to aspirin might explain why some aspirin-treated women develop preeclampsia.
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This work was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development Grant 1 U01 HD087198 (SWW, CEC) and by the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Office of Research Subjects Protection of Virginia Commonwealth University (HM20005160) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Electronic Supplementary Material
All eicosanoid and sphingolipid data for normal pregnancy, mild preeclampsia and severe preeclampsia are presented in the Supplemental Figures.
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Walsh, S.W., Reep, D.T., Alam, S.M.K. et al. Placental Production of Eicosanoids and Sphingolipids in Women Who Developed Preeclampsia on Low-Dose Aspirin. Reprod. Sci. (2020). https://doi.org/10.1007/s43032-020-00234-2
- Low-dose aspirin