Potential of Pravastatin for the Prevention and Treatment of Preeclampsia
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Abstract
Preeclampsia (PE) is a severe pregnancy complication affecting 5–10% of pregnancies worldwide and remains a leading cause of maternal and neonatal morbidity and mortality. Although low-dose aspirin is widely used for prevention, its efficacy is limited, necessitating the development of novel therapeutic strategies. This review examines the potential of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, as a preventive and therapeutic agent for PE.
Pravastatin exerts pleiotropic effects, including upregulation of placental growth factor, suppression of soluble fms-like tyrosine kinase-1, and anti-inflammatory and antioxidative properties. Preclinical studies demonstrate its ability to mitigate PE-like symptoms in animal models, whereas clinical studies suggest its potential to reduce the incidence of severe PE in high-risk pregnancies. However, its effectiveness is limited when administered after 35 weeks of gestation, and its optimal dosage remains undetermined.
Building on existing clinical evidence, well-designed large-scale randomized controlled trials are crucial to establish the safety and efficacy of pravastatin in PE prevention. Further research is needed to evaluate its potential for reducing long-term cardiovascular risk in women with a history of PE. An ongoing clinical trial in Japan (jRCTs031230067) aims to address these gaps and contribute to future PE prevention strategies.
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References
GBD 2015 Child Mortality Collaborators. Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388: 1725-74.
GBD 2015 Child Mortality Collaborators. Global, regional, and national levels of maternal mortality, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388: 1775-812.
Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ 2019;366:l2381.
Montgomery KS, Hensley C, Winseman A, Marshall C, Robles A. A systematic review of complications following pre-eclampsia. Matern Child Health J 2024;28:1876-85.
Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335:974.
Ferreira I, Peeters LL, Stehouwer CD. Preeclampsia and increased blood pressure in the offspring: meta-analysis and critical review of the evidence. J Hypertens 2009;27:1955-9.
Poon LC, Kametas NA, Chelemen T, Leal A, Nicolaides KH. Maternal risk factors for hypertensive disorders in pregnancy: a multivariate approach. J Hum Hypertens 2010;24:104-10.
Francisco C, Wright D, Benko Z, Syngelaki A, Nicolaides KH. Hidden high rate of pre-eclampsia in twin compared with singleton pregnancy. Ultrasound Obstet Gynecol 2017;50:88-92.
Wongcharoenrut K, Yamasmit W. Outcomes of pregnancy with chronic hypertension. Thai J Obstet Gynaecol 2014;22:8-14.
Aksornphusitaphong A, Phupong V. Risk factors of early and late onset pre-eclampsia. J Obstet Gynaecol Res 2013;39:627-31.
Chantanahom N, Phupong V. Clinical risk factors for preeclampsia in twin pregnancies. PLoS One 2021;16:e0249555.
Luealon P, Phupong V. Risk factors of preeclampsia in Thai women. J Med Assoc Thai 2010;93:661-6.
Allen R, Rogozinska E, Sivarajasingam P, Khan KS, Thangaratinam S. Effect of diet- and lifestyle-based metabolic risk-modifying interventions on preeclampsia: a meta-analysis. Acta Obstet Gynecol Scand 2014;93:973-85.
Chelbi ST, Vaiman D. Genetic and epigenetic factors contribute to the onset of preeclampsia. Mol Cell Endocrinol 2008;282:120-9.
Rosen EM, Munoz MI, McElrath T, Cantonwine DE, Ferguson KK. Environmental contaminants and preeclampsia: a systematic literature review. J Toxicol Environ Health B Crit Rev 2018;21:291-319.
Prakansamut N, Phupong V. Serum SHARP1 and uterine artery Doppler for the prediction of preeclampsia. Sci Rep 2019;9:12266.
Tianthong W, Phupong V. Serum hypoxia-inducible factor-1alpha and uterine artery Doppler ultrasound during the first trimester for prediction of preeclampsia. Sci Rep 2021;11:6674.
Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension 2009;53:812-8.
Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649-58.
Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab 2003;88:2348-51.
Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350: 672-83.
Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta 2009;30 Suppl A:S32-7.
Yamanaka-Tatematsu M, Nakashima A, Fujita N, Shima T, Yoshimori T, Saito S. Autophagy induced by HIF1alpha overexpression supports trophoblast invasion by supplying cellular energy. PLoS One 2013;8:e76605.
Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med 2016;374:13-22.
Phupong V, Areeruk W, Tantbirojn P, Lertkhachonsuk R. Soluble fms-like tyrosine kinase 1 and placental growth factor ratio for predicting preeclampsia in elderly gravida. Hypertens Pregnancy 2020;39: 139-44.
Bian X, Biswas A, Huang X, Lee KJ, Li TK, Masuyama H, et al. Short-term prediction of adverse outcomes using the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio in Asian women with suspected preeclampsia. Hypertension 2019;74:164-72.
Ohkuchi A, Saito S, Yamamoto T, Minakami H, Masuyama H, Kumasawa K, et al. Short-term prediction of preeclampsia using the sFlt-1/PlGF ratio: a subanalysis of pregnant Japanese women from the PROGNOSIS Asia study. Hypertens Res 2021;44: 813-21.
Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus placebo in pregnancies at high risk for preterm Preeclampsia. N Engl J Med 2017;377:613-22.
ACOG Committee Opinion No. 743: Low-dose aspirin use during pregnancy. Obstet Gynecol 2018;132:e44-e52.
Richards EMF, Giorgione V, Stevens O, Thilaganathan B. Low-dose aspirin for the prevention of superimposed preeclampsia in women with chronic hypertension: a systematic review and meta-analysis. Am J Obstet Gynecol 2023;228:395-408.
LeFevre ML, Force USPST. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161:819-26.
Wheeler SM, Myers SO, Swamy GK, Myers ER. Estimated prevalence of risk factors for preeclampsia among individuals giving birth in the US in 2019. JAMA Netw Open 2022;5:e2142343.
Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med 2001;5:378-87.
Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 1976;72: 323-6.
Yoshino G, Kazumi T, Iwai M, Kasama T, Iwatani I, Matsuba K, et al. CS-514 suppresses plasma triglyceride in hypertriglyceridemic subjects without modifying a lipoprotein structural model. Horm Metab Res 1987;19:513-4.
Williams Obstetrics. In: Cunningham FG, Lenovo KJ, Dashe JS, Hoffman BL, Spong CY, Casey BM, editors. 26th ed. New York: McGraw Hill; 2022.
Zarek J, Koren G. The fetal safety of statins: a systematic review and meta-analysis. J Obstet Gynaecol Can 2014;36:506-9.
Bateman BT, Hernandez-Diaz S, Fischer MA, Seely EW, Ecker JL, Franklin JM, et al. Statins and congenital malformations: cohort study. BMJ 2015;350:h1035.
Lecarpentier E, Morel O, Fournier T, Elefant E, Chavatte-Palmer P, Tsatsaris V. Statins and pregnancy: between supposed risks and theoretical benefits. Drugs 2012;72:773-88.
Winterfeld U, Allignol A, Panchaud A, Rothuizen LE, Merlob P, Cuppers-Maarschalkerweerd B, et al. Pregnancy outcome following maternal exposure to statins: a multicentre prospective study. BJOG 2013;120:463-71.
Kumasawa K, Ikawa M, Kidoya H, Hasuwa H, Saito-Fujita T, Morioka Y, et al. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A 2011;108: 1451-5.
Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, et al. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol 2016;214:720. e1- e17.
Costantine MM, Cleary K, Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 2013;121:349-53.
Bauer AJ, Banek CT, Needham K, Gillham H, Capoccia S, Regal JF, et al. Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension. Hypertension 2013;61:1103-10.
Kanda M, Kumasawa K, Nemoto K, Miyatake R, Inaba K, Sayama S, et al. The effects of low concentrations of pravastatin on placental cells. Reprod Sci 2024;31:3139-47.
Saad AF, Kechichian T, Yin H, Sbrana E, Longo M, Wen M, et al. Effects of pravastatin on angiogenic and placental hypoxic imbalance in a mouse model of preeclampsia. Reprod Sci 2014;21:138-45.
Lefkou E, Mamopoulos A, Dagklis T, Vosnakis C, Rousso D, Girardi G. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest 2016;126:2933-40.
Costantine MM, West H, Wisner KL, Caritis S, Clark S, Venkataramanan R, et al. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol 2021;225:666. e1- e15.
Dobert M, Varouxaki AN, Mu AC, Syngelaki A, Ciobanu A, Akolekar R, et al. Pravastatin versus placebo in pregnancies at high risk of term preeclampsia. Circulation 2021;144:670-9.
Akbar MIA, Azis MA, Riu DS, Wawengkang E, Ernawati E, Bachnas MA, et al. INOVASIA Study: A multicenter randomized clinical trial of pravastatin to prevent preeclampsia in high-risk patients. Am J Perinatol 2024;41:1203-11.
Meszaros B, Veres DS, Nagyistok L, Somogyi A, Rosta K, Herold Z, et al. Pravastatin in preeclampsia: A meta-analysis and systematic review. Front Med (Lausanne) 2022;9:1076372.
