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DOI: 10.1055/a-1673-5603
INOVASIA Study: A Randomized Open Controlled Trial to Evaluate Pravastatin to Prevent Preeclampsia and Its Effects on sFlt1/PlGF Levels
Funding None.![](https://www.thieme-connect.de/media/ajp/202403/lookinside/thumbnails/10-1055-a-1673-5603_210746-1.jpg)
Abstract
Objectives This study aimed to evaluate the effect of pravastatin to prevent preeclampsia (PE) in pregnant women at a high risk of developing PE and the maternal and perinatal outcomes and the soluble fms-like tyrosine kinase 1/placental growth factor (sFlt1/PlGF) ratio.
Study Design This is an open-labeled randomized controlled trial (RCT), a part of INOVASIA (Indonesia Pravastatin to Prevent Preeclampsia study) trial. Pregnant women at a high risk of developing PE were recruited and randomized into an intervention group (40) and a control group (40). The inclusion criteria consisted of pregnant women with positive clinical risk factor and abnormal uterine artery Doppler examination at 10 to 20 weeks' gestational age. The control group received low dose aspirin (80 mg/day) and calcium (1 g/day), while the intervention group received additional pravastatin (20-mg twice daily) starting from 14 to 20 weeks' gestation until delivery. Research blood samples were collected before the first dose of pravastatin and before delivery. The main outcome was the rate of maternal PE, maternal–perinatal outcomes, and sFlt-1, PlGF, sFlt-1/PlGF ratio, and soluble endoglin (sEng) levels.
Results The rate of PE was (nonsignificantly) lower in the pravastatin group compared with the control group (17.5 vs. 35%). The pravastatin group also had a (nonsignificant) lower rate of severe PE, HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, acute kidney injury, and severe hypertension. The rate of (iatrogenic) preterm delivery was significantly (p = 0.048) lower in the pravastatin group (n = 4) compared with the controls (n = 12). Neonates in the pravastatin group had significantly higher birth weights (2,931 ± 537 vs. 2,625 ± 872 g; p = 0.006), lower Apgar's scores < 7 (2.5 vs. 27.5%, p = 0.002), composite neonatal morbidity (0 vs. 20%, p = 0.005), and NICU admission rates (0 vs. 15%, p = 0.026). All biomarkers show a significant deterioration in the control group compared with nonsignificant changes in the pravastatin group.
Conclusion Pravastatin holds promise in the secondary prevention of PE and placenta-mediated adverse perinatal outcomes by improving the angiogenic imbalance.
Key Points
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Prophylactic pravastatin was associated with a significantly lower rate of adverse perinatal outcome.
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The sFlt1/PlGF ratio stabilized in the pravastatin group compared with a deterioration in the control group.
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Pravastatin holds promise in the secondary prevention of PE and placenta-mediated adverse perinatal outcomes.
Note
This study is registered with Clinical Trial Gov. (ID: NCT03648970).
Data Availability Statement
The data of this study will be available on request for IPD analysis and systematic review.
Authors' Contributions
M.I.A.A. played a pivotal role in conceptualizing and designing the study, overseeing its implementation and execution, interpreting and analyzing the data, and drafting and revising the various versions of the manuscript. Additionally, M.I.A.A. took charge of the final version and managed the submission and communication with the journal. A.Y., R.E.P., N.L.F., S.S., F.Z.A., and E.E. were actively involved in patient selection, recruitment, and maternal-perinatal data collection. E.G.D., M.D.A., and G.D. significantly contributed to the study's conceptualization and design, as well as the drafting and revision processes, ultimately preparing the final version of the manuscript.
Publication History
Received: 05 October 2021
Accepted: 15 October 2021
Accepted Manuscript online:
19 October 2021
Article published online:
20 December 2021
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References
- 1 Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ 2019; 366: l2381
- 2 Redman CWG, Staff AC. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. Am J Obstet Gynecol 2015; 213 (4, suppl): S9–S11 9.e1
- 3 Redman CWG, Sargent IL. Placental stress and pre-eclampsia: a revised view. Placenta 2009; 30 (suppl A): S38-S42
- 4 Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: updates in pathogenesis, definitions, and guidelines. Clin J Am Soc Nephrol 2016; 11 (06) 1102-1113
- 5 Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ 2019; 366: 12381
- 6 Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res 2019; 124 (07) 1094-1112
- 7 Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia. Annu Rev Pathol 2010; 5: 173-192
- 8 Levine RJ, Maynard SE, Qian C. et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350 (07) 672-683
- 9 Kim S-Y, Ryu H-M, Yang J-H. et al. Increased sFlt-1 to PlGF ratio in women who subsequently develop preeclampsia. J Korean Med Sci 2007; 22 (05) 873-877
- 10 Levine RJ, Maynard SE, Qian C. et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350 (07) 672-683
- 11 Kim SY, Ryu HM, Yang JH. et al. Increased sFlt-1 to PlGF ratio in women who subsequently develop preeclampsia. J Korean Med Sci 2007; 22 (05) 873-877
- 12 Reddy A, Suri S, Sargent IL, Redman CWG, Muttukrishna S. Maternal circulating levels of activin A, inhibin A, sFlt-1 and endoglin at parturition in normal pregnancy and pre-eclampsia. PLoS One 2009; 4 (02) e4453
- 13 ACOG. Gestational hypertension and preeclampsia. Obstet Gynecol 2019; 133 (76) 168-186 Available at https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2020/06/gestational-hypertension-and-preeclampsia
- 14 Mayrink J, Costa ML, Cecatti JG. Preeclampsia in 2018: revisiting concepts, physiopathology, and prediction. ScientificWorldJournal 2018; 2018: 6268276
- 15 Brown MA, Magee LA, Kenny LC. et al. Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension 2018; 72 (01) 24-43
- 16 Ramma W, Ahmed A. Therapeutic potential of statins and the induction of heme oxygenase-1 in preeclampsia. J Reprod Immunol 2014; ;101-102 (01) 153-160
- 17 Ahmed A, Ramma W. Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm?. Br J Pharmacol 2015; 172 (06) 1574-1586
- 18 Ahmed A, Cudmore MJ. Can the biology of VEGF and haem oxygenases help solve pre-eclampsia?. Biochem Soc Trans 2009; 37 (pt. 6): 1237-1242
- 19 Ahmed A, Ramma W. Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm?. Br J Pharmacol 2015; 172 (06) 1574-1586
- 20 Vahedian-Azimi A, Karimi L, Reiner Ž, Makvandi S, Sahebkar A. Effects of statins on preeclampsia: a systematic review. Pregnancy Hypertens 2021; 23: 123-130
- 21 Katsi V, Georgountzos G, Kallistratos MS. et al. The role of statins in prevention of preeclampsia: a promise for the future?. Front Pharmacol 2017; 8: 247
- 22 Smith DD, Costantine MM. The role of statins in the prevention of preeclampsia. Am J Obstet Gynecol 2022; 226 (2S): S1171-S1181
- 23 Putra RA, Effendi JS, Permadi W, Bandiara R, Fauziah PN. Role of statin as inducer of Hmox-1 system in treatment of preeclampsia. Cell Mol Biol 2018; 64 (10) 1-4
- 24 Cudmore M, Ahmad S, Al-Ani B. et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 2007; 115 (13) 1789-1797
- 25 Akbar MIA, Yosediputra A, Pratama RE, Fadhilah NL, Sulistyowati S, Amani FZ, Dachlan EG, Dikman AngsarM, Dekker GA. Pravastatin suppresses inflammatory cytokines and endothelial activation in patients at risk of developing preeclampsia: INOVASIA study. J Matern Fetal Neonatal Med 2022; 35 (25) 5375-5382
- 26 Ahmed A, Williams DJ, Cheed V. et al; StAmP trial Collaborative Group. Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial. BJOG 2020; 127 (04) 478-488
- 27 Ohkuchi A, Hirashima C, Suzuki H. et al. Evaluation of a new and automated electrochemiluminescence immunoassay for plasma sFlt-1 and PlGF levels in women with preeclampsia. Hypertens Res 2010; 33 (05) 422-427
- 28 Costantine MM, West H, Wisner KL, Caritis S, Clark S, Venkataramanan R, Stika CS, Rytting E, Wang X, Ahmed MS. Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Centers (OPRC) Network, Bethesda, MD. A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia. Am J Obstet Gynecol 2021; 225 (06) 666.e1-666.e15
- 29 Costantine MM, Cleary K, Hebert MF. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric-Fetal Pharmacology Research Units Network. 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 (06) 720.e1-720.e17
- 30 Kupferminc MJ, Kliger C, Rimon E, Asher-Landsberg J, Skornick-Rapaport A, Gamzu R, Yogev Y. Pravastatin is useful for prevention of recurrent severe placenta-mediated complications - a pilot study. J Matern Fetal Neonatal Med 2022; 35 (25) 8055-8061
- 31 Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can 2007; 29 (11) 906-908
- 32 Brown MA, Magee LA, Kenny LC. et al; International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension 2018; 72 (01) 24-43
- 33 Itoh HKanayama N. Obesity and risk of preeclampsia. Med J Obstet Gynecol 2014; 2 (02) 1024
- 34 Rocha RS, Alves JAG, Maia E Holanda Moura SB. et al. Simple approach based on maternal characteristics and mean arterial pressure for the prediction of preeclampsia in the first trimester of pregnancy. J Perinat Med 2017; 45 (07) 843-849
- 35 Obstetri P, Indonesia G, Kedokteran H, Maternal F. National Protocol Health Services, Diagnosis and Management of Preeclampsia, Indonesia Obstetricians and Gynecologists Association, Indonesia Maternal Fetal Medicine Association. 2016 https://pogi.or.id/publish/download/pnpk-dan-ppk/
- 36 Maternal Fetal Medicine Surabaya. Hypertens Pregnancy 2017
- 37 Human Endoglin/CD 105 Quantikine ELISA kit. Accessed November 11, 2021 at: https://www.rndsystems.com/products/human-endoglin-cd105-quantikine-elisa-kit_dndg00
- 38 Richard JL, Chun L, Chong Q, Sharon EM, Benjamin PS, Baha MS. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006; 64355 (10) 992-1005
- 39 Ofori B, Rey E, Bérard A. Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol 2007; 64 (04) 496-509
- 40 Karalis DG, Hill AN, Clifton S, Wild RA. J Clin Lipidol 2016; 10 (05) 1081-1090
- 41 Hatanaka T. Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clin Pharmacokinet 2000; 39 (06) 397-412
- 42 Enrique E-V, Raquel F-O, Natàlia G-A, Antònia B-F, Elisa L, Jaume A-R. Obstetrical & Gynecological Survey 2018; 73 (01) 40-55
- 43 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 (2, pt. 1): 349-353
- 44 Brownfoot FC, Tong S, Hannan NJ. et al. Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia. Hypertension 2015; 66 (03) 687-697 , discussion 445
- 45 Mendoza M, Ferrer-Oliveras R, Bonacina E, Garcia-Manau P, Rodo C, Carreras E, Alijotas-Reig J. Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study. Am J Perinatol 2021; 38 (14) 1472-1479