Opportunities for preeclampsia prevention: today and tomorrow

Authors

  • V. M. Guryeva State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow
  • A. A. Travkina State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow
  • M. O. Matveev State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow
  • L. S. Morokhotova State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow
  • Y. B. Kotov M.V. Keldysh Institute of Applied Mathematics of the Russian Academy of Sciences, Moscow
  • T. A. Semenova National Research Nuclear University MEPhI, Moscow

DOI:

https://doi.org/10.18370/2309-4117.2020.55.99-104

Keywords:

preeclampsia, placenta-associated complications, prevention of preeclampsia, antiplatelet agents, heparin

Abstract

Purpose of this review was to highlight the current and future possibilities of medicine in prevention of preeclampsia (PE) and placenta-associated complications (PAO). PE remains one of the most important causes of maternal and perinatal morbidity and mortality, and is responsible for the mass of premature births. The urgency of PE and PAO problem is primarily due to the lack of effective treatment for extensive clinical symptoms, as well as need to terminate pregnancy regardless of the gestational age and prognosis for fetus. In this regard, PE prevention is of great importance for clinical practice.

This review presents the modern concept of PE pathogenesis, highlights the key points of hemostatic system disorders, leading to the clinical symptoms and PE. It was also shown that the imbalance between thromboxane and endothelial prostacyclin as well as between pro- and anti-angiogenic factors in pregnant women with PE can be considered as a therapeutic target in PE prevention and treatment; prescription of antiplatelet agents and anticoagulants for PE prevention is justified.

Modern systematic reviews and meta-analysis have shown some effectiveness of antiplatelet agents and anticoagulants in PAO prevention. This review highlights the role of some nutrient deficiencies in the development of PAO and folate supplementation for their prevention. Presented data indicate that today there are methods for PAO prevention, which can significantly reduce their probability by 17–30% in pregnant women with a high risk of this obstetric pathology. However, a complete prevention and effective treatment of PAO at the stage of advanced clinical symptoms has not yet been developed, which leads to early termination of pregnancy, perinatal morbidity and mortality. Therefore, the development of new therapies that completely prevent or cure PE would be a major advance for practical obstetrics. This review presents the main scientific developments in this direction, in particular, clinical trials of drugs that can reduce sFlt-1 and soluble endoglin secretion, thus curing endothelial dysfunction in PE.

Author Biographies

V. M. Guryeva, State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow

MD, leading researcher, Obstetric Physiological Department

A. A. Travkina, State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow

PhD, senior researcher, Obstetric Physiological Department

M. O. Matveev, State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow

Clinical resident

L. S. Morokhotova, State Budgetary Health Care Institution of the Moscow Region “Moscow Regional Research Institute of Obstetrics and Gynecology”, Moscow

PhD, doctor of the Observational Department

Y. B. Kotov, M.V. Keldysh Institute of Applied Mathematics of the Russian Academy of Sciences, Moscow

Leading researcher

T. A. Semenova, National Research Nuclear University MEPhI, Moscow

PhD, associate professor

References

Say, L., Chou, D., Gemmill, A., et al. “Global causes of maternal death: a WHO systematic analysis.” Lancet Glob Health 2 (2014): e323–33.

Shalina, R.I., Mikhaleva, L.M., Simukhina, M.A., et al. “Peculiarities of the current of heavy forms of preeclampsia in modern conditions.” Issues of gynecology, obstetrics and perinatology 16.6 (2017): 16–23.

Sharp, A., Jackson, R., Cornforth, C., et al. “A prediction model for short-term neonatal outcomes in severe early-onset fetal growth restriction.” Eur J Obstet Gynecol Reprod Biol 241 (2019): 109–18.

Lecarpentier, E., Haddad, B., Goffinet, F., Tsatsaris, V. “Medical approaches for managing preeclampsia.” Presse Med 45.7–8 Pt. 1 (2016): 638–45. DOI: 10.1016/j.lpm.2016.04.017

Walsh, S.W. “Eicosanoids in preeclampsia.” Prostaglandins Leukot Essent Fatty Acids 70 (2004): 223–32.

Walsh, S.W. “Low-dose aspirin: treatment for the imbalance of increased thromboxane and decreased prostacyclin in preeclampsia.” Am J Perinatol 6 (1989): 124–32.

Perneby, C., Vahter, M., Akesson, A., et al. “Thromboxane metabolite excretion during pregnancy – influence of preeclampsia and aspirin treatment.” Thromb Res 127 (2011): 605–6. DOI: 10.1016/j.thromres.2011.01.005

Sibai, B.M., Mirro, R., Chesney, C.M., Leffler, C. “Low-dose aspirin in pregnancy.” Obstet Gynecol 74 (1989): 551–5.

Scazzocchio, E., Oros, D., Diaz, D., et al. “Impact of aspirin on trophoblastic invasion in women with abnormal uterine artery Doppler at 11–14 weeks: a randomized controlled study.” Ultrasound Obstet Gynecol Off J Int Soc Ultrasound Obstet Gynecol 49 (2017): 435–41.

Harker, L.A., Kadatz, R.A. “Mechanism of action of dipyridamole.” Thromb Res 29 (1983): 39–46.

Vieillefosse, S., Guibourdenche, J., Atallah, A., et al. “Predictive and prognostic factors of preeclampsia: interest of PlGF and sFLT-1.” J Gynecol Obstet Biol Reprod (Paris) 45 (2016): 999–1008.

Li, C., Raikwar, N.S., Santillan, M.K., et al. “Aspirin inhibits expression of sFLT1 from human cytotro- phoblasts induced by hypoxia, via cyclo-oxygenase 1.” Placenta 36 (2015): 446–53.

Duley, L., Meher, S., Hunter, K.E., et al. “Antiplatelet agents for preventing pre-eclampsia and its complications.” Cochrane Database Syst Rev 10 (2019): CD004659. DOI: 10.1002/14651858.

Duley, L., Henderson-Smart, D.J., Meher, S., King, J.F. “Antiplatelet agents for preventing pre-eclampsia and its complications.” Cochrane Database Syst Rev 2 (2007): CD004659.

Meher, S., Duley, L., Hunter, K., Askie, L. “Antiplatelet therapy before or after 16 weeks' gestation for preventing preeclampsia: an individual participant data meta-analysis.” Am J Obstet Gynecol 216.2 (2017): 121–28.e2. DOI: 10.1016/j.ajog.2016.10.016

North, R.A., Ferrier, C., Gamble, G., et al. “Prevention of preeclampsia with heparin and antiplatelet drugs in women with renal disease.” Aust N Z J Obstet Gynaecol 35.4 (1995): 357–62.

Kozlovskaya, N.L., Sidorova, I.S., Rogov, V.A., et al. “Condition of endothelium and platelets in pregnant women with chronic glomerulonephrite and therapeutic capabilities of acetylsalicylic acid and dipyridamol.” Ther Arch 76.12 (2004): 58–64.

McLaughlin, K., Drewlo, S., Parker, J.D., Kingdom, J.C. “Current theories on the prevention of severe preeclampsia with low-molecular weight heparin.” Hypertension 66 (2015): 1098–103.

Gris, J.C., Chauleur, C., Molinari, N., et al. “Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia. The pilot randomised controlled NOH-PE trial.” Thromb Haemost 106 (2011): 1053–61.

Rey, E., Garneau, P., David, M., et al. “Dalteparin for the prevention of recurrence of placental- mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial.” J Thromb Haemost 7 (2009): 58–64.

de Vries, J.I., van Pampus, M.G., Hague, W.M., et al. “Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT.” J Thromb Haemost 10 (2012): 64–72.

Kupferminc, M., Rimon, E., Many, A., et al. “Low molecular weight heparin versus no treatment in women with previous severe pregnancy complications and placental findings without thrombophilia.” Blood Coagul Fibrinolysis 22 (2011): 123–6.

North, R.A., Ferrier, C., Gamble, G., et al. “Prevention of preeclampsia with heparin and antiplatelet drugs in women with renal disease.” Aust N Z J Obstet Gynaecol 35 (1995): 357–62.

van Hoorn, M.E., Hague, W.M., van Pampus, M.G., et al. “Low-molecular-weight heparin and aspirin in the prevention of recurrent early-onset pre-eclampsia in women with antiphospholipid antibodies: the FRUIT-RCT.” Eur J Obstet Gynecol Reprod Biol 197 (2016): 168–73.

Martinelli, I., Ruggenenti, P., Cetin, I., et al. “Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.“ Blood 119 (2012): 3269–75.

Rodger, M.A., Hague, W.M., Kingdom, J., et al. “Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial.” Lancet (London, England) 384 (2014): 1673–83.

Haddad, B., Winer, N., Chitrit, Y., et al. “Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications: a randomized controlled trial.” Obstet Gynecol 128 (2016): 1053–63.

Groom, K.M., McCowan, L.M., Mackay, L.K., et al. “Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.” Am J Obstet Gynecol 216 (2017): 296.e1–14.

Dodd, J.M., McLeod, A., Windrim, R.C., Kingdom, J. “Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction.” Cochrane Database Syst Rev 7 (2013): CD006780. DOI: 10.1002/14651858.CD006780.pub3

Roberge, S., Demers, S., Nicolaides, K.H., et al. “Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: a meta-analysis.” Ultrasound Obstet Gynecol 47 (2016): 548–53. DOI: 10.1002/uog.15789

Rodger, M.A., Carrier, M., Le Gal, G., et al. “Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications.” Blood 123 (2014): 822–28.

Rodger, M.A., Gris, J.C., de Vries, J.I., et al. “Low-molecular-weight heparin and recurrent placenta- mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.” Lancet (London, England) 388 (2016): 2629–41.

van Hoorn, M.E., Hague, W.M., van Pampus, M.G., et al.; FRUIT Investigators. “Low-molecular-weight Heparin and Aspirin in the Prevention of Recurrent Early-Onset Pre-Eclampsia in Women With Antiphospholipid Antibodies: The FRUIT-RCT.” Eur J Obstet Gynecol Reprod Biol 197 (2016): 168–73.

Martinelli, I., Ruggenenti, P., Cetin, I., et al.; HAPPY Study Group. “Heparin in Pregnant Women With Previous Placenta-Mediated Pregnancy Complications: A Prospective, Randomized, Multicenter, Controlled Clinical Trial.” Blood 119.14 (2012): 3269–75.

Kingdom, J.C., Walker, M., Proctor, L.K., et al. “Unfractionated heparin for second trimester placental insufficiency: a pilot randomized trial.” J Thromb Haemost 9 (2011):1483–92.

D’Souza, R., Keating, S., Walker, M., et al. “Unfractionated heparin and placental pathology in high-risk pregnancies: secondary analysis of a pilot randomized controlled trial.” Placenta 35 (2014): 816–23.

Mello, G., Parretti, E., Fatini, C., et al. “Low-molecular-weight heparin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women.” Hypertension 45 (2005): 86–91.

Baldus, S., Rudolph, V., Roiss, M., et al. “Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase.” Circulation 113 (2006): 1871–8.

Yinon, Y., Ben Meir, E., Margolis, L., et al. “Low molecular weight heparin therapy during pregnancy is associated with elevated circulatory levels of placental growth factor.” Placenta 36 (2015): 121–4.

Hagmann, H., Bossung, V., Belaidi, A.A., et al. “Low-molecular weight heparin increases circulating sFlt-1 levels and enhances urinary elimination.” PloS One 9 (2014): e85258.

Tasatargil, A., Ogutman, C., Golbasi, I., et al. “Comparison of the vasodilatory effect of nadroparin, enoxaparin, dalteparin, and unfractioned heparin in human internal mammary artery.” J Cardiovasc Pharmacol 45 (2005): 550–4.

Georgescu, A., Alexandru, N., Nemecz, M., et al. “Enoxaparin reduces adrenergic contraction of resistance arterioles in aging and in aging associated with diabetes via engagement of MAP kinase pathway.” Blood Coagul Fibrinolysis 22 (2011): 310–6.

Sobel, M.L., Kingdom, J., Drewlo, S. “Angiogenic response of placental villi to heparin.” Obstet. Gynecol 117 (2011): 1375–83.

McLaughlin, K., Baczyk, D., Potts, A., et al. “Low molecular weight heparin improves endothelial function in pregnant women at high risk of preeclampsia.” Hypertension 69 (2017): 180–8.

D’Souza, R., Keating, S., Walker, M., et al. “Unfractionated heparin and placental pathology in high-risk pregnancies: secondary analysis of a pilot randomized controlled trial.” Placenta 35 (2014): 816–23.

Williams, P.J., Bulmer, J.N., Innes, B.A., Broughton Pipkin, F. “Possible roles for folic acid in the regulation of trophoblast invasion and placental development in normal early human pregnancy.” Biol Reprod 84 (2011): 1148–53.

Mignini, L.E., Latthe, P.M., Villar, J., et al. “Mapping the theories of preeclampsia: the role of homocysteine.” Obstet Gynecol 105 (2005): 411–25.

Makedos, G., Papanicolaou, A., Hitoglou, A., et al. “Homocysteine, folic acid and B12 serum levels in pregnancy complicated with preeclampsia.” Arch Gynecol Obstet 275 (2007): 121–4.

Ray, J.G., Laskin, C.A. “Folic acid and homocysteine metabolic defects and the risk of placenta abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review.” Placenta 20 (1999): 519–29.

Pustotina, O.A., Akhmedova, A.E. “The role of folates in the development of complications of pregnancy. Effective pharmacotherapy.” Obstetr Gynecol 3.35 (2014): 66–74.

Holm, P.I., Hustad, S., Ueland, P.M., et al. “Modulation of the homocysteinebetaine relationship by methylenetetrahydrofolate reductase 677 C>t genotypes and B-vitamin status in a large-scale epidemiological study.” J Clin Endocrinol Metab 92.4 (2007): 1535–41.

Pietrzik, K., Bailey, L., Shane, B. “Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics.” Clin Pharmacokinet 49.8 (2010): 535–48.

Ministry of Health of the Russian Federation. Order No. 572n of 12 November 2012 “On Approval of the Procedure for the Provision of Medical Care in the Profile of Obstetrics and Gynaecology (Except for the Use of Assisted Reproductive Technologies).”

Prinz-Langenohl, R., Brämswig, S., Tobolski, O., et al. “[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C>T polymorphism of methylenetetrahydrofolate reductase.” Br J Pharmacol 158.8 (2009): 2014–21.

Obeid, R., Holzgreve, W., Pietrzik, K. “Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?” J Perinat Med 41.5 (2013): 469–83.

Lamers, Y., Prinz-Langenohl, R., Moser, R., Pietrzik, K. “Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women.” Am J Clin Nutr 79.3 (2004): 473–8.

Gromova, O.A., Torshin, I.Y., Limanova, O.A. “Omega-3 polyunsaturated fatty acids and active folates - prospects of complex application for nutritial support of pregnancy and prevention of developmental defects.” Gynecology 2 (2013): 71–7.

Kulkarni, A., Dangat, K., Kale, A., et al. “Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats.” PLoS One 6.3 (2011): e17706.

Brownfoot, F.C., Hastie, R., Hannan, N.J., et al. “Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction.” Am J Obstet Gynecol 214.3 (2016): 356.e1–356.e15.

Romero, R., Erez, O., Hüttemann, M., et al. “Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity.” Am J Obstet Gynecol 217.3 (2017): 282–302.

Kaitu'u-Lino, T.J., Brownfoot, F.C., Beard, S., et al. “Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction – implications for treating preeclampsia.” PLoS One 13.2 (2018): e0188845.

Kalafat, E., Sukur, Y.E., Abdi, A., et al. “Metformin for prevention of hypertensive disorders of pregnancy in women with gestational diabetes or obesity: systematic review and meta-analysis of randomized trials.” Ultrasound Obstet Gynecol 52.6 (2018): 706–14.

Alqudah, A., McKinley, M.C., McNally, R., et al. “Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.” Diabet Med 35.2 (2018): 160–72.

Costantine, M.M., Tamayo, E., Lu, F., et al. “Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase- 1-induced preeclampsia.” Obstet Gynecol 116 (2010): 114–20.

Fox, K.A., Longo, M., Tamayo, E., et al. “Effects of pravastatin on mediators of vascular function in a mouse model of soluble Fms-like tyrosine kinase-1-induced preeclampsia.” Am J Obstet Gynecol 205 (2011): 366.e1–5.

Kumasawa, K., Ikawa, M., Kidoya, H., et al. “Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model.“ Proc Natl Acad Sci USA 108 (2011): 1451–5.

Bauer, A.J., Banek, C.T., Needham, K., et al. “Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension.” Hypertension 61 (2013): 1103–10.

Brownfoot, F.C., Tong, S., Hannan, N.J., et al. “Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta.” BMC Pregnancy Childbirth 16 (2016): 117.

Costantine, M.M., Cleary, K., Hebert, M.F., 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 214.6 (2016): 720.e1–720.e17.

Esteve-Valverde, E., Ferrer-Oliveras, R., Gil-Aliberas, N., et al. “Pravastatin for Preventing and Treating Preeclampsia: A Systematic Review.” Obstet Gynecol Surv 73.1 (2018): 40–55.

Published

2020-11-30

Issue

Section

Analytical review