Modern view on the etiology and pathogenesis of preeclampsia as the main cause of perinatal losses




preeclampsia, etiology, pathogenesis, angiogenic growth factors, antiangiogenic growth factors, genetic polymorphisms


Preeclampsia (PE) is one of the most important problems of modern obstetrics. There is an opinion that the nature of PE is different when it starts before or after 34 weeks of pregnancy. Early onset of PE correlates with high neonatal morbidity and mortality and maternal complications. Being a multifactorial disease, PE has a number of candidate genes that are involved in the complex regulation of various endothelial functions.

The article provides an overview of modern medical literature on the etiology and pathogenesis of PE. For a more detailed understanding of the pathogenesis, each angiogenesis factor is considered separately, as well as variations in the genes encoding them and the influence of these factors on the development of PE.

Purpose - to clarify the causes of PE development, the role of timely diagnosis of genetic polymorphisms and angiogenesis markers for constructing an algorithm for diagnosing and predicting the development of PE.

It has been established that the main pathogenetic moment in the development of PE is the lack of reconstruction of the junction of the spiral arteries and the trophoblast, which reflects a defect in deep placentation. This contributes to increased production of vasoconstrictor mediators from the very beginning of pregnancy and their progressive increase with gestational age. This does not allow the formation of adequate uteroplacental bleeding, which leads to relative hypoxia in the trophoblastic tissue, thereby causing oxidative stress of the entire placenta. This phenomenon further compromises placental villous angiogenesis and leads to an imbalance in the production of angiogenic and antiangiogenic growth factors. It has been proven that the presence of polymorphism in the angiogenesis genes worsens the pathomorphological conditions caused by PE. This is due to a genetically programmed decrease in the production of angiogenic factors, which further exacerbates the aforementioned imbalance. That is why a comprehensive genetic examination of a woman at the stage of preconception preparation will make it possible to predict the risks of developing PE. This prognosis will provide the possibility of earlier administration of drugs that can improve the effects of primary placentation and reduce rates of gestational complications and perinatal losses.

No conflict of interests was declared by the authors.


Baig S, Kothandaraman N, Manikandan J, Rong L, Ee KH et al. (2014). Proteomic analysis of human placental syncytiotrophoblast microvesicles in preeclampsia. Clinical proteomics. 11 (1): 40.; PMid:25469110 PMCid:PMC4247627

Bányász I, Szabó S, Bokodi G, Vannay A, Vásárhelyi B, Szabó A, Tulassay T, Rigó JJr. (2006). Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia. Molecular human reproduction. 12: 4.; PMid:16517614

Barrett PM, McCarthy FP, Kublickiene K, Cormican S, Judge C, Evans M, Kublickas M, Perry IJ, Stenvinkel P, Khashan AS. (2020). Adverse Pregnancy Outcomes and Long-term Maternal Kidney Disease: A Systematic Review and Meta-analysis. JAMA network open. 3 (2): e1920964.; PMid:32049292

Boeldt DS, Bird IM. (2017). Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. The Journal of endocrinology. 232 (1): R27-R44.; PMid:27729465 PMCid:PMC5115955

Bonnans C, Chou J, Werb Z. (2014). Remodelling the extracellular matrix in development and disease. Nature reviews. Molecular cell biology. 15 (12): 786-801.; PMid:25415508 PMCid:PMC4316204

Brosens I, Brosens JJ, Muter J, Puttemans P, Benagiano G. (2019). Preeclampsia: the role of persistent endothelial cells in uteroplacental arteries. American journal of obstetrics and gynecology. 221 (3): 219-226.; PMid:30738027

Brosens I, Puttemans P, Benagiano G. (2019). Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes. American journal of obstetrics and gynecology. 221 (5): 437-456.; PMid:31163132

Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP et al. (2018). Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice. Hypertension (Dallas, Tex.: 1979). 72 (1): 24-43.; PMid:29899139

Cardenas-Mondragon MG, Vallejo-Flores G, Delgado-Dominguez J, Romero-Arauz JF, Gomez-Delgado A et al. (2014). Preeclampsia is associated with lower production of vascular endothelial growth factor by peripheral blood mononuclear cells. Archives of medical research. 45 (7): 561-569.; PMid:25450585

Carter AM, Enders AC, Pijnenborg R. (2015). The role of invasive trophoblast in implantation and placentation of primates. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 370 (1663): 20140070.; PMid:25602074 PMCid:PMC4305171

Chelbi ST, Vaiman D. (2008). Genetic and epigenetic factors contribute to the onset of preeclampsia. Molecular and cellular endocrinology. 282 (1-2): 120-129.; PMid:18177994

De Vivo A, Baviera G, Giordano D, Todarello G, Corrado F, D'anna R. (2008). Endoglin, PlGF and sFlt-1 as markers for predicting pre-eclampsia. Acta obstetricia et gynecologica Scandinavica. 87 (8): 837-842.; PMid:18607829

Demir R, Kayisl UA, Seval Y, Celik-Ozenci C, Korgun ET, Demir-Weusten AY, Huppertz B. (2004). Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: differences between placental vasculogenesis and angiogenesis. Placenta. 25 (6): 560-572.; PMid:15135240

Demir R, Kayisli UA, Cayli S, Huppertz B. (2006). Sequential steps during vasculogenesis and angiogenesis in the very early human placenta. Placenta. 27 (6-7): 535-539.; PMid:16029887

Fogacci F, Tocci G, Presta V, Fratter A, Borghi C, Cicero A. (2019). Effect of resveratrol on blood pressure: A systematic review and meta-analysis of randomized, controlled, clinical trials. Critical reviews in food science and nutrition. 59 (10): 1605-1618.; PMid:29359958

Francisco C, Wright D, Benkő Z, Syngelaki A, Nicolaides KH. (2017). Competing-risks model in screening for pre-eclampsia in twin pregnancy by maternal characteristics and medical history. Ultrasound in obstetrics & gynecology: the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 50 (4): 501-506.; PMid:28508528

Gannoun MBA, Zitouni H, Raguema N, Maleh W, Gris JC, Almawi W, Mahjoub T. (2015). Association of common eNOS/NOS3 polymorphisms with preeclampsia in Tunisian Arabs. Gene. 569 (2): 303-307.; PMid:26049094

Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, Robson SC, Bulmer JN. (2006). Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. Journal of leukocyte biology. 80 (3): 572-580.; PMid:16816146

Leonardo DP, Albuquerque DM, Lanaro C, Baptista LC, Cecatti JG et al. (2015). Association of Nitric Oxide Synthase and Matrix Metalloprotease Single Nucleotide Polymorphisms with Preeclampsia and Its Complications. PloS one. 10 (8): e0136693.; PMid:26317342 PMCid:PMC4552660

Levine RJ, Maynard SE, Qian C, Lim KH, England LJ et al. (2004). Circulating angiogenic factors and the risk of preeclampsia. The New England journal of medicine. 350 (7): 672-683.; PMid:14764923

Loskutova TO, Demchenko TV, Bredihina OA. (2021). Oksidativnij stres ta antioksidantnij zahist pri rannij ta piznij preeklampsiyi vagitnih. Aktualni pitannya pediatriyi, akusherstva ta ginekologiyi. 1: 93-98.

Loskutova TO, Demchenko TV, Kryachkova NV. (2020). Gene polymorphism of blood coagulation factors and endothelial dysfunction in early and late preeclampsia. Medicni perspektivi (Medical perspectives). 25 (2): 66-71.

Loskutova TO. (2018). Polimorfizm geniv sistemi gemostazu, endotelialnoyi disfunkciyi ta regulyaciyi arterialnogo tisku u vagitnih iz preeklampsiyeyu ta zatrimkoyu rozvitku ploda. Patologiya. 15 (1): 29-33.

Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R, Waugh R, McKenzie P, Kirwan P, Hennessy A. (2007). Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney international. 71 (10): 977-984.; PMid:17377512

Masoura S, Kalogiannidis I, Makedou K, Theodoridis T, Koiou K, Gerou S, Athanasiadis A, Agorastos T. (2014). Biomarkers of endothelial dysfunction in preeclampsia and neonatal morbidity: a case-control study. European journal of obstetrics, gynecology, and reproductive biology. 175: 119-123.; PMid:24485669

Nagase H, Visse R, Murphy G. (2006). Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular research. 69 (3): 562-573.; PMid:16405877

Nagy B, Savli H, Molvarec A, Várkonyi T, Rigó B, Hupuczi P, Rigó JJr (2008). Vascular endothelial growth factor (VEGF) polymorphisms in HELLP syndrome patients determined by quantitative real-time PCR and melting curve analyses. Clinica chimica acta; international journal of clinical chemistry. 389 (1-2): 126-131.; PMid:18167313

National Collaborating Centre for Women's and Children's Health (UK). (2010). Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy. RCOG Press. PMID: 22220321. URL:

O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A et al. (2017). Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation: comparison with NICE guidelines and ACOG recommendations. Ultrasound in obstetrics & gynecology: the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 49 (6): 756-760.; PMid:28295782

O'Gorman N, Wright D, Rolnik DL, Nicolaides KH, Poon LC. (2016). Study protocol for the randomised controlled trial: combined multimarker screening and randomised patient treatment with ASpirin for evidence-based PREeclampsia prevention (ASPRE). BMJ open. 6 (6): e011801.; PMid:27354081 PMCid:PMC4932292

Oshovskij V, Nikolenko M, Polyakova Ye. (2021). Rezultati vagitnostej u paciyentok z nadzvichajno visokim spivvidnoshennyam sFlt-1/PlGF: ceriya klinichnih vipadkiv. Reproduktivne zdorov'ya zhinki. 1: 17-20.

Oshovskyy V, Arbuzova S, Nikolenko M, Mylytsya K. (2022). Pregnancy outcomes in women with extremely high sflt-1/pigf ratio: case series. Wiadomosci lekarskie (Warsaw, Poland: 1960). 75 (1): 141-143.; PMid:35092264

Oshovskyy V, Mylytsya K. (2021). Extremely early intrauterine growth restriction with dramatic sFlt-1/PLGF ratio. Gazzetta Medica Italiana. 180: 3.

Palei AC, Granger JP, Tanus-Santos JE. (2013). Matrix metalloproteinases as drug targets in preeclampsia. Current drug targets. 14 (3): 325-334.

Pandey AK, Bhattacharya P, Shukla SC, Paul S, Patnaik R. (2015). Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: a molecular docking study exploring possible neuroprotection. Neural regeneration research. 10 (4): 568-575.; PMid:26170816 PMCid:PMC4424748

Papazoglou D, Galazios G, Koukourakis MI, Panagopoulos I, Kontomanolis EN, Papatheodorou K, Maltezos E. (2004). Vascular endothelial growth factor gene polymorphisms and pre-eclampsia. Molecular human reproduction. 10 (5): 321-324.; PMid:14997002

Perez-Sepulveda A, Torres MJ, Khoury M, Illanes SE. (2014). Innate immune system and preeclampsia. Frontiers in immunology. 5: 244.; PMid:24904591 PMCid:PMC4033071

Perlik M, Seremak-Mrozikiewicz A, Barlik M, Kurzawińska G, Kraśnik W, Drews K. (2012). Warianty genetyczne sródbłonkowej syntazy tlenku azotu (eNOS) w nadciśnieniu ciazowym i stanie przedrzucawkowym [Genetic variants of endothelial nitric synthase in gestational hypertension and preeclampsia]. Ginekologia polska. 83 (9): 652-659.

Sakar MN, Atay AE, Demir S, Bakir VL, Demir B, Balsak D, Akay E, Ulusoy AI, Verit FF. (2015). Association of endothelial nitric oxide synthase gene G894T polymorphism and serum nitric oxide levels in patients with preeclampsia and gestational hypertension. The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 28 (16): 1907-1911.; PMid:25275587

Salimi S, Naghavi A, Mokhtari M, Noora M, Yaghmaei M. (2012). Lack of relationship between endothelial nitric oxide synthase gene 4b/a and T-786C polymorphisms with preeclampsia in southeast of Iran. Archives of gynecology and obstetrics. 285 (2): 405-409.; PMid:21713426

Shibuya M. (2006). Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis. 9 (4): 225-231.; PMid:17109193

Staines-Urias E, Paez MC, Doyle P, Dudbridge F, Serrano NC, Ioannidis JP, Keating BJ, Hingorani AD, Casas JP. (2012). Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis. International journal of epidemiology. 41 (6): 1764-1775.; PMid:23132613

Valensise H, Vasapollo B, Gagliardi G, Novelli GP. (2008). Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease. Hypertension (Dallas, Tex.: 1979). 52 (5): 873-880.; PMid:18824660

Van Rijn BB, Bruinse HW, Veerbeek JH, Post Uiterweer ED, Koenen SV, van der Bom JG, Rijkers GT, Roest M, Franx A. (2016). Postpartum Circulating Markers of Inflammation and the Systemic Acute-Phase Response After Early-Onset Preeclampsia. Hypertension (Dallas, Tex.: 1979). 67 (2): 404-414.; PMid:26711734

Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE. (2000). Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine. 12 (8): 1232-1235.; PMid:10930302

Wright D, Syngelaki A, Akolekar R, Poon LC, Nicolaides KH. (2015). Competing risks model in screening for preeclampsia by maternal characteristics and medical history. American journal of obstetrics and gynecology. 213 (1): 62.e1-62.e10.; PMid:25724400

Yamamoto K, Murphy G, Troeberg L. (2015). Extracellular regulation of metalloproteinases. Matrix biology: journal of the International Society for Matrix Biology. 44-46: 255-263.; PMid:25701651

Zhou Y, Bellingard V, Feng KT, McMaster M, Fisher SJ. (2003). Human cytotrophoblasts promote endothelial survival and vascular remodeling through secretion of Ang2, PlGF, and VEGF-C. Developmental biology. 263 (1): 114-125.; PMid:14568550

Zhu JY, Pang ZJ, Yu YH. (2012). Regulation of trophoblast invasion: the role of matrix metalloproteinases. Reviews in obstetrics & gynecology. 5 (3-4): e137-e143.