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Reimpressão oficial do UpToDate www.uptodate.com © 2025 UpToDate, Inc. e/ou suas afiliadas. Todos os direitos reservados. Pré-eclâmpsia: Patogênese INTRODUÇÃO A pré-eclâmpsia é uma síndrome específica da gravidez caracterizada pelo início de hipertensão e proteinúria ou hipertensão e disfunção de órgão-alvo com ou sem proteinúria após 20 semanas de gestação ( tabela 1 ). Sinais e sintomas adicionais que podem ocorrer incluem distúrbios visuais, dor de cabeça, dor epigástrica, trombocitopenia e função renal e hepática anormal. Essas manifestações clínicas resultam de microangiopatia leve a grave de órgãos-alvo, incluindo cérebro, fígado, rim e placenta [ 1 ]. Sequelas maternas potencialmente graves incluem descolamento prematuro da placenta, edema pulmonar, hemorragia cerebral, insuficiência hepática, lesão renal aguda, convulsão (ou seja, eclâmpsia) e morte. Manifestações fetais e neonatais incluem restrição de crescimento fetal, oligoidrâmnio, prematuridade, pequeno para a idade gestacional e natimorto. Complicações maternas e fetais são uma das principais causas de morte materna e neonatal em todo o mundo. A fisiopatologia da pré-eclâmpsia provavelmente envolve fatores maternos e fetais/placentários. Anormalidades no desenvolvimento da vasculatura placentária no início da gestação podem resultar em hipoperfusão/hipóxia/isquemia placentária relativa, o que leva à liberação progressiva de fatores antiangiogênicos na circulação materna, alterando a função endotelial sistêmica materna e causando hipertensão, vasoespasmo, agregação plaquetária e outras manifestações da doença. No entanto, o gatilho para o desenvolvimento placentário anormal e a subsequente cascata de eventos permanece desconhecido. Nossa compreensão atual dos mecanismos que causam as alterações patológicas observadas na pré-eclâmpsia será revisada aqui. Predição, prevenção, características clínicas ® AUTORES: S Ananth Karumanchi, MD, Phyllis August, MD, MPH, Sarosh Rana, MD, MPH, FACOG EDITOR DE SEÇÃO: Charles J Lockwood, MD, MHCM EDITOR ADJUNTO: Dra. Kristen Eckler, FACOG Todos os tópicos são atualizados conforme novas evidências se tornam disponíveis e nosso processo de revisão por pares é concluído. Revisão de literatura atualizada até: agosto de 2025. Este tópico foi atualizado pela última vez em: 19 de março de 2025. https://www.uptodate.com/ https://www.uptodate.com/contents/image?imageKey=OBGYN%2F79977&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/image?imageKey=OBGYN%2F79977&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/1 https://www.uptodate.com/contents/preeclampsia-pathogenesis/contributors https://www.uptodate.com/contents/preeclampsia-pathogenesis/contributors https://www.uptodate.com/contents/preeclampsia-pathogenesis/contributors https://www.uptodate.com/contents/preeclampsia-pathogenesis/contributors https://www.uptodate.com/contents/preeclampsia-pathogenesis/contributors https://www.uptodate.com/home/editorial-policy https://www.uptodate.com/home/editorial-policy e manejo da pré-eclâmpsia são discutidos separadamente. PAPEL DA PLACENTA NO DESENVOLVIMENTO DE DOENÇAS Overview — Early epidemiologic studies established that the placenta has a critical role in the pathogenesis of preeclampsia based on observations that [2-4]: Examination of human placentas at various stages of gestation in pregnancies with and without preeclampsia has informed understanding of normal placental morphology and changes in morphology that are likely relevant to preeclampsia. In pregnancies that eventually manifest the clinical findings associated with preeclampsia, early placental development is characterized by defective extravillous trophoblast (EVT) invasion and defective spiral artery remodeling, two separate but related processes [5,6]. Largely because of these defects, the placenta is suboptimally perfused, leading to placental ischemia and placental release of soluble factors that cause systemic endothelial dysfunction resulting in the preeclamptic phenotype. These processes are summarized in the algorithm ( algorithm 1) and discussed in more detail in the following sections of this topic. Defects in trophoblast differentiation/invasion — Defective trophoblast invasion is likely the sequelae of defective differentiation of the invading EVT [7]. Trophoblast differentiation involves alteration in expression of a number of different classes of molecules, including cytokines, adhesion molecules, extracellular matrix molecules, metalloproteinases, and the class Ib major histocompatibility complex molecule, human leukocyte antigen (HLA-G) [8,9]. During normal differentiation, invading trophoblasts alter their adhesion molecule expression from those that are characteristic of epithelial cells (integrin alpha6/beta1, alphav/beta5, and E-cadherin) to those of endothelial cells (integrin alpha1/beta1, alphav/beta3, and VE-cadherin), a process referred to as pseudo-vasculogenesis [10]. Trophoblasts obtained from patients with preeclampsia do not show upregulated adhesion molecule expression or pseudovasculogenesis. (Consulte "Previsão de pré-eclâmpsia em pacientes grávidas assintomáticas" .)● (Veja "Pré-eclâmpsia: Prevenção" .)● (Consulte "Pré-eclâmpsia: características clínicas e diagnóstico" .)● (Consulte "Pré-eclâmpsia: manejo pré-parto e momento do parto" .)● (Consulte "Pré-eclâmpsia: manejo intraparto e pós-parto e prognóstico a longo prazo" .)● Placental tissue is necessary for development of the disease, but the fetus is not● The clinical manifestations of preeclampsia resolve within days to weeks after delivery of the placenta ● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/2-4 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/5,6 https://www.uptodate.com/contents/image?imageKey=OBGYN%2F79431&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/image?imageKey=OBGYN%2F79431&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/7 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/8,9 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/10 https://www.uptodate.com/contents/prediction-of-preeclampsia-in-asymptomatic-pregnant-patients?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-prevention?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-antepartum-management-and-timing-of-delivery?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-intrapartum-and-postpartum-management-and-long-term-prognosis?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link Transcriptomics and culture studies using human trophoblasts from patients with preeclampsia with severe features have suggested that semaphorin 3B may be a candidate protein that contributes to the impaired trophoblast differentiation and invasion by inhibiting vascular endothelial growth factor (VEGF) signaling [11]. A study using laser microdissection enabled the identification of novel messenger RNAs and noncoding RNAs that were differentially expressed by various trophoblast subpopulations in patients with preeclampsia with severe features [12]. Gene ontology analysis of the syncytiotrophoblast data highlighted the dysregulation of immune functions, morphogenesis, transport, and responses to VEGF and progesterone. Additional studies are needed to evaluate the specific pathways that aretherapy to prevent preeclampsia. Semin Nephrol 2004; 24:557. 35. Yinon Y, Nevo O, Xu J, et al. Severe intrauterine growth restriction pregnancies have increased placental endoglin levels: hypoxic regulation via transforming growth factor- beta 3. Am J Pathol 2008; 172:77. 36. Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia. Semin Immunopathol 2007; 29:151. 37. Maynard S, Epstein FH, Karumanchi SA. 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The role of pravastatin in preventing preeclampsia in high-risk pregnant women: a meta-analysis with trial sequential analysis. Am J Obstet Gynecol MFM 2024; 6:101260. 171. Eddy AC, Chiang CY, Rajakumar A, et al. Bioflavonoid luteolin prevents sFlt-1 release via HIF-1α inhibition in cultured human placenta. FASEB J 2023; 37:e23078. 172. Brownfoot FC, Hastie R, Hannan NJ, 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 2016; 214:356.e1. 173. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12:642. 174. Luft FC. Soluble endoglin (sEng) joins the soluble fms-like tyrosine kinase (sFlt) receptor as a pre-eclampsia molecule. Nephrol Dial Transplant 2006; 21:3052. 175. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. 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Hypertension 2015; 65:863. 186. Biwer LA, Lu Q, Ibarrola J, et al. Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia. Circ Res 2023; 132:674. 187. Chambers JC, Fusi L, Malik IS, et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001; 285:1607. 188. Saxena AR, Karumanchi SA, Brown NJ, et al. Increased sensitivity to angiotensin II is present postpartum in women with a history of hypertensive pregnancy. Hypertension 2010; 55:1239. 189. Levine RJ, Vatten LJ, Horowitz GL, et al. Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based study. BMJ 2009; 339:b4336. 190. Goel A, Maski MR, Bajracharya S, et al. Epidemiology and Mechanisms of De Novo and Persistent Hypertension in the Postpartum Period. Circulation 2015; 132:1726. 191. Skurnik G, Hurwitz S, McElrath TF, et al. 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Topic 6760 Version 60.0 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/180 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/180 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/180 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/181 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/181 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/181 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/182 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/182 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/183 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/183 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/184 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/184 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/184 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/185 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/185 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/186 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/186 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/187 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/187 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/188 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/188 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/188 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/189 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/189 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/189 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/190 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/190 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/191 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/191 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/192 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/192 GRAPHICS Diagnostic criteria for preeclampsia Systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on at least 2 occasions at least 4 hours apart after 20 weeks of gestation in a previously normotensive patient AND the new onset of 1 or more of the following*: Proteinuria ≥0.3 g in a 24-hour urine specimen or protein/creatinine ratio ≥0.3 (30 mg/mmol) in a random urine specimen or dipstick ≥2+ if a quantitative measurement is unavailable Platelet count 1.1 mg/dL (97.2 micromol/L) or doubling of the creatinine concentration in the absence of other kidney disease Liver transaminases at least twice the upper limit of the normal concentrations for the local laboratory Pulmonary edema New-onset and persistentheadache not accounted for by alternative diagnoses and not responding to usual doses of analgesics Visual symptoms (eg, blurred vision, flashing lights or sparks, scotomata) Preeclampsia is considered superimposed when it occurs in a patient with chronic hypertension. Superimposed preeclampsia is characterized by worsening or resistant hypertension (especially acutely), the new onset of proteinuria or a sudden increase in proteinuria, and/or significant new end- organ dysfunction in a patient with chronic hypertension. It typically occurs after 20 weeks of gestation or postpartum. Definitions/diagnostic criteria for preeclampsia are generally similar worldwide except the International Society for the Study of Hypertension in Pregnancy (ISSHP) definition also includes signs of uteroplacental dysfunction (eg, fetal growth restriction, abnormal angiogenic markers, abnormal umbilical artery Doppler, abruption, fetal demise). The ISSHP also considers a platelet count 150 mg/dL, nonfasting], elevated blood pressure, elevated glucose, and low HDL cholesterol[160 mg/dL and constitutes a risk-enhancing factor. ABI (disrupted. Decidual factors may also play a role [13]. Microarray studies of chorionic villus samples have provided evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders [14]. The decidual cells of patients who go on to develop preeclampsia have greater soluble fms-like tyrosine kinase-1 (sFlt-1) expression during decidualization, which may contribute to failed spiral artery modification and shallow placentation [15]. Decidual natural killer (NK) cells contribute to spiral artery remodeling and NK dysfunction has been implicated in the genesis of preeclampsia [16]. Defects in transformation of the spiral arteries — In normal pregnancies, invading trophoblastic cells migrate through the decidua and part of the myometrium to reach both the endothelium and highly muscular tunica media of the spiral arteries, the terminal branches of the uterine artery that supply blood to the placenta. As a result, these vessels undergo transformation from small muscular arterioles to high-capacitance low-resistance vessels, thus greatly facilitating blood flow to the placenta compared with other areas of the uterus [10,17]. Spiral artery remodeling probably begins in the late first trimester and is completed by 18 to 20 weeks of gestation, although the exact gestational age at which trophoblast invasion of these arteries ceases is unclear. By comparison, in preeclampsia, invading trophoblast infiltrates the decidual portion of the spiral arteries but fails to penetrate the myometrial segment [18,19]. The spiral arteries fail to develop into large, tortuous vascular channels created by replacement of the musculoelastic wall with fibrinoid material; instead, the vessels remain narrow, resulting in placental hypoperfusion and relatively hypoxic trophoblast tissue ( figure 1). This shallow placentation has been associated with development of preeclampsia and multiple other adverse pregnancy outcomes, including second-trimester fetal death, abruption, fetal growth restriction, preterm labor, and preterm prelabor rupture of membranes [20]. In preeclampsia, the frequency and severity of placental changes are more prominent in patients who present with preterm disease [21]. https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/11 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/12 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/13 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/14 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/15 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/16 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/10,17 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/18,19 https://www.uptodate.com/contents/image?imageKey=OBGYN%2F144565&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/image?imageKey=OBGYN%2F144565&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/20 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/21 Defective placental perfusion — Hypoperfusion in preeclampsia primarily results from defective spiral artery remodeling but other factors can contribute. For example, maternal conditions associated with vascular insufficiency (eg, chronic hypertension, diabetes, systemic lupus erythematosus, kidney disease, acquired and inherited thrombophilias) and obstetric conditions that increase placental mass without a corresponding increase in placental blood flow (eg, hydatidiform mole, hydrops fetalis, diabetes mellitus, multiple gestation) can result in suboptimal placental perfusion [22,23]. Hypoperfusion becomes more pronounced (ischemia) as pregnancy progresses since the abnormal uterine vasculature is unable to accommodate the normal increase in blood flow to and metabolic demand of the fetus/placenta with increasing gestational age [24-26]. Vascular lesions that may develop as pregnancy advances include atherosis (lipid-laden cells in the wall of the arteriole), fibrinoid necrosis, thrombosis, sclerotic narrowing of arterioles, and placental infarction [10,24,25,27,28]. Although all of these lesions are not uniformly found in patients with preeclampsia, there appears to be a correlation between the early onset and severity of the disease and the extent of these lesions [29,30]. Hypoperfusion/ischemia is likely responsible for placental production and release into the maternal circulation of antiangiogenic factors, such as sFlt-1 and soluble endoglin (sEng) that bind/inhibit proangiogenic factors (VEGF, placental growth factor [PlGF]). This results in widespread maternal vascular inflammation, vascular injury, and endothelial dysfunction, leading to hypertension, vasospasm, platelet adhesion and aggregation, proteinuria, and the other clinical manifestations of preeclampsia [31-39]. (See 'Role of angiogenic and antiangiogenic factors' below.) FACTORS CONTRIBUTING TO DISEASE DEVELOPMENT It is not known why the normal sequence of events for normal placental development does not occur in some pregnancies. Multiple factors that appear to play a role will be reviewed in the following discussion [40]. Immunologic factors Epidemiologic data – The focus on immunologic factors as a possible contributor to abnormal placental development was based, in part, upon the observation that prior exposure to paternal/fetal antigens appears to protect against preeclampsia [41-49]. Nulliparous females and those who change male partners between pregnancies, have long interpregnancy intervals, use barrier contraception, conceive in the first cycle of in vitro fertilization with same sperm donor, or conceive via intracytoplasmic sperm injection have less exposure to paternal antigens and higher risks of developing preeclampsia in some studies. In addition, meta-analyses have found that females who conceive through oocyte ● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/22,23 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/24-26 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/10,24,25,27,28 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/29,30 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/31-39 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/40 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/41-49 donation have a more than twofold higher rate of preeclampsia than those who conceive via other assisted reproductive techniques and a fourfold higher rate of preeclampsia than those who have a natural conception, which also supports the hypothesis that immunologic intolerance between the mother and fetus may play a role in the pathogenesis of preeclampsia [50,51]. In vitro data for immunologic abnormalities● Human leukocyte antigen (HLA) – Immunologic abnormalities, similar to those observed in organ rejection, have been observed in patients with preeclampsia [52]. The extravillous trophoblast (EVT) cells express an unusual combination of HLA class I antigens: HLA-C, HLA-E, and HLA-G. Natural killer (NK) cells that express a variety of receptors (CD94, killer immunoglobulin receptors [KIR], and ILT) known to recognize these antigens infiltrate the decidua in close contact with the EVT cells [53]. Subsequent interaction between the NK cells and EVT cells has been hypothesized to regulate placental implantation. • Definitive evidence for the role of HLA and T-cell abnormalities is lacking. Genetic studies looking at polymorphisms in the KIRs on maternal NK cells and the fetal HLA-C haplotype suggest that mothers with KIR-AA genotype and fetal HLA-C2 genotype are at greatly increased risk of preeclampsia [54]. However, a systematic review found no clear evidence thatone or several specific HLA alleles were involved in the pathogenesis of preeclampsia [55]. The authors suggested that interaction between maternal, paternal, and fetal HLA types, rather than any individual genotype alone, was probably an important factor to consider when studying immunogenetic determinants of preeclampsia. (See "Immunology of the maternal-fetal interface".) T cells – Additional regulators of immune tolerance at the maternal-fetal interface with potential relevance include regulatory T cells (Tregs), a specialized CD4 T-cell subset that may play an important role in protecting the fetus by dampening the inflammatory immune response; these cells appear to be reduced in the systemic circulation as well as the placental bed in patients with preeclampsia [56]. In preeclampsia, conflict between maternal and paternal genes is believed to induce abnormal placental implantation through increased NK cell activity, decreased T regs, and other mediators of the immune response. • Dendritic cells – Placental bed biopsies from patients with preeclampsia have revealed increased dendritic cell infiltration in decidual tissue of patients with preeclampsia [57]. The dendritic cells are an important initiator of antigen-specific T-cell responses to transplantation antigens. It is possible that increased number of dendritic cells may result in alteration in presentation of maternal and fetal antigens at the decidual level, • https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/50,51 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/52 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/53 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/54 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/55 https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/56 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/57 Genetic factors — Most cases of preeclampsia are sporadic, but genetic factors are thought to play a role in disease susceptibility in about one-third of cases [68-78]. The body of data suggest that both maternal and paternal contributions to fetal genes may have a role in defective placentation and subsequent preeclampsia. A genetic predisposition to preeclampsia is supported by the following observations; however, a study of preeclampsia in twins failed to find a genetic link [79]. leading to either abnormal implantation or altered maternal immunologic response to fetal antigens. AT-1 agonists – Patients with preeclampsia have increased levels of agonistic antibodies to the angiotensin II receptor type 1 (AT-1) receptor. This antibody can mobilize intracellular free calcium and may account for increased plasminogen activator inhibitor- 1 production and shallow trophoblast invasion seen in preeclampsia [58-61]. Agonistic AT-1 receptor antibody also stimulates soluble fms-like tyrosine kinase-1 (sFlt-1) secretion [62]. In addition, since angiotensin II is the endogenous ligand for the AT-1 receptor, increased activation of this receptor by auto-antibodies could induce hypertension and vascular injury observed in preeclampsia. Studies in mice support this theory [63,64]. Other studies in mice suggest that endothelial dysfunction induced by circulating anti-angiogenic factors are sufficient to induce angiotensin II sensitivity [65]. It is unclear if these alterations are pathogenic or epiphenomena. (See 'Role of angiogenic and antiangiogenic factors' below.) • In addition, bradykinin (B2) receptor upregulation leads to heterodimerization of B2 receptors with AT-1 receptors, and this AT-1/B2 heterodimer increases responsiveness to angiotensin II in vitro [66]. Interestingly, amlodipine therapy promoted AT-1/B2 downregulation and prevented preeclampsia in a mouse model [67]. Epidemiologic data● Primigravidas with a family history of preeclampsia (eg, affected mother or sister) have a two- to fivefold higher risk of the disease than primigravidas without this history [69,70,77,80]. The maternal contribution to development of preeclampsia can be partially explained by imprinted genes [81]. In a study of sisters with preeclampsia, it was demonstrated that preeclampsia developed only when the fetus/placenta inherited a maternal STOX1 missense mutation on 10q22; when the fetus/placenta carried the imprinted paternal homolog, the preeclampsia phenotype was not expressed. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.) • The risk of preeclampsia is increased more than sevenfold in individuals who had preeclampsia in a previous pregnancy [82]. • https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/68-78 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/79 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/58-61 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/62 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/63,64 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/65 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/66 https://www.uptodate.com/contents/amlodipine-drug-information?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/67 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/69,70,77,80 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/81 https://www.uptodate.com/contents/inheritance-patterns-of-monogenic-disorders-mendelian-and-non-mendelian?sectionName=Parent-of-origin%20effects%20%28imprinting%29&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H1457606458&source=see_link#H1457606458 https://www.uptodate.com/contents/inheritance-patterns-of-monogenic-disorders-mendelian-and-non-mendelian?sectionName=Parent-of-origin%20effects%20%28imprinting%29&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H1457606458&source=see_link#H1457606458 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/82 A female impregnated by sperm from a male who was the product of a pregnancy complicated by preeclampsia is more likely to develop preeclampsia than a female impregnated by sperm from a male without this history [71,77]. • A female impregnated by sperm from a male whose previous female partner had preeclampsia is at higher risk of developing the disorder than if the previous female partner did not have preeclampsia [72]. • Genomic data● PAI-1 4G/5G polymorphism – A meta-analysis of studies of PAI-1 4G/5G polymorphism (recessive model) showed strong consistent evidence for an association with risk for preeclampsia [51]. • Chromosome 13 – The genes for sFlt-1 and Flt1 are carried on chromosome 13. Fetuses with an extra copy of this chromosome (eg, trisomy 13) should produce more of these gene products than their euploid counterparts. In fact, the incidence of preeclampsia in mothers who carry fetuses with trisomy 13 is greatly increased compared with all other trisomies or with control pregnant patients [83]. In addition, the sFlt-1:placental growth factor (PlGF) ratio is significantly increased in these pregnancies, thus accounting for their increased risk for preeclampsia [84]. • GWAS studies• A large genome-wide association study (GWAS) of offspring from preeclamptic pregnancies identified a genome-wide susceptibility locus near the Flt1 gene encoding Fms-like tyrosine kinase 1 and provided convincing replication in an independent cohort [85]. These findings were confirmed in additional European cohorts [86,87]. This GWAS finding provides compelling evidence that alterations in chromosome 13 near the Flt1 locus in the human fetal genomeare causal in the development of preeclampsia. (See 'sFlt-1, VEGF, PlGF' below.) - Multiple maternal GWAS have reported potential susceptibility genes for preeclampsia, eclampsia, and gestational hypertension [73,74,88-91]. The largest of these evaluated the association of maternal DNA sequence variants with preeclampsia (>20,000 cases and >700,000 controls) and with gestational hypertension (>11,000 cases and >400,000 controls) across discovery and follow-up cohorts using multi- ancestry meta-analysis [91]. Eighteen independent genomic loci associated with preeclampsia/eclampsia and/or gestational hypertension were identified and supported the role of angiogenesis and endothelial function (Flt1 and ZBTB46), natriuretic peptide signaling (NPPA, NPR3 and FURIN), glomerular function (TRPC6, TNS2 and PLCE1) and immune dysregulation (MICA and SH2B3) in the pathogenesis of these conditions, with some loci (Flt1 and WNT3A) previously described - https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/71,77 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/72 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/51 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/83 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/84 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/85 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/86,87 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/73,74,88-91 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/91 Environmental and maternal susceptibility factors to influence risk via the fetal genome. When the results were used to train and test polygenic risk scores for each outcome in independent datasets, polygenic risk score was modestly predictive of risk of a hypertensive disorder of pregnancy among nulliparous females independent of first-trimester risk factors. 12q locus – A locus at 12q may be linked to HELLP syndrome (ie, hemolysis, elevated liver enzymes, and low platelets), but not preeclampsia without severe features (ie, de novo hypertension and proteinuria), suggesting that genetic factors important in HELLP syndrome may be distinct from those in preeclampsia without severe features [75]. Alterations in long noncoding RNA at 12q23 have been implicated as one potential mechanism that may lead to HELLP syndrome [92]. This long noncoding RNA regulates a large set of genes that may be important for EVT migration. • High body mass index (BMI) – A prospective study demonstrated a linear relationship between increasing BMI and increasing risk of developing preeclampsia [93]. In this cohort, the adjusted odds ratio (aOR) for preeclampsia rose from aOR 1.65 in pregnant individuals with BMI 25 to 30 kg/m to aOR 6.04 in those with BMI ≥40 kg/m . It is likely that obesity increases susceptibility to preeclampsia by inducing chronic inflammation and endothelial dysfunction, which may synergize with placental angiogenic factors to induce the microangiopathic features of preeclampsia [94]. For example, preeclampsia is associated with elevated circulating interleukin (IL)-6 and adipose-derived leptin levels as well as three- and fivefold increases in IL-6 and leptin receptor expression, respectively, in Hofbauer cells from preeclamptic placentas [95]. Furthermore, leptin stimulates IL-6 expression in Hofbauer cells in a concentration-dependent manner, promoting a proinflammatory phenotype in the placenta. ● 2 2 In vitro fertilization (IVF) – Compared with spontaneous conception, pregnancies after IVF have been associated with a higher risk of adverse pregnancy outcomes, including preeclampsia and fetal growth restriction [96,97]. The strength of association is greatest in oocyte donation pregnancies [98,99]. ● Preexisting vascular disease – Rates of preeclampsia are significantly higher in pregnant individuals with comorbid vascular disease, including chronic hypertension, diabetes, chronic kidney disease, and autoimmune diseases. Although the precise pathophysiologic pathways relating these disorders to preeclampsia are not clear, preexisting endothelial cell damage may play a role [100]. Preexisting endothelial damage may also explain why individuals who develop preeclampsia are also at increased risk of developing cardiovascular disease and chronic kidney disease later in life [101-103]. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Cardiovascular disease, kidney disease, type 2 diabetes'.) ● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/75 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/92 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/93 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/94 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/95 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/96,97 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/98,99 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/100 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/101-103 https://www.uptodate.com/contents/preeclampsia-intrapartum-and-postpartum-management-and-long-term-prognosis?sectionName=Cardiovascular%20disease%2C%20kidney%20disease%2C%20type%202%20diabetes&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H3075617923&source=see_link#H3075617923 https://www.uptodate.com/contents/preeclampsia-intrapartum-and-postpartum-management-and-long-term-prognosis?sectionName=Cardiovascular%20disease%2C%20kidney%20disease%2C%20type%202%20diabetes&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H3075617923&source=see_link#H3075617923 Trophoblast cell-free DNA and inflammation – Signs of maternal inflammation are present in normal pregnancies at term but are exaggerated in preeclampsia. Circulating syncytiotrophoblast debris have been hypothesized to contribute to maternal inflammation and some of the features of the maternal syndrome [104,105]. Specifically, trophoblast cell-free DNA released into the maternal circulation could play a role in driving the systemic inflammatory response of preeclampsia [106]. Placental hypoxia increases placental necrosis and apoptosis, which releases trophoblast cell-free DNA into the maternal circulation. As early as 17 weeks of gestation, individuals who develop preeclampsia appear to have higher levels of trophoblast cell-free DNA compared with controls, with a sharp rise three weeks before clinical signs of preeclampsia become apparent [107]. The cell-free fetal DNA rise correlates with sFlt-1 rise, and syncytial microparticles that carry the cell-free fetal DNA are loaded with sFlt-1 and other toxic syncytial proteins [108,109]. It may be that the inflammatory state increases the vascular endothelial sensitivity to toxic factors such as sFlt-1 and soluble endoglin (sEng), although definitive evidence is lacking. ● Infection – Maternal infection can also induce a systemic inflammatory response. A meta- analysis of observational studies that examined the relationship between maternal infection and preeclampsia reported that the risk of preeclampsia was increased in pregnant individuals with urinary tract infection (pooled odds ratio [OR] 1.57, 95% CI 1.45- 1.70) or periodontal disease (pooled OR 1.76, 95% CI 1.43-2.18) [110]. There were no associations between preeclampsia and presence of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus; treated and nontreated HIV infection; malaria; herpes simplex virus type 2; bacterial vaginosis; or Mycoplasma hominis. ● Complement activation – Increasing evidence suggests that complement dysregulation/activation may play a role in the pathogenesis of preeclampsia [111,112]. Preeclampsia is more common in pregnant individuals with autoimmune diseases, particularlysystemic lupus erythematosus and antiphospholipid syndrome [113,114]. Activation of the classical pathway of complement in the placenta has been observed in such patients [115,116]. Preliminary clinical studies have reported increased markers of the alternative complement pathway activation in serum and urine of patients with preeclampsia with severe features [117,118]. In pregnant patients without preexisting autoimmune disease, pathogenic variants in complement regulatory proteins predispose to preeclampsia [119]. Germline variants in the alternative complement pathway were also reported in patients with HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), a severe complication of preeclampsia [120]. The similarities between HELLP syndrome and thrombotic microangiopathies in nonpregnant patients suggest that this is an interesting area of investigation with potential therapeutic applications [121]. ● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/104,105 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/106 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/107 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/108,109 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/110 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/111,112 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/113,114 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/115,116 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/117,118 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/119 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/120 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/121 ROLE OF ANGIOGENIC AND ANTIANGIOGENIC FACTORS sFlt-1, VEGF, PlGF — Mammalian placentation requires extensive angiogenesis for the establishment of a suitable vascular network to supply oxygen and nutrients to the fetus. A variety of proangiogenic (vascular endothelial growth factor [VEGF], placental growth factor [PlGF]) and antiangiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1]) are released by the developing placenta, and the balance among these factors is important for normal placental development. Increased placental production of antiangiogenic factors disturbs this balance and results in the systemic endothelial dysfunction characteristic of preeclampsia. Fetuses of mothers with preeclampsia do not have abnormal concentrations of these factors, which may be the reason that they do not manifest the same clinical features (eg, hypertension, proteinuria) as their mothers [122]. sFlt-1 is a naturally occurring, circulating antagonist to VEGF ( figure 2). VEGF is an endothelial specific mitogen that has a key role in promoting angiogenesis [123,124]. Its activities are mediated primarily by interaction with two high-affinity receptor tyrosine kinases, vascular endothelial growth factor receptor-1 (VEGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2), which are selectively expressed on the vascular endothelial cell surface. VEGFR-1 has two isoforms: a transmembranous isoform and a soluble isoform (sFlt-1). PlGF is another member of the VEGF family that is made predominantly by placental trophoblasts. It also binds to the VEGFR-1 receptor. (See "Overview of angiogenesis and angiogenesis inhibitors", section on 'Physiologic angiogenesis in the embryo and beyond'.) sFlt-1 antagonizes the proangiogenic biologic activity of circulating VEGF and PlGF by binding to them and preventing their interaction with their endogenous receptors. Increased placental expression and secretion of sFlt-1 appear to play a central role in the pathogenesis of the preeclampsia phenotype, based on the following observations [65,125-134]: Low calcium intake – Various dietary and lifestyle factors have been associated with an increased risk of preeclampsia; however, causality has been difficult to prove. A possible role for low dietary intake of calcium as a risk factor for preeclampsia is suggested by epidemiologic studies linking low calcium intake with increased rates of preeclampsia and prevention of preeclampsia with calcium supplementation in high-risk patients. The mechanism of this association is not clear but may involve either immunologic or vascular effects of calcium regulatory hormones that are altered in preeclampsia. (See "Preeclampsia: Prevention", section on 'Calcium supplementation when baseline dietary calcium intake is low'.) ● Animal studies – Transgenic overexpression of sFlt-1 in murine placentas led to impaired spiral artery remodeling and fetal growth restriction that was accompanied by maternal ● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/122 https://www.uptodate.com/contents/image?imageKey=OBGYN%2F54562&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/image?imageKey=OBGYN%2F54562&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/123,124 https://www.uptodate.com/contents/overview-of-angiogenesis-and-angiogenesis-inhibitors?sectionName=Physiologic%20angiogenesis%20in%20the%20embryo%20and%20beyond&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H335428678&source=see_link#H335428678 https://www.uptodate.com/contents/overview-of-angiogenesis-and-angiogenesis-inhibitors?sectionName=Physiologic%20angiogenesis%20in%20the%20embryo%20and%20beyond&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H335428678&source=see_link#H335428678 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/65,125-134 https://www.uptodate.com/contents/preeclampsia-prevention?sectionName=Calcium%20supplementation%20when%20baseline%20dietary%20calcium%20intake%20is%20low&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H3331389734&source=see_link#H3331389734 https://www.uptodate.com/contents/preeclampsia-prevention?sectionName=Calcium%20supplementation%20when%20baseline%20dietary%20calcium%20intake%20is%20low&search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&anchor=H3331389734&source=see_link#H3331389734 Triggers for increased sFlt-1 production — The triggers for increased sFlt-1 production by the placenta are unknown. The most likely trigger is placental ischemia ( algorithm 1) hypertension and proteinuria [135]. sFlt-1 administered to pregnant rats induces albuminuria, hypertension, and the unique pathologic changes of glomerular endotheliosis ( picture 1A-C) [125]. In pregnant mice, sFlt-1 overexpression induces angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) activity [65]. In vitro studies – Removal of sFlt-1 from supernatants of preeclamptic tissue culture restores endothelial function and angiogenesis to normal levels. Conversely, exogenous administration of VEGF and PlGF reverses the antiangiogenic state induced by excess sFlt- 1. Serum from patients with preeclampsia causes endothelial activation in human umbilical vein endothelial cell culture studies in some in vitro studies [136]. ● Human studies – Compared with normotensive controls, circulating levels of sFlt-1 levels are increased and free VEGF and free PlGF are decreased in patients with preeclampsia. Studies using banked sera showed that these patients had decreases in PlGF and VEGF levels well before the onset of clinical disease [132,137-142]. In the aggregate, the following observations suggest a major role for sFlt-1 and related angiogenic factors in the pathogenesis of at least some features of preeclampsia ( figure 3) [143]. ● A nested case-control study using banked sera to measure serum sFlt-1, as well as PlGF and VEGF, across gestation found that changes in sFlt-1 were predictive of the subsequent development ofpreeclampsia [132]. sFlt-1 levels increased during pregnancy in all pregnant people; however, compared with normotensive controls, those who went on to develop preeclampsia began this increase earlier in gestation (at 21 to 24 weeks versus 33 to 36 weeks) and reached higher levels ( figure 4). A significant difference in the serum sFlt-1 concentration between the two groups was apparent five weeks before the onset of clinical disease. PlGF and VEGF levels fell concurrently with the rise in sFlt-1 ( figure 5), which may have been related, in part, to binding by sFlt-1. • In another study, the concentration of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) correlated with increasing severity of disease: sVEGFR-1 concentrations were higher in patients with early (aspirin may inhibit sFlt-1 production and could reverse angiogenic imbalance noted in placentas of patients with preeclampsia [169]. RNA interference therapies against sFlt-1 have also shown promise in nonhuman primate models of preeclampsia [149]. A number of other compounds and drugs that inhibit sFlt-1 are also promising as a treatment for preeclampsia in preclinical models [170-172]. Soluble endoglin — It is likely that synergistic factors elaborated by the placenta other than sFlt-1 also play a role in the pathogenesis of the generalized endothelial dysfunction noted in preeclampsia. Consistent with this hypothesis is the observation that the plasma concentration of sFlt-1 protein needed to produce the preeclampsia phenotype in rats was severalfold higher than the levels typically seen in patients with preeclampsia, and no coagulation or liver function abnormalities were reported in the sFlt-1-treated animals [125]. Endoglin (Eng) is a coreceptor for transforming growth factor (TGF)-beta and is highly expressed on cell membranes of vascular endothelium and syncytiotrophoblasts [173]. A novel placenta-derived soluble form of Eng, referred to as soluble endoglin (sEng), is an anti- angiogenic protein that appears to be another important mediator of preeclampsia [66,173- 175]. Although the precise relationship of sEng to sFlt-1 is unknown, it appears that both sEng and sFlt-1 contribute to the pathogenesis of the maternal syndrome through separate mechanisms. Several lines of evidence support this hypothesis [66,173-175]: sEng is elevated in the sera of patients with preeclampsia two to three months before the onset of clinical manifestations, correlates with disease severity, and falls after delivery. An increased level of sEng accompanied by an increased ratio of sFlt-1:PlGF is more predictive of developing preeclampsia than sFlt-1:PlGF alone. ● In vivo, sEng increases vascular permeability and induces hypertension. In pregnant rats, it appears to potentiate the vascular effects of sFlt-1 to induce a severe preeclampsia-like state, including the development of HELLP syndrome and fetal growth restriction. ● sEng inhibits TGF-beta-1 signaling in endothelial cells and blocks TGF-beta-1-mediated activation of eNOS and vasodilation, suggesting that dysregulated TGF-beta signaling may be involved in the pathogenesis of preeclampsia. ● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/161,162 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/163-167 https://www.uptodate.com/contents/aspirin-drug-information?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/168 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/169 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/149 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/170-172 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/125 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/173 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/66,173-175 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/66,173-175 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/66,173-175 Other changes PREECLAMPSIA AND POSTPARTUM CARDIOVASCULAR DISEASE Although clinical signs and symptoms of preeclampsia commonly resolve after placental delivery, patients with preeclampsia have a significantly elevated risk of developing persistent chronic hypertension, ischemic heart disease, and stroke many years postpartum. In a meta-analysis including almost 200,000 patients with preeclampsia, these individuals had an approximately threefold increased risk of developing hypertension and a twofold increased risk of heart attack and stroke compared with those without preeclampsia after 10 to 14 years of follow-up [102]. Patients at highest risk appear to be those with recurrent preeclampsia, preeclampsia with fetal compromise (fetal growth restriction or fetal death), or preeclampsia with severe features [179-181]. Using data from the observational UK Biobank, a causal mediation analysis confirmed that hypertension following preeclampsia was the major driver for cardiovascular disease (eg, coronary artery disease, heart failure) observed in individuals with a past history of preeclampsia [182]. Preeclampsia should therefore be considered a risk-enhancing factor [183] ( table 2) for informing and shaping the clinician- patient discussion of atherosclerotic cardiovascular disease risk and primary prevention therapies. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults".) Whether a pregnancy affected by preeclampsia directly accelerates cardiovascular disease, or prepregnancy shared risk factors contribute to development of both preeclampsia and cardiovascular disease, is not resolved. More data are needed to better understand the association between preeclampsia and accelerated cardiovascular disease and strategies to prevent cardiovascular disease in this large and expanding population of high-risk females. Available data are limited. In a large prospective cohort study of 5475 individuals, mid- trimester decreases in PlGF was associated with larger left ventricular mass and higher average systolic blood pressure six to nine years after pregnancy compared with those with higher PlGF levels [184]. In a mouse model, exposure to preeclampsia induced angiotensin II sensitivity and exacerbated the vascular proliferative and fibrotic responses to future vascular injury [185]. Soluble fms-like tyrosine kinase-1 (sFlt-1)-induced vascular injury in pregnant mice has also been associated with enhanced sensitivity of smooth muscle cell mineralocorticoid receptors and postpartum hypertension in response to common stressors Decreased production of endothelial-derived vasodilators, such as nitric oxide and prostacyclin, and increased production of vasoconstrictors, such as endothelins and thromboxanes may also play a role in the vascular changes in preeclampsia. ● Impaired flow-mediated vasodilation [176,177] and impaired acetylcholine mediated vasorelaxation [178] may contribute to the vasoconstriction in patients with preeclampsia. ● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/102 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/179-181 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/182 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/183 https://www.uptodate.com/contents/image?imageKey=PC%2F131708&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/image?imageKey=PC%2F131708&topicKey=OBGYN%2F6760&search=biomarcadores%20e%20pre%20eclampsia&source=see_link https://www.uptodate.com/contents/atherosclerotic-cardiovascular-disease-risk-assessment-for-primary-prevention-in-adults?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/atherosclerotic-cardiovascular-disease-risk-assessment-for-primary-prevention-in-adults?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/184 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/185 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/176,177 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/178 such as salt and angiotensin II [186]. In humans, impaired endothelial function can be demonstrated by brachial artery flow-mediated dilation three years after a preeclamptic pregnancy [187]. Similarly, increased sensitivity to angiotensin II persists in the postpartum period in individuals with a prior history of preeclampsia [188]. It is unknown whether this is a cause or effect of the preeclampticpregnancy. Increased serum concentration of sFlt-1 in individuals with preeclampsia is associated with subclinical hypothyroidism during pregnancy and may predispose them to future development of reduced thyroid function [189]. POSTPARTUM PREECLAMPSIA Although uncommon, postpartum hypertension and preeclampsia can occur up to 6 to 8 weeks after delivery. The factors involved in the clinical expression of preeclampsia after delivery of the placenta are unclear, but may involve delayed clearance of antiangiogenic factors, activation of the complement system after delivery, and/or response to mobilization of extracellular fluid into the intravascular compartment [190-192]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertensive disorders of pregnancy".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) th th th th Beyond the Basics topics (see "Patient education: Preeclampsia (Beyond the Basics)")● https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/186 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/187 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/188 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/189 https://www.uptodate.com/contents/preeclampsia-pathogenesis/abstract/190-192 https://www.uptodate.com/contents/society-guideline-links-hypertensive-disorders-of-pregnancy?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/society-guideline-links-hypertensive-disorders-of-pregnancy?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link https://www.uptodate.com/contents/preeclampsia-beyond-the-basics?search=biomarcadores%20e%20pre%20eclampsia&topicRef=6760&source=see_link SUMMARY AND RECOMMENDATIONS ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Kee-Hak Lim, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lain KY, Roberts JM. Contemporary concepts of the pathogenesis and management of preeclampsia. JAMA 2002; 287:3183. 2. Moore-Maxwell CA, Robboy SJ. Placental site trophoblastic tumor arising from antecedent molar pregnancy. Gynecol Oncol 2004; 92:708. Role of the placenta – Abnormal development of the uteroplacental circulation occurs long before clinical manifestations of preeclampsia become evident. Very early in pregnancy, cytotrophoblast infiltrates the decidual portion of the spiral arteries but fails to penetrate the myometrial portion, which prevents development of the large, tortuous vascular channels characteristic of the normal placenta; instead, the vessels remain narrow, resulting in hypoperfusion and ischemia ( algorithm 1). Early abnormal placental development is particularly prominent in patients who develop preterm preeclampsia. (See 'Role of the placenta in disease development' above.) ● Contributing factors – Multiple environmental, immunologic, and genetic factors appear to play a role in abnormal placental development. (See 'Factors contributing to disease development' above.) ● Role of antiangiogenic factors – The ischemic placenta appears to elaborate factors (eg, antiangiogenic proteins) into the maternal circulation that alter maternal endothelial cell function and lead to the characteristic systemic signs and symptoms of preeclampsia ( algorithm 1). (See 'Role of angiogenic and antiangiogenic factors' above.) ● sFlt-1 and PlGF – Soluble fms-like tyrosine kinase-1 (sFlt-1) is a circulating antagonist to vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). It is released by the abnormal placenta and is an important mediator of the maternal signs and symptoms of preeclampsia. The sFlt-1:PlGF ratio in combination with other clinical assessments aids in predicting disease development and adverse outcomes. 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Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia. Am J Pathol 1997; 151:1809. 10. Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997; 99:2152. 11. Zhou Y, Gormley MJ, Hunkapiller NM, et al. Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia. J Clin Invest 2013; 123:2862. 12. Gormley M, Ona K, Kapidzic M, et al. Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations. Am J Obstet Gynecol 2017; 217:200.e1. 13. Garrido-Gomez T, Dominguez F, Quiñonero A, et al. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc Natl Acad Sci U S A 2017; 114:E8468. 14. Rabaglino MB, Conrad KP. Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration. FASEB J 2019; 33:11682. 15. Sahu MB, Deepak V, Gonzales SK, et al.Decidual cells from women with preeclampsia exhibit inadequate decidualization and reduced sFlt1 suppression. Pregnancy Hypertens 2019; 15:64. 16. Sones JL, Lob HE, Isroff CE, Davisson RL. Role of decidual natural killer cells, interleukin- 15, and interferon-γ in placental development and preeclampsia. 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