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Preeclampsia: Pathogenesis

Preeclampsia: Pathogenesis
Authors:
S Ananth Karumanchi, MD
Phyllis August, MD, MPH
Sarosh Rana, MD, MPH, FACOG
Section Editor:
Charles J Lockwood, MD, MHCM
Deputy Editor:
Vanessa A Barss, MD, FACOG
Literature review current through: Apr 2025. | This topic last updated: Mar 19, 2025.

INTRODUCTION — 

Preeclampsia is a pregnancy-specific syndrome characterized by the onset of hypertension and proteinuria or hypertension and end-organ dysfunction with or without proteinuria after 20 weeks of gestation (table 1). Additional signs and symptoms that can occur include visual disturbances, headache, epigastric pain, thrombocytopenia, and abnormal kidney and liver function. These clinical manifestations result from mild to severe microangiopathy of target organs, including the brain, liver, kidney, and placenta [1]. Potential serious maternal sequelae include placental abruption, pulmonary edema, cerebral hemorrhage, hepatic failure, acute kidney injury, seizure (ie, eclampsia) and death. Fetal and neonatal manifestations include fetal growth restriction, oligohydramnios, prematurity, small for gestation age, and stillbirth. Maternal and fetal complications are a leading cause of maternal and neonatal death worldwide.

The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. Abnormalities in the development of placental vasculature early in pregnancy may result in relative placental underperfusion/hypoxia/ischemia, which leads to the progressive release of antiangiogenic factors into the maternal circulation that alter maternal systemic endothelial function and cause hypertension, vasospasm, platelet aggregation, and the other manifestations of the disease. However, the trigger for abnormal placental development and the subsequent cascade of events remains unknown.

Our current understanding of mechanisms causing the pathologic changes observed in preeclampsia will be reviewed here. Prediction, prevention, clinical features, and management of preeclampsia are discussed separately.

●(See "Prediction of preeclampsia in asymptomatic pregnant patients".)

●(See "Preeclampsia: Prevention".)

●(See "Preeclampsia: Clinical features and diagnosis".)

●(See "Preeclampsia: Antepartum management and timing of delivery".)

●(See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis".)

ROLE OF THE PLACENTA IN DISEASE DEVELOPMENT

Overview — Early epidemiologic studies established that the placenta has a critical role in the pathogenesis of preeclampsia based on observations that [2-4]:

●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

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.

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 are 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].

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 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 that one 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, 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].

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].

●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].

•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 genome are 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 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.

Environmental and maternal susceptibility factors

●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/m2 to aOR 6.04 in those with BMI ≥40 kg/m2. 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.

●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'.)

●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, particularly systemic 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].

●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'.)

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 inhibitors".)

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]:

●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 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 of preeclampsia [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 (<34 weeks) preeclampsia or preeclampsia with severe features than in those with late preeclampsia or preeclampsia without severe features [129]. Furthermore, individuals with preeclampsia had higher sVEGFR-1 levels than those who remained normotensive two to five weeks before onset of clinical disease [129].

•Multiple studies have shown that alterations in both sFlt-1 and PlGF correlate with adverse maternal and neonatal outcomes associated with preeclampsia [114,144-150].

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) [151]. In vitro, trophoblasts possess a unique property to enhance sFlt-1 production when oxygen availability is reduced [152]. The increased expression of hypoxia-inducible transcription factors (HIFs) in placentas of individuals who develop preeclampsia is consistent with this hypothesis [153]. It is not known whether increased sFlt-1 secretion is responsible for the early placental developmental abnormalities characteristic of preeclampsia, a secondary response to placental ischemia caused by some other factor or a combination through a positive feedback loop. Genetic factors and placental size (eg, multiple gestation) may also play a role in excess production of sFlt-1 [154]. (See 'Role of the placenta in disease development' above and 'Genetic factors' above.)

Experimental studies in animals suggest that sFlt-1 leads to an exaggerated state of oxidative stress, which in turn adversely affects villous angiogenesis and increases sensitivity to vasopressors such as angiotensin II. These data suggest that endothelial dysfunction secondary to the abnormal anti-angiogenic state may be the primary event leading to vasopressor sensitivity and hypertension [65]. It is likely that secondary, counter-regulatory systems may also play a role. For example, glomerular endotheliosis leads to modest reductions in GFR and blood flow to the kidney [65]. Alterations in the renin angiotensin system such as suppressed plasma renin activity in patients with preeclampsia are consistent with sodium volume retention [155]. This sequence of events, similar to that observed in nonpregnant patients with glomerulonephritis, may also contribute to maternal hypertension.

sFlt-1:PlGF ratio — Measurement of sFlt-1:PlGF ratio in serum appears to be a useful test to rule in or rule out preeclampsia in patients with suspected preeclampsia [156,157]. In pregnant hypertensive patients, a high plasma sFlt-1:PlGF identifies those at risk of requiring delivery within two weeks because of severe preeclampsia [144,158]. A large prospective study across 18 sites in the United States confirmed the prognostic utility of sFlt-1:PlGF in this symptomatic population and noted that it outperformed all other standard-of-care tests for predicting preeclampsia with severe features within two weeks of presentation [158]. Based on the results of this study, in 2023, the United States Food and Drug Administration (FDA) approved the use of sFlt-1:PlGF to aid in the risk assessment of pregnant patients with singleton pregnancies between 23+0 to 34+6 weeks of gestation and hospitalized for a hypertensive disorder of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension) to predict progression to preeclampsia with severe features [159].

Guidance from the American College of Obstetricians and Gynecologists (ACOG) states that the sFlt-1/PlGF ratio is a complementary test for risk assessment of preeclampsia with severe features but should not replace current clinical criteria for diagnosing preeclampsia [160].

In patients with preeclampsia at term (ie, ≥37 weeks), an abnormal angiogenic profile (sFlt-1:PlGF) also identifies those with excess inflammatory profiles and at higher risk of adverse outcomes [161,162].

sFlt and PlGF as targets for medical therapy — In the future, apheresis or drugs that reduce sFlt-1 levels or promote PlGF levels may be useful to prevent or treat preeclampsia [163-167]. Low-dose aspirin therapy was effective in preventing preeclampsia in individuals with low PlGF levels measured during the first trimester [168]. Cell culture studies have shown 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.

Other changes

●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.

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 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 preeclamptic pregnancy.

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 5th to 6th 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 10th to 12th 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.)

●Beyond the Basics topics (see "Patient education: Preeclampsia (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●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. (See 'Role of angiogenic and antiangiogenic factors' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Kee-Hak Lim, MD, who contributed to earlier versions of this topic review.

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  134. Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 2004; 95:884.
  135. Vogtmann R, Heupel J, Herse F, et al. Circulating Maternal sFLT1 (Soluble fms-Like Tyrosine Kinase-1) Is Sufficient to Impair Spiral Arterial Remodeling in a Preeclampsia Mouse Model. Hypertension 2021; 78:1067.
  136. Roberts JM, Edep ME, Goldfien A, Taylor RN. Sera from preeclamptic women specifically activate human umbilical vein endothelial cells in vitro: morphological and biochemical evidence. Am J Reprod Immunol 1992; 27:101.
  137. Taylor RN, Grimwood J, Taylor RS, et al. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol 2003; 188:177.
  138. Tjoa ML, van Vugt JM, Mulders MA, et al. Plasma placenta growth factor levels in midtrimester pregnancies. Obstet Gynecol 2001; 98:600.
  139. Su YN, Lee CN, Cheng WF, et al. Decreased maternal serum placenta growth factor in early second trimester and preeclampsia. Obstet Gynecol 2001; 97:898.
  140. Tidwell SC, Ho HN, Chiu WH, et al. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol 2001; 184:1267.
  141. Polliotti BM, Fry AG, Saller DN, et al. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol 2003; 101:1266.
  142. Thadhani R, Mutter WP, Wolf M, et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 2004; 89:770.
  143. Widmer M, Villar J, Benigni A, et al. Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review. Obstet Gynecol 2007; 109:168.
  144. Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012; 125:911.
  145. Moore AG, Young H, Keller JM, et al. Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia. J Matern Fetal Neonatal Med 2012; 25:2651.
  146. Chaiworapongsa T, Romero R, Korzeniewski SJ, et al. Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study. J Matern Fetal Neonatal Med 2014; 27:132.
  147. March MI, Geahchan C, Wenger J, et al. Circulating Angiogenic Factors and the Risk of Adverse Outcomes among Haitian Women with Preeclampsia. PLoS One 2015; 10:e0126815.
  148. Rana S, Salahuddin S, Mueller A, et al. Angiogenic biomarkers in triage and risk for preeclampsia with severe features. Pregnancy Hypertens 2018; 13:100.
  149. Salahuddin S, Wenger JB, Zhang D, et al. KRYPTOR-automated angiogenic factor assays and risk of preeclampsia-related adverse outcomes. Hypertens Pregnancy 2016; 35:330.
  150. Vaisbuch E, Whitty JE, Hassan SS, et al. Circulating angiogenic and antiangiogenic factors in women with eclampsia. Am J Obstet Gynecol 2011; 204:152.e1.
  151. Gilbert JS, Ryan MJ, LaMarca BB, et al. Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction. Am J Physiol Heart Circ Physiol 2008; 294:H541.
  152. Nagamatsu T, Fujii T, Kusumi M, et al. Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology 2004; 145:4838.
  153. Rajakumar A, Doty K, Daftary A, et al. Impaired oxygen-dependent reduction of HIF-1alpha and -2alpha proteins in pre-eclamptic placentae. Placenta 2003; 24:199.
  154. Bdolah Y, Lam C, Rajakumar A, et al. Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol 2008; 198:428.e1.
  155. Buhl KB, Friis UG, Svenningsen P, et al. Urinary plasmin activates collecting duct ENaC current in preeclampsia. Hypertension 2012; 60:1346.
  156. Zeisler H, Llurba E, Chantraine F, et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med 2016; 374:13.
  157. Bian X, Biswas A, Huang X, et al. Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia. Hypertension 2019; 74:164.
  158. Thadhani R, Lemoine E, Rana S, et al. Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy. NEJM Evid 2022; 1:EVIDoa2200161.
  159. Re: DEN220027. US Food and Drug Administration (FDA) approval letter. May 18, 2023. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf22/DEN220027.pdf (Accessed on September 01, 2023).
  160. Biomarker Prediction of Preeclampsia With Severe Features. Obstet Gynecol 2024.
  161. Moses J, Sandberg K, Winberry G, et al. Clinical Practice Survey of Repeat Endoscopy in Pediatric Inflammatory Bowel Disease in North America. J Pediatr Gastroenterol Nutr 2021; 73:61.
  162. Chaiworapongsa T, Romero R, Gomez-Lopez N, et al. Preeclampsia at term: evidence of disease heterogeneity based on the profile of circulating cytokines and angiogenic factors. Am J Obstet Gynecol 2024; 230:450.e1.
  163. Thadhani R, Kisner T, Hagmann H, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 2011; 124:940.
  164. 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 U S A 2011; 108:1451.
  165. Rana S, Rajakumar A, Geahchan C, et al. Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1α pathway. FASEB J 2014; 28:4324.
  166. Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia. J Am Soc Nephrol 2016; 27:903.
  167. Matin M, Mörgelin M, Stetefeld J, et al. Affinity-Enhanced Multimeric VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) Variants for Specific Adsorption of sFlt-1 to Restore Angiogenic Balance in Preeclampsia. Hypertension 2020; 76:1176.
  168. Rolnik DL, Wright D, Poon LCY, et al. ASPRE trial: performance of screening for preterm pre-eclampsia. Ultrasound Obstet Gynecol 2017; 50:492.
  169. Li C, Raikwar NS, Santillan MK, et al. Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1. Placenta 2015; 36:446.
  170. Provinciatto H, Barbalho ME, Almeida J, et al. 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. N Engl J Med 2006; 355:992.
  176. McCarthy AL, Woolfson RG, Raju SK, Poston L. Abnormal endothelial cell function of resistance arteries from women with preeclampsia. Am J Obstet Gynecol 1993; 168:1323.
  177. Cockell AP, Poston L. Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia. Hypertension 1997; 30:247.
  178. Pascoal IF, Lindheimer MD, Nalbantian-Brandt C, Umans JG. Preeclampsia selectively impairs endothelium-dependent relaxation and leads to oscillatory activity in small omental arteries. J Clin Invest 1998; 101:464.
  179. Magnussen EB, Vatten LJ, Smith GD, Romundstad PR. Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. Obstet Gynecol 2009; 114:961.
  180. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005; 366:1797.
  181. Lykke JA, Langhoff-Roos J, Sibai BM, et al. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009; 53:944.
  182. Honigberg MC, Zekavat SM, Aragam K, et al. Long-Term Cardiovascular Risk in Women With Hypertension During Pregnancy. J Am Coll Cardiol 2019; 74:2743.
  183. Countouris ME, Bello NA. Advances in Our Understanding of Cardiovascular Diseases After Preeclampsia. Circ Res 2025; 136:583.
  184. Benschop L, Schalekamp-Timmermans S, Broere-Brown ZA, et al. Placental Growth Factor as an Indicator of Maternal Cardiovascular Risk After Pregnancy. Circulation 2019; 139:1698.
  185. Pruthi D, Khankin EV, Blanton RM, et al. Exposure to experimental preeclampsia in mice enhances the vascular response to future injury. 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. Labor therapeutics and BMI as risk factors for postpartum preeclampsia: A case-control study. Pregnancy Hypertens 2017; 10:177.
  192. Ditisheim A, Sibai B, Tatevian N. Placental Findings in Postpartum Preeclampsia: A Comparative Retrospective Study. Am J Perinatol 2020; 37:1217.
Topic 6760 Version 58.0

References

1 : Contemporary concepts of the pathogenesis and management of preeclampsia.

2 : Placental site trophoblastic tumor arising from antecedent molar pregnancy.

3 : Persistence of partial molar placenta and severe preeclampsia after selective termination in a twin pregnancy.

4 : Late postpartum eclampsia: report of two cases managed by uterine curettage and review of the literature.

5 : Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia.

6 : The uterine spiral arteries in human pregnancy: facts and controversies.

7 : Placental origins of preeclampsia: challenging the current hypothesis.

8 : Implantation and the placenta: key pieces of the development puzzle.

9 : Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia.

10 : Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?

11 : Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia.

12 : Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations.

13 : Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.

14 : Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration.

15 : Decidual cells from women with preeclampsia exhibit inadequate decidualization and reduced sFlt1 suppression.

16 : Role of decidual natural killer cells, interleukin-15, and interferon-γin placental development and preeclampsia.

17 : Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts.

18 : Pre-eclampsia: more than pregnancy-induced hypertension.

19 : A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies.

20 : The "Great Obstetrical Syndromes" are associated with disorders of deep placentation.

21 : The frequency and severity of placental findings in women with preeclampsia are gestational age dependent.

22 : Risk factors for preeclampsia.

23 : The rate of severe preeclampsia is increased in triplet as compared to twin gestations.

24 : The pathological response of the vessels of the placental bed to hypertensive pregnancy.

25 : Morphological changes of the spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation.

26 : The role of the spiral arteries in the pathogenesis of preeclampsia.

27 : Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants.

28 : The ultrastructure of acute atherosis in hypertensive pregnancy.

29 : Clinical correlations of patterns of placental pathology in preterm pre-eclampsia.

30 : Pre-eclampsia.

31 : Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1.

32 : A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency.

33 : Preeclampsia and the systemic inflammatory response.

34 : Antioxidant therapy to prevent preeclampsia.

35 : Severe intrauterine growth restriction pregnancies have increased placental endoglin levels: hypoxic regulation via transforming growth factor-beta 3.

36 : Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia.

37 : Preeclampsia and angiogenic imbalance.

38 : Vascular biology of preeclampsia.

39 : Angiogenic factors and preeclampsia.

40 : Preeclampsia--a pressing problem: an executive summary of a National Institute of Child Health and Human Development workshop.

41 : Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception.

42 : Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid?

43 : Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia.

44 : Sperm exposure and development of preeclampsia.

45 : Increased incidence of preeclampsia in women conceiving by intrauterine insemination with donor versus partner sperm for treatment of primary infertility.

46 : An epidemiologic study of contraception and preeclampsia.

47 : Barrier contraceptive methods and preeclampsia.

48 : Cumulative exposure to paternal seminal fluid prior to conception and subsequent risk of preeclampsia.

49 : Higher incidence of preeclampsia among participants undergoing in-vitro fertilization after fewer sperm exposures.

50 : Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis.

51 : Genetic and non-genetic risk factors for pre-eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies.

52 : Why much of the pathophysiology of preeclampsia-eclampsia must be of an autoimmune nature.

53 : Immunology of implantation.

54 : Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.

55 : Immunogenetic determinants of preeclampsia and related pregnancy disorders: a systematic review.

56 : Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia.

57 : Pre-eclampsia is associated with dendritic cell recruitment into the uterine decidua.

58 : Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells.

59 : AT1 receptor agonistic antibodies, hypertension, and preeclampsia.

60 : AT(1) receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor.

61 : Antibodies from preeclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation.

62 : Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling.

63 : Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.

64 : Angiotensin II type 1 receptor antibodies and increased angiotensin II sensitivity in pregnant rats.

65 : Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia.

66 : Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness.

67 : Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers.

68 : Searching for preeclampsia genes: the current position.

69 : Familial occurrence of preeclampsia.

70 : Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas.

71 : Paternal and maternal components of the predisposition to preeclampsia.

72 : Fetal and maternal contributions to risk of pre-eclampsia: population based study.

73 : A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13.

74 : A genome scan in families from Australia and New Zealand confirms the presence of a maternal susceptibility locus for pre-eclampsia, on chromosome 2.

75 : A genome-wide scan for preeclampsia in the Netherlands.

76 : Maternal and fetal genetic factors account for most of familial aggregation of preeclampsia: a population-based Swedish cohort study.

77 : Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort.

78 : The importance of genetic and environmental effects for pre-eclampsia and gestational hypertension: a family study.

79 : An Australian twin study of the genetic basis of preeclampsia and eclampsia.

80 : A sister's risk: family history as a predictor of preeclampsia.

81 : Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family.

82 : Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies.

83 : Pre-eclampsia and trisomy 13.

84 : Circulating angiogenic proteins in trisomy 13.

85 : Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

86 : C-allele of rs4769613 Near FLT1 Represents a High-Confidence Placental Risk Factor for Preeclampsia.

87 : Genetic Variants Associated With Preeclampsia and Maternal Serum sFLT1 Levels.

88 : Microsatellite marker association at chromosome region 2p13 in Finnish patients with preeclampsia and obstetric cholestasis suggests a common risk locus.

89 : Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families.

90 : Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

91 : Polygenic prediction of preeclampsia and gestational hypertension.

92 : HELLP babies link a novel lincRNA to the trophoblast cell cycle.

93 : Clinical risk factors for preeclampsia in the 21st century.

94 : The association of body mass index with serum angiogenic markers in normal and abnormal pregnancies.

95 : Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis.

96 : Assisted reproductive technology and hypertensive disorders of pregnancy: systematic review and meta-analyses.

97 : Association between in vitro fertilization and ischemic placental disease by gestational age.

98 : Correction to: Risk of adverse perinatal outcomes after oocyte donation: a systematic review and meta-analysis.

99 : Impact of oocyte donation on perinatal outcome in twin pregnancies.

100 : Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women.

101 : Preeclampsia: at risk for remote cardiovascular disease.

102 : Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.

103 : Preeclampsia and the risk of end-stage renal disease.

104 : Latest advances in understanding preeclampsia.

105 : Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles.

106 : The role of shed placental DNA in the systemic inflammatory syndrome of preeclampsia.

107 : Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia.

108 : Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia.

109 : Characterisation of syncytiotrophoblast vesicles in normal pregnancy and pre-eclampsia: expression of Flt-1 and endoglin.

110 : Maternal infection and risk of preeclampsia: systematic review and metaanalysis.

111 : Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia.

112 : The Complement Alternative Pathway and Preeclampsia.

113 : Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study.

114 : Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study.

115 : Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.

116 : Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss.

117 : Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy.

118 : Urinary excretion of C5b-9 is associated with the anti-angiogenic state in severe preeclampsia.

119 : Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.

120 : Germline mutations in the alternative pathway of complement predispose to HELLP syndrome.

121 : Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy.

122 : Circulating concentrations of soluble endoglin (CD105) in fetal and maternal serum and in amniotic fluid in preeclampsia.

123 : Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.

124 : The biology of vascular endothelial growth factor.

125 : Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.

126 : Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome.

127 : Amniotic fluid--soluble vascular endothelial growth factor receptor-1 in preeclampsia.

128 : Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia.

129 : Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award.

130 : Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop.

131 : Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.

132 : Circulating angiogenic factors and the risk of preeclampsia.

133 : Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences.

134 : Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia.

135 : Circulating Maternal sFLT1 (Soluble fms-Like Tyrosine Kinase-1) Is Sufficient to Impair Spiral Arterial Remodeling in a Preeclampsia Mouse Model.

136 : Sera from preeclamptic women specifically activate human umbilical vein endothelial cells in vitro: morphological and biochemical evidence.

137 : Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies.

138 : Plasma placenta growth factor levels in midtrimester pregnancies.

139 : Decreased maternal serum placenta growth factor in early second trimester and preeclampsia.

140 : Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia.

141 : Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia.

142 : First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.

143 : Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review.

144 : Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.

145 : Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia.

146 : Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study.

147 : Circulating Angiogenic Factors and the Risk of Adverse Outcomes among Haitian Women with Preeclampsia.

148 : Angiogenic biomarkers in triage and risk for preeclampsia with severe features.

149 : KRYPTOR-automated angiogenic factor assays and risk of preeclampsia-related adverse outcomes.

150 : Circulating angiogenic and antiangiogenic factors in women with eclampsia.

151 : Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction.

152 : Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia.

153 : Impaired oxygen-dependent reduction of HIF-1alpha and -2alpha proteins in pre-eclamptic placentae.

154 : Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?

155 : Urinary plasmin activates collecting duct ENaC current in preeclampsia.

156 : Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia.

157 : Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia.

158 : Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy.

159 : Circulating Angiogenic Factor Levels in Hypertensive Disorders of Pregnancy.

160 : Biomarker Prediction of Preeclampsia With Severe Features.

161 : Clinical Practice Survey of Repeat Endoscopy in Pediatric Inflammatory Bowel Disease in North America.

162 : Preeclampsia at term: evidence of disease heterogeneity based on the profile of circulating cytokines and angiogenic factors.

163 : Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.

164 : Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model.

165 : Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1αpathway.

166 : Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia.

167 : Affinity-Enhanced Multimeric VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) Variants for Specific Adsorption of sFlt-1 to Restore Angiogenic Balance in Preeclampsia.

168 : ASPRE trial: performance of screening for preterm pre-eclampsia.

169 : Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1.

170 : The role of pravastatin in preventing preeclampsia in high-risk pregnant women: a meta-analysis with trial sequential analysis.

171 : Bioflavonoid luteolin prevents sFlt-1 release via HIF-1αinhibition in cultured human placenta.

172 : Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction.

173 : Soluble endoglin contributes to the pathogenesis of preeclampsia.

174 : Soluble endoglin (sEng) joins the soluble fms-like tyrosine kinase (sFlt) receptor as a pre-eclampsia molecule.

175 : Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.

176 : Abnormal endothelial cell function of resistance arteries from women with preeclampsia.

177 : Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia.

178 : Preeclampsia selectively impairs endothelium-dependent relaxation and leads to oscillatory activity in small omental arteries.

179 : Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors.

180 : Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.

181 : Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother.

182 : Long-Term Cardiovascular Risk in Women With Hypertension During Pregnancy.

183 : Advances in Our Understanding of Cardiovascular Diseases After Preeclampsia.

184 : Placental Growth Factor as an Indicator of Maternal Cardiovascular Risk After Pregnancy.

185 : Exposure to experimental preeclampsia in mice enhances the vascular response to future injury.

186 : Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia.

187 : Association of maternal endothelial dysfunction with preeclampsia.

188 : Increased sensitivity to angiotensin II is present postpartum in women with a history of hypertensive pregnancy.

189 : Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based study.

190 : Epidemiology and Mechanisms of De Novo and Persistent Hypertension in the Postpartum Period.

191 : Labor therapeutics and BMI as risk factors for postpartum preeclampsia: A case-control study.

192 : Placental Findings in Postpartum Preeclampsia: A Comparative Retrospective Study.