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Preeclampsia: Pathogenesis

Preeclampsia: Pathogenesis
Literature review current through: Jan 2024.
This topic last updated: Aug 07, 2023.

INTRODUCTION — Preeclampsia is a 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 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 pulmonary edema, cerebral hemorrhage, hepatic failure, renal failure, and death. The fetal/neonatal burden of disease results from placental hypoperfusion and dysfunction and, in turn, the frequent need for preterm birth.

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 then leads to release of antiangiogenic factors into the maternal circulation that alter maternal systemic endothelial function and cause hypertension and other manifestations of the disease (hematologic, neurologic, cardiac, pulmonary, renal, and hepatic dysfunction). 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. The clinical features and management of preeclampsia, and treatment of hypertension during pregnancy are discussed separately. (See "Preeclampsia: Clinical features and diagnosis" and "Preeclampsia: Antepartum management and timing of delivery" and "Treatment of hypertension in pregnant and postpartum patients".)

ABNORMAL DEVELOPMENT OF THE PLACENTA — The critical role of the placenta in the pathophysiology of preeclampsia, particularly early onset-preeclampsia, is supported by epidemiologic and experimental data that show:

Placental tissue is necessary for development of the disease, but the fetus is not [2-4].

Preeclampsia is always cured within days to weeks after delivery of the placenta; however, in rare cases postpartum hypertension and preeclampsia can occur up to 6 to 8 weeks postdelivery. 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 [5-7]. (See "Preeclampsia: Clinical features and diagnosis", section on 'Natural history/course of disease'.)

Examination of human placentas at various stages of gestation in women with normal pregnancies, as well as those with preeclampsia, has led to an understanding of normal placental morphology and pathologic changes in the uteroplacental circulation that are likely relevant to preeclampsia. It is clear that defects in spiral artery remodeling and trophoblast invasion, two related but separate processes, are characteristic of hypertensive disorders of pregnancy and fetal growth restriction [8,9]. These processes result in impaired placentation and placental ischemia, which are thought to be the primary events leading to placental release of soluble factors that cause systemic endothelial dysfunction resulting in the preeclamptic phenotype. (See 'Role of systemic endothelial dysfunction in clinical findings' below.)

Abnormal remodeling of spiral arteries — In normal pregnancies, the cytotrophoblast cells of the developing placenta migrate through the decidua and part of the myometrium to invade both the endothelium and highly muscular tunica media of the maternal spiral arteries, the terminal branches of the uterine artery that supply blood to the developing fetus/placenta (figure 1). As a result, these vessels undergo transformation from small muscular arterioles to high capacitance vessels of low resistance, thus greatly facilitating blood flow to the placenta compared with other areas of the uterus [10,11]. Remodeling of the spiral arteries 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, cytotrophoblast cells infiltrate the decidual portion of the spiral arteries but fail to penetrate the myometrial segment [12,13]. 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 2 and figure 3). This defect in deep placentation has been associated with development of multiple adverse pregnancy outcomes, including second trimester fetal death, abruptio placentae, preeclampsia with or without intrauterine growth restriction, intrauterine growth restriction without maternal hypertension, preterm labor, and prelabor rupture of membranes [14].

It is not known why the normal sequence of events in development of the uteroplacental circulation does not occur in some pregnancies. Vascular, environmental, immunological, and genetic factors all appear to play a role [15]. These factors will be reviewed in the following discussion.

Defective trophoblast differentiation — Defective differentiation of trophoblast is one possible mechanism responsible for defective trophoblast invasion of the spiral arteries [16]. Trophoblast differentiation during endothelial invasion 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, HLA-G [17,18]. 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 women with preeclampsia do not show upregulated adhesion molecule expression or pseudo-vasculogenesis.

Transcriptomics and culture studies using human trophoblasts from women with severe preeclampsia 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 signaling [19]. A laser microdissection approach enabled the identification of novel messenger RNAs and noncoding RNAs that were differentially expressed by various trophoblast subpopulations in severe preeclampsia [20]. Gene ontology analysis of the syncytiotrophoblast data highlighted the dysregulation of immune functions, morphogenesis, transport, and responses to vascular endothelial growth factor and progesterone. Additional studies are needed to evaluate the specific pathways that are disrupted.

Placental hypoperfusion, hypoxia, ischemia — Hypoperfusion appears to be both a cause and a consequence of abnormal placental development. A causal relationship between poor placental perfusion, abnormal placental development, and preeclampsia is supported by the following examples:

Animal models that have successfully reproduced at least some of the findings of preeclampsia have involved mechanically reducing uteroplacental blood flow [21,22].

Medical conditions associated with vascular insufficiency (eg, hypertension, diabetes, systemic lupus erythematosus, renal disease, acquired and inherited thrombophilias) increase the risk of abnormal placentation and preeclampsia [23].

Obstetric conditions that increase placental mass without correspondingly increasing placental blood flow (eg, hydatidiform mole, hydrops fetalis, diabetes mellitus, twin and triplet gestation) result in relative ischemia and are associated with preeclampsia [23,24].

Preeclampsia is more common in women who live at high altitudes (>3100 meters) [25].

Hypoperfusion is also a result of abnormal placental development. Hypoperfusion becomes more pronounced as pregnancy progresses since the abnormal uterine vasculature is unable to accommodate the normal increase in blood flow to the fetus/placenta with increasing gestational age [26-28]. Late placental changes consistent with ischemia include atherosis (lipid-laden cells in the wall of the arteriole), fibrinoid necrosis, thrombosis, sclerotic narrowing of arterioles, and placental infarction [10,26,27,29,30]. 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 [31,32].

Hypoperfusion, hypoxia, and ischemia are critical components in the pathogenesis of preeclampsia and, as pregnancy advances, are likely to be responsible for placental production of a variety of factors that, when released into the maternal bloodstream, secrete antiangiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1] and endoglin) that bind vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), which results in widespread maternal vascular inflammation, endothelial dysfunction, and vascular injury, leading to hypertension, proteinuria, and the other clinical manifestations of preeclampsia [22,33-40]. (See 'Role of systemic endothelial dysfunction in clinical findings' below.)

Decidual pathology — Some studies have suggested that failed decidualization in some patients may lead to downregulated cytotrophoblast invasion [41]. Microarray studies of chorionic villus samples have also revealed a signature of impaired decidualization [42]. Interestingly, decidual cells from women with preeclampsia also overexpress sFLT1, suggesting that inadequate suppression of anti-angiogenic factors during the implantation period may lead to shallow implantation [43]. Additional work is needed to better understand endometrial antecedents in the genesis of preeclampsia.

IMMUNOLOGIC FACTORS — 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 [44-52]. Nulliparous women and women who change 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 women who conceive through oocyte donation have a more than twofold higher rate of preeclampsia than women who conceive via other assisted reproductive techniques and a fourfold higher rate of preeclampsia than women 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 [53,54].

Immunologic abnormalities, similar to those observed in organ rejection, have been observed in preeclamptic women [55]. 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, KIR, and ILT) known to recognize class I molecules infiltrate the maternal decidua in close contact with the EVT cells [56]. Interaction between NK cells, and EVT cells has been hypothesized to regulate placental implantation. Additional regulators of immune tolerance at the maternal-fetal interface with potential relevance included 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 [57]. 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.

Placental bed biopsies from women with preeclampsia have revealed increased dendritic cell infiltration in preeclamptic decidual tissue [58]. 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.

However, definitive evidence for this theory is lacking. Genetic studies looking at polymorphisms in the killer immunoglobulin receptors (KIR) on maternal NK cells and the fetal HLA-C haplotype suggest that women with KIR-AA genotype and fetal HLA-C2 genotype were at greatly increased risk of preeclampsia [59]. A systematic review found no clear evidence that one or several specific HLA alleles were involved in the pathogenesis of preeclampsia [60]. 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".)

Another interesting finding is that patients with preeclampsia have increased levels of agonistic antibodies to the angiotensin 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 [61-64]. In addition, angiotensin AT-1 receptor antibody stimulates sFlt-1 secretion [65]. It is unclear if these alterations are pathogenic or epiphenomena. (See 'Role of systemic endothelial dysfunction in clinical findings' below.)

GENETIC FACTORS — Although most cases of preeclampsia are sporadic, genetic factors are thought to play a role in disease susceptibility in about one-third of cases [66-76]. A genetic predisposition to preeclampsia is suggested by the following observations:

Primigravid women with a family history of preeclampsia (eg, affected mother or sister) have a two- to fivefold higher risk of the disease than primigravid women with no such history [67,68,75,77]. The maternal contribution to development of preeclampsia can be partially explained by imprinted genes [78]. In a study of sisters with preeclampsia, it was demonstrated that the mother developed preeclampsia 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 women who have had preeclampsia in a previous pregnancy [79].

The spouses of men who were the product of a pregnancy complicated by preeclampsia are more likely to develop preeclampsia than spouses of men without this history [69,75].

A woman who becomes pregnant by a man whose previous partner had preeclampsia is at higher risk of developing the disorder than if the pregnancy with the previous partner was normotensive [70].

Although a study of preeclampsia in twins failed to find a genetic link [80], the bulk of data suggest that both maternal and paternal contributions to fetal genes may have a role in defective placentation and subsequent preeclampsia.

The genes for sFlt-1 and Flt-1 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 normal 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 [81]. In addition, the ratio of circulating sFlt-1 to PlGF is significantly increased in these pregnancies, thus accounting for their increased risk for preeclampsia [82]. A large genome-wide association study (GWAS) identified a genetic risk variant with genome-wide significance, and provided convincing replication in an independent cohort [83]. These findings were confirmed in additional European cohorts [84]. 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.)

A meta-analysis reported studies of PAI-1 4G/5G polymorphism (recessive model) showed strong consistent evidence for an association with risk for preeclampsia [54]. Multiple maternal GWAS have reported potential susceptibility genes for preeclampsia, eclampsia, and gestational hypertension [71,72,85-88]. 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 [88]. 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 (NPPANPR3 and FURIN), renal glomerular function (TRPC6TNS2 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 female individuals independent of first-trimester risk factors.

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 [73]. Alterations in long noncoding RNA at 12q23 have been implicated as one potential mechanism that may lead to HELLP syndrome [89]. This long noncoding RNA regulates a large set of genes that may be important for extravillous trophoblast migration.

ENVIRONMENTAL AND MATERNAL SUSCEPTIBILITY FACTORS

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 women. 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'.)

High body mass index — A prospective study demonstrated a linear relationship between increasing body mass index and increasing risk of developing preeclampsia [90]. In this cohort, the odds ratio (OR) for preeclampsia rose from OR 1.65 in women with body mass index of 25 to 30 kg/m2 to OR 6.04 in women whose body mass index was ≥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 [91].

In vitro fertilization — Compared with spontaneous conception, pregnancies after in vitro fertilization (IVF) have been associated with a higher risk of adverse pregnancy outcomes, including preeclampsia and fetal growth restriction [92,93]. The strength of association is greatest in oocyte donation pregnancies [94,95].

INFLAMMATION — Signs of maternal inflammation, which appear to be present in normal pregnancies at term, are exaggerated in preeclampsia. Circulating syncytiotrophoblast debris have been hypothesized to contribute to maternal inflammation and some of the features of the maternal syndrome [96,97]. Placental cell-free DNA released into the maternal circulation could play a role in driving the systemic inflammatory response of preeclampsia [98]. Placental hypoxia increases placental necrosis and apoptosis, which releases cell-free DNA into the maternal circulation. As early as 17 weeks of gestation, women 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 [99]. The cell-free fetal DNA rise correlates with sFlt1 rise, and syncytial microparticles that carry the cell-free fetal DNA are loaded with sFlt1 and other toxic syncytial proteins [100,101]. It is likely that the inflammatory state may also increase the vascular endothelial sensitivity to toxic factors such as sFlt1 and sEng, although definitive evidence is lacking.

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 women with urinary tract infection (pooled odds ratio [OR] 1.57, 95% CI 1.45-1.70) and periodontal disease (pooled OR 1.76, 95% CI 1.43-2.18) [102]. 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.

INCREASED SENSITIVITY TO ANGIOTENSIN II — Increased sensitivity to angiotensin II has been described in preeclampsia [103], and may be related to increased bradykinin (B2) receptor upregulation in preeclamptic patients. Upregulation leads to heterodimerization of B2 receptors with angiotensin II type I receptors (AT1), and this AT1/B2 heterodimer increases responsiveness to angiotensin II in vitro [104]. Interestingly, amlodipine therapy promoted AT1/B2 downregulation and prevented preeclampsia in a mouse model [105].

As discussed above, patients with preeclampsia have increased levels of agonistic antibodies to the angiotensin AT-1 receptor. Angiotensin II is the endogenous ligand for the AT-1 receptor, thus increased activation of this receptor by auto-antibodies could induce the hypertension and vascular injury observed in preeclampsia. Studies in mice support this theory [106,107].

Other studies in mice suggest that endothelial dysfunction induced by circulating anti-angiogenic factors are sufficient to induce angiotensin II sensitivity [108]. These studies have provided a strong biological rationale for studying compounds that improve endothelial health for the treatment of preeclampsia.

COMPLEMENT ACTIVATION — Increasing evidence suggests that complement dysregulation/activation may play a role in the pathogenesis of preeclampsia [109,110]. Preeclampsia is more common in pregnant women with autoimmune diseases, particularly systemic lupus erythematosus and the antiphospholipid antibody syndrome [111,112]. Activation of the classical pathway of complement in the placenta has been observed in such patients [113,114]. Preliminary clinical studies have reported increased markers of the alternative complement pathway activation in maternal serum and urine in women with severe preeclampsia [115,116]. In women without preexisting autoimmune disease, mutations in complement regulatory proteins have been shown to predispose to preeclampsia [117]. Germline mutations in the alternative complement pathway were also recently reported in hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, a severe complication of preeclampsia [118]. The similarities between HELLP syndrome and thrombotic microangiopathies in nonpregnant patients suggest that this is an interesting area of investigation with potential therapeutic applications [119].

ROLE OF SYSTEMIC ENDOTHELIAL DYSFUNCTION IN CLINICAL FINDINGS

Overview — All of the clinical features of preeclampsia can be explained as clinical responses to generalized endothelial dysfunction [120,121]. As an example, hypertension results from disturbed endothelial control of vascular tone, proteinuria and edema are caused by increased vascular permeability, and coagulopathy is the result of abnormal endothelial expression of procoagulants. Headache, seizures, visual symptoms, epigastric pain, and fetal growth restriction are the sequelae of endothelial dysfunction in the vasculature of target organs, such as the brain, liver, kidney, and placenta.

Laboratory evidence supporting generalized endothelial dysfunction in preeclamptic women includes the following:

Increased concentrations of circulating cellular fibronectin, factor VIII antigen, and thrombomodulin [122-124].

Impaired flow-mediated vasodilation [125,126] and impaired acetylcholine mediated vasorelaxation [127].

Decreased production of endothelial-derived vasodilators, such as nitric oxide and prostacyclin, and increased production of vasoconstrictors, such as endothelins and thromboxanes.

Enhanced vascular reactivity to angiotensin II [103].

Serum from preeclamptic women causes endothelial activation in human umbilical vein endothelial cell culture studies in some in vitro studies [128].

Impaired endothelial function can be demonstrated by brachial artery flow-mediated dilation three years after a preeclamptic pregnancy [129]. It is unknown whether this is a cause or effect of the preeclamptic pregnancy.

Preexisting maternal vascular/metabolic/kidney/autoimmune disease — Rates of preeclampsia are significantly higher in women with comorbidities known to be associated with vascular disease, including 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 [130]. Preexisting endothelial damage may also explain why women who develop preeclampsia are also at increased risk of developing cardiovascular disease later in life [131,132]. Women with a history of preeclampsia are also at increased risk for end stage renal disease and hypothyroidism in the long term [133,134]. (See "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Cardiovascular disease, kidney disease, type 2 diabetes'.)

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 (VEGF, PlGF) and antiangiogenic factors (sFlt-1) are elaborated by the developing placenta, and the balance among these factors is important for normal placental development. Increased production of antiangiogenic factors disturbs this balance and results in the systemic endothelial dysfunction characteristic of preeclampsia.

Soluble fms-like tyrosine kinase 1 (sFlt-1 or sVEGFR-1) is a naturally occurring, circulating antagonist to vascular endothelial growth factor (VEGF) (figure 4). VEGF is an endothelial specific mitogen that has a key role in promoting angiogenesis [135,136]. Its activities are mediated primarily by interaction with two high-affinity receptor tyrosine kinases, VEGFR-1 (VEGF receptor-1 or fms-like tyrosine kinase-1 [Flt-1]) and VEGFR-2 (kinase-insert domain region [KDR]/Flk-1), which are selectively expressed on the vascular endothelial cell surface. VEGFR-1 has two isoforms: a transmembranous isoform and a soluble isoform (sFlt-1 or sVEGFR-1). Placental growth factor (PlGF) is another member of the VEGF family that is made predominantly in the placenta. It also binds to the VEGFR-1 receptor. (See "Overview of angiogenesis inhibitors", section on 'Vascular endothelial growth factor'.)

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 preeclampsia, based on the following observations [108,137-146]:

sFlt-1 administered to pregnant rats induces albuminuria, hypertension, and the unique renal pathologic changes of glomerular endotheliosis (picture 1A-C).

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 [147].

In vitro, 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. In pregnant mice, sFLT1 overexpression induces angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase activity.

Compared with normotensive controls, circulating levels of sFlt-1 levels are increased and free VEGF and free PlGF are decreased in preeclamptic women. Studies using banked sera showed that preeclamptic women had decreases in PlGF and VEGF levels well before the onset of clinical disease [144,148-153]. For example:

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 [144]. sFlt-1 levels increased during pregnancy in all women; however, compared with normotensive controls, women 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 5). 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 6), which may have been related, in part, to binding by sFlt-1.

In another study, the concentration of sVEGFR-1 correlated with increasing severity of disease: sVEGFR-1 concentrations were higher in women with severe or early (<34 weeks) preeclampsia than in those with mild or late preeclampsia [141]. Furthermore, women with preeclampsia had higher sVEGFR-1 levels than women who remained normotensive two to five weeks before onset of clinical disease [141].

Alterations in both sFlt1 and PlGF correlate with adverse maternal and neonatal outcomes associated with preeclampsia [112,154-159].

In the aggregate, these observations suggest a major role for sFlt-1 and related angiogenic factors in the pathogenesis of at least some features of preeclampsia (figure 7) [160]. However, the trigger for increased sFlt-1 production by the placenta is unknown. The most likely trigger is placental ischemia [161]. In vitro, placental cytotrophoblasts possess a unique property to enhance sFlt-1 production when oxygen availability is reduced [162]. The increased expression of hypoxia-inducible transcription factors (HIFs) in preeclamptic placentas is consistent with this hypothesis [163]. It is not known whether increased sFlt-1 secretion is responsible for the early placental developmental abnormalities characteristic of preeclampsia or a secondary response to placental ischemia caused by some other factor. Genetic factors may also play a role in excess production of sFlt-1 and placental size (eg, multiple gestation) may play a role [164].

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 abnormal anti-angiogenic state may be the primary event leading to vasopressor sensitivity and hypertension [108]. It is likely that secondary, counter-regulatory systems may also play a role. For example, the renal disorder associated with preeclampsia, glomerular endotheliosis, leads to modest reductions in GFR and renal blood flow [108]. Alterations in the renin angiotensin system such as suppressed plasma renin activity in women with preeclampsia are consistent with sodium volume retention [165]. This sequence of events, similar to that observed in nonpregnant patients with glomerulonephritis, may also contribute to maternal hypertension.

Measurement of sFlt-1:PlGF ratio in serum appears to be a useful test to rule in or rule out preeclampsia in women with suspected preeclampsia [166,167]. In pregnant hypertensive women, a high plasma sFlt-1:PlGF identifies those at risk of requiring delivery within two weeks because of severe preeclampsia [154,168]. A large prospective study across 18 sites in the United States confirmed the prognostic utility of sFlt-1:PlGF in this population and noted that it outperformed all other standard-of-care tests for predicting preeclampsia with severe features within two weeks of presentation [168]. 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 women 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 [169]. (See "Preeclampsia: Clinical features and diagnosis", section on 'Evidence'.)

In the future, apheresis or drugs that reduce sFlt-1 levels or promote PlGF levels may be useful to prevent or treat preeclampsia [170-174]. Low-dose aspirin therapy was highly effective in individuals with low PlGF levels measured during the first trimester [175]. Cell culture studies have shown aspirin may inhibit sFlt-1 production and could reverse angiogenic imbalance noted in preeclamptic placentae [176]. RNA interference therapies against sFlt-1 have also shown promise in nonhuman primate models of preeclampsia [159].

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 [137].

Eng is a coreceptor for transforming growth factor (TGF)-beta and is highly expressed on cell membranes of vascular endothelium and syncytiotrophoblasts [177]. 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 [104,177-179].

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 [104,177-179]:

sEng is elevated in the sera of preeclamptic women two to three months before the onset of clinical signs of preeclampsia, correlates with disease severity, and falls after delivery. An increased level of sEng accompanied by an increased ratio of sFlt-1:PlGF is most predictive of developing preeclampsia.

In vivo, sEng increases vascular permeability and induces hypertension. In pregnant rats, as an example, it appears to potentiate the vascular effects of sFlt-1 to induce a severe preeclampsia-like state, including the development of hemolysis, elevated liver function tests, low platelets (HELLP) syndrome and restriction of fetal growth.

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.

Fetuses of preeclamptic mothers do not have high circulating concentrations of either sEng or sFlt-1 [180]. This suggests that fetuses do not experience proteinuria or hypertension like their mothers because they are not exposed to high concentrations of antiangiogenic factors.

PREECLAMPSIA IN THE PATHOGENESIS OF CARDIOVASCULAR DISEASE — Although clinical signs and symptoms of preeclampsia resolve after placental delivery, affected women have a significantly elevated risk of developing chronic hypertension, ischemic heart disease, and stroke many years postpartum. In a meta-analysis, women diagnosed with preeclampsia had an approximately three-fold increased risk of developing hypertension and a twofold increased risk of heart attack and stroke compared with women without preeclampsia [132]. 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 [181-183]. Preeclampsia is considered a risk-enhancing factor (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: Our approach".)

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 women. Available data are limited. In a large prospective cohort study of 5475 women, mid-trimester decreases in placental growth factor (a marker of angiogenic imbalance) was associated with larger left ventricular mass and higher average systolic blood pressure six to nine years after pregnancy compared with women with higher placental growth factor [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].

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

Vascular developmental factors – Development abnormalities of the uteroplacental circulation occur long before clinical manifestations of preeclampsia become evident. In preeclampsia, the cytotrophoblast infiltrates the decidual portion of the spiral arteries, but fails to penetrate the myometrial portion. Thus, the large, tortuous vascular channels characteristic of the normal placenta do not develop; instead, the vessels remain narrow, resulting in hypoperfusion and ischemia. Environmental, immunological, and genetic factors all appear to play a role in this process. (See 'Abnormal development of the placenta' above.)

Immunologic factors – The focus on immunologic factors as a possible contributor to the placental abnormality is based, in part, upon the observation that prior exposure to paternal/fetal antigens appears to protect against preeclampsia, as well as evidence of dysregulated immunity at the maternal-fetal interface. Alterations in circulating immunity, including a relative deficiency in regulatory T cells, and increased agonistic autoantibodies directed at the angiotensin-1 receptor have also been observed in women with preeclampsia. (See 'Immunologic factors' above.)

Genetic factors – Both maternal and paternal contributions to fetal genes may have a role in defective placentation and subsequent preeclampsia. In particular, a genetic locus on chromosome 13 appears to be associated with development of preeclampsia and may be responsible for the production of circulating anti-endothelial factors. (See 'Genetic factors' above.)

Endothelial factors

Endothelial cell function in preeclampsia – The ischemic placenta appears to elaborate factors (eg, antiangiogenic proteins, inflammatory cytokines) into the maternal bloodstream that alter maternal endothelial cell function and lead to the characteristic systemic signs and symptoms of preeclampsia. Many of the clinical features of preeclampsia can be explained as clinical responses to generalized endothelial dysfunction. (See 'Role of systemic endothelial dysfunction in clinical findings' 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 diseased placenta (algorithm 1) and is an important mediator of the maternal signs and symptoms of preeclampsia. Soluble endoglin (sEng) appears to be another important mediator, but the precise relationship between sEng and sFlt-1 is unknown. (See 'Role of systemic endothelial dysfunction in clinical findings' above.)

Preexisting vascular disease – There is a relationship between preexisting vascular disease, often present in women with comorbidities such as hypertension, diabetes, chronic kidney disease, and autoimmune diseases, and susceptibility to developing preeclampsia. Preexisting endothelial damage is often present in these disorders and may also explain why women who develop preeclampsia are also at increased risk of developing cardiovascular disease later in life. (See 'Role of systemic endothelial dysfunction in clinical findings' above.)

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Topic 6760 Version 55.0

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