JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
14, 2020
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THE PRESENT AND FUTURE
JACC STATE-OF-THE-ART REVIEW
Preeclampsia—Pathophysiology and
Clinical Presentations
JACC State-of-the-Art Review
Christopher W. Ives, MD,a Rachel Sinkey, MD,b,c Indranee Rajapreyar, MD,d Alan T.N. Tita, MD, PHD,b,c
Suzanne Oparil, MDd
ABSTRACT
Preeclampsia is a hypertensive disorder of pregnancy. It affects 2% to 8% of pregnancies worldwide and causes sig-
nificant maternal and perinatal morbidity and mortality. Hypertension and proteinuria are the cornerstone of the disease,
though systemic organ dysfunction may ensue. The clinical syndrome begins with abnormal placentation with subsequent
release of antiangiogenic markers, mediated primarily by soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin
(sEng). High levels of sFlt-1 and sEng result in endothelial dysfunction, vasoconstriction, and immune dysregulation,
which can negatively impact every maternal organ system and the fetus. This review comprehensively examines the
pathogenesis of preeclampsia with a specific focus on the mechanisms underlying the clinical features. Delivery is the
only definitive treatment. Low-dose aspirin is recommended for prophylaxis in high-risk populations. Other treatment
options are limited. Additional research is needed to clarify the pathophysiology, and thus, identify potential therapeutic
targets for improved treatment and, ultimately, outcomes of this prevalent disease.
(J Am Coll Cardiol 2020;76:1690–702) © 2020 by the American College of Cardiology Foundation.
P reeclampsia is a hypertensive disorder of
pregnancy (HDP). It impacts 2% to 8% of
all pregnancies and is a major cause of
maternal and perinatal morbidity and mortality
cornerstone of the syndrome and is often, but not
always, accompanied by proteinuria. Severe forms
of preeclampsia can be complicated by renal, car-
diac, pulmonary, hepatic, and neurological dysfunc-
(1–3). In the United States, HDP were responsible tion; hematologic disturbances; fetal growth
for 212 (7%) of approximately 3,000 pregnancy- restriction; stillbirth; and maternal death (3,7)
related deaths between 2011 and 2015 (4). Pre- (Table 1). Underlying mechanisms contributing to
eclampsia is a complex disease process originating the pathophysiology of preeclampsia are poorly un-
at the maternal–fetal interface that affects derstood, though this is an active area of interna-
multiple organ systems (5,6). Hypertension is the tional research (5).
From the aTinsley Harrison Internal Medicine Residency Program, Department of Medicine, University of Alabama at Birmingham,
Birmingham, Alabama; bDivision of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, University of Alabama at
Birmingham, Birmingham, Alabama; cCenter for Women’s Reproductive Health, University of Alabama at Birmingham, Bir-
mingham, Alabama; and the dDivision of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham,
Birmingham, Alabama. Dr. Sinkey has received a grant from GestVision. Dr. Oparil has received grants and nonfinancial support
from NIH/National Heart, Lung, and Blood Institute during the conduct of the study; has received personal fees from Preventric
Diagnostics, Inc.; has received personal fees and other from CinCor Pharma Inc. outside the submitted work; and is Editor-in-Chief
of Current Hypertension Reports (Springer Science Business Media LLC). All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the JACC author instructions page.
Manuscript received May 8, 2020; revised manuscript received July 14, 2020, accepted August 3, 2020.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2020.08.014
JACC VOL. 76, NO. 14, 2020
OCTOBER 6, 2020:1690–702
HIGHLIGHTS
 Preeclampsia, a hypertensive disorder of
pregnancy, affects 2% to 8% of pregnant
women and causes considerable
mortality.
 Pre-existing cardiovascular disease likely
plays a role in the development of
preeclampsia.
 Delivery is the only definitive treatment.
Low-dose aspirin is recommended for
prophylaxis in high-risk women.
 Further research is needed to identify
therapies that reduce maternal and
neonatal morbidity and mortality.
PREECLAMPSIA OVERVIEW
Preeclampsia is defined as new-onset hypertension
and new-onset end-organ damage, including pro-
teinuria, after 20 weeks of gestation (Table 2) (3,7).
The pathophysiology of this complex process in-
volves multiple organ systems and is summarized in
the Central Illustration. The clinical syndrome begins
with abnormal trophoblast invasion before many
women know they are pregnant, and long before
clinical manifestations of the disease
apparent (6,8). During normal implantation, tropho-
blasts invade the decidualized endometrium, leading
to spiral artery remodeling and obliteration of the
tunica media of myometrial spiral arteries, allowing
increased blood flow to the placenta, all independent
of maternal vasomotor changes (9). In preeclampsia,
trophoblasts fail to adopt an endothelial phenotype,
which leads to impaired trophoblast invasion and
incomplete spiral artery remodeling (6). The resultant
placental ischemia leads to an increase in angiogenic
markers such as soluble fms-like tyrosine kinase-1
(sFlt-1) and soluble endoglin (sEng) (6,10). sFlt-1 has
been proposed as an underlying mechanism to
explain disease in the maternal and fetal units. sFlt-1
binds to and decreases levels of vascular endothelial
growth factor (VEGF) and placental growth factor,
which are important mediators of endothelial cell
function, especially in fenestrated endothelium
(brain, liver, glomeruli) (6,8,10,11). Thus, endothelial
dysfunction develops in maternal vasculature (10).
sEng is a cell surface coreceptor that binds to and
decreases levels of transforming growth factor (TGF)-
b, which normally induces migration and prolifera-
tion of endothelial cells (8,11). These
mediate downstream effects that create endothelial
Ives et al. 1691
Pathophysiology of Preeclampsia
dysfunction, a vasoconstrictive state, oxida- ABBREVIATIONS
AND ACRONYMS
tive stress, and microemboli that contribute
to the involvement of multiple organ sys-
Ang II = angiotensin II
tems, and thus, the clinical features of pre-
AT1R = angiotensin II receptor
eclampsia (8,9,12). It is also likely that pre-
type 1
existing endothelial stress, such as
BP = blood pressure
increased sympathetic nervous system tone
HDP = hypertensive disorders
from reduced intravascular volume, may of pregnancy
further predispose to development of pre-
IL = interleukin
eclampsia (2).
RAAS = renin-angiotensin-
In addition to endothelial dysfunction, aldosterone system
immunologic aberrations contribute to the sEng = soluble endoglin
preeclampsia phenotype. In normal preg-
sFlt = soluble fms-like tyrosine
nancy, T helper cells shift toward the anti- kinase
inflammatory Th2 phenotype, which helps Stat3 = signal transducer and
to neutralize proinflammatory cytokines, activator or transcription3
angiotensin II type 1 receptor (AT1R) auto- TGF = transforming growth
antibodies, placental reactive oxygen species, factor
and endothelin-1 (2). However, in pre- VEGF = vascular endothelial
growth factor
eclampsia, T helper cells shift toward the Th1
phenotype, increasing release of proinflammatory
cytokines such as interleukin (IL)-12 and IL-18, and
decreasing IL-10, which leads to apoptosis and
reduced trophoblast invasion (13). Increased
CD19 þCD5 þ B lymphocytes may contribute to pro-
duction of antiangiogenic factors. Uterine natural
killer cells, which differ from peripheral natural killer
cells, are likely involved, because inhibition of uter-
become ine natural killer cells may lead to defective spiral
artery remodeling. Syncytial knots, vesicles that shed
from trophoblasts, may stimulate an inflammatory
response in the placenta (2). LIN28 is an RNA binding
protein that affects cell metabolism, differentiation,
growth, and invasion. Two paralogs exist: LIN28A and
LIN28B. LIN28B is increased in extravillous tropho-
blasts/placenta in normal pregnancy. In preeclamp-
sia, levels are decreased in the placenta, suggesting a
role in preeclampsia by reducing trophoblast differ-
entiation and invasion, and by promoting inflamma-
tion (14). Elevated complement levels in
preeclampsia result in complement system dysregu-
lation and additional increases in sFlt-1 (2). Women
with preeclampsia have reduced histocompatibility
complex human leukocyte antigen-G and -E, also
suggestive of immune imbalance (13).
Multiple genetic components have been implicated
in the pathogenesis of preeclampsia. Mutations in
complement component 3 are associated with pre-
eclampsia, which may partly account for complement
system dysregulation (2). Corin, a cardiac protein that
activates atrial natriuretic peptide, has also been
localized to uterine tissue, and mutations in corin
factors associated with preeclampsia have been identified
(2,15). Global transcriptional profiling of chorionic
1692 Ives et al. JACC VOL. 76, NO. 14, 2020

Pathophysiology of Preeclampsia OCTOBER 6, 2020:1690–702

T A B L E 1 Highlights of Clinical Features of Preeclampsia

Clinical Feature Underlying Abnormalities Clinical Consequences

Hypertension Increased SVR and afterload Heart failure

Decreased CO and intravascular volumes Pulmonary edema
Activation of RAAS, ET-1, SNS Renal dysfunction
AT1R down-regulated, placental hypoxia, and AT1R autoantibodies Neurological injury
Increased vasoconstrictors, decreased vasodilators
Increased sFlt-1 and sEng, oxidative stress
Proteinuria Glomerular endotheliosis Hypertension
Disruption of filtration barrier Ischemic heart disease
Increased tubular permeability Stroke
Chronic kidney disease
End-stage renal disease
Renal dysfunction Decreased RBF and GFR Hypertension
Glomerular endotheliosis Chronic kidney disease
Increased tissue factor expression End-stage renal disease
Thrombotic microangiopathy
Neurological abnormalities Headache: loss of fenestrae on choroid plexus, periventricular edema, Seizures
vasogenic edema in posterior cerebral circulation PRES
Visual disturbances: retinopathy, retinal detachment, cortical blindness, Permanent blindness
central serous chorioretinopathy, hypertensive retinopathy, diabetic
retinopathy
Eclampsia Unknown (potentially vasogenic or cytotoxic edema) Permanent neurological dysfunction
Cardiac dysfunction Increased SVR, afterload Heart failure
Concentric LV hypertrophy, LA enlargement Peripartum cardiomyopathy
Increased RVSP, increased LV filling pressures, LV diastolic dysfunction,
Pulmonary edema Increased vascular permeability Acute hypoxemic respiratory failure
Cardiac dysfunction
Corticosteroids/tocolytics
Iatrogenic volume overload
Hepatic dysfunction Hepatic microcirculatory deterioration, hepatocellular injury Liver failure, hepatic rupture
Hematologic dysfunction Procoagulant state Thrombocytopenia, DIC
Fetal growth restriction Incomplete spiral artery remodeling Fetal growth <10th percentile
Decidual vasculopathy
Uterine and placental dysfunction

This table depicts the key aspects underlying the pathophysiology of each clinical feature of preeclampsia. Subsequent clinical consequences that can be observed with each
feature are listed.
AT1R ¼ angiotensin II receptor type 1; CO ¼ cardiac output; DIC ¼ disseminated intravascular coagulation; ET ¼ endothelin; GFR ¼ glomerular filtration rate; LA ¼ left atrial;
LV ¼ left ventricular; PRES ¼ posterior reversible encephalopathy syndrome; RAAS ¼ renin-angiotensin-aldosterone system; RBF ¼ renal blood flow; RVSP ¼ right ventricular
systolic pressure; sEng ¼ soluble endoglin; sFlt ¼ soluble fms-like tyrosine kinase; SNS ¼ sympathetic nervous system; SVR ¼ systemic vascular resistance.

villus samples of women with preeclampsia suggests
a genetic susceptibility to preeclampsia (2,16). Endo-
metrial stromal cells from nonpregnant women with a
history of severe preeclampsia failed to decidualize
in vitro and were transcriptionally inert, and decidual
tissue from women with preeclampsia revealed de-
fects in gene expression (17).
hydroxyacyl-CoA dehydrogenase deficiency, a disor-
der of fatty acid metabolism, has been associated with
preeclampsia (18). One study (19) found that women
who develop preeclampsia are more likely to carry
loss-of-function mutations in 43 genes associated
with both idiopathic dilated and peripartum cardio-
myopathy. The TTN gene, which encodes the sarco-
meric protein titin, had the highest frequency of
mutations (19). Genome-wide association studies
have identified both single nucleotide polymorphism
rs4769613, near the FMS-like tyrosine kinase 1 gene,
and Rs9478812, within protein PLEKHGI, which is
implicated in blood pressure (BP) regulation, to be
associated with preeclampsia
mutations of placental growth factor, sFlt-1, or sEng
genes have been identified to date (13). However,
next-generation sequencing, or massive parallel
sequencing, enables affordable analysis of large
genomic regions and is a promising tool for studying
genetic influence on preeclampsia (20).
Long-chain L-3 Lastly, certain acquired risk factors have been
shown to increase risk of preeclampsia. Obesity (body
mass index >30) and diabetes each carries a relative
risk increase of 3.5 (2). Chronic hypertension, chronic
kidney disease, obstructive sleep apnea, pre-
gestational diabetes, systemic lupus erythematosus,
antiphospholipid syndrome, rheumatoid arthritis,
maternal age over 35 years, nulliparity, multifetal
gestations, fetal hydrops, hydatidiform moles, and
assisted reproductive technologies are also associated
with preeclampsia (2,3,13,21–23). Though abnormal
placentation may drive the more immediate devel-
opment of preeclampsia, the preceding information
suggests an underlying role of pre-existing cardio-
(2). No causal vascular and other organ dysfunction before
JACC VOL. 76, NO. 14, 2020 Ives et al. 1693
OCTOBER 6, 2020:1690–702 Pathophysiology of Preeclampsia

T A B L E 2 Diagnostic Criteria for Preeclampsia

Always necessary. . .
Hypertension
 SBP $140 mm Hg or DBP $90 mm Hg on 2 occasions at least 4 h apart after 20 weeks’ gestation in a woman with previously normal BP
 SBP $160 mm Hg or DBP $110 mm Hg on 1 occasion
. . .And 1 of the following
Proteinuria
 $300 mg per 24-h urine collection (or extrapolated from timed collection), or
 Protein/creatinine ratio of $0.3 mg/dl, or
 Dipstick reading of 2þ (used only when other methods not available)
OR any 1 of the following (in the absence of proteinuria)
Thrombocytopenia
 Platelet count <100,000/mm 3
Renal insufficiency
 Serum creatinine concentration >1.1 mg/dl or a doubling of serum creatinine concentration in the absence of other renal disease
Impaired liver function
 Elevated concentration of liver transaminases to 2 normal
 Severe persistent right upper quadrant or epigastric pain unresponsive to medication
Pulmonary edema
 Diagnosed by physical examination or chest x-ray
Neurological signs
 New-onset headache unresponsive to medication and not accounted for by alternative diagnoses or visual symptoms
 Visual disturbances
Fetal growth restriction*
 Estimated fetal weight <10th percentile

Adapted from ACOG Practice Bulletin No. 202 (3) and ISSHP recommendations (7). *Included in ISSHP definition of preeclampsia though not in ACOG definition.
ACOG ¼ American College of Obstetricians and Gynecologists; BP ¼ blood pressure; DBP ¼ diastolic blood pressure; ISSHP ¼ International Society for the Study of Hypertension
in Pregnancy; SBP ¼ systolic blood pressure.

conception. Additionally, preeclampsia is associated
with long-term consequences following delivery,
particularly cardiovascular effects. Studies demon-
strate prior occurrence of preeclampsia to be associ-
ated with higher rates of hypertension, ischemic
heart disease/recurrent acute coronary syndrome,
heart failure, stroke, and death (24–28). Further study
into abnormalities in cardiovascular structure and
function may identify potential areas for clinical
intervention to reduce disease risk and burden. The
following discussion reviews the current under-
standing of the pathophysiology of each clinical
manifestation of preeclampsia (highlights in Table 1).
HYPERTENSION
Hypertension in pregnancy is defined as elevated
systolic BP $140 mm Hg
BP $90 mm Hg on 2 measurements 4 h apart at rest
(3). Hypertension is a necessary diagnostic criterion
for the preeclampsia syndrome (3). Compared with
normotensive pregnant control patients, hyperten-
sion in preeclampsia occurs in the setting of increased
systemic vascular resistance and afterload, and
decreased cardiac output and intravascular volumes.
Multiple factors contribute to this change. Conduit
artery compliance decreases, and the usual fall in
nocturnal BP is mitigated or obliterated (11). Despite
activation of the renin-angiotensin-aldosterone sys-
tem (RAAS), levels of renin, angiotensin II (Ang II),
and aldosterone are lower in preeclampsia compared
with normal pregnancy (though still higher than
nonpregnant individuals), and sensitivity to Ang II
and norepinephrine is increased (6). The reasons for
hypertensive complications in preeclampsia despite
lower levels of components of RAAS are 2-fold. First,
in normal pregnancy, AT1R is down-regulated by
reactive oxygen species. In preeclampsia, AT1R com-
plexes with bradykinin receptor B2 to form a
heterodimer that enhances the pressor effects of
Ang II (29). Second, placental hypoxia contributes to
production of circulating antibodies to AT1R, which in
turn increases vasoconstriction via activation of
endothelin-1, increased sensitivity to circulating
Ang II, and increased placental production of sFlt-1
and sEng (30).
Down-regulation of heme oxygenase-1 results in
and/or diastolic decreased carbon monoxide generation, which then
leads to further increases in sFlt-1 and sEng release
(31). sFlt-1 increases peripheral vascular resistance,
which in turn increases BP (32). Activation of the
sympathetic nervous system, RAAS, and endothelin-1
in an attempt to correct the relative hemoconcentra-
tion in preeclampsia increases vasoconstrictors, such
as thromboxane A1 and endothelins, and decreases
vasodilators, such as prostacyclin and nitric oxide,
creating intense vasoconstriction (3,31,33). These de-
rangements result in endothelial dysfunction and
attenuate endothelium-dependent vasodilation due
to oxidative stress (9,11,31). An observational study
1694 Ives et al. JACC VOL. 76, NO. 14, 2020

Pathophysiology of Preeclampsia OCTOBER 6, 2020:1690–702

C E NT R AL IL L U STR AT IO N Pathogenesis of Preeclampsia

Ives, C.W. et al. J Am Coll Cardiol. 2020;76(14):1690–702.

Acquired, genetic, and immune risk factors contribute to early placental dysfunction (Stage 1). Placental dysfunction results in release of anti-angiogenic factors,
leading to later multiorgan dysfunction (Stage 2). Solid arrows represent progression of disease. Dashed arrows represent SNS effect on respective organs.
Ang II ¼ angiotensin II; ER ¼ endoplasmic reticulum; HA ¼ headache; HIF ¼ hypoxia-inducible transcription factor; HIF ¼ hypoxia-inducible transcription factor;
NO ¼ nitric oxide; PlGF ¼ placental growth factor; PRES ¼ posterior reversible encephalopathy syndrome; RAAS ¼ renin-angiotensin-aldosterone system;
sEng ¼ soluble endoglin; sFlt ¼ soluble fms-like tyrosine kinase; SNS ¼ sympathetic nervous system; TGF ¼ transforming growth factor; VEGF ¼ vascular endothelial
growth factor.

(34) of 205 women with preeclampsia
Netherlands found that hypertension can take up to 2
years to resolve following delivery. Both the severity
of preeclampsia and time to delivery were positively
associated with time to resolution (34). Hypertension
in the setting of preeclampsia contributes to the
development of target organ damage, including heart
failure, pulmonary edema, renal dysfunction and
acute kidney injury, and neurological injury and
stroke (3,8,35).
PROTEINURIA
Proteinuria in the setting of preeclampsia is the result
of increased renal tubular permeability to most large-
molecular-weight proteins, such as albumin, glob-
ulin, transferrin, and hemoglobin (3). High circulating
sFlt-1 and decreased nitric oxide are both involved in
mediating renal tubular injury in the setting of pre-
eclampsia (6,9). sFlt-1 inhibition of VEGF also causes
glomerular endothelial injury, a process termed
glomerular endotheliosis that is pathognomonic for
in the preeclampsia (8,11,31,32). Glomerular endotheliosis is
characterized by swollen, vacuolated endothelial
cells with fibrils, swollen mesangial cells, sub-
endothelial deposits of protein reabsorbed from the
glomerular filtrate, and tubular casts (3). There is an
enlarged bloodless glomerulus with an obliterated
capillary lumen (usually not accompanied by promi-
nent capillary thrombi as in thrombotic micro-
angiopathy) (31). High sFlt-1 levels inhibit podocyte-
specific VEGF, disturbing the glomerular filtration
barrier and resulting in formation of fenestrae
contributing to proteinuria (36). The damage to
podocytes is largely responsible for the proteinuria.
Slit diaphragm proteins (nephrin, podocin, synapto-
podin, podocalyxin) play a key role in maintaining
glomerular barrier integrity, and detection of these
proteins in the urine precedes the clinical features of
preeclampsia by several weeks, indicating that dam-
age to these proteins leads to the development of
further proteinuria (31). Urine samples from pre-
eclamptic patients have increased levels of proteins
involved in the coagulation, complement, RAAS, and
JACC VOL. 76, NO. 14, 2020
OCTOBER 6, 2020:1690–702
cell adhesion pathways (37). Proteins detected in the
urine of preeclamptic patients are also often mis-
folded (9). It is likely that imbalance between proan-
giogenic and antiangiogenic factors leads to podocyte
injury and that this damage contributes to the higher
risk of later hypertension, chronic kidney disease,
ischemic heart disease, stroke, persistent proteinuria,
and end-stage renal disease seen in patients with
preeclampsia (31). Proteinuria can take up to 2 years
to resolve following preeclampsia, with the severity
of preeclampsia and time to delivery positively
associated with time to resolution (34).
RENAL DYSFUNCTION
Renal dysfunction in preeclampsia is defined as
serum creatinine >1.1 mg/dl or a doubling of baseline
creatinine (38). Renal blood flow and glomerular
filtration rate are often decreased in preeclampsia
(11). Biopsy changes in these patients include diffuse
fibrin deposition, endothelial swelling, loss of podo-
cytes, and loss of capillary space (glomerular endo-
theliosis) (6,8). Dysregulation of the glomerular
filtration apparatus occurs in the setting of glomer-
ular endotheliosis (6). In normal pregnancy,
increased tissue factor release from the maternal
decidua and placenta shifts endothelial cells to a
procoagulant balance (36). Increased proin-
flammatory cytokines in preeclampsia further stimu-
late tissue factor expression by endothelial cells and
leukocytes (8,39). Damaged endothelial cells then
further induce clotting and lose anticoagulant ability
as prostaglandin and nitric oxide levels decrease,
leading to thrombotic microangiopathy in the kidneys
(36). Increased toll-like receptor 4 leads to increased
inflammatory cytokines, which in turn increase both
placental and renal dysfunction (10). Electrolyte ab-
normalities occur as urinary calcium decreases due to
increased tubular calcium reabsorption (3). Reduction
in intravascular volumes in preeclampsia increases
sodium and free-water retention (3). Lastly, the same
mechanisms that trigger hypertension, particularly
involving sFlt-1 and the RAAS system, predispose to
renal dysfunction and acute kidney injury, which in-
crease later risk of hypertension, chronic kidney dis-
ease, and end-stage renal disease (8,29,31).
NEUROLOGICAL DYSFUNCTION
Preeclampsia may lead to multiple neurological
problems, including headache, visual disturbances,
seizure, posterior reversible encephalopathy syn-
drome, and hemorrhagic stroke (35,38). Multiple
variants of primary headache including tension type
headache, migraine without aura, and migraine with
Ives et al. 1695
Pathophysiology of Preeclampsia
aura are associated with preeclampsia (40). Second-
ary headache accounts for 35% of headache in preg-
nancy. HDPs, most commonly preeclampsia, are the
most frequent cause of secondary headache and
become more common as gestational age increases
(40,41). Use of nifedipine for severe hypertension and
intravenous magnesium sulfate for eclampsia pro-
phylaxis may also cause headache (41). The charac-
teristic preeclampsia headache is progressive,
bilateral (frontal or occipital), pulsating/throbbing,
associated with visual changes, worse with higher BP,
aggravated by physical activity, and unresponsive to
over-the-counter medications (40,41). Symptoms can
also be vague and typical of tension-type headache
(41). The characteristic posterior reversible encepha-
lopathy syndrome headache is bilateral, occipital,
dull, and with no prodrome (40). One theory of the
pathophysiology of headache in preeclampsia is that
blocking VEGF and TGF- b leads to loss of fenestrae on
the choroid plexus, resulting in endothelial cell
instability and periventricular edema (5). These
changes may then precipitate seizures and posterior
reversible encephalopathy syndrome, defined by
neurological abnormalities with neuroimaging find-
ings of vasogenic edema in the distribution of the
posterior cerebral circulation (5,42).
Visual disturbance in preeclampsia may be due to
retinopathy, retinal detachment, or cortical blind-
ness, which typically resolves following delivery
(35,43). Central serous chorioretinopathy occurs as
fluid accumulates behind the retina, leading to
detachment (44). It is thought to arise from hormonal
fluctuations, such as progesterone level changes (45).
Hypertensive retinopathy is a condition of retinal
microvascular damage secondary to elevated blood
pressure (46). It results from severe vascular spasm in
the setting of the angiogenic imbalance of pre-
eclampsia (45,46). In central serous chorioretinop-
athy and hypertensive retinopathy, delivery results
in spontaneous resolution of subretinal fluid, with
generally good outcomes, so these conditions are not
emergent indications for delivery (45). By contrast,
diabetic retinopathy can progress quickly in preg-
nancy and up to 1 year postpartum, so close moni-
toring and treatment with laser photocoagulation
after progression to severe pre-proliferative diabetic
retinopathy is recommended (44,45). However,
regression to a prior state of retinopathy can occur in
the postpartum period (44). Retinal artery occlusion
can also occur and is associated with Protein S defi-
ciency, elevated factor VIII, and primary anti-
phospholipid antibody syndrome (45). Cortical
blindness is vision loss due to lesions of the occipital
cortex, possibly due to cerebral edema. It generally
1696 Ives et al.
Pathophysiology of Preeclampsia
resolves in hours to days (44). Though some visual
disturbances are temporary, others can result in per-
manent visual disturbance or blindness despite
prompt clinical recognition and management.
ECLAMPSIA
Eclampsia is defined as new-onset tonic-clonic, focal,
or multifocal seizures in the setting of HDP in the
absence of other causes (3). Although progesterone
raises the seizure threshold, estrogen lowers the
seizure threshold via down-regulation of gamma
aminobutyric acid (8). A Cochrane review of medica-
tions for preeclampsia found that intravenous mag-
nesium sulfate reduced the risk of eclampsia by 59%,
superior to phenytoin (47). It is unknown why mag-
nesium sulfate works or why it is more effective than
other medications, though it appears to be through
mechanisms other than anticonvulsant properties.
The mechanism may be related to mitigating the
endothelial injury underlying preeclampsia (48).
Patients with eclampsia who undergo magnetic
resonance imaging typically have findings suggestive
of posterior reversible encephalopathy syndrome.
However, these findings were seen in areas of the
brain other than the posterior cerebrum (42).
Eclampsia can develop with systolic BP <160 mm Hg,
suggesting that it may not be BP alone that drives
eclampsia but also endothelial dysfunction (42).
There are 2 proposed pathogenic mechanisms: vaso-
genic and cytotoxic edema. Vasogenic edema may
result from a sudden rise in BP over 150 mm Hg,
which increases cerebral blood flow, causing hyper-
perfusion and edema as intrinsic mechanisms to
autoregulate cerebral perfusion are overwhelmed.
Cytotoxic edema is thought to be due to profound
vasospasm from excessive cerebrovascular regulation
in an attempt to correct overperfusion. It has been
suggested that damage from vasogenic edema may be
reversible, whereas cytotoxic edema may be irre-
versible, resulting in permanent neurological
dysfunction (42).
New multidisciplinary studies are investigating
novel methods of diagnosing neurological dysfunc-
tion in preeclampsia (49). Magnetic resonance imag-
ing can reveal vasogenic edema, thought to occur as a
result of a combination of vasoconstriction, impaired
autoregulation, and endothelial dysfunction, as well
as posterior reversible encephalopathy syndrome.
Additionally, biomarkers, such as S100 calcium-
binding protein B, neuron-specific enolase, neuro-
filament light chain, and tau, are being studied as
possible diagnostic techniques to identify patients at
risk of developing preeclampsia/eclampsia (49).
JACC VOL. 76, NO. 14, 2020
OCTOBER 6, 2020:1690–702
Identification of an imaging finding or reliable
biomarker may provide insight into the otherwise
unknown mechanism of eclampsia and may allow
clinicians to target at-risk patients for closer moni-
toring and/or prophylactic treatment.
CARDIAC DYSFUNCTION
Cardiac output increases by 30% to 50% in the first 2
trimesters of normal pregnancy then plateaus after
20 weeks. The increase in cardiac output is accom-
plished by a heart rate increase, 50% increase in
plasma volume, and to compensate for the increased
intravascular volume, transient left ventricular
eccentric hypertrophy. These changes fully recover
postpartum (8). In preeclampsia, the increased after-
load from higher vascular resistance created by
impaired placentation leads to worsening of left
ventricular remodeling, resulting in mild-to-
moderate isolated left ventricular diastolic dysfunc-
tion with concentric left ventricular hypertrophy (8).
Whereas eccentric remodeling is a physiological
compensatory response, concentric remodeling in-
dicates an abnormal cardiac response to the increased
systemic vascular resistance seen in preeclampsia.
One study (50) examined echocardiographic findings
in women with acute preeclampsia and found higher
right ventricular systolic pressures, increased left
atrial size, increased left ventricular wall thickness,
diastolic dysfunction, and increased left ventricular
filling pressures. Another study (51) used cardiovas-
cular magnetic resonance imaging and found that
postpartum women with preeclampsia had left atrial
enlargement compared with the control group of
postpartum women without preeclampsia. HDP in-
crease the risk of peripartum cardiomyopathy, a
serious complication of pregnancy (52,53). Peri-
partum cardiomyopathy is defined as reduced left
ventricular ejection fraction (<45%) toward the end
of pregnancy or in the first few months postpartum
and is a diagnosis of exclusion (8,54). It occurs in 1 in
1,000 pregnancies worldwide and in 1 in about 3,000
live births in the United States (53,54).
The balance between antioxidant capacity and
oxidative stress is upset in peripartum cardiomyopa-
thy, which is worsened by preeclampsia, likely due to
the higher levels of sFlt-1 (8,54,55). The antioxidant
signaling pathway, which is protective in normal
pregnancies, involves mitochondrial superoxide dis-
mutase 2 and includes peroxisome proliferator-
activated receptor g coactivator 1-a and signal trans-
ducer and activator of transcrition3 (Stat3) (54).
Peroxisome proliferator-activated receptor g coac-
tivator 1- a , a transcriptional coactivator important in
JACC VOL. 76, NO. 14, 2020 Ives et al. 1697
OCTOBER 6, 2020:1690–702 Pathophysiology of Preeclampsia

F I G U R E 1 Pathophysiology of Cardiac Dysfunction in Preeclampsia

Preexisting CVD and subsequent impaired placentation drive an angiogenic imbalance and disrupt normal cardiac changes in pregnancy.
Concentric LVH and/or PPCM may develop, which increase risk for later CVD complications. CO ¼ cardiac output; CVD ¼ cardiovascular
disease; ET ¼ endothelin; HR ¼ heart rate; LA ¼ left atrial; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy; PPARg ¼ peroxisome
proliferator-activated receptor g coactivator; PPCM ¼ peripartum cardiomyopathy; RVSP ¼ right ventricular systolic pressure; sEng ¼ soluble
endoglin; sFlt ¼ soluble fms-like tyrosine kinase; Stat3 ¼ signal transducer and activator of transcrition3; SVR ¼ systemic vascular resis-
tance; VEGF ¼ vascular endothelial growth factor.

mitochondrial biogenesis, is highly expressed in the vasorelaxation, worsening endothelial dysfunction

heart and is also important in angiogenesis, as it in-
creases VEGF (55). Mice lacking
proliferator-activated receptor g coactivator 1-a have
been shown to have abnormal cardiac energy re-
serves, suggesting involvement in the pathogenesis
of peripartum cardiomyopathy (55). Stat3 is a protein
that up-regulates antioxidative enzymes, promotes
myocardial angiogenesis, and can mediate car-
diomyocyte hypertrophy (56,57). Expression and
activation of Stat3 is decreased in the placentas of
preeclampsia rat models (57). Further, Stat3 deletion
in rat models leads to increased cathepsin D, which
cleaves the proangiogenic 23-kDa prolactin protein
into the antiangiogenic 16-kDa prolactin (54,56); 16-
kDa prolactin disrupts capillaries
(54). Female mice with a cardiomyocyte-specific
peroxisome deletion of Stat3 develop peripartum cardiomyopa-
thy (56). Additionally, Stat3 levels have been found to
be decreased in preeclamptic placentas of humans
(Figure 1) (58). Given the high prevalence and asso-
ciated morbidity of cardiac dysfunction in pre-
eclampsia, further study of the underlying
mechanisms, and thus, potential preventative stra-
tegies and novel therapies is warranted to reduce
morbidity in afflicted women.
PULMONARY EDEMA
Pulmonary edema in preeclampsia is rare (0.6% to
and blocks 0.7%) (59) but carried significant morbidity and
1698 Ives et al.
Pathophysiology of Preeclampsia
mortality in 1 study (60). It can occur antepartum or
postpartum (60). Generally, there are 4 components
of pulmonary edema in preeclampsia: increased
vascular permeability, cardiac dysfunction, cortico-
steroids/tocolytics, and iatrogenic volume overload.
The increased vascular permeability results from
endothelial damage of preeclampsia coupled with the
decreased colloid osmotic pressure of pregnancy (60).
The combination of diastolic dysfunction
increased vascular resistance increase hydrostatic
forces in the pulmonary vasculature (8,60). Admin-
istration of corticosteroids to women with pre-
eclampsia to reduce neonatal complications
prematurity can result in significant maternal pul-
monary edema, although by an unknown mechanism
(61,62). However, these patients are also generally
receiving tocolytics or magnesium sulfate, making it
difficult to decipher which predisposes to pulmonary
edema (60,61). Many women with preeclampsia
receive large volumes of intravenous fluids, leading
to volume overload, especially with mobilization of
fluids postpartum (60). Further, the edema may be
worsened by renal retention of salt and water (31).
Though rare, the morbidity and mortality associated
with pulmonary edema in preeclampsia necessitates a
deeper understanding of its pathogenesis and an
attempt to limit iatrogenic insults which may pro-
mote its development.
HEPATIC DYSFUNCTION
Hepatic dysfunction in preeclampsia is defined as
transaminases $2 the upper limit of normal and
persistent severe right upper quadrant or epigastric
tenderness (38). Aspartate aminotransferase is usu-
ally higher than alanine aminotransferase in pre-
eclampsia, as aspartate aminotransferase is related to
periportal necrosis (3). However, alanine amino-
transferase should not be tested in isolation, because
at least 1 case has been reported of alanine amino-
transferase deficiency in the setting of a HDP diag-
nosis (63). Preeclampsia also causes elevation in
lactate dehydrogenase and alterations in hepatic
synthetic function, resulting in abnormalities in pro-
thrombin time, partial thromboplastin time, and
fibrinogen (3). Liver failure and hepatic rupture can
occur. Both are related to endothelial dysfunction,
which causes hepatic microcirculatory deterioration
and hepatocellular necrosis (8). Decreased expression
of endothelial nitric oxide synthase resulting from
sFlt-1 antagonism of VEGF also leads to liver
dysfunction and thrombocytopenia (8). Further study
is needed to better detect and quantify hepatic
JACC VOL. 76, NO. 14, 2020
OCTOBER 6, 2020:1690–702
dysfunction in preeclampsia and to assess its long-
term effects.
HEMATOLOGIC DISTURBANCE
The most common hematologic disturbances are
thrombocytopenia and disseminated intravascular
coagulopathy, a disruption of the clotting cascade
leading to intravascular coagulation accompanied by
and
secondary fibrinolysis (8). Thrombocytopenia
(platelets <100,000) is likely due to increased platelet
activation, aggregation, and consumption (3,38).
Pregnancy is a procoagulant state because of in-
of
creases in fibrinogen and other clotting factors, and
decreases in anticoagulants (Protein C and S) (8). It
has been hypothesized that syncytiotrophoblasts
shed extracellular vessels that augment platelet
activation, leading to release of soluble factors and
extracellular vesicles, which might contribute to
placental and systemic microvascular ischemia (64).
An imbalance in angiogenic factors, specifically sFlt-1
and sEng, may also be involved (65). Another theory
is that sudden activation of the vascular endothelial
cascade leads to the release of von Willebrand factor
multimers that bind platelets, causing excessive
platelet aggregation and subsequent thrombus for-
mation in the microcirculation, resulting in
consumptive thrombocytopenia, hemolytic anemia,
and hepatic dysfunction (8,65). This phenomenon
usually resolves 6 to 7 days postpartum (8). Decreased
nitric oxide levels also contribute to qualitative
platelet dysfunction (9). Possible mechanisms of
disseminated intravascular coagulopathy include:
consumption coagulopathy, hepatic injury (decreased
clotting factor production), and/or systemic maternal
inflammatory response (8). It is important to monitor
women with preeclampsia for hematologic abnor-
malities to support them through this potentially
deadly feature of preeclampsia.
FETAL GROWTH RESTRICTION/
FETAL IMPLICATIONS
Preeclampsia leads to uterine and placental
dysfunction, which causes fetal growth restriction,
defined as an estimated fetal weight <10th percentile
for gestational age (66). As spiral arteries fail to
develop appropriately and lead to incomplete pseu-
dovasculogenesis, placental vascular insults such as
placental infarcts occur (3,5,11). Incomplete spiral
artery remodeling leads to atherosis of maternal
radial arteries (lipid-laden macrophages in the lumen,
fibrinoid necrosis in the wall, and mononuclear peri-
vascular infiltrate) (2). Decidual vasculopathy,
including loose, edematous endothelium,
JACC VOL. 76, NO. 14, 2020
OCTOBER 6, 2020:1690–702
F I G U R E 2 Interventions to Reduce Preeclampsia
Benefit
Delivery
Aspirin
Calcium*
Overview of evidence of treatments to reduce risk of preeclampsia. Interventions with proven benefit are delivery for treatment, and aspirin
and calcium for prophylaxis. Pravastatin, metformin, and exercise are currently being investigated and are showing promise. *Only in
nutritional deficiency in low-middle income countries.
hypertrophy of the vessel media, loss of smooth
muscle modifications, and up-regulation of hypoxia-
inducible transcription factor-1 a , results from these
changes (2). Structural changes of the glycocalyx and
hyaluronic acid are also seen (10). Inhibition of TGF-b
by sEng also leads to impaired endothelial vasodila-
tion (5). These changes cause impaired diastolic
placental flow on ultrasound and placental ischemia
(2,10). The resultant ischemia can lead to decidual
and placental endoplasmic reticulum stress and
further oxidative stress (2).
Biopsies of preeclamptic placentas
shallow invasion of trophoblasts and failure of spi-
ral artery remodeling. Evaluation of the decidua
shows decreased prolactin and insulin-like growth
factor binding protein (both decidualization
markers). Decidual cells in vitro have also been
shown to fail to promote cytotrophoblast invasion
(possibly due to reduced nitric oxide) (13). Women
with uncomplicated pregnancies who
adverse outcomes in later pregnancies are more
likely to have maternal vascular malperfusion le-
sions in the placentas from the initial, uncompli-
cated pregnancy. These placentas are also more
likely to have a decidual vasculopathy (67). Taken
together, these factors contribute to fetal growth
restriction that commonly occurs in pregnancies
complicated by preeclampsia.
Ives et al. 1699
Pathophysiology of Preeclampsia
No Benefit
Bed rest
Potential
Fish oil
Pravastatin
Folic acid
Metformin
Garlic
Exercise
Sodium restriction
Vitamins C, D, E
PREVENTION
A concerted effort has been made to reduce the
burden of preeclampsia (Figure 2). Unfortunately, bed
rest, fish oil, folic acid, garlic, sodium restriction, vi-
tamins C and E, and vitamin D studies have not
translated to clinical benefit (68–74). The only defin-
itive treatment for preeclampsia is delivery, but daily
aspirin is recommended by the American College of
Obstetricians and Gynecologists (75), the United
States Preventive Services Task Force (76), and the
confirm International Society for the Study of Hypertension in
Pregnancy (7) for high-risk women after 12 weeks
gestation to reduce their risk of preeclampsia.
Aspirin is proposed to reduce preeclampsia risk via
inhibition of cyclooxygenase-1 and cyclooxygenase-2,
which contribute to prostaglandin biosynthesis and
subsequent endothelial dysfunction (75,76). A recent
Cochrane review (77) summarized evidence from 60
develop trials including 36,716 women and found an 18%
reduced risk of preeclampsia with aspirin prophylaxis
(relative risk: 0.82,; 95% confidence interval: 0.77 to
0.88).
Exercise is recommended by the International So-
ciety for the Study of Hypertension in Pregnancy for
preeclampsia prevention, because they cite a low risk
of adverse events and potential benefit (7). The So-
ciety recommends following the protocol of a
1700 Ives et al.
Pathophysiology of Preeclampsia
previous study (78) of 50 min at least 3 days per week
of exercise, which was associated with reduced
weight gain and incidence of HDP (7). However, a
systematic review and meta-analysis (79) found ex-
ercise in overweight or obese women to reduce
weight gain, but not incidence of HDP. Another
strategy to reduce preeclampsia is calcium supple-
mentation, though this applies mainly to women with
nutritional deficiency or in low- to middle-income
countries (7,80). A meta-analysis of 13 trials (15,730
women) reported a significant reduction in pre-
eclampsia with calcium supplementation, with the
greatest effect among women with low-baseline cal-
cium intake (80). A 2018 meta-analysis update
including 27 trials (18,064 women) confirmed similar
results (81). A proposed mechanism is that hypocal-
cemia may stimulate parathyroid hormone or renin
release, which may increase intracellular calcium in
vascular smooth muscle, resulting in vasoconstriction
and higher blood pressure (80,81). Calcium supple-
mentation may reduce parathyroid release, thereby
reducing intracellular calcium and smooth muscle
contractility (80,81). Similarly, calcium supplemen-
tation may reduce uterine smooth muscle contrac-
tility and potentially improve uteroplacental blood
flow, preventing preterm labor and delivery (80,81).
Pravastatin has been proposed as adjunctive ther-
apy to reduce the risk of preeclampsia. Data from a
mouse model of preeclampsia demonstrated that pra-
vastatin prevented vascular dysfunction (82). Another
study in a rat model of preeclampsia (83) showed that
pravastatin reversed postpartum cardiac dysfunction,
suggesting a potential role for secondary prevention
of cardiovascular disease following preeclampsia in
humans. Preliminary human data did not identify
safety concerns (84), and a clinical trial (85) is
ongoing to investigate the role of pravastatin in the
prevention of preeclampsia in high-risk pregnancy
women (Pravastatin for Prevention of Preeclampsia;
NCT01717586). Proposed mechanisms of pravastatin
benefit include reversal of angiogenic imbalance,
improvement of endothelial function, and prevention
of injury from oxidation and inflammation (85).
Metformin has also been proposed to reduce the
risk of preeclampsia. Preliminary data from a ran-
domized controlled trial (86) of metformin for the
prevention of large-for-gestational age fetuses in
obese pregnant women without diabetes are prom-
ising. Although the primary outcome of reduction in
neonatal birthweight was negative, metformin was
associated with a 76% reduction in the incidence of
preeclampsia (3.0% vs. 11.3%; odds ratio: 0.24,; 95%
confidence interval: 0.10 to 0.61) (86). Further study
is warranted.
JACC VOL. 76, NO. 14, 2020
OCTOBER 6, 2020:1690–702
CONCLUSIONS
Despite the proven benefit of aspirin and other
promising therapies under development for its pre-
vention, preeclampsia remains a leading cause of
morbidity and mortality in the developing and
developed world. Shallow trophoblast invasion and
incomplete transformation of spiral arteries during
placentation are the hallmarks of preeclampsia.
Recent evidence supporting shared risk factors for
preeclampsia and cardiovascular disease suggest a
role for pre-existing cardiovascular disease in the
development of HDP (87). The physiological stress of
preeclampsia may then more promptly unmask car-
diovascular disease in women with a history of the
disorder. In acknowledgement of these associations,
the American Heart Association recently issued a
statement (88) that provides guidance on cardiovas-
cular conditions in women of reproductive age and
urges clinicians to maintain an understanding of
cardiovascular disease during pregnancy. Little is
known about the mechanisms underlying most clin-
ical features of preeclampsia, particularly super-
imposed eclampsia, hepatic dysfunction, hematologic
disturbances, and cardiac remodeling and dysfunc-
tion. Nonetheless, the clinical relevance of this dis-
ease process is well-documented, given the
substantial effect on maternal and perinatal
morbidity and mortality, in both the short and
long term. Many ongoing research activities are
actively seeking to better understand this common
disorder that impacts 2% to 8% of pregnancies.
Opportunities for future research include defining
the roles of pre-existing diseases in the pathogenesis
of preeclampsia, elucidating immunologic predis-
positions and genetic etiologies (such as LIN28B), and
further refining the link between preeclampsia
and short- and long-term cardiovascular diseases.
Meanwhile, prompt diagnosis, close observation, and
delivery when indicated are the mainstays of treat-
ment to reduce maternal and fetal morbidity and
mortality.
ACKNOWLEDGMENT The authors thank Mikako
Kawai, who assisted with the Central Illustration and
Figure 1 design.
ADDRESS FOR CORRESPONDENCE: Dr. Christopher
W. Ives, Tinsley Harrison Internal Medicine Resi-
dency Program, Department of Medicine, University
of Alabama at Birmingham, 1720 2nd Avenue
South, ZRB 1034, Birmingham, Alabama 35294-0007.
E-mail: cives@uabmc.edu. Twitter: @UABCardiology,
@UAB_CWRH, @uabmedicine.
JACC VOL. 76, NO. 14, 2020
OCTOBER 6, 2020:1690–702
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KEY WORDS hypertension, hypertensive
disorders of pregnancy, maternal morbidity,
pathogenesis, pregnancy