Expert Review ajog.

org

Preeclampsia and eclampsia: the conceptual

evolution of a syndrome
Offer Erez, MD; Roberto Romero, MD, DMedSci; Eunjung Jung, MD; Piya Chaemsaithong, MD, PhD;
Mariachiara Bosco, MD; Manaphat Suksai, MD; Dahiana M. Gallo, MD, PhD; Francesca Gotsch, MD

Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the
placenta and cured only by delivery. This article traces the condition—once thought to be a disease of the central nervous system,
recognized by the occurrence of seizures (ie, eclampsia)—from its origins to the present time when preeclampsia is conceptualized
primarily as a vascular disorder. We review the epidemiologic data that led to the recommendation to use diastolic hypertension and
proteinuria as diagnostic criteria, as their combined presence was associated with an increased risk of fetal death and the birth of
small-for-gestational-age neonates. However, preeclampsia is a multisystemic disorder with protean manifestations, and the condition
can be present even in the absence of hypertension and proteinuria. Toxins gaining access to the maternal circulation have been
proposed to mediate the clinical manifestations—hence, the term “toxemia of pregnancy,” which was used for several decades. The
search for putative toxins has challenged investigators for more than a century, and a growing body of evidence suggests that products
of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome. The discovery that the
placenta can produce antiangiogenic factors, which regulate endothelial cell function and induce intravascular inflammation in the mother,
has been a major step forward in the understanding of preeclampsia. We view the release of antiangiogenic factors by the placenta as an
adaptive response to improve uterine perfusion by modulating endothelial function and maternal cardiovascular performance. However, this
homeostatic response can become maladaptive and damage target organs during pregnancy or the postpartum period. Early-onset
preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch
of fetal demands and maternal supply, that is, a metabolic crisis. Preeclampsia, as it is understood today, is essentially a vascular
dysfunction unmasked or caused by pregnancy. A subset of patients diagnosed with preeclampsia are at greater risk for the subsequent
development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease. Given the toll on
maternal and infant health as well as the long-term consequences of the syndrome, the understanding, prediction, prevention, and
treatment of preeclampsia are healthcare priorities.
Key words: acute fatty liver, albuminuria, angiogenic factor, biomarker, blood pressure, cardiovascular disease, chronic hypertension,
convulsion, eclampsia, edema, fetal death, genetic predisposition, gestational hypertension, great obstetrical syndromes, Hemolysis,
Elevated Liver enzymes and Low Platelets (HELLP) syndrome, history, hypertension, hysterotonin, imitator, ischemia, placental growth
factor (PlGF), postpartum preeclampsia, pregnancy-induced hypertension, proteinuria, severe preeclampsia, soluble fms-like tyrosine
kinase-1 (sFlt-1), small for gestational age (SGA), stillbirth, toxemia, toxin, uteroplacental ischemia, vascular endothelial growth factor
(VEGF)

From the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver
National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD,
and Detroit, MI (Drs Erez, Romero, Jung, Chaemsaithong, Bosco, Suksai, Gallo, and Gotsch); Department of Obstetrics and Gynecology, Wayne State
University School of Medicine, Detroit, MI (Drs Erez, Jung, Chaemsaithong, Bosco, Suksai, Gallo, and Gotsch); Department of Obstetrics and
Gynecology, HaEmek Medical Center, Afula, Israel (Dr Erez); Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI (Dr
Romero); Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI (Dr Romero); Center for Molecular Medicine and
Genetics, Wayne State University, Detroit, MI (Dr Romero); Detroit Medical Center, Detroit, MI (Dr Romero); and Faculty of Medicine, Department of
Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (Dr Chaemsaithong).
Received Nov. 9, 2021; revised Dec. 2, 2021; accepted Dec. 3, 2021.
The authors report no conflict of interest.
This review was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural
Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and
Human Services (NICHD/NIH/DHHS) and, in part, with federal funds from the NICHD/NIH/DHHS under contract number HHSN275201300006C. Dr.
Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.
This paper is part of a supplement.
Corresponding author: Roberto Romero, MD, DMedSci. prbchiefstaff@med.wayne.edu
0002-9378/$36.00
ª 2021 Published by Elsevier Inc.
https://doi.org/10.1016/j.ajog.2021.12.001

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Introduction
Preeclampsia is a syndrome considered
unique to pregnant women; its causes,
pathophysiology, prediction, manage-
ment, and prevention present formi-
dable challenges. This article reviews the
conceptual evolution of this disorder.
An Enigmatic Pregnancy-Specific
Disorder
Convulsions in pregnant women:
epilepsy vs eclampsia
For centuries, ancient texts from Egypt,
China, India, and Europe have recorded
that pregnant women were at greater
risk for seizures (Figure 1).1 Convul-
sions were reported to occur more
frequently in primigravidae, both ante-
partum and postpartum, and to have a
poor prognosis. A fundamental issue
was whether seizures represented epi-
lepsy or a unique, specific complication
of pregnancy. The term “eclampsia”
(derived from the Greek eklampsis,
meaning “a shining forth”2,3) was
introduced by Johannes Varandaeus.
François Boissier de Sauvages de
Lacroix, a French physician and botanist
interested in the taxonomy of diseases,
is credited with distinguishing
eclampsia from epilepsy.4,5 He
proposed that eclampsia differed from
epilepsy because the latter was chronic
and recurred throughout the life
span while Eclampsia parturientium did
not.1
Convulsions and albuminuria
The association of convulsions, edema,
and albuminuria was reported in 1843 by
John C. W. Lever at Guy’s Hospital in
London, England,6 and James Young
Simpson at the University of Edinburgh,
Scotland.7 Lever was interested in the
similarities between patients with
eclampsia and those with glomerulone-
phritis, who were cared for by Richard
Bright at Guy’s Hospital (glomerulone-
phritis was known as “Bright’s disease”
at the time).6 Lever tested the urine of 10
women diagnosed with puerperal con-
vulsions and found albumin in most
cases (9/10) (Figure 2).6 The exception
was a patient who died from meningitis.
Lever proposed that eclampsia differed
from glomerulonephritis because albu-
minuria disappeared after delivery.
The triad: hypertension, albuminuria,
and edema
Hypertension was recognized as a feature
of eclampsia in 1885 by John William
Ballantyne at the University of Edin-
burgh, who reported abnormalities in
sphygmographic tracings (Figure 3) in
three cases of pregnant women with
“Bright’s disease.”8 Tracings were ob-
tained during pregnancy, labor, and the
postpartum period. Glomerulonephritis
had been suspected in these cases given
the combination of edema and albu-
minuria. Some have credited Louis
Henri Vaquez and Pierre Nobécourt in
1897 with the discovery of eclamptic
hypertension.9
The origin of the term “preeclampsia”
The association of hypertension, pro-
teinuria, and convulsions was subse-
quently confirmed by other
investigators, and importantly, some
noted that hypertension and proteinuria
were present before seizures, hence the
name “preeclampsia.”5 Leon Chesley
credited the introduction of this term to
John Clarence Webster10 in 1903 in the
United States and to Bar11 in France
(eclampsisme, meaning eclampsia
without convulsions).11 The concept
took hold and has since been a driving
force in the organization of prenatal care,
which is largely structured to detect
preeclampsia by measuring blood

FIGURE 1
The Kahun Gynaecological Papyrus

A, The Kahun Gynaecological Papyrus was a medical text from the late Middle Kingdom (1850e1700 BC) addressing women’s health. The Papyrus was
found near the modern-day Egyptian town of El Lahun in 1889 by Flinders Petrie. The Kahun Gynaecological Papyrus (UC 32057) is housed at University
College London, London, United Kingdom. Pages 1, 2, and 3 of Plate VI are shown in the figure. Information was obtained from https://en.wikipedia.org/
wiki/Kahun_Gynaecological_Papyrus. B, The Kahun Gynaecological Papyrus was translated in 1893 by Frederick Griffiths and published as “The Petrie
Papyri: hieratic papyri from Kahun and Gurob (principally of the Middle Kingdom).” The figure shows the translation of Prescription No. XXXIII from page 3
of the Plate VI (Medical Papyrus). It describes a cure to prevent a woman from biting her tongue the day of birth. Some modifications were made from “The
Petrie Papyri: hieratic papyri from Kahun and Gurob (principally of the Middle Kingdom).”
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

FEBRUARY 2022 American Journal of Obstetrics & Gynecology S787

Expert Review
FIGURE 2
First description of albuminuria in eclampsia
The title page of the “Cases of puerperal convulsions, with remarks,” in which Dr John C. W. Lever, a
British obstetrical physician, reported the association between puerperal convulsions and albu-
minuria. Modified from Lever.6
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
pressure, proteinuria, and by increasing
the frequency of prenatal visits as term
approaches.
“Toxemia of pregnancy”
Eclampsia and preeclampsia were origi-
nally attributed to “toxins” or “poisons”
believed to enter the maternal circula-
tion—hence, the term toxemia of
pregnancy,5,11e13 although there was
debate14 over whether the source of the
toxins was exogenous or endogenous.
One exogenous source was thought to be
bacteria, and Gerdes proposed that
eclampsia was caused by products of a
bacillus, which he named Bacillus
eclampsiae.15,16 The endogenous sources
(autotoxicity) were proposed to be
metabolic products of the fetus, mother,
or placenta.17 The term “toxemias of
pregnancy” included eclampsia, hyper-
emesis gravidarum, acute yellow atrophy
of the liver, pruritus gravidarum, and
ptyalism.18
S788 American Journal of Obstetrics & Gynecology FEBRUARY 2022
The search for the toxins responsible
for preeclampsia and eclampsia has lasted
for more than a century. In 1914, James
Young reported an association between
placental infarctions and eclampsia and
showed that placental extracts adminis-
tered to guinea pigs induced seizures and
other pathologic abnormalities.19 Subse-
quently, Hunter and Howard20,21
demonstrated the presence of a “pressor
substance” in placental and decidual ex-
tracts as well as in the plasma of patients
with preeclampsia: they named this sub-
stance “hysterotonin.” Later, Tatum and
Mulé obtained whole blood from patients
with severe preeclampsia and retrans-
fused it into the same patients after de-
livery, resulting in a transient, but
significant, increase in systolic and dia-
stolic blood pressure.22 Similar observa-
tions were made by Pirani and
MacGillivray,23 who collected plasma
from pregnant women and then retrans-
fused aliquots on postpartum day 6 and at
ajog.org
six weeks after delivery (Figure 4). Plasma
from patients with preeclampsia—but
not normal pregnancy—elicited a hy-
pertensive response on postpartum day 6.
This finding led to the conclusion that a
soluble factor present in the plasma of
patients with preeclampsia could induce
hypertension—supporting the concept of
a circulating “toxin.” However, when a
similar aliquot of plasma was retrans-
fused six weeks after delivery, hyperten-
sion did not occur. This was interpreted
as indicating that the increased vascular
response of patients to the circulating
pressor substances (toxins) had dis-
appeared. This conclusion was strength-
ened by subsequent observations that
women with preeclampsia and those
destined to develop preeclampsia are
more sensitive to the pressor effects of
angiotensin II.24 The search for the
“toxins” has continued to date, but the
use of the term “toxemia” has progres-
sively been abandoned. The anti-
angiogenic factor (soluble fms-like
tyrosine kinase-1 [sFlt-1]) has emerged as
a major candidate for one of the “toxins”
responsible for preeclampsia.
A Shift in Focus: From Maternal Signs
to Fetal and Neonatal Adverse
Outcomes
A major change in the conceptualization
of preeclampsia and eclampsia occurred
when investigators refocused the
emphasis from maternal health out-
comes (eg, seizures and death) to fetal
and neonatal outcomes (eg, fetal death,
fetal growth restriction, and small-for-
gestational-age [SGA]). Two major
studies conducted in the United States
shaped the classification of hypertensive
disorders and the importance of
proteinuria.25,26
Page and Christianson25 reported the
results of a prospective study of nearly
13,000 pregnancies between 1959 and
1967, which were part of the Child and
Health Development studies conducted
in the United States. Patients were
classified according to the mean arterial
blood pressure measured in the second
and third trimesters and to the presence
or absence of proteinuria. Preeclampsia
was defined as an elevated blood pres-
sure in the third trimester with
ajog.org Expert Review

proteinuria. If the patient presented

FIGURE 3
with an elevated blood pressure in the
second trimester, the disorder was
First demonstration of hypertension in eclampsia
considered to represent chronic hyper-
tension.25 The major finding of the
study indicated that the rate of fetal
death was higher in patients diagnosed
with preeclampsia or chronic hyper-
tension, but not in those with gesta-
tional hypertension (Figure 5).25 Of
interest, proteinuria (defined as 2þ or
greater) was also a risk factor for fetal
death, regardless of the presence of
hypertension.
A major epidemiologic effort to
examine the relationship among blood
pressure, proteinuria, and adverse preg-
nancy outcome was undertaken as part
of the Collaborative Perinatal Project,
sponsored by the National Institutes of
Health, which began in 1958 and pro-
spectively enrolled 58,806 pregnancies at
12 university centers in the United
States.26 The results of the systematic
evaluation of blood pressure, protein-
uria, and pregnancy outcome were
published in the book “Pregnancy hy-
pertension” by Friedman and Neff The sphygmographic tracings record blood pressure from women with preeclampsia (A) during
(Figure 6).26 One of the conclusions of pregnancy and (B) in the postpartum period. Modified from Ballantyne.8
this study was that edema, whether Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
diagnosed by history or by physical

FIGURE 4
Evidence supporting the existence of circulating “toxin(s)” in preeclampsia: autotransfusion of maternal blood
induces hypertension

Changes in diastolic blood pressure in patients with preeclampsia and controls (A) on postpartum day 6 and (B) at 6 weeks postpartum after plasma
autotransfusion. Modified from Pirani and MacGillivray.23
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

FEBRUARY 2022 American Journal of Obstetrics & Gynecology S789

Expert Review
FIGURE 5
Risk of fetal death in patients with normal blood pressure, gestational
hypertension, chronic hypertension, and the different conditions with
proteinuria with hypertension
Modified from Page et al.25
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
examination, had minimal influence on
outcome. This observation strengthened
the case to remove edema from the triad
of hypertension, proteinuria, and
edema, which had formerly been used to
diagnose preeclampsia. Moreover, the
study was key in generating important
data about the relationships among hy-
pertension, proteinuria, and adverse
pregnancy outcome.
Table 1 shows the rate ratios of fetal
mortality by diastolic blood pressure ac-
cording to gestational age.26 Before 36
weeks of gestation, fetal mortality was
associated with values of 85 mm Hg
(diastolic blood pressure).26 After 36
completed weeks of gestation, fetal mor-
tality was associated with a diastolic blood
pressure of 95 mm Hg.26 Moreover,
fetal mortality was associated with pro-
teinuria exceeding 1þ, and the greater the
proteinuria, the higher the risk of fetal
mortality (Table 2). Importantly, a syn-
ergistic effect was noted between diastolic
blood pressure and proteinuria
(Figure 7). For example, fetal mortality
S790 American Journal of Obstetrics & Gynecology FEBRUARY 2022
was increased 9-fold (Table 3, red circle) if
diastolic blood pressure (95e104 mm
Hg) and proteinuria 2þ were present.
The data from the Collaborative Perinatal
Project indicated that an elevation in
systolic blood pressure was associated
with virtually the same fetal outcome as
an elevation in diastolic blood pressure.26
However, diastolic pressure was consid-
ered a better risk indicator than systolic
pressure, given that low systolic pressure
was not associated with a poor outcome
but low diastolic pressure was.
The clinical implementation of
these observations followed the
recommendation of the World Health
Organization and the American College
of Obstetricians and Gynecologists
(ACOG). The selection of 90 mm Hg as
a cutoff value for diastolic blood pres-
sure was made because it is a midpoint
between 85 mm Hg and 95 mm Hg (85
mm Hg was associated with fetal mor-
tality when combined with proteinuria,
and 95 mm Hg was associated with fetal
mortality regardless of proteinuria).26
ajog.org
Recent recommendations of the Amer-
ican College of Cardiology and the
American Heart Association to lower
the threshold for the diagnosis of hy-
pertension in nonpregnant subjects to
130/80 mm Hg27 have now stimulated a
dialogue about whether the threshold
should also be applied to the diagnosis
of preeclampsia.28,29 Early evidence
suggests that perinatal outcomes in
pregnant women with stage 1 hyper-
tension before 20 weeks of gestation are
worse than those with normal blood
pressure (stage 1 hypertension is
defined as BP range 130-139/80-89 mm
Hg).30 However, more work is neces-
sary to determine whether the diag-
nostic criteria should be modified.
Preeclampsia: More than Pregnancy-
Induced Hypertension
The hallmark of the clinical diagnosis of
preeclampsia has been hypertension.
However, the involvement of other or-
gans has been known for decades based
on autopsy findings and clinical reports
(Figure 8).31,32 The most frequent organs
involved are the kidney (proteinuria),32,33
liver (elevation of transaminases, liver
hematoma, and rupture),32,34e37 he-
matopoietic system (hemolysis, leukocy-
tosis, and thrombocytopenia),38e44 brain
(seizures, cortical blindness, intracranial
hemorrhage, and infarction),45e47 and
uteroplacental circulation (fetal growth
restriction, abruption, and fetal
death).19,48e56 Other organs and systems
that may be involved include the lung
(ventilation-perfusion mismatch and
adult respiratory distress syndrome),57
heart (systolic and diastolic
dysfunction),58e63 pancreas (pancrea-
titis),64 eyes (retinal problems including
detachment),65,66 small and large in-
testines (ischemia),67 endocrine organs
(adrenal glands, thyroid, and
parathyroid),68e72 and immune system
(exaggerated intravascular inflammation
and changes in B and T cells as well as in T
regulatory cells).73e76
An Atypical Form of Preeclampsia:
Hemolysis, Elevated Liver Enzymes,
and Low Platelet Syndrome
Clinicians and investigators realized that
“toxemia of pregnancy” could occur
ajog.org Expert Review

without hypertension. For example,

FIGURE 6
approximately 15% of patients with
HELLP syndrome have normal diastolic
The book cover of “Pregnancy hypertension: a systematic evaluation of
blood pressure at admission,38,77 and
clinical diagnostic criteria” authored by Emanuel A. Friedman and
10% to 15% of patients with
Raymond K. Neff and published in 1977
eclampsia78e80 do not develop hyper-
tension. Goodlin81 emphasized this
point with a case series of patients with
atypical presentation and proposed that
preeclampsia was another “great
imitator” (others include syphilis,
tuberculosis, and Lyme disease)
(Figure 9). In 1982, Louis Weinstein
coined the term “HELLP syndrome” to
describe the combination of hemolysis,
elevated liver enzymes, and low platelet
count and proposed it to be a severe
consequence of hypertension in preg-
nancy (Figure 10).82 However, this
cluster of laboratory findings, often
associated with abdominal pain, can
occur in the absence of hypertension and
proteinuria83,84: sometimes, thrombo-
cytopenia and liver dysfunction can
resolve before delivery.83 Thrombocyto-
penia and an elevated SGOT (serum In this book, the authors reported results from the Collaborative Perinatal Project conducted in the
glutamic-oxaloacetic transaminase) level United States. Modified from Friedman and Neff26
are independent risk factors for adverse Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

pregnancy outcome after adjusting for

hypertension and proteinuria. Patients
may present with unusual clinical man-
ifestations, such as visual
disturbances,85e87 renal failure,88,89
congestive heart failure,63 abdominal
pain,90,91 and headaches.92,93.
Preeclampsia Without Proteinuria?
Proteinuria has been a requirement for
the diagnosis of preeclampsia for de-
cades, as it reflects renal involvement;
however, in the 1990s, several groups of
investigators began to question whether
proteinuria should be a necessary
criterion.94e97 Multiple studies reported
that patients with severe gestational hy-
pertension had a high rate of adverse
pregnancy outcome, despite the absence
of proteinuria.94e96 The frequency of
preterm birth, SGA, placental abruption,
neonatal respiratory distress syndrome,
and perinatal death is higher among
women with severe gestational hyper-
tension than in those with mild
preeclampsia.95 Additionally, approxi-
mately 50% of women with an initial
diagnosis of gestational hypertension
will subsequently develop proteinuria
or end-organ damage.96,98 Two
additional arguments favored abandon-
ing the requirement of proteinuria for

TABLE 1
Rate ratios of fetal mortality by diastolic blood pressure according to gestational age
Diastolic blood pressure (mm Hg)
Gestational ages, (wk) n <65 65e74 (reference) 75e84 85e94 95e104 >105
28e32 24,640 0.7 1.0 1.0 2.3 5.9 10.2
33e34 19,340 0.9 1.0 1.1 2.3 7.1 8.3
35e36 20,593 0.8 1.0 1.3 2.0 8.8 7.8
37e38 20,243 1.0 1.0 1.2 1.8 2.8 -
39e41 15,797 0.8 1.0 1.0 1.2 3.2 2.6
26
Modified from Friedman and Neff.
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FEBRUARY 2022 American Journal of Obstetrics & Gynecology S791

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the diagnosis of preeclampsia: the stan-

TABLE 2 dard definition (300 mg in a 24-hour
Fetal mortality rates and rate ratios by proteinuria maxima urine collection or a 0.3 protein-to-
Proteinuria Fetal mortality rate, % Fetal mortality rate ratio creatinine ratio) is based on limited
None (reference) 0.9 1.0 data,99,100 and dipstick testing for pro-
teinuria is unreliable.101,102
Trace 0.9 1.0
Collectively, this set of observations,
1þ 1.2 1.3 coupled with the lack of difference in the
2þ 2.3 2.6 clinical management of gestational hy-
3þ 4.4 4.9 pertension and conventionally defined
preeclampsia, led the ACOG Task Force
4þ 5.7 6.3
on Hypertension in Pregnancy to modify
Modified from Friedman and Neff.26
the definition of preeclampsia in 2013 as
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
follows103: hypertension that develops
after 20 weeks of gestation with pro-
teinuria or evidence of end-organ dam-
FIGURE 7
age, such as an abnormal renal function
The synergistic effect of diastolic blood pressure and proteinuria on the test, an elevation of liver enzymes, or
risk of fetal death thrombocytopenia without proteinuria.
The modification reflected consensus
that the crucial factor was blood pressure
coupled with other manifestations of
end-organ damage, one of which could
be renal involvement. Although this
recommendation was aimed at opti-
mizing clinical management of patients,
it has also led to an increase in the fre-
quency of diagnoses of preeclampsia. It
is unclear whether this change in diag-
nostic criteria will translate into
improved maternal and perinatal out-
comes because most of the newly diag-
nosed cases have a mild form of the
disease.104 A more objective definition of
preeclampsia is required to supersede
the current approach of relying largely
on blood pressure measurement. The
identification of biomarkers for the early
detection of the different forms of the
syndrome will be crucial for improved
diagnosis, taxonomy, prediction, and
prevention.

Antiangiogenic factors in
preeclampsia
The discovery that the placenta from
patients with preeclampsia overex-
pressed mRNA and protein for sFlt-1,
an antiangiogenic factor, was a break-
through.105,106 The experiment con-
sisted of a comparison of the
transcriptomes of placentas from
patients with and without pre-
The synergistic effect of diastolic blood pressure and proteinuria is evident, and it determines a
eclampsia. Karumanchi’s group found
considerable increase in the risk of fetal mortality. Modified from Friedman and Neff.26
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
that two antiangiogenic factors—sFlt-1
and soluble endoglin (sEng)—were

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overexpressed in the placentas of women

with preeclampsia.106e109 Around the
same time, it became known that the
blockade of angiogenesis with vascular
endothelial growth factor (VEGF) an-
tagonists (monoclonal antibodies
against VEGF) in nonpregnant patients
with cancer would lead to hypertension
and proteinuria.110 Encouraged by this
finding, the investigators pursued a sys-
tematic series of studies that demon-
strated that overproduction of sFlt-1 in
pregnant animals recapitulated the fea-
tures of preeclampsia and renal lesions
associated with this condition (glomer-
ular endotheliosis).106,111 This informa-
tion, coupled with previous observations
in patients with a low maternal serum
concentration of the angiogenic factor—
placental growth factor (PlGF)—
strengthened the case for a role of an
antiangiogenic imbalance in pre-
eclampsia. The antiangiogenic factor,
endoglin, is also elevated in patients with
preeclampsia and may explain why a
subset of patients develop HELLP syn-
drome (Figure 11).112
The realization that antiangiogenic
factors are linked to preeclampsia has
improved the understanding of the
pathophysiology and has allowed clas-
sification according to the presence or
absence of an abnormal antiangiogenic
profile. Antiangiogenic factors meet the
criteria to be one, if not the major,
“toxin” responsible for preeclampsia
and eclampsia. The scientific basis for
this claim is provided in companion
articles in this Supplement.113,114
The syndromic nature of
preeclampsia
Obstetrical disorders, by contrast with
diseases in the nonpregnant state,
develop in the context of a unique
biological situation—two individuals
with different genomes coexisting,
one inside the other. The common in-
terest of the mother and her fetus is
successful reproduction; however, con-
flict can occur when the interests of the
mother and the fetus diverge, perhaps
as the result of an insult (such as an
infection or a compromised blood
supply). The term “great obstetrical
syndromes” was coined to describe the
TABLE 3
Rate ratios for fetal mortality by diastolic blood pressure and proteinuria
combination
Proteinuria
Diastolic pressure (mm Hg) None Trace 1D 2D 3D 4D
<65 2.5 2.3 1.0 — — —
65e74 1.5 1.3 0.8 5.5 7.0 —
75e84 1.0 a
1.3 1.0 3.2 — —
85e94 1.5 1.5 4.0 — 3.7 —
95e104 3.2 2.8 4.5 9.3 19.2 23.8
105 3.3 4.7 10.5 11.5 20.8 18.5
Modified from Friedman and Neff.26
a
Reference rate of fetal mortality: 0.6% or 6 per 1000 births.
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
unique nature of obstetrical diseases. subset of patients, and sometimes fetal
These features include (1) multiple growth deceleration precedes the diag-
etiologies, (2) a long subclinical phase, nosis of preeclampsia. Other subtle he-
(3) fetal involvement, (4) the adaptive matological abnormalities such as
nature of clinical manifestations, thrombocytopenia and neutropenia
and (5) complex gene-environment have also been reported.125 Remarkably,
interactions.115e117 This section sum- some neonates born to mothers with
marizes the evidence that preeclampsia preeclampsia have been noted to have
has many of these features. dilatation of the right coronary artery
and to be at risk for developing long-
Multiple etiologies term cardiovascular disease as well as
Preeclampsia is not one disorder but attention deficit and hyperactivity
rather different entities recognized by a disorders.125,126
common phenotype. Maternal, fetal,
and placental causes of preeclampsia Clinical manifestations are adaptive
have been identified. The causative risk Hypertension can be considered an
factors, or etiologies, of preeclampsia are adaptive response generated by an
reviewed in detail by Jung et al.118 injured placenta, which signals to the
mother the need to maintain perfusion;
Long subclinical phase this is accomplished by increasing
Although preeclampsia is diagnosed maternal cardiac output, by an eleva-
typically in the late second or third tion of maternal blood pressure, or, in
trimester, there is evidence of a patho- some cases, by a combination of both.
logic process weeks or months before the That hypertension is an adaptive
diagnosis. Some women have an response is supported by a set of clin-
abnormal pressor response to angio- ical observations including the resolu-
tensin II,119 an abnormal uterine artery tion of maternal hypertension
Doppler velocimetry measurement, or following the death of a growth-
abnormal angiogenic and antiangiogenic restricted fetus in a twin
profiles well before the clinical pregnancy,127e130 after SARS-CoV-2
diagnosis.108,120e124 infection,131 or after transfusion to
correct fetal anemia with fetal parvo-
Fetal involvement virus infection.132 Notably, pharmaco-
The diagnosis of the syndrome depends logic treatment of maternal
exclusively on maternal signs. Nonethe- hypertension does not improve fetal
less, fetal involvement, typically in the outcomes. In some cases, the adaptive
form of growth restriction, is present in a responses can become maladaptive, and

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Expert Review ajog.org

a hypertensive crisis can result in ce-

rebrovascular accidents, liver rupture,
and maternal death.

Complex gene-environment
interaction
The occurrence of preeclampsia is likely
influenced by a combination of genetic
and environmental factors. A genetic
predisposition has been suspected
because preeclampsia clusters in fam-
ilies. Although most genetic association
studies have focused on mothers,133,134
an association between a fetal DNA
variant and the syndrome has been
recently reported.135 Indeed, a fetal
genome DNA variant near FLT1 (the
gene encoding sFlt-1) is associated with
the risk of preeclampsia.136 In addition
to the potential contributions of fetal
and maternal DNA variants to a
particular obstetrical syndrome, the
interaction and incompatibility of ge-
notypes may also confer risk (e.g. spe-
Preeclampsia as a multisystemic disease that involves virtually every organ system

cific combinations of major

histocompatibility complex, class I, C
(HLA-C) genotypes in the fetus and
killer-cell immunoglobulin-like re-
ceptors in the mother and increased
risk of other combinations of DNA
variants in the genes encoding for the
von Willebrand factor, alpha-2 chain of
type IV collagen [COL4A2], and lym-
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

photoxin alpha).137e140

Implications
Considering preeclampsia as one of the
great obstetrical syndromes has several
consequences. Given that preeclampsia
has multiple etiologies, it is unlikely that
there will be a single diagnostic or
prognostic test, treatment, or preventive
strategy.
The long subclinical phase creates a
window of opportunity for prediction
and prevention, which have been
accomplished with assessment in the
first trimester and with the adminis-
tration of aspirin. Early evidence sug-
gests that prediction and prevention
may also be possible for late-onset
preeclampsia, but this may require
FIGURE 8

different biomarkers, and serial testing

and interventions (e.g. induction of
labor).141,142

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FIGURE 9
Atypical presentations of “toxemia of pregnancy,” first published in 1976 in AJOG

Modified from Goodlin.81

Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

Classification: Early vs Late, Mild vs
Severe Disease
Preeclampsia has been classified accord-
ing to gestational age at the time of diag-
nosis or delivery as early onset (<34
weeks) or late onset (34 weeks).
Although other gestational-age cutoff
values have been proposed, 34 weeks re-
mains the most commonly used, likely
because the rate of neonatal morbidities
declines considerably after this gestational
age.143,144 Specifically, in women with
severe preeclampsia, expectant manage-
ment is not considered, and induction of
labor is recommended after 34 weeks of
gestation. In addition, preeclampsia can
be classified according to its severity
(Table 4).103,145
Multiple lines of evidence have now
coalesced, proposing that early and
late preeclampsia are different condi-
tions (Table 5). Early-onset pre-
eclampsia is characterized by a higher
frequency of HELLP syndrome,142,147
abnormal uterine artery Doppler
waveforms,142 atherosis,148,149
placental lesions consistent with
maternal vascular malperfusion,142,150
SGA,141,142 and fetal growth restric-
tion.142 Moreover, abnormal maternal
plasma ratios of PlGF-to-sFLT-1 or
PlGF-to-sEng are present in 80% to
90% of patients with early-onset pre-
eclampsia, but in only 40% to 50% of
patients with late-onset preeclamp-
sia.141,151,152 Early-onset preeclampsia
can be considered a clinical manifes-
tation of atherosclerosis in pregnancy
while late-onset disease is a metabolic
crisis emerging from a mismatch be-
tween fetal demands and maternal
supply.
Postpartum Preeclampsia
This condition has been an enigma as
delivery of the placenta is considered to
be the cure of preeclampsia. Retained
fragments of the placenta have been
implicated in postpartum preeclampsia
and eclampsia for decades.153 In 1960,
while investigating the etiology of hy-
pertension in “toxemia of pregnancy,”
Hunter and Howard20 reported that the
decidua of patients with toxemia and
molar pregnancy produced a pressor
substance: “hysterotonin.” Although the
molecule responsible for this pressor
response was never characterized,
Hunter et al154 proposed that post-
partum curettage of the decidua could
improve the condition. Indeed, curettage
was reported to ameliorate hypertension
in 69 patients. In one patient with post-
partum eclampsia, convulsions did not
recur after curettage (Figure 12).154
Approximately 30 years later, Magann
et al155 reported the results of a ran-
domized clinical trial of immediate
postpartum curettage in 32 patients with
severe preeclampsia and observed that
patients who had undergone curettage
had significantly lower blood pressure

FIGURE 10
The origin of the term “HELLP syndrome,” first published in 1982 in AJOG

Adapted from Weinstein.82

HELLP, hemolysis, elevated liver enzymes, and low platelet count.
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

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FIGURE 11
The role of sFlt-1 in preeclampsia

A, Remodeling of the spiral arteries increases blood supply to the fetus. B, In preeclampsia, sFlt-1 is overexpressed in the placenta, leading to hy-
pertension and proteinuria. Modified from Luttun et al.105
PlGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor.
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

(Figure 13, A) as well as a significantly
higher urinary output and platelet count
(Figure 13, B) than those who did not
undergo a curettage. Collectively, these
observations suggest that material pre-
sent in the uterus after the delivery of the
placenta can still have biological prop-
erties. Although Hunter et al154 attrib-
uted this to the decidua, trophoblasts are
also present in the uterus after delivery of
the placenta and are consistently
observed in histologic examinations of
hysterectomy specimens. Therefore, it is
possible that trophoblasts may continue
to be a source of bioactive material. Why
some patients develop hypertension and
proteinuria only after delivery remains
an unanswered question.
Postpartum preeclampsia belongs to
a group of conditions of unknown
etiology diagnosed after delivery that
include cardiomyopathy, renal failure,
uremic hemolytic syndrome, and acute
fatty liver. Insights into the patho-
physiology of these conditions can be
gleaned by recent progress made in the
understanding of peripartum cardio-
myopathy, which is now recognized as
the result of the antiangiogenic factor
sFlt-1 in a two-hit model.156 The first
is an increased concentration of sFlt-1
in the maternal circulation, which can
impair cardiac function, and the sec-
ond is a lack of local proangiogenic
defenses in the maternal heart. Peri-
partum cardiomyopathy can be exper-
imentally induced in pregnant mice by
the combination of increased sFlt-1
(through an adenovirus vector) and
gene deletion of a regulator of angio-
genesis called “peroxisome pro-
liferator-activated receptor gamma

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TABLE 4
Severe features of preeclampsia (‡1 finding)

Systolic blood pressure of 160 mm Hg or diastolic blood pressure of 110 mm Hg on 2 occasions at least 4 hours apart while the patient is on
bed rest (unless antihypertensive therapy is initiated before this time)

Thrombocytopenia (platelet count<100,000/mL)

Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (twice the normal concentration), severe
persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses, or both

Progressive renal insufficiency (serum creatinine concentration>1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of
other renal diseases)

Pulmonary edema

New-onset cerebral or visual disturbances
Adapted from the American College of Obstetricians and Gynecologists.103
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

coactivator (PGC)-1 alpha”.156 Simi-
larly, pregnant women with peri-
partum cardiomyopathy have an
increased concentration of sFlt-1 in the
postpartum period, which has been
detected four to six weeks after de-
livery (elevated sFlt-1 typically returns
to normal range within three days of
delivery).156
A similar pathophysiological process
can be responsible for other post-
partum syndromes, including post-
partum renal failure. VEGF is essential
for the maintenance of glomerular
health, and its blockade damages the
fenestrated endothelium, causing pro-
teinuria.157,158 It is now recognized
that a subset of patients with
preeclampsia have impaired subclinical
renal function and proteinuria after
delivery, which may persist for
months. The antepartum sFlt-1 con-
centration correlates with a lower
glomerular filtration rate, and a high
concentration is a risk factor for renal
impairment at six and 12 months
postpartum.159 Recent observations
suggest that the pathophysiology of
acute fatty liver of pregnancy may also
be related to an excessive concentra-
tion of sFlt-1 (Figure 14).160,161 Why
and how an excess of sFlt-1 or other
antiangiogenic factors may target the
heart, kidney, liver, or brain (in some
cases of postpartum eclampsia) are
unknown. We believe that several
enigmatic postpartum syndromes
represent the clinical manifestations of
vascular dysfunction in the peripartum
period.
Vascular Dysfunction of Pregnancy:
Unmasked, Induced, Protean
The most important adaptation for a
successful pregnancy is the establish-
ment and development of an adequate
blood supply to the placenta and
conceptus. The clinical consequences of
suboptimal perfusion range from fetal
growth restriction, SGA, preeclampsia,
abruptio placenta, and fetal death
(Figure 15). A fundamental question is:
why does maternal malperfusion lead to
one particular syndrome rather than to

TABLE 5
Early-onset vs late-onset preeclampsia
Variable Early Late
Gestational age at onseta <34 wk 34 wk
146
Prevalence 0.38% (12% of all preeclampsia) 2.72% (88% of all preeclampsia)
142
HELLP syndrome 40.0% 11.1%
142
Fetal growth restriction 60.0% 25.0%
Small for gestational ageb,142 66.7% 31.9%
146
Neonatal death or severe neonatal morbidity 21.8% 2.3%
c,147
Combined adverse maternal outcomes 20.9% 9.2%
Uterine artery Doppler PI > 95 percentile
th 142
88.6% 48.6%
Abnormal maternal plasma PlGF/sFlt-1 ratio141 w80.0%e90.0% w40.0%e50.0%
HELLP, hemolysis, elevated liver enzymes, and low platelet count; PI, pulsatility index; PlGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase.
a
Gestational age at diagnosis or delivery; b birthweight <5th percentile; c combined adverse maternal outcome includes maternal mortality or one or more serious central nervous system,
cardiorespiratory, hepatic, renal, or hematological morbidity.
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

FEBRUARY 2022 American Journal of Obstetrics & Gynecology S797

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adaptive response may be spontaneous

FIGURE 12
preterm birth. Why some cases of fetal
Effect of uterine curettage on blood pressure in a woman with postpartum growth restriction attributable to
eclampsia placental malperfusion are associated
with preeclampsia and others are not is
unknown.
It is now clear that a subset of
women who develop preeclampsia have
preexisting vascular dysfunction, which
manifests clinically during pregnancy
and remains operative in the post-
partum period. This realization offers
unique opportunities to improve the
healthcare of women by implementing
strategies to prevent cardiovascular
disease. Figure 16 illustrates the long-
term adverse events associated with
preeclampsia. These include not only
maternal hypertension and coronary
artery disease but also vascular
dementia and end-stage renal dis-
ease.162 This article has focused on
preeclampsia. However, patients with
other complications of pregnancy, such
In one patient with postpartum eclampsia and three episodes of convulsions, curettage was per- as fetal death, are also at risk of sub-
formed, maternal hypertension improved, and convulsions did not recur. Modified from Hunter sequent cardiovascular diseases. There-
et al.154 fore, vascular dysfunction during
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
pregnancy diagnosed through pre-
eclampsia or other great obstetrical
syndromes has important implications
others? The timing and magnitude of the supply results in fetal death. Lesser de- for women’s health.163
insult and the genetic makeup of the grees of maternal malperfusion could be
mother, fetus, and placenta are likely to compensated by a reduction in fetal Conclusion
determine the clinical presentation. growth, maternal hypertension, or a The implications of preeclampsia in
Extreme compromise of the blood combination of both. In some cases, the maternal and infant health have been a

FIGURE 13
Effects of uterine curettage in patients with preeclampsia

Postpartum uterine curettage has an effect not only on blood pressure (A) but also on platelet count (B) in patients with preeclampsia. Modified from
Magann et al.155
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

S798 American Journal of Obstetrics & Gynecology FEBRUARY 2022

ajog.org Expert Review

major determinant in the organization

FIGURE 14
of prenatal care for more than a century.
Initially thought to be a disorder of the
Plasma concentration of sFlt-1 in women with normal pregnancy,
central nervous system, and then to
preeclampsia, HELLP syndrome, and acute fatty liver of pregnancy
involve the kidneys, it is now considered
fundamentally a cardiovascular disorder.
The view that preeclampsia is a preg-
nancy-specific condition caused by the
placenta and cured only by delivery, has
been the accepted dogma. We now know
that vascular dysfunction, clinically
recognized by the combination of hy-
pertension and proteinuria, is not spe-
cific to pregnancy; it can occur in non-
pregnant subjects after a viral infection
such as SARS-CoV-2,164e167 the
administration of VEGF inhibitors,110 or
in the context of other disorders such as
diabetes. What makes pregnant women
particularly prone to develop vascular
dysfunction is the placenta, an organ that
produces antiangiogenic factors in
response to insults. However, it is not
clear if all cases of preeclampsia require
placental involvement. The notion that
preeclampsia can be cured only by de-
livery also needs to be revisited. Indeed,
hypertension and proteinuria in preg- Women with acute fatty liver of pregnancy have a higher plasma concentration of sFlt-1 than women
nant women with SARS-CoV-2 infection with other conditions. Data are presented as individual values (dot) and median (bar). Modified from
can disappear after the viral infection is Neuman et al.161
cleared.131 Moreover, preeclampsia can HELLP, hemolysis, elevated liver enzymes, and low platelet count; sFlt-1, soluble fms-like tyrosine kinase-1.
resolve in twin gestations with selective Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
fetal growth restriction after the death of

FIGURE 15
Vascular dysfunction of pregnancy can lead to the great obstetrical syndromes

Vascular dysfunction during pregnancy may result in one of several obstetrical syndromes. The timing and magnitude of the insult may determine the
clinical syndromes.
PROM, premature rupture of membranes.
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FIGURE 16
Relative risk of cardiometabolic disease in women with a history of
preeclampsia
Modified from Ramlakhan et al.162
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
the affected twin128,129 or after treatment
of fetal anemia caused by parvovirus B19
infection.132 These clinical observations
about the reversibility of preeclampsia
are buttressed by experimental evidence
that the molecular abnormalities of tro-
phoblasts obtained from patients with
preeclampsia can resolve in vitro.168,169
Perhaps, it is time to reframe our
conceptualization of preeclampsia. Has
too much weight been given to the re-
sults of a sphygmomanometer to identify
this complex syndrome? The identifica-
tion of biological markers that detect the
pathophysiologic derangements of this
syndrome in early pregnancy, or even
before, is necessary to the diagnosis,
classification, treatment, prediction, and
prevention of this elusive disorder. -
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