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

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six weeks after delivery (Figure 4). Plasma

FIGURE 2
from patients with preeclampsia—but
First description of albuminuria in eclampsia 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
The title page of the “Cases of puerperal convulsions, with remarks,” in which Dr John C. W. Lever, a a major candidate for one of the “toxins”
British obstetrical physician, reported the association between puerperal convulsions and albu- responsible for preeclampsia.
minuria. Modified from Lever.6
Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
A Shift in Focus: From Maternal Signs
to Fetal and Neonatal Adverse
Outcomes
pressure, proteinuria, and by increasing The search for the toxins responsible A major change in the conceptualization
the frequency of prenatal visits as term for preeclampsia and eclampsia has lasted of preeclampsia and eclampsia occurred
approaches. for more than a century. In 1914, James when investigators refocused the
Young reported an association between emphasis from maternal health out-
“Toxemia of pregnancy” placental infarctions and eclampsia and comes (eg, seizures and death) to fetal
Eclampsia and preeclampsia were origi- showed that placental extracts adminis- and neonatal outcomes (eg, fetal death,
nally attributed to “toxins” or “poisons” tered to guinea pigs induced seizures and fetal growth restriction, and small-for-
believed to enter the maternal circula- other pathologic abnormalities.19 Subse- gestational-age [SGA]). Two major
tion—hence, the term toxemia of quently, Hunter and Howard20,21 studies conducted in the United States
pregnancy,5,11e13 although there was demonstrated the presence of a “pressor shaped the classification of hypertensive
debate14 over whether the source of the substance” in placental and decidual ex- disorders and the importance of
toxins was exogenous or endogenous. tracts as well as in the plasma of patients proteinuria.25,26
One exogenous source was thought to be with preeclampsia: they named this sub- Page and Christianson25 reported the
bacteria, and Gerdes proposed that stance “hysterotonin.” Later, Tatum and results of a prospective study of nearly
eclampsia was caused by products of a Mulé obtained whole blood from patients 13,000 pregnancies between 1959 and
bacillus, which he named Bacillus with severe preeclampsia and retrans- 1967, which were part of the Child and
eclampsiae.15,16 The endogenous sources fused it into the same patients after de- Health Development studies conducted
(autotoxicity) were proposed to be livery, resulting in a transient, but in the United States. Patients were
metabolic products of the fetus, mother, significant, increase in systolic and dia- classified according to the mean arterial
or placenta.17 The term “toxemias of stolic blood pressure.22 Similar observa- blood pressure measured in the second
pregnancy” included eclampsia, hyper- tions were made by Pirani and and third trimesters and to the presence
emesis gravidarum, acute yellow atrophy MacGillivray,23 who collected plasma or absence of proteinuria. Preeclampsia
of the liver, pruritus gravidarum, and from pregnant women and then retrans- was defined as an elevated blood pres-
ptyalism.18 fused aliquots on postpartum day 6 and at sure in the third trimester with

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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
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Recent recommendations of the Amer-

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

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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- however, in the 1990s, several groups of and perinatal death is higher among
ifestations, such as visual investigators began to question whether women with severe gestational hyper-
disturbances,85e87 renal failure,88,89 proteinuria should be a necessary tension than in those with mild
congestive heart failure,63 abdominal criterion.94e97 Multiple studies reported preeclampsia.95 Additionally, approxi-
pain,90,91 and headaches.92,93. that patients with severe gestational hy- mately 50% of women with an initial
pertension had a high rate of adverse diagnosis of gestational hypertension
Preeclampsia Without Proteinuria? pregnancy outcome, despite the absence will subsequently develop proteinuria
Proteinuria has been a requirement for of proteinuria.94e96 The frequency of or end-organ damage.96,98 Two
the diagnosis of preeclampsia for de- preterm birth, SGA, placental abruption, additional arguments favored abandon-
cades, as it reflects renal involvement; neonatal respiratory distress syndrome, 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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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 TABLE 3
same time, it became known that the Rate ratios for fetal mortality by diastolic blood pressure and proteinuria
blockade of angiogenesis with vascular combination
endothelial growth factor (VEGF) an- Proteinuria
tagonists (monoclonal antibodies Diastolic pressure (mm Hg) None Trace 1D 2D 3D 4D
against VEGF) in nonpregnant patients <65 2.5 2.3 1.0 — — —
with cancer would lead to hypertension
and proteinuria.110 Encouraged by this 65e74 1.5 1.3 0.8 5.5 7.0 —
finding, the investigators pursued a sys- 75e84 1.0 a
1.3 1.0 3.2 — —
tematic series of studies that demon- 85e94 1.5 1.5 4.0 — 3.7 —
strated that overproduction of sFlt-1 in
95e104 3.2 2.8 4.5 9.3 19.2 23.8
pregnant animals recapitulated the fea-
tures of preeclampsia and renal lesions 105 3.3 4.7 10.5 11.5 20.8 18.5
associated with this condition (glomer- Modified from Friedman and Neff.26
ular endotheliosis).106,111 This informa- a
Reference rate of fetal mortality: 0.6% or 6 per 1000 births.
tion, coupled with previous observations Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
in patients with a low maternal serum
concentration of the angiogenic factor—
placental growth factor (PlGF)— unique nature of obstetrical diseases. subset of patients, and sometimes fetal
strengthened the case for a role of an These features include (1) multiple growth deceleration precedes the diag-
antiangiogenic imbalance in pre- etiologies, (2) a long subclinical phase, nosis of preeclampsia. Other subtle he-
eclampsia. The antiangiogenic factor, (3) fetal involvement, (4) the adaptive matological abnormalities such as
endoglin, is also elevated in patients with nature of clinical manifestations, thrombocytopenia and neutropenia
preeclampsia and may explain why a and (5) complex gene-environment have also been reported.125 Remarkably,
subset of patients develop HELLP syn- interactions.115e117 This section sum- some neonates born to mothers with
drome (Figure 11).112 marizes the evidence that preeclampsia preeclampsia have been noted to have
The realization that antiangiogenic has many of these features. dilatation of the right coronary artery
factors are linked to preeclampsia has and to be at risk for developing long-
improved the understanding of the Multiple etiologies term cardiovascular disease as well as
pathophysiology and has allowed clas- Preeclampsia is not one disorder but attention deficit and hyperactivity
sification according to the presence or rather different entities recognized by a disorders.125,126
absence of an abnormal antiangiogenic common phenotype. Maternal, fetal,
profile. Antiangiogenic factors meet the and placental causes of preeclampsia Clinical manifestations are adaptive
criteria to be one, if not the major, have been identified. The causative risk Hypertension can be considered an
“toxin” responsible for preeclampsia factors, or etiologies, of preeclampsia are adaptive response generated by an
and eclampsia. The scientific basis for reviewed in detail by Jung et al.118 injured placenta, which signals to the
this claim is provided in companion mother the need to maintain perfusion;
articles in this Supplement.113,114 Long subclinical phase this is accomplished by increasing
Although preeclampsia is diagnosed maternal cardiac output, by an eleva-
The syndromic nature of typically in the late second or third tion of maternal blood pressure, or, in
preeclampsia trimester, there is evidence of a patho- some cases, by a combination of both.
Obstetrical disorders, by contrast with logic process weeks or months before the That hypertension is an adaptive
diseases in the nonpregnant state, diagnosis. Some women have an response is supported by a set of clin-
develop in the context of a unique abnormal pressor response to angio- ical observations including the resolu-
biological situation—two individuals tensin II,119 an abnormal uterine artery tion of maternal hypertension
with different genomes coexisting, Doppler velocimetry measurement, or following the death of a growth-
one inside the other. The common in- abnormal angiogenic and antiangiogenic restricted fetus in a twin
terest of the mother and her fetus is profiles well before the clinical pregnancy,127e130 after SARS-CoV-2
successful reproduction; however, con- diagnosis.108,120e124 infection,131 or after transfusion to
flict can occur when the interests of the correct fetal anemia with fetal parvo-
mother and the fetus diverge, perhaps Fetal involvement virus infection.132 Notably, pharmaco-
as the result of an insult (such as an The diagnosis of the syndrome depends logic treatment of maternal
infection or a compromised blood exclusively on maternal signs. Nonethe- hypertension does not improve fetal
supply). The term “great obstetrical less, fetal involvement, typically in the outcomes. In some cases, the adaptive
syndromes” was coined to describe the form of growth restriction, is present in a responses can become maladaptive, and

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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 abnormal uterine artery Doppler implicated in postpartum preeclampsia
Severe Disease waveforms,142 atherosis,148,149 and eclampsia for decades.153 In 1960,
Preeclampsia has been classified accord- placental lesions consistent with while investigating the etiology of hy-
ing to gestational age at the time of diag- maternal vascular malperfusion,142,150 pertension in “toxemia of pregnancy,”
nosis or delivery as early onset (<34 SGA,141,142 and fetal growth restric- Hunter and Howard20 reported that the
weeks) or late onset (34 weeks). tion.142 Moreover, abnormal maternal decidua of patients with toxemia and
Although other gestational-age cutoff plasma ratios of PlGF-to-sFLT-1 or molar pregnancy produced a pressor
values have been proposed, 34 weeks re- PlGF-to-sEng are present in 80% to substance: “hysterotonin.” Although the
mains the most commonly used, likely 90% of patients with early-onset pre- molecule responsible for this pressor
because the rate of neonatal morbidities eclampsia, but in only 40% to 50% of response was never characterized,
declines considerably after this gestational patients with late-onset preeclamp- Hunter et al154 proposed that post-
age.143,144 Specifically, in women with sia.141,151,152 Early-onset preeclampsia partum curettage of the decidua could
severe preeclampsia, expectant manage- can be considered a clinical manifes- improve the condition. Indeed, curettage
ment is not considered, and induction of tation of atherosclerosis in pregnancy was reported to ameliorate hypertension
labor is recommended after 34 weeks of while late-onset disease is a metabolic in 69 patients. In one patient with post-
gestation. In addition, preeclampsia can crisis emerging from a mismatch be- partum eclampsia, convulsions did not
be classified according to its severity tween fetal demands and maternal recur after curettage (Figure 12).154
(Table 4).103,145 supply. Approximately 30 years later, Magann
Multiple lines of evidence have now et al155 reported the results of a ran-
coalesced, proposing that early and Postpartum Preeclampsia domized clinical trial of immediate
late preeclampsia are different condi- This condition has been an enigma as postpartum curettage in 32 patients with
tions (Table 5). Early-onset pre- delivery of the placenta is considered to severe preeclampsia and observed that
eclampsia is characterized by a higher be the cure of preeclampsia. Retained patients who had undergone curettage
frequency of HELLP syndrome,142,147 fragments of the placenta have been 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 to be a source of bioactive material. Why the result of the antiangiogenic factor
higher urinary output and platelet count some patients develop hypertension and sFlt-1 in a two-hit model.156 The first
(Figure 13, B) than those who did not proteinuria only after delivery remains is an increased concentration of sFlt-1
undergo a curettage. Collectively, these an unanswered question. in the maternal circulation, which can
observations suggest that material pre- Postpartum preeclampsia belongs to impair cardiac function, and the sec-
sent in the uterus after the delivery of the a group of conditions of unknown ond is a lack of local proangiogenic
placenta can still have biological prop- etiology diagnosed after delivery that defenses in the maternal heart. Peri-
erties. Although Hunter et al154 attrib- include cardiomyopathy, renal failure, partum cardiomyopathy can be exper-
uted this to the decidua, trophoblasts are uremic hemolytic syndrome, and acute imentally induced in pregnant mice by
also present in the uterus after delivery of fatty liver. Insights into the patho- the combination of increased sFlt-1
the placenta and are consistently physiology of these conditions can be (through an adenovirus vector) and
observed in histologic examinations of gleaned by recent progress made in the gene deletion of a regulator of angio-
hysterectomy specimens. Therefore, it is understanding of peripartum cardio- genesis called “peroxisome pro-
possible that trophoblasts may continue myopathy, which is now recognized as 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- preeclampsia have impaired subclinical enigmatic postpartum syndromes
larly, pregnant women with peri- renal function and proteinuria after represent the clinical manifestations of
partum cardiomyopathy have an delivery, which may persist for vascular dysfunction in the peripartum
increased concentration of sFlt-1 in the months. The antepartum sFlt-1 con- period.
postpartum period, which has been centration correlates with a lower
detected four to six weeks after de- glomerular filtration rate, and a high Vascular Dysfunction of Pregnancy:
livery (elevated sFlt-1 typically returns concentration is a risk factor for renal Unmasked, Induced, Protean
to normal range within three days of impairment at six and 12 months The most important adaptation for a
delivery).156 postpartum.159 Recent observations successful pregnancy is the establish-
A similar pathophysiological process suggest that the pathophysiology of ment and development of an adequate
can be responsible for other post- acute fatty liver of pregnancy may also blood supply to the placenta and
partum syndromes, including post- be related to an excessive concentra- conceptus. The clinical consequences of
partum renal failure. VEGF is essential tion of sFlt-1 (Figure 14).160,161 Why suboptimal perfusion range from fetal
for the maintenance of glomerular and how an excess of sFlt-1 or other growth restriction, SGA, preeclampsia,
health, and its blockade damages the antiangiogenic factors may target the abruptio placenta, and fetal death
fenestrated endothelium, causing pro- heart, kidney, liver, or brain (in some (Figure 15). A fundamental question is:
teinuria.157,158 It is now recognized cases of postpartum eclampsia) are why does maternal malperfusion lead to
that a subset of patients with unknown. We believe that several 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.

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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.

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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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16. Loudon I. Some historical aspects of tox-

FIGURE 16 aemia of pregnancy. A review. Br J Obstet
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preeclampsia 17. Stander HJ. The toxemias of pregnancy.
Baltimore: The Williams & Wilkins Company; 1929.
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tions. In: Pre-eclampsia: the hypertensive dis-
ease of pregnancy. W.B. Saunders Company;
1983:1–12.
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morrhage. Trans Edinb Obstet Soc 1914;39:
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23. Pirani BB, MacGillivray I. The effect of
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Modified from Ramlakhan et al.162 the puerperium. Am J Obstet Gynecol
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