HHS Public Access: The Etiology of Preeclampsia

HHS Public Access
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Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.
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Published in final edited form as:

Am J Obstet Gynecol. 2022 February ; 226(2 Suppl): S844–S866. doi:10.1016/j.ajog.2021.11.1356.
The etiology of preeclampsia

Eunjung JUNG, MD1,2, Roberto ROMERO, MD, DMedSci1,3,4,5,6, Lami YEO, MD1,2, Nardhy
GOMEZ-LOPEZ, PhD1,2,7, Piya CHAEMSAITHONG, MD, PhD1,2,8, Adithep JAOVISIDHA,
MD8, Offer EREZ, MD1,2,9
1Perinatology 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
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(NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI.

2Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit,
MI.
3Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI.
4Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI.
5Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI.
6Detroit Medical Center, Detroit, MI.
7Department of Biochemistry, Microbiology and Immunology, Wayne State University School of
Medicine, Detroit, MI.
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8Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol

University, Bangkok, Thailand.
9Department of Obstetrics and Gynecology, HEmek Medical Center, Afula, Israel.
Abstract
A fundamental task in medicine is the understanding of the causes of diseases. Preeclampsia
and eclampsia, an enigmatic and elusive disorder, have been labeled the “disease of theories.”
Preeclampsia is one of the “great obstetrical syndromes” in which multiple and sometimes
overlapping pathologic processes activate a common pathway composed of endothelial cell
activation, intravascular inflammation, and syncytiotrophoblast stress. This article addresses the
potential etiologies, or causal explanations, for preeclampsia. The role of uteroplacental ischemia
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is well established, based upon a solid body of clinical and experimental evidence. A causal role
for microorganisms has gained recognition through the realization that periodontal disease and
Correspondence: Roberto Romero, MD, D.Med.Sci., Perinatology Research Branch, NICHD/NIH/DHHS, Hutzel Women’s Hospital,
3990 John R, 4 Brush, Detroit, Michigan 48201, USA, Telephone: (313) 993-2700, [email protected].
Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.
Disclosure: The authors declare no conflicts of interest.
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JUNG et al. Page 2
maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with
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preeclampsia. The recent reports indicating that SARS-CoV-2 infection appears to be causally
linked to preeclampsia are reviewed as well as the mechanisms whereby this viral infection
can cause this syndrome. Particular etiological factors, such as the breakdown of maternal-fetal
immune tolerance, thought to account for the excess of preeclampsia in primipaternity and
egg donation—may operate, in part, through uteroplacental ischemia, while another, such as
placental aging, may operate largely through syncytiotrophoblast stress. This article also examines
the nature of the association between gestational diabetes mellitus and maternal obesity in
preeclampsia. The various roles of autoimmunity, fetal diseases, and endocrine disorders are also
discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve
treatment and prevention.
Condensation:
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This article describes the causal risk factors, or etiology, of preeclampsia.
Keywords
Angiotensin receptor II; atherosclerosis; autoantibodies; Ballantyne syndrome; body mass index;
COVID-19; Cushing’s syndrome; endothelial cell dysfunction; genetic incompatibility; gestational
diabetes mellitus; hydatidiform mole; hydrops fetalis; hyperaldosteronism; hyperparathyroidism;
hypertension; infection; inflammation; insulin resistance; intestinal dysbiosis; maternal anti-
fetal rejection; metabolic syndrome; mirror syndrome; molar pregnancy; obesity; placental
aging; placental ischemia; placental lesions of maternal vascular malperfusion; primipaternity;
proteinuria; SARS-CoV-2; sleep-disordered breathing; sleep disorders; snoring; tolerance
Introduction
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A fundamental task in medicine is the understanding of the causes of diseases.

Preeclampsia and eclampsia, the enigmatic, elusive disorders of pregnancy, have been
labeled the “diseases of theories”. Preeclampsia and eclampsia are among the “great
obstetrical syndromes” in which multiple and sometimes overlapping pathologic processes
activate a common pathway that leads to the clinical recognition of these disorders.
Just as the syndrome of preterm labor is recognized by the clinical manifestations
of activation of the common pathway of parturition (ie increased uterine contractility,
cervical remodeling, and membrane and decidual activation), so are preeclampsia and
eclampsia. Their common pathway consists of endothelial cell activation, intravascular
inflammation, and syncytiotrophoblast stress, and the diagnosis has traditionally rested
in the detection of hypertension and proteinuria, although professional organizations had
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recently recommended that the diagnosis can be made in the absence of proteinuria when
patients have evidence of multi-systemic involvement.
A rich body of literature describes the risk factors for preeclampsia and eclampsia (ie the
conditions that increase the likelihood of these syndromes but are not necessarily causal).
However, the elucidation of etiologic, or causal, factors is necessary to successfully treat
and prevent disease. This article reviews the evidence linking these etiologic factors with
preeclampsia and eclampsia, which is summarized in Figure 1.

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Uteroplacental ischemia
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The principal mechanism of disease implicated in the etiology of preeclampsia and

eclampsia is uteroplacental ischemia. In 1914, James Young proposed that interference of
the uterine blood supply to the placenta would lead to placental infarctions that, in turn,
would release toxins into the maternal circulation, thus causing eclampsia.1 This theory
was based on the demonstration that placental infarctions were observed in patients with
eclampsia and on animal studies that showed subcutaneous injections of extracts of the
autolyzed human placenta into guinea pigs elicited convulsions, hepatic focal necrosis, and
renal lesions, similar to those observed in women who died of eclampsia.1 Dixon and
Taylor reported that intravenous injections of extracts of fresh human placenta induced an
increase in blood pressure in cats, rabbits, and dogs, resembling the effects of adrenaline.2
Therefore, the search for the causes of preeclampsia and eclampsia and for the identity of
the circulating “toxins” began more than 100 years ago.
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Additional evidence supporting a role for uteroplacental ischemia came from studies by
Ogden, Hildebrand, and Page who reported that clamping of the abdominal aorta below the
renal arteries (to avoid renovascular hypertension) in dogs reduced uteroplacental perfusion;
furthermore, this response was followed by maternal hypertension that resolved after the
clamp was released.3 Because this hypertensive response was not observed in non-pregnant
animals, the investigators concluded that the signals responsible for hypertension must have
originated within the gravid uterus.3 Another observation buttressed this interpretation: after
removal of the pregnant uterus, the clamping of the aorta did not elicit hypertension (Figure
2).3, 4
Subsequent studies strengthened this concept, demonstrating that placental ischemia,

generated by placing silver clips in the uterine arteries of pregnant dogs, led to hypertension
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and proteinuria.5 Two lines of evidence supported the view that placental ischemia rather
than uterine ischemia was key. First, patients with an abdominal pregnancy were known to
develop preeclampsia given that the implantation site was outside of the uterus.6 Second,
the placement of a Z suture through the placenta to generate ischemia resulted in the
development of hypertension and proteinuria (Figure 3A-3C).7 Moreover, the existence of
a circulating “toxin,” supported by the observation that the administration of blood from a
rabbit with experimental placental ischemia caused by the Z suture, resulted in hypertension
in non-pregnant animals (Figure 3D).7
The first in vivo evidence indicating that women with preeclampsia had decreased maternal-
placental blood flow was reported by McClure Browne and Veall,8 who described the
injection of radioactive sodium into the choriodecidual space of women with a normal
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pregnancy and in those affected by preeclampsia. The investigators noted that the blood flow
at term was 600 mL/minute, but it was substantially lower in patients with preeclampsia.
These observations have been confirmed with different radioactive tracers in subsequent
studies.9-13 For example, Lunell et al 13 reported that uteroplacental blood flow was reduced
by 50% in patients with preeclampsia and that the reduction was greater in those with severe
preeclampsia than in those with mild disease.

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The role of placental ischemia in the pathogenesis of preeclampsia is now well established.
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Indeed, the most frequently implemented animal model of the syndrome is chronic reduction
of uteroplacental perfusion in pregnant rats, generated by the placement of a constriction
clip around the aorta below the renal arteries and before the origin of the uterine arteries at
14 days of gestation.14 In addition, this effect led to a reduction in placental blood flow by
approximately 40%, an increase in arterial blood pressure by 20-25 mm Hg by day 19 of
pregnancy, increased vascular resistance, decreased cardiac output and glomerular filtration
rate, and the frequent appearance of proteinuria.14 This model recapitulated two of the many
findings of preeclampsia: (1) an increase in circulating concentrations of soluble vascular
endothelial growth factor receptor-1 (sVEGFR-1; also known as soluble fms-like tyrosine
kinase 1 [sFlt-1]) and endoglin, and (2) a rise in the concentrations of pro-inflammatory
cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). A similar
non-human primate model of preeclampsia, developed in pregnant baboons by selective
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ligation of one uterine artery, led to the development of hypertension, proteinuria, and
increased production of sFlt-1.15 Importantly, the administration of short interfering RNAs,
which silence three of the sFlt-1 mRNA isoforms, suppressed sFlt-1 overexpression and
reduced hypertension and proteinuria.16 These studies suggest that the soluble factor, or
“toxin,” responsible for hypertension is, at least in part, sFlt-1. The reader is referred to the
review by Bakrania, George, and Granger17 in this Supplement for more details about the
model and the pathophysiologic events caused by uteroplacental ischemia.
What is the cause of placental ischemia in women with preeclampsia? The traditional
explanation has been that a defect in placentation leads to ischemia18, 19 but more recently,
a dysfunctional maternal cardiovascular system has been implicated.20 The developmental
abnormalities include failure of physiologic transformation of the spiral arteries which are
characterized by a narrow diameter and retention of the muscle in the media of the vessel
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wall.18, 19 The persistence of the muscular coat is thought to make the vessels susceptible to
the effect of vasoconstrictive agents. In addition, arteries affected by failure of physiologic
transformation are more likely to develop atherosis (Figure 4), which also narrows the vessel
lumen and further compromises placental perfusion.21-26 Atherosis is a lesion specific to the
spiral arteries, which is equivalent to the atherosclerotic lesions observed in the coronary
arteries. Figure 5 illustrates the typical lesions of atherosis in the spiral arteries and shows
lipid-laden macrophages with the deposition of fat droplets detected with oil red-O stain. A
systematic review and meta-analysis showed that placental lesions consistent with maternal
vascular malperfusion (eg placental infarction, failure of physiologic transformation of the
spiral arteries, acute atherosis) is four-fold to seven-fold higher in patients with preeclampsia
than in those with a normal pregnancy.27 A comprehensive review of the failure of
physiological transformation and spiral artery atherosis by Staff et al 28 is available as
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part of this Supplement. Atherosis is not specific to preeclampsia, and this type of lesion
has been reported in other pregnancy-related conditions, such as spontaneous abortion,29
preterm labor,30 preterm prelabor rupture of the membranes,31 fetal growth restriction,32, 33
and fetal death.25, 29 We have proposed that placental ischemia is a major mechanism of
disease in various obstetrical syndromes and that the timing, severity, and duration of the
insult may explain the clinical occurrence of different obstetrical syndromes.34

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The following evidence supports a causal link between placental ischemia and preeclampsia:
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(1) experimentally induced ischemia in several animal models leads to hypertension and
proteinuria;3, 5, 7 (2) uterine blood flow is lower in patients with preeclampsia than in
normal pregnant women;8, 11, 13 (3) placental histopathologic lesions indicative of ischemia
(often referred to as maternal vascular malperfusion) are frequent, consistent findings
in preeclampsia and eclampsia; 27 (4) the failure of physiologic transformation of the
spiral arteries and atherosis are typical features of preeclampsia;28, 35 (5) the pulsatility
index of the uterine artery (a parameter to assess resistance to flow) is higher in patients
with preeclampsia than in normal pregnant women; this finding can be observed during
the midtrimester of pregnancy, weeks or even months before the development of the
disease;36, 37 (6) the maternal plasma placental growth factor (PlGF)/sFlt-1 ratio, a non-
invasive marker of lesions of maternal vascular malperfusion, is elevated at the time of the
onset of disease and prior to the development of preeclampsia;38-44 and (7) a blockade of
sFlt-1 mRNA reduces hypertension and proteinuria.16 The frequency of placental lesions
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of maternal vascular malperfusion, of abnormalities in the uterine artery Doppler, and of

alterations of biomarkers (eg PlGF/sFlt-1) is higher in preterm preeclampsia than in term
preeclampsia, suggesting that ischemia plays a different role in early-onset versus late-onset
preeclampsia.45-48
The case for ischemia as an etiologic factor could be even more persuasive if the treatment
of ischemia could prevent the occurrence of preeclampsia. This evidence is difficult to
generate in pregnant humans. Nonetheless, it can be argued that the efficacy of aspirin in
reducing the rate of preterm preeclampsia49 is achieved through the prevention of arterial
thrombosis in the spiral arteries and intervillous space, as this is the proposed mechanism
for aspirin in the prevention of myocardial infarction in atherosclerosis.50 This interpretation
would also explain the lack of efficacy of aspirin in preventing preeclampsia at term, given
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that ischemia seems to play a lesser role.
Maternal infection
Maternal infection has been implicated in the etiology for preeclampsia and eclampsia
since the beginning of the 20th century. Albert51 proposed that the “toxins” responsible
for eclampsia were the product of putrefactive changes in the uterine cavity caused by the
action of bacteria (“a latent microbic endometritis”). Indeed, a microorganism ‘Bacillus
eclampsiae’ was proposed to be the cause.52, 53 This view progressively fell out of favor
because preeclampsia and eclampsia do not present the typical features, eg a fever, of
an infectious disease. Nonetheless, the idea that microorganisms may be involved in the
genesis of preeclampsia and eclampsia recurs in the literature every few years, and it has
reemerged recently based on the relationship between periodontal disease, urinary tract
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infection, SARS-CoV-2 infection, and maternal gut dysbiosis.
Periodontal disease—The best evidence to support a relationship between

microorganisms and preeclampsia derives from studies of periodontal disease, which
increases the risk of developing this pregnancy-related syndrome (OR 1.76; 95% confidence
interval (CI) 1.43-2.18).54 The term periodontal disease refers to an inflammatory condition
caused by immune dysfunction initiated by bacteria within the oral cavity.55 The spectrum

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of disease ranges from gingivitis (inflammation of the soft tissues only) to the destruction
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of the connective tissue attachment and alveolar bone, which can eventually lead to
tooth loss.55 Bacteria in the periodontal space can be released during dental procedures
or in the course of severe disease, leading to a systemic inflammatory response that
can cause damage and seed sites in the cardiovascular system.56 Indeed, strong evidence
indicates that periodontal disease is a risk factor for atherosclerotic cardiovascular diseases,
including atherosclerosis, coronary artery disease, stroke, and atrial fibrillation.57, 58 In brief,
such evidence denotes that 1) microorganisms found in the periodontal space can cause
bacteremia;59 2) bacteria from the oral cavity have been found in atheromatous plaques;60
and 3) periodontal infections can induce vascular lesions in the aorta and coronary
arteries.57, 61 In an animal model of hyperlipidemia, ie apolipoprotein E null mice, an oral
infection with Porphyromonas gingivalis led to plaque in the aorta (Figure 6).61 Similar
findings have been reported in an integrin β6 null mice model with polymicrobial infection
and periodontal pathogens.62 The etiologic role of periodontal disease in preeclampsia is
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predicated on the same mechanisms linking periodontal disease and atherosclerosis.
Offenbacher, Beck, Boggess, and Murtha63 have provided clinical, epidemiologic, and
experimental evidence that periodontal disease is causally linked to preeclampsia. For
example, women with periodontal disease who have an elevated C-reactive protein (CRP)
concentration are at increased risk for the development of preeclampsia compared to those
without periodontal disease (adjusted relative risk (aRR) 5.8; 95% CI 1.2–26.9).63 An
elevated CRP would indicate that periodontal disease has led to a systemic inflammatory
process, thus it provides a link between periodontal disease and preeclampsia.
Urinary tract infection—The relationship between microbial colonization of the maternal

urinary tract and preeclampsia has also been reported. A systematic review noted that
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urinary tract infections are associated with preeclampsia (OR 1.57; 95% CI 1.45-1.70).54
However, the case definitions have been broad and have included pyelonephritis,
lower urinary tract infections, and asymptomatic bacteriuria as a group.64, 65 When
subgroup analysis is performed, evidence for the association with preeclampsia either
weakens or disappears. We have doubts that asymptomatic bacteriuria, which is not
associated with a systemic inflammatory response,66 could cause preeclampsia. Isolated
cases have documented instances in which preeclampsia is associated with malaria,67-69
cytomegalovirus (CMV),70, 71 human immunodeficiency virus,72, 73 but the evidence is
insufficient to support causality.
Experimental observations supporting a causal relationship between infection and systemic

inflammation and preeclampsia indicate that intravenous low-dose endotoxin administration
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in pregnant rats on day 14 of gestation results in the development of high blood pressure,
proteinuria, low platelet count, and glomerular fibrinogen deposits.74 Bacterial endotoxin is
a method utilized to induce a systemic inflammatory response and the activation of thrombin
through the release of tissue factor. These mechanisms are implicated in the pathogenesis of
preeclampsia.
SARS-CoV-2 Infection—Early during the COVID-19 pandemic, it was recognized

that a subset of non-pregnant patients developed hypertension,75-77 proteinuria,78-81

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thrombocytopenia,82, 83 and elevated liver enzymes,84, 85 which resemble preeclampsia and

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hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. A recent
meta-analysis demonstrated that SARS-CoV-2 infection during pregnancy is associated with
a significant increase in the odds of developing preeclampsia (OR 1.58; 95% CI 1.39-1.8),
preeclampsia with severe features (OR 1.76; 95% CI 1.18-2.63), eclampsia (OR 1.97; 95%
CI 1.01-3.84), and HELLP syndrome (OR 2.01; 95% CI 1.48-2.97).86 In addition, there is a
dose-response relationship between SARS-CoV-2 infection and the subsequent development
of preeclampsia (Figure 7).87 Patients with severe COVID-19 had a 5-fold greater risk of
preeclampsia than those with asymptomatic COVID-19.87 The median interval between
maternal SARS-CoV-2 infection and the subsequent development of preeclampsia is 3.8
weeks (interquartile range, 0.29-11.5).88
One mechanism whereby SARS-CoV-2 infection can be causally linked to preeclampsia

has been proposed to involve endothelial dysfunction. Indeed, SARS-CoV-2 can infect
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endothelial cells that normally express angiotensin-converting enzyme 2 (ACE2), one of

the cell entry receptors for the virus, leading to endothelitis.89, 90 Endothelial infection
can induce the activation of thrombin, intravascular inflammation (ie a cytokine storm),
and damage of the microvasculature in target organs; this susceptibility ultimately leads
to the multi-systemic nature of the syndrome, which includes not only renal involvement
but also central nervous system dysfunction and seizures.91-93 Therefore, an infectious
process, which targets the endothelium, could lead to a syndrome similar to preeclampsia
and eclampsia (Figure 8).
Of interest, pregnant women with COVID-19 infection who developed preeclampsia-like

symptoms: their recovery from SARS-CoV-2 infection, followed by the resolution of
hypertension, occurred without the delivery of the fetus and placenta.94 It remains an
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open question whether preeclampsia, after SARS-CoV-2 infection, may or may not require
placental involvement. Serum and plasma concentrations of sFlt-1, a marker of endothelial
dysfunction, were elevated in non-pregnant subjects with COVID-19.95 This finding is
consistent with another study in pregnant women with severe COVID-19 who presented
an elevated maternal plasma concentration of sFlt-1 and a high sFlt-1/PlGF ratio.96
Genetic susceptibility may explain why some women with COVID-19 infection develop
preeclampsia but others do not.97, 98
Maternal intestinal dysbiosis—The human gut microbiota plays an important role in

host nutrition, harvesting of energy, and immune responses to potential pathogens.99-103
Normal pregnancy represents a state in which a major reorganization of energy distribution
(harvesting, storage, and expenditure) is related to the need to support the growth and
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development of the fetus and placenta. Remodeling of the gut microbiota during normal
human pregnancy, reported for the third trimester of pregnancy, indicated an overall increase
in Proteobacteria and Actinobacteria and a reduction in microbial richness.104 When the
intestinal content from normal pregnant women in the third trimester was administered to
germ-free mice, it increased adiposity and insulin resistance,105 which have been attributed
to the proinflammatory effects of the gut microbiota.104

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Gut dysbiosis, or an imbalance among the human gut’s microbial communities, is now
implicated in the development of atherosclerosis,106, 107 hypertension,108, 109 proteinuria,110
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cardiometabolic syndrome,111, 112 and recently, preeclampsia.113-117 A causal link between

gut dysbiosis and cardiovascular disease has been derived from an observation that the
transplant of fecal material from hypertensive, non-pregnant, human subjects to germ-free
mice led to hypertension.108 Similarly, fecal transplants from mice prone to atherosclerosis
can transmit the condition to susceptible mice (eg apolipoprotein E null mice).118 This effect
has been attributed, at least in part, to trimethylamine-N-oxide (TMAO), a bacteria-derived
metabolite from choline and carnitine that is present in gut dysbiosis and has been shown to
accelerate the development of atherosclerosis.107, 118
Changes in the human gut microbiota have been reported in preeclampsia,114, 115, 117, 119
which persist 6 weeks postpartum.120 The changes include a reduction in microbial
burden with Firmicutes, Clostridia, Clostridiales, and Ruminococcus and an increase
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in Bacteroidetes, Proteobacteria, Actinobacteria, Bacteroidia, Gammaproteobacteria, and

Enterobacteriaceae (Figure 9A).119 Moreover, the study provides evidence to support
causality: fecal transplants from pregnant women with preeclampsia into mice led to the
development of the syndrome.115 The experimental paradigm required the administration of
fecal material from pregnant women with and without preeclampsia to non-pregnant mice
that had received antibiotics for 5 days (to change gut flora); the mice were housed in
pathogen-free facilities.115 Six weeks after the first fecal inoculation, mice were mated.115
Pregnant mice that had received the fecal microbiota transplantation from mothers with
preeclampsia developed high systolic blood pressure and proteinuria, and they delivered
less live pups than mice that receive fecal microbiota transplantation from women with
normotensive pregnancy (Figure 9B).115 Collectively, this evidence suggests a role for
gut dysbiosis in preeclampsia. However, further investigation into the precise mechanisms
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that may explain this phenomenon as well as the susceptibility of some pregnant women
compared to others is necessary.
Gestational diabetes mellitus, maternal obesity, and the metabolic syndrome

Gestational diabetes mellitus—Gestational diabetes mellitus is an independent risk
factor for preeclampsia, after adjusting for confounders.121, 122 In a retrospective study of
647,392 pregnancies, women with gestational diabetes had an increased risk of preeclampsia
(adjusted odds ratio (aOR) 1.29; 95% CI 1.19-1.41).121 Preexisting diabetes mellitus had
also been linked to the development of preeclampsia: a systematic review reported that
diabetes mellitus prior to pregnancy was associated with an increased risk of preeclampsia
(aRR 3.56; 95% CI 2.54-4.99).123 Diabetes mellitus is considered to be strongly associated
with late-onset rather than early-onset preeclampsia (early onset: aOR 1.87, 95% CI
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1.6-2.18; late onset: aOR 2.46, 95% CI 2.32-2.61).124 The Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) Study Cooperative Research Group reported a significant
positive association between the degree of maternal hyperglycemia and preeclampsia: the
odds ratio for each 1-SD increase in glucose concentrations (fasting, one hour, and two
hours after a 75mg glucose tolerance test) ranged from 1.21 to 1.28.125

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A causal role was strengthened by the observation that the treatment of gestational diabetes
mellitus with diet,126 insulin,127, 128 and metformin129-132 reduces the risk of preeclampsia.
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Two randomized clinical trials have shown that the treatment of gestational diabetes mellitus
with insulin reduces the risk of preeclampsia (adjusted treatment effect: 0.70; 95% CI
0.51-0.95).127, 128 Metformin is associated with a reduced risk of preeclampsia (RR 0.68;
95% CI 0.48–0.95)131 and prolongation of gestation in women with preterm preeclampsia
(median, 18 days).133 Prenatal exercise has also been reported to decrease the rate of
gestational diabetes mellitus by 38% and preeclampsia by 41% based on the results of a
systematic review and meta-analysis.134
Collectively, the evidence suggests a causal relationship between gestational diabetes

mellitus and preeclampsia given the consistency of association, its magnitude, the temporal
relationship, and the efficacy of interventions, such as insulin and metformin, in reducing the
rate of preeclampsia.
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Maternal obesity—Obesity, defined by a body mass index (BMI) of 30.0 kg/m2 or more,
is strongly associated with preeclampsia.135-137 A meta-analysis of 29 prospective cohort
studies (1,980,761 participants and 67,075 cases of preeclampsia) showed that maternal
obesity was significantly associated with the development of preeclampsia (aOR 2.93; 95%
CI 2.58-3.33), and the risk was even higher in severe obesity (BMI ≥ 35 kg/m2; aOR 4.14;
95% CI 3.61-4.75).138 A similar finding was reported overweight women (BMI: 26.1-29.0
kg/m2) who had an increased risk of preeclampsia in comparison to women with a normal
BMI (RR 1.57; 95% CI 1.49-1.64).139
Moreover, a dose-dependent relationship was found between pre-pregnancy BMI and the
risk of preeclampsia in both nulliparous and parous women in a large epidemiological
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study (41,000 nulliparous and 29,000 multiparous) (Figures 10).140 Data from the USA
Collaborative Perinatal Project indicated similar results for Caucasian and for African-
American women (severe preeclampsia: African American, OR 3.2, 95% CI 2.5-5.0;
Caucasian, OR 3.4, 95% CI 2.1-5.6).141 Most studies considered that obesity predisposes
mainly to late-onset preeclampsia.123, 141 However, a recent population-based study, which
used US vital statistics data and included 15.8 million women (48,007 cases of early-onset
disease and 777,715 cases of late-onset disease), demonstrated that maternal obesity is
associated with an increased risk of both early-onset and late-onset disease (eg BMI 40
kg/m2 or greater: early-onset disease, aRR 2.18, 95% CI 2.12–2.24; late-onset disease: aRR
3.93, 95% CI 3.91–3.96).142 In addition, preconceptional maternal weight loss, either with
lifestyle modification or by bariatric surgery, was shown to be effective in reducing the risk
of preeclampsia (OR 0.67; 95% CI 0.51-0.88).143
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Metabolic syndrome—The term “metabolic syndrome” refers to a cluster of

metabolic abnormalities that includes central obesity, insulin resistance, atherogenic
dyslipidemia, and hypertension.144, 145 This syndrome is strongly associated with systemic
inflammation, oxidative stress, and endothelial dysfunction, all of which are features of
preeclampsia.146-149 A retrospective cohort study of 212,463 women showed that the
presence of pre-pregnancy metabolic syndrome was associated with an increased risk of
preeclampsia (aOR 1.48; 95% CI 1.26-1.74).150 Preeclampsia is also a risk factor for the

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subsequent development of metabolic syndrome after delivery.151-154 Moreover, bariatric

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surgery performed before pregnancy as a treatment for metabolic syndrome was associated
with a lower rate of preeclampsia or eclampsia (aOR 0.2; 95% CI 0.09-0.44).155
The mechanisms whereby insulin resistance predisposes to the development of preeclampsia

are related to intravascular inflammation and endothelial cell dysfunction,156, 157 which is
the common pathway of the syndrome. Nonetheless, insulin resistance is neither required
nor sufficient for the development of preeclampsia. The reason why some, but not other,
patients with insulin resistance develop preeclampsia is unknown.
Sleep disorders
Sleep-disordered breathing, a term encompassing obstructive sleep apnea, snoring, periodic
episodes of hypoxia, central apnea, and sleep hypopnea, during pregnancy is a risk factor
of preeclampsia. A systematic review and meta-analysis of 120 studies, which included
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a total of 58,123,250 pregnant women, indicated that maternal sleep disturbances during
pregnancy were associated with an increased risk of preeclampsia (OR 2.80; 95% CI
2.38-3.30);158 these disturbances included subjective sleep-disordered breathing (OR 3.52;
95% CI 2.58-4.79), obstructive sleep apnea (OR 2.36; 95% CI 2.00-2.79), and the restless
legs syndrome (OR 1.83; 95% CI 1.04-3.21).158
Snoring is defined as the vibration of respiratory structures resulting from turbulent

flow when the upper airway narrows during sleep.159 It is more common in pregnant
women than in non-pregnant women (14%-23% vs 4%)160, 161 and increases the risk of
hypertension,162 and new-onset snoring during pregnancy is associated with preeclampsia
(OR 1.59; 95% CI 1.06-2.37).163 Evidence supporting a causal relationship between snoring
and preeclampsia indicated that treatment with nasal continuous positive airway pressure
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(CPAP) improved blood pressure in women with preeclampsia.164, 165 Edwards et al164
reported that autosetting nasal CPAP administered through sleep resulted in a marked
reduction in blood pressure (before treatment: mean systolic 146 mm Hg and mean diastolic
92 mm Hg; after treatment: mean systolic 128 mm Hg and mean diastolic 73 mm Hg).
Recently, Bourjeily et al166 reported that pregnant women with obstructive sleep apnea
presented a higher maternal plasma sFlt-1/PlGF concentration ratio than those in a control
group and that maternal sFlt-1 concentrations were decreased after CPAP treatment.167
In normal pregnancy, blood pressure has a circadian rhythm and is at its highest during
the daytime. A reversed diurnal blood-pressure rhythm (ie the nocturnal blood pressure
was higher than the diurnal blood pressure) has been reported in preeclampsia.168, 169
Sleep architecture, using polysomnography, has shown that patients with preeclampsia
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had altered sleeping patterns,170 specifically spending more time in slow-wave sleep, in
comparison to those with a normal pregnancy (43 ± 3 vs 21 ± 2; p < 0.001).170 One possible
explanation for this finding is that cytokines, such as IL-1 and TNF-α, can increase the
amount of slow-wave sleep,170 as they are elevated in the maternal circulation of those
with preeclampsia.171-173 Collectively, the proposed mechanisms linking sleep disorders and
preeclampsia involve intravascular inflammation and endothelial cell dysfunction.

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Molar pregnancy
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A hydatidiform mole, a gestational trophoblastic disease characterized by abnormal

proliferation of trophoblast and hydropic changes of the chorionic villi, is associated with
preeclampsia174 and sometimes presents before 20 weeks of gestation.175-178 The frequency
of preeclampsia in patients with a hydatidiform mole ranges from 27% to 40% and is
probably higher in patients who are left untreated until the second trimester.175-178
The mechanism whereby a complete hydatidiform mole causes preeclampsia involves

the excess production of sFlt-1. Maternal serum sFlt-1 concentrations were 2-fold to
3-fold higher in patients with a hydatidiform mole than in those with a gestational age-
matched control;179 an increased expression of sFlt-1 within the molar tissue has also been
reported.180 Moreover, placentas with a hydatidiform mole had an increased expression of
LIGHT (TNFSF14, or TNF superfamily member 14), which was co-localized with sFlt-1
in the molar tissue.181 Chorionic villi in the molar tissue are edematous or hydropic, which
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are often avascular or display markedly reduced vessel density.175 These villus capillary
changes may lead to excessive production of sFlt-1 that enters maternal circulation and,
consequently, to the development of the preeclampsia syndrome.
Fetal diseases
Specific fetal diseases associated with the development of preeclampsia include 1)
Ballantyne or mirror syndrome;225, 226 2) Trisomy 13 or triploidy;227, 228 and 3) a unique
complication of multiple gestations (eg twin-to-twin transfusion syndrome or selective
fetal growth restriction).229 Ballantyne or mirror syndrome reflects the simultaneously
edematous state of the mother, fetus, and placenta (also called triple edema).230, 231
This syndrome has been observed in fetal hydrops caused by rhesus isoimmunization,230
CMV,232 or parvovirus 19 infections,233 Ebstein’s anomaly,234 aneurysms of the vein
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of Galen,235 fetal supraventricular tachycardia,236, 237 and placental chorioangioma.238

In mirror syndrome, the mother may develop proteinuria, hypertension, and even severe
preeclampsia.225, 226, 234, 239 The frequency of hypertension in patients with mirror
syndrome is about 60%.225, 226, 234, 239 The reversal of preeclampsia and Ballantyne
syndrome can occur after intrauterine transfusion in parvovirus-induced hydrops without
delivery.240 All patients with mirror syndrome presented an increased maternal plasma
concentration of sFlt-1 (above the 95th percentile for gestational age).241 In addition, it
has been shown that the maternal sFlt-1 concentration returns to normal after intrauterine
transfusion.242, 243
Another example of preeclampsia with fetal disease is Trisomy 13 or triploidy.227, 228, 244 A
case control study of 25 cases with Trisomy 13 showed that the incidence of preeclampsia
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was significantly higher than detected in the normal karyotype control (44% vs 8%,
p=0.001).245 Women with a Trisomy 13 pregnancy have a higher serum concentration of
sFlt-1/PlGF ratio,246 and the placentas had an increased staining for sFlt-1 when compared
to euploid as well as Trisomy 21.247 Interestingly, sFlt-1 is located on chromosome 13,
suggesting the possibility that an extra copy of chromosome 13 may lead to increased
production of sFlt-1.244, 247

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Multiple gestations with twin-to-twin transfusion syndrome or selective fetal growth

restriction can also predispose to the development of preeclampsia.229 Resolution
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of hypertension and proteinuria generally occur after the selective termination of

pregnancy248-251 or after the fetal death of one twin.252 An improvement in angiogenic
and anti-antiangiogenic profiles has also been demonstrated after selective termination or
fetal demise of one twin.253, 254 Collectively, these observations indicate that preeclampsia
can resolve without delivery and suggest that fetal compromise may induce the syndrome in
some cases.
Autoimmune mechanisms: a role for antibodies against angiotensin II type I receptor

Preeclampsia is not traditionally considered an autoimmune disorder. However, a role
for autoimmune mechanisms of disease has been investigated for several decades, given
that patients with a systemic autoimmune disease, such as systemic lupus erythematosus
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(SLE) or antiphospholipid syndrome (APS), were at an increased risk for preeclampsia

(SLE: RR 1.91, 95% CI 1.44-2.53; APS: RR 1.81, 95% CI 1.33-2.45).255-258 Similarly,
several studies have shown that some specific autoantibodies, such as anti-β2 glycoprotein-I
(ab2GPI), anti-cardiolipin antibodies (aCL), or lupus anti-coagulant (LA), are associated
with preeclampsia.256, 259 However, the most compelling case for a role of an autoimmune
mechanism is exemplified by antibodies against the angiotensin II receptor.
Nearly two decades ago, Wallukat et al260 reported that women with preeclampsia
had antibodies that bind to the angiotensin II type I receptor (AT1-AA). Subsequently,
substantial evidence has accumulated that supports a role for AT1-AA in the pathogenesis
of preeclampsia. Such evidence comprises the following findings: 1) 80% of women with
preeclampsia have increased concentrations of AT1-AA in maternal serum at the time of
diagnosis;261 2) the concentration of AT1-AA in maternal serum correlates with the severity
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of hypertension and proteinuria;262 and 3) the administration of AT1-AA (either produced

endogenously in response to transgenic expression of human renin and angiotensinogen,
or administered by an injection of purified AT1-AA from women with preeclampsia) to
pregnant rats led to hypertension, proteinuria, glomerular capillary endotheliosis,263 and the
increased production of sFlt-1 as well as soluble endoglin,264 which can be attenuated by
the administration of an AT1-receptor blocker (Losartan). However, one longitudinal study,
conducted to determine whether the concentration of AT1-AA is increased before the onset
of preeclampsia, did not produce such a result.265
What causes the production of AT1-AA? Placental ischemia after a reduction in uterine
perfusion pressure has been shown to increase the concentration of serum AT1-AA.266 Also,
the inhibition of AT1-AA by the administration of an epitope-binding peptide (‘n7AAc’)
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can reduce maternal blood pressure and plasma concentrations of endothelin-1, sFlt-1,
and isoprostanes, a marker of oxidative stress.267 Moreover, the administration of the
inflammatory mediators TNF-α,266, 268 IL-6,268, 269 and IL-17270 to pregnant rats can
induce preeclampsia and enhance AT1-AA activity, which is abrogated by an AT1-AA
blockade.267

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Placental Aging
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Cells and organisms have a finite lifespan. Human cells in culture can multiply (mitosis)
a limited number of times (Hayflick limit) before they stop dividing and, subsequently,
undergo programmed cell death, or apoptosis.271 The placenta is also thought to have a pre-
specified lifetime, and as age advances, the functional capacity of placental cells declines.
Placental aging has been described for several decades,272, 273 and premature aging has been
implicated as a mechanism of disease for obstetric outcomes, eg preeclampsia,274, 275 fetal
growth restriction,274, 276 fetal death,277 and preterm labor.278
Cytotrophoblasts are replicating cells, but the syncytiotrophoblast is generated by fusion

and, therefore, is in a state of senescence (ie defined as the inability to multiply). Evidence
supporting the concept that senescence is present in the normal syncytiotrophoblast
includes the following findings: 1) high lysosomal activity indicated by staining with
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beta-galactosidase; 2) increased expression of cyclin-dependent kinase, p53, p21, p16; and

3) the presence of syncytial knots, proposed to be equivalent to senescence-associated
heterochromatic foci, which are clusters of chromatin in the nucleus of senescent
cells.279-281 Cindrova-Davies et al 280 demonstrated that markers of senescence increase
in normal placentas as a function of advancing gestational age.
Placentas of patients with preeclampsia exhibit greater expression of p53, p21, and p16,
shorter telomeres,274 and reduced telomerase activity.282, 283 Redman et al 279 proposed
that with advancing gestational age some patients develop a “twilight placenta,” a condition
in which the organ is affected by senescence. When placental growth reaches its limits
at term, terminal villi become overcrowded with diminished intervillous pore size, leading
to respiratory failure of the placenta (Figure 12) and contributing to intervillous hypoxia
and syncytiotrophoblast stress.284-286 A twilight placenta has been invoked as a potential
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cause for late pregnancy problems such as late-onset preeclampsia,46, 287 unexplained term
stillbirth, or fetal death in prolonged pregnancy.277, 283, 288 At present, there is not an easy
or practical way to determine placental age; however, recent studies have identified an
epigenetic clock for placental dating,289 which may be used to examine the role of placental
aging in pregnancy complications in the future.
Breakdown of maternal-fetal immune tolerance

Viviparity involves the temporal coexistence of two individuals (mother and fetus) with
different genetic makeup. The placenta and fetus together are viewed as the most successful
semi-allograft (with maternal and paternal contributions), and the mechanisms responsible
for the immune tolerance have been the subject of investigation for decades.182-187
Two typical features of the adaptive immune system are memory and specificity.188-190
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A role for the immune system has been proposed because preeclampsia is more
common in primigravidas than in parous women and in multigravidas with different
fathers (primipaternity) than in subsequent pregnancies with the same father.191, 192
The predilection for primigravidas has been attributed to a memory-like phenomenon
that protects mothers against paternal antigens in subsequent pregnancies.193 The higher
frequency of preeclampsia in multigravidas whose pregnancy is from a different father
supports the concept that the immune phenomenon is specific to paternally derived

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antigens.194, 195 Moreover, this syndrome is more common in pregnancies that occur from
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an egg donation in which the placenta and fetus represent a full allograft rather than a
semi-allograft.196
The placenta and fetus express both paternal and maternal antigens; they are a
semiallograft.197-199 The syncytiotrophoblast is in direct contact with maternal blood and
the decidua, thus the maternal immune system is exposed to paternal antigens expressed
by the fetus.182 Immune tolerance is a requirement for a successful pregnancy,185, 200, 201
and a breakdown of tolerance leads to maternal anti-fetal rejection, placental damage, and
pregnancy complications that may include preeclampsia. Placental lesions, which represent
manifestations of maternal anti-fetal rejection, are villitis of unknown etiology,202-205
massive perivillous fibrin deposition,206, 207 chronic chorioamnionitis,208-210 and chronic
deciduitis of the placental basal plate.209 The frequency of chronic villitis is higher in
preeclampsia than in normal pregnancy (25% vs 17%).203, 211 Massive perivillous fibrin
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deposition was present in 20% of patients with preeclampsia.212
Maternal-fetal genetic incompatibility has been implicated in preeclampsia. Placentation is

regulated by interactions between members of the killer cell immunoglobulin-like receptors
(KIRs) expressed by decidual natural killer (dNK) cells and trophoblast human leukocyte
antigen-C (HLA-C) molecules (Figure 11).213-216 Extravillous trophoblasts are specialized
fetal cells that invade the decidua basalis, where they come into direct contact with
maternal immune cells, eg dNK cells, macrophages, T cells, B cells, and dendritic cells.217
Extravillous trophoblasts do not express major T-cell ligands such as HLA-A and HLA-B
molecules. Instead, these fetal cells express HLA-C, HLA-E, and HLA-G.218 The latter two
are largely monomorphic, while HLA-C is polymorphic, and therefore will vary according
to the genetic makeup of the father.219 On the other hand, the dNK cells express the
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receptors for HLA-C proteins; these receptors are called KIRs.220 Both maternal KIR and
fetal HLA-C genes are highly polymorphic, and the interaction between HLA-C and KIR
has a unique role in placentation through the facilitation of trophoblast invasion of the
decidua and the physiologic transformation of the spiral artery. The molecular machinery
implicated in this process involves chemokines (CXCL-10 and CXCL8, or IL-8) that can
attract trophoblasts expressing their receptors (CXCR3 and CXCR1), metalloproteinases,
and growth factors, including the angiogenic factors (PlGF, VEGF, etc.).221, 222 Moffett
et al 213-215 has shown that normal pregnancy is more common when a mother has
the KIR BB genotype and the fetus has HLA-C1 genes, whereas preeclampsia is more
frequent when a mother has the KIR AA genotype with additional fetal HLA-C2 genes
(HLA-C2 vs HLA-C1 in KIR AA mothers: 45% vs 20%; OR 2.38; 95% CI 1.45-3.90). By
contrast, Staff et al 223 reported that fetal HLA-C2 combined with maternal KIR-BB was
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associated with placental lesions of acute atherosis. Patients with preeclampsia and acute
atherosis presented this specific genetic combination in 60% of cases.223 The mechanisms
whereby a breakdown of maternal-fetal immune tolerance leads to preeclampsia appear to
involve defective placentation, an example of the convergence of an immune disorder with
uteroplacental ischemia. Such can be the case for other etiologic factors in preeclampsia. For
further details of immunological mechanisms of preeclampsia, the reader is referred to the
review article by Robillard et al 224 in this Supplement.

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Endocrine disorders
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An association among several endocrine disorders and preeclampsia has been

reported,290-297 yet the evidence for causality is the weakest among those reviewed in
this article. Two explanations are plausible: the low frequency of endocrine disorders in
pregnancy and the paucity of experimental evidence from animal studies of endocrine
disorders. These investigations have not focused on the effect of such disorders in the
development of preeclampsia. Hence, this section will review the evidence of an association
and the proposed mechanism for activation of the common pathway.
Hyperparathyroidism—Normal pregnancy is characterized by changes in maternal

calcium hemostasis, which are thought to occur to meet fetal demands. By term, the fetus
has 30g of calcium, 20g of phosphorus, and 0.8g of magnesium, and 80% of calcium is
deposited during the third trimester.298 The evidence that links altered calcium hemostasis
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to preeclampsia is as follows: 1) hypocalcemia is a risk factor for preeclampsia (OR 7.63;

95% CI 1.64-35.37);290 2) low vitamin D concentration in early pregnancy is associated
with a 5-fold increased risk for preeclampsia;299 3) hyperparathyroidism is commonly
found in pregnant women with low calcium and vitamin D;300, 301 4) patients diagnosed
with parathyroid adenoma are at an increased risk for preeclampsia (OR 6.89; 95% CI
2.30-20.58);291 5) the absence of a vitamin D prophylaxis in the mother’s childhood is
associated with a subsequent higher risk of preeclampsia;302 and 6) the administration of
vitamin D combined with calcium or a multivitamin supplement has been shown to reduce
blood pressure and the frequency of preeclampsia in a randomized trial.303, 304 The proposed
mechanisms whereby primary hyperparathyroidism leads to preeclampsia are thought to
involve endothelial cell damage, increased insulin resistance, left ventricular hypertrophy,
and dyslipidemia.305, 306
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Cushing’s syndrome, aldosteronism, pheochromocytoma, and paraganglioma

—Cushing’s syndrome is associated with an increased risk of preeclampsia (aOR 2.20;
95% CI 1.18–4.41).292, 293 In non-pregnant subjects, the chronic glucocorticoid excess
of Cushing’s syndrome is commonly associated with an increased cardiometabolic risk
through an increase in pro-inflammatory adipokine production, alteration of coagulation and
thrombosis factor, platelet function, and endothelial activation.307-309
Primary aldosteronism is the most common form of endocrine hypertension, and it can be
caused by aldosterone-producing adenoma or bilateral adrenal hyperplasia.310, 311 Increased
aldosterone secretion suppresses renin activity, leading to hypertension, hypokalemia,
and hypernatremia.312, 313 Twenty-five percent of women with this disorder develop
preeclampsia.294, 295
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Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors, with

a reported frequency of 1/54,000 pregnancies.314 An excess of catecholamine released
by these tumors can elicit signs or symptoms similar to preeclampsia (eg hypertension,
headache, and proteinuria), making the diagnosis of pheochromocytoma during pregnancy
difficult.314, 315 A recent meta-analysis that included 204 pregnant patients with
pheochromocytoma paraganglioma showed that 20% of patients are initially misdiagnosed

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as preeclampsia.316 Maternal and fetal mortality are as high as 28% and 27%, respectively,
when there is a delay in diagnosis and treatment.316, 317 Only a few studies have reported
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that patients with pheochromocytoma developed superimposed preeclampsia;296, 297

therefore, the existence of such a relationship is not clear yet.316
Conclusion
Multiple and sometimes overlapping insults can induce an adaptive homeostatic vascular
response in pregnancy, which can be recognized clinically by the presence of hypertension
and proteinuria (or other signs of multi-systemic involvement). When this response becomes
maladaptive, it can cause target organ damage and becomes potentially life-threatening
to the mother and fetus. This article has reviewed the etiological factors responsible for
preeclampsia and eclampsia.
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At present, the classification of the syndrome is largely based on the gestational age at
the time of diagnosis (early-onset vs late-onset preeclampsia). Early-onset preeclampsia is
associated with defective placentation, while late-onset preeclampsia appears to be related
to the mismatch between maternal perfusion and feto-placental demands, together with a
maternal predisposition to cardiovascular disease. However, it is necessary to identify the
fundamental causes of the vascular dysfunction responsible for preeclampsia and to develop
comprehensive predictive models and preventive interventions. This review highlights the
multiple etiologies of the syndrome of preeclampsia. We propose that multiple etiologic
factors converge to cause endothelial cell dysfunction, intravascular inflammation, and
syncytiotrophoblast stress. The recognition that a viral infection as a result of SARS-CoV-2
infection can induce preeclampsia brings challenging questions of whether preeclampsia is
a pregnancy-specific disorder caused by the placenta and cured only by delivery. Further
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research is required to assess the relative contribution of each cause and the effect of
interventions to prevent this syndrome. A greater understanding of the differences in the
etiology of each subtype of preeclampsia and the pathophysiology of other great obstetrical
syndromes are required in order to improve the understanding of this elusive disease.
Funding:
This research 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, U.S. Department of Health and Human Services (NICHD/NIH/
DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C.
This research was also supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child
Health (NG-L).
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Figure 1.
Multiple etiologies implicated in preeclampsia. Uteroplacental ischemia, maternal infection
and inflammation (eg periodontal disease, urinary tract infection, COVID-19), maternal
intestinal dysbiosis, maternal obesity, sleep disorders, hydatidiform mole, fetal diseases (eg
hydrops fetalis, viral infection, Trisomy 13, and unique complications of multiple gestation),
autoimmune disorders, placental aging, breakdown of maternal-fetal immune tolerance, and
endocrine disorders (eg hyperparathyroidism, Cushing’s syndrome, hyperaldosteronism).
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Figure 2.
A diagrammatic depiction of experiments demonstrating that uterine ischemia in pregnant
animals, but not in non-pregnant animals, can cause hypertension. A. In the Goldblatt
model of renovascular hypertension, clamping the renal artery leads to development of
hypertension through renal ischemia and the release of renin in non-pregnant animals.
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B. By contrast, clamping the aorta below the renal arteries does not induce hypertension
in non-pregnant animals. C. Clamping of the aorta in pregnant animals below the renal
arteries leads to hypertension. D. The hypertension disappears after a hysterectomy has
been performed; this suggests that the source of the signals leading to maternal systemic
hypertension are derived from the gravid uterus. Modified from Chaiworapongsa T. et al.
Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol. 2014
Aug; 10 (8):466-80.
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JUNG et al. Page 34
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Figure 3.
Experimental demonstration that placental ischemia causes maternal hypertension and that a
soluble factor in the blood of an animal with placental ischemia can induce hypertension in a
non-pregnant animal. A. The Z suture is placed in the uterus to generate placental ischemia.
B. Placental ischemia causes hypertension. Rabbit A had undergone a bilateral nephrectomy;
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therefore, the kidney is not a cause of the hypertension. After Z sutures were placed through
several placentas, hypertension developed. C. Gross evidence that the suture has caused
a placental infarction. The pale portion of the placenta with the arrow represents a large
infarction. A control placenta of the same animal is illustrated on the right. D. Transfusions
of blood from Rabbit A (a pregnant rabbit with placental ischemia) to a non-pregnant
rabbit (Rabbit B) caused hypertension; this suggests that a circulating factor generated after
placental ischemia is present in the maternal blood and that it can induce hypertension in a
non-pregnant rabbit. Modified from Berger M. and Cavanagh D. Toxemia of pregnancy: The
hypertensive effect of acute experimental placental ischemia. Am J Obstet Gynecol. 1963
Oct 1;87:293-305.
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Figure 4.
A. Diagram of maternal blood supply to the placenta. The spiral arteries undergo
physiologic changes in normal pregnancy (grey). In preeclampsia, the myometrial segment
of the spiral artery fails to undergo physiological transformation (blue), which is thought to
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explain the uteroplacental ischemia observed in preeclampsia. Moreover, non-transformed

spiral arteries are prone to atherosis (yellow), characterized by the presence of lipid-laden
macrophages within the lumen. Placental basal plate spiral arteries with hematoxylin-eosin
stain (B, C, and D). B. Transformed spiral arteries are characterized by the presence of
intramural trophoblasts (arrowheads) and fibrinoid degeneration (arrows) of the arterial wall.
C. Non-transformed spiral arteries lack intramural trophoblasts and fibrinoid degeneration,
and they retain smooth muscle. Arrowheads indicate the presence of trophoblasts in

JUNG et al. Page 36
myometrium, but not in the wall of the spiral artery. D. Acute atherosis in decidual spiral
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artery. Many lipid-laden macrophages (arrows) are seen in the spiral artery with the lack
of invasion of the trophoblast (arrowhead) into myometrial segment of the spiral artery.
Images (B, C, and D) stained with cytokeratin 7 (brown) and periodic acid–Schiff (pink),
original magnification ×200. Immunohistochemistry of placental basal plate spiral arteries
(E, F, and G). E. Presence of endothelium (arrow, blue) in vessels with normal trophoblastic
invasion, original magnification × 640. F. spiral artery with presence of endothelium
(blue, arrowhead) and smooth muscle cells (green, arrow), original magnification ×640.
G. Atherosis lesions show the presence of numerous macrophages CD36-reactive (red
reactivity, blue arrow) and smooth muscle cells in the vessel wall (green reactivity, yellow
arrow), original magnification x400. *lumen of spiral artery. Modified from McMaster-Fay
RA. Uteroplacental vascular syndromes: theories, hypotheses and controversies. Clin Obstet
Gynecol Reprod Med 2018;4:1–5. Espinoza J et al. Normal and abnormal transformation
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of the spiral arteries during pregnancy. J Perinat Med. 2006;34(6):447-58. Labarrere CA et

al. Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell
activation, and acute atherosis in the basal plate of the placenta. Am J Obstet Gynecol. 2017
Mar;216(3):287.e1-287.e16.
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Figure 5.
Acute atherosis on oil-red O staining. Fat droplets (arrows) in the non-transformed spiral
artery are stained red. *Lumen of spiral artery. Cover, Am J Obstet Gynecol. November
2014 Yeon Mee Kim, Roberto Romero.
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JUNG et al. Page 38
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Figure 6.
Periodontal diseases and association with atherosclerotic disease. A. Bacteria found in the
periodontal space can enter the bloodstream (bacteremia) and eventually the heart, resulting
in atherosclerotic plaque in the heart blood vessels. Compared with uninfected control
(B), periodontal infection with Porphyromonas gingivalis causes atherosclerotic aortic arch
plaques (C, arrow) in apoE-null mice. Scale bar =1 mm. Oil red O staining of cryosections
at the aortic sinus shows few small fatty streaks (control, D), whereas atherosclerotic lesions
were greater in number and size (arrow) in infected animals (E). Scale bar=50 μm. Modified
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from Hajishengallis G et al. Local and systemic mechanisms linking periodontal disease
and inflammatory comorbidities. Nat Rev Immunol. 2021 Jul;21(7):426-440 and Lalla
E. et al, Oral infection with a periodontal pathogen accelerates early atherosclerosis in
apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1405-11.
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JUNG et al. Page 39
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Figure 7.
Association between SARS-CoV-2 infection severity and subsequent development of
preeclampsia. The most severe COVID-19, the greater the risk of preeclampsia.
Modified from Lai J et al. SARS-COV-2 and the subsequent development of preeclampsia
and preterm birth: evidence of a dose response relationship supporting causality. Am J
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Obstet Gynecol. 2021 Aug 26:S0002-9378(21)00947-9.

JUNG et al. Page 40
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Figure 8.
Placental syncytiotrophoblast stress induces excessive sFlt-1 into the maternal circulation.
sFlt-1 binds to free PlGF or VEGF (proangiogenic factors) with high affinity, thus
preventing their interaction with their cell-surface receptors (i.e. VEGR-1) on the endothelial
cells, leading to endothelial dysfunction. SARS-CoV-2 also targets the endothelium which
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normally express angiotensin-converting-enzyme 2 (ACE-2), one of the cell entry receptors

for the virus, leading to endothelitis, which induces intravascular inflammation (i.e. cytokine
storm) and endothelial dysfunction.
ACE2; angiotensin-converting enzyme 2, COVID-19; Coronavirus disease 2019, SARS-
CoV-2; severe acute respiratory syndrome coronavirus 2, sFlt-1; Soluble Fms-Like Tyrosine
Kinase-1, VEGFR-1; vascular endothelial growth factor receptor-1

JUNG et al. Page 41
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Figure 9.
(A) Gut microbiota in patients with preeclampsia (red) and those with normal pregnancy
(blue). The significantly different genera (Firmicutes, Bacteroidetes, Proteobacterias, and
Actinobacteria) at the phylum level in the two groups. The boxes represent the interquartile
range (IQR) between first and third quartiles and the line inside represents the median.
*p < 0.05. (B) Maternal intestinal dysbiosis and preeclampsia. Mice that received fecal
microbiota from patients with preeclampsia (red) had higher systolic blood pressure than
mice that received fecal microbiota from normotensive pregnant women (blue) or those
that received the phosphate-buffered saline (control, grey). Modified from Wang J et al.
Gut Microbiota Dysbiosis and Increased Plasma LPS and TMAO Levels in Patients with
Preeclampsia. Front Cell Infect Microbiol. 2019 Dec 3;9:409 and Chen X. et al. Gut
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dysbiosis induces the development of pre-eclampsia through bacterial translocation. Gut.

2020 Mar;69(3):513-522.
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JUNG et al. Page 42
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Figure 10.
Probability of preeclampsia according to the pre-pregnancy body mass index in both
nulliparous (top line, red) and multiparous (bottom line, blue) women. Modified from Catov
JM et al. Risk of early or severe pre-eclampsia related to pre-existing conditions. Int J
Epidemiol. 2007 Apr;36(2):412-9.
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JUNG et al. Page 43
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Figure 11.
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Interactions between maternal KIR and fetal HLA-C at the site of placentation. If the mother
has a KIR BB genotype, which binds to trophoblast HLA-C1 molecules, this activates
dNK cells, producing increased levels of cytokines such as GM-CSF that can enhance
placentation. In contrast, when the mother has a KIR AA genotype and fetal HLA-C2
alleles, this inhibits dNK cells, leading to defective placentation.
KIR; killer cell immunoglobulin like receptors, HLA; human leukocyte antigen,
dNK; decidual natural killer cells, GM-CSF; granulocyte-macrophage colony-stimulating
factor. Modified from https://www.ivi-rmainnovation.com/maternal-killer-immunoglobulin-
receptors-predictive-live-birth-rate/
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JUNG et al. Page 44
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Figure 12.
A. Optimal villi density for maximal oxygen uptake in the human placenta. Placentas with
low villi density (rarefied villi) have low oxygen uptake, as fetal villi are rare. By contrast, in
placentas with high villous density (villous overcrowding), there is no space for intervillous
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space for oxygen exchange. The optimal villi density for the oxygen uptake was 0.47 ± 0.06,
calculated from histomorphometrical data for villi and intervillous volumes of placentas.
B. Cross-section of the placenta: 1) rarefied villi in preeclampsia; 2) normal placenta; and
3) villous overcrowding in diabetes mellitus. H&E stained and scale represents 50 μm.
Modified from Serov AS et al. Optimal villi density for maximal oxygen uptake in the
human placenta. J Theor Biol. 2015 Jan 7;364:383-96.

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The etiology of preeclampsia

(NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI.

8Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol

This article describes the causal risk factors, or etiology, of preeclampsia.

A fundamental task in medicine is the understanding of the causes of diseases.

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

The principal mechanism of disease implicated in the etiology of preeclampsia and

Subsequent studies strengthened this concept, demonstrating that placental ischemia,

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

of maternal vascular malperfusion, of abnormalities in the uterine artery Doppler, and of

that ischemia seems to play a lesser role.

infection, SARS-CoV-2 infection, and maternal gut dysbiosis.

Periodontal disease—The best evidence to support a relationship between

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

predicated on the same mechanisms linking periodontal disease and atherosclerosis.

Urinary tract infection—The relationship between microbial colonization of the maternal

Experimental observations supporting a causal relationship between infection and systemic

SARS-CoV-2 Infection—Early during the COVID-19 pandemic, it was recognized

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

thrombocytopenia,82, 83 and elevated liver enzymes,84, 85 which resemble preeclampsia and

One mechanism whereby SARS-CoV-2 infection can be causally linked to preeclampsia

endothelial cells that normally express angiotensin-converting enzyme 2 (ACE2), one of

Of interest, pregnant women with COVID-19 infection who developed preeclampsia-like

Maternal intestinal dysbiosis—The human gut microbiota plays an important role in

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

cardiometabolic syndrome,111, 112 and recently, preeclampsia.113-117 A causal link between

in Bacteroidetes, Proteobacteria, Actinobacteria, Bacteroidia, Gammaproteobacteria, and

Gestational diabetes mellitus, maternal obesity, and the metabolic syndrome

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

Collectively, the evidence suggests a causal relationship between gestational diabetes

Metabolic syndrome—The term “metabolic syndrome” refers to a cluster of

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

subsequent development of metabolic syndrome after delivery.151-154 Moreover, bariatric

The mechanisms whereby insulin resistance predisposes to the development of preeclampsia

Snoring is defined as the vibration of respiratory structures resulting from turbulent

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

A hydatidiform mole, a gestational trophoblastic disease characterized by abnormal

The mechanism whereby a complete hydatidiform mole causes preeclampsia involves

of Galen,235 fetal supraventricular tachycardia,236, 237 and placental chorioangioma.238

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

Multiple gestations with twin-to-twin transfusion syndrome or selective fetal growth

of hypertension and proteinuria generally occur after the selective termination of

Autoimmune mechanisms: a role for antibodies against angiotensin II type I receptor

(SLE) or antiphospholipid syndrome (APS), were at an increased risk for preeclampsia

of hypertension and proteinuria;262 and 3) the administration of AT1-AA (either produced

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

Cytotrophoblasts are replicating cells, but the syncytiotrophoblast is generated by fusion

beta-galactosidase; 2) increased expression of cyclin-dependent kinase, p53, p21, p16; and

Breakdown of maternal-fetal immune tolerance

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

deposition was present in 20% of patients with preeclampsia.212

Maternal-fetal genetic incompatibility has been implicated in preeclampsia. Placentation is

Am J Obstet Gynecol. Author manuscript; available in PMC 2023 February 01.

An association among several endocrine disorders and preeclampsia has been

Hyperparathyroidism—Normal pregnancy is characterized by changes in maternal