Preeclampsia: Pathogenesis, Prevention, and

Long-Term Complications

Belinda Jim, MD,* and S. Ananth Karumanchi, MD

Summary: Preeclampsia continues to afflict 5% to 8% of all pregnancies throughout the world and is
associated with significant morbidity and mortality to the mother and the fetus. Although the pathogenesis of the
disorder has not yet been fully elucidated, current evidence suggests that imbalance in angiogenic factors is
responsible for the clinical manifestations of the disorder, and may explain why certain populations are risk. In
this review, we begin by demonstrating the roles that angiogenic factors play in pathogenesis of preeclampsia
and its complications in the mother and the fetus. We then continue to report on the use of angiogenic markers
as biomarkers to predict and risk-stratify disease. Strategies to treat preeclampsia by correcting the angiogenic
balance, either by promoting proangiogenic factors or by removing antiangiogenic factors in both animal and
human studies, are discussed. We end the review by summarizing status of the current preventive strategies
and the long-term cardiovascular outcomes of women afflicted with preeclampsia.
Semin Nephrol 37:386-397 C 2017 Elsevier Inc. All rights reserved.
Keywords: Antiangiogenic factors, cardiovascular complications, hypertension, preeclampsia, pregnancy

P
reeclampsia continues to elude physicians and
scientists as an enigma, or a disease of theo-
ries. Signicant progress, however, has been
made in the last 15 years in our understanding of their
pathogenesis, which gives hope to early identication
and rational treatments to come. In this review, we will
describe the pathogenesis, prevention, and current
treatment options. It is meant to shed a little more
light onto this intriguing entity.
PATHOGENESIS
The pathogenesis of preeclampsia, though not fully
elucidated, is generally believed to be initiated by
placental ischemia followed by placental release of
antiangiogenic factors into the circulation. In normal
pregnancy, invasion of uterine arteries transforms cyto-
trophoblasts from an epithelial to an endothelial pheno-
type, a process called pseudovasculogenesis.1 This
remodeling is meant to increase the supply of oxygen
and nutrients to the fetus.2 In doing so, the cytotropho-
basts upregulate expression of molecules that are impor-
tant to uterine invasion such as those from the vascular
*Division of Nephrology, Department of Medicine, Jacobi Medical
Center, Albert Einstein College of Medicine, Bronx, NY.
endothelial growth factor (VEGF) family (e.g., VEGF-A,
VEGF-C, placental growth factor [PlGF]).3 In preeclamp-
sia, however, pseudovasculogenesis is incomplete, thus
resulting in placental ischemia and the triggering of
hypoxia inducible factors and other placenta-derived
factors. Similarly, expression of the important VEGF
family of molecules is downregulated, yet its inhibitor
(see below) is upregulated.4
Some of these placenta-derived factors have been
characterized in the last decade. Several groups have
demonstrated that the soluble fms-like tyrosine kinase 1
(sFlt-1) is upregulated in placentae of preeclamptic
women.57 sFlt-1 is a circulating decoy receptor that
binds to PlGF, preventing their interaction with cell
surface receptors on endothelial cells and leading to
endothelial dysfunction.8 Early studies showed that sFlt-
1 levels were elevated in the sera of preeclamptic women
throughout their pregnancies and that their upregulation
was associated with decreased levels of circulating free
VEGF and free PlGF.5,9,10 Experimental studies also
suggested that sFlt-1 made by preeclamptic villous tissue
induced an antiangiogenic state that was reversed by
removal of sFlt-1.11 When sFlt-1 was administered to
pregnant rats, it induced the hallmark features of pree-
clampsia: hypertension, glomerular endotheliosis, and
proteinuria.5 VEGF induces nitric oxide formation that

Departments of Medicine, Obstetrics, and Gynecology, Beth Israel
Deaconess Medical Center and Harvard Medical School, Boston,
MA.
Conict of interest statement: S. Ananth Karumanchi is a co-
inventor on patents related to preeclampsia biomarkers that are
held by Beth Israel Deaconess Medical Center. S. Ananth
Karumanchi has nancial interest in Aggamin LLC and reports
serving as a consultant to Siemens Diagnostics, Roche, and
Thermo Fisher.
Address reprint requests to Belinda Jim, MD, 1400 Pelham Pkwy,
Bronx, NY 10461. E-mail: belindajim286@gmail.com
0270-9295/ - see front matter
& 2017 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.semnephrol.2017.05.011
neutralizes reactive oxygen species and vasoconstrictor
signaling. In the presence of excess sFlt-1, lack of
endothelial nitric oxide leads to vasoconstrictor sensitivity
and hypertension.12 As an example in modern medicine,
VEGF antagonists used as chemotherapy for solid tumors
have occasionally produced a preeclampsia-like phenotype
of severe hypertension and proteinuria as well as an
eclampsia picture of reversible posterior leukoencephalop-
athy.1315 VEGF inhibitors in cancer patients have been
associated with impaired nitric oxide production, suggest-
ing that impaired nitric oxide signaling may be a nal
common pathway that mediates hypertension.16

386 Seminars in Nephrology, Vol 37, No 4, July 2017, pp 386397

Pathogenesis and treatment of preeclampsia 387

Similarly, a second placenta-derived protein, soluble
endoglin (sEng), was later found to be upregulated in
preeclampsia.17 sEng is an inhibitory factor that binds to
transforming growth factor beta (TGF-) in circulation,
disallowing its binding to the in situ TGF- receptor.
Inactivation of both VEGF and/or TGF- signaling have
led to impaired endothelium-mediated vasodilation and
vascular autoregulation by demonstrating elevated surface
adhesion molecule expression and increased leukocyte
adhesion.18 Indeed, the administration of both sEng and
sFlt-1 has been shown to induce signs of severe pree-
clampsia in pregnant rats consisting of liver necrosis and
hemolysis, all of which is consistent with the phenotype of
HELLP (hemolysis, elevated liver enzymes, and low
platelets) syndrome and fetal growth restriction. Because
receptors for VEGF and TGF- have been found on the
choroid plexus of the brain, blockade of VEGF and TGF-
have shown to result in loss of fenestrae on the choroid
plexus, causing endothelial cell instability and periventric-
ular edema.19 Clinically, this may manifest as seizures and
the reversible posterior leukoencephalopathy syndrome on
magnetic resonance imaging. Elevated levels of sFlt-1 and
sEng in preeclampsia in humans have been subsequently
replicated by other groups.5,11,2022 To demonstrate
whether preeclampsia and eclampsia share similar patho-
physiology, the derangements of sFlt-1, sEng, and PlGF
were similar to those with severe preeclampsia, suggesting
that they share a common pathogenic pathway.23 Recent
work suggests that sFlt-1 and sEng are largely expressed in
syncytial knots in the placenta and released into maternal
circulation as syncytial microparticles.24
The etiology of the abnormal placentation is still
being debated. Various pathways have been proposed
to have key roles in inducing placental disease,
including decient heme oxygenase expression,
impaired corin expression, placental hypoxia, genetic
factors, autoantibodies against the angiotensin receptor,
oxidative stress, inammation, altered natural killer
cell signaling, and decient catechol-O-methyl trans-
ferase (Fig. 1).25,26 Interestingly, most of these were
shown to increase placental production of the anti-
angiogenic factors in vitro or in vivo rodent studies.
Still, the underlying events that induce placental
disease activating the cascade of placental damage
and antiangiogenic factor production in humans remain
unknown.
More recently, preeclampsia and endothelial dys-
function have been reported in mothers without pla-
cental disease (maternal preeclampsia).27 This form of
preeclampsia presents at term with usually milder
features of the disease. We have argued that increased
vascular sensitivity (from pre-existing maternal risk
factors such as obesity or chronic hypertension) to
circulating sFlt-1 that increases prior to delivery in all
women may contribute to term disease; however,
denitive evidence is still lacking.
EPIDEMIOLOGIC STUDIES
The risk factors for preeclampsia have been well
described and are summarized in Table 1. Again,
altered angiogenic factors may explain the mechanism

Proposed pathways
Nitric oxide Oxidative stress
Stage I Heme oxygenase Genetic/environmental
AT1-AA immunologic factors
COMT

Stage II sFlt-1/sVEGFR1/sEng
Placental Abnormal Circulating VEGF/ PlGF1 Inappropriate
ischemia placentation Misfolded placental proteins spiral artery
Unknown maternal factors remodeling

HTN Capillary leak Headache LFTs Activated coagulation

Proteinuria Pulmonary Seizure Hepatic system
AKI edema PRES infarction Thrombocytopenia

Figure 1. Pathogenesis for preeclampsia: two-stage model. AKI, acute kidney injury; AT1-AA, autoantibodies to
angiotensin receptor 1; COMT, catechol-O-methyltransferase; HTN, hypertension; LFT, liver function test; PlGF1,
placental growth factor 1; PRES, posterior reversible encephalopathy syndrome; sEng, soluble endoglin; sFlt-1,
soluble fms-like tyrosine kinase 1; sVEGFR1, soluble vascular endothelial growth factor receptor 1; VEGF,
vascular endothelial growth factor. Reprinted with permission from Bramham et al.126
388
Table 1. Risk Factors for Preeclampsia
Prior preeclampsia114,115
Renal disease116
Chronic hypertension117
Diabetes mellitus114
Primiparity118
Systemic lupus erythematosus119
Antiphospholipid antibody syndrome114
Multiple gestations120
Strong family history of cardiovascular disease121
Obesity (body mass index 4 30 kg/m2)122
Family history of preeclampsia123
Advanced maternal age (4 40 y)114,124
Excessive gestational weight gain (4 16 kg)125
Reprinted with permission from Bramham et al.126
behind some of these risk factors. For example, sFlt-1
levels were found to be 2.2 times higher in the
maternal serum of nonpreeclamptic twin pregnancies
(a known risk factor for preeclampsia) than in singleton
pregnancies, which correlated well with placental
mass.28 Likewise sFlt-1 was found to be markedly
upregulated in molar pregnancies as compared with
normal controls.29,30 Other risk factors such as mulit-
parous women,31 smoking,32 African American
women,33 and diabetes have all shown altered angio-
genic proles.34 Interestingly, trisomy 13 pregnancies,
often plagued by a disproportionate high incidence of
preeclampsia, have demonstrated increased sFlt-1
staining in their placentae35 and higher plasma levels
in early pregnancy.36
ANGIOGENIC FACTORS AS BIOMARKERS
One huge boon that has resulted from the discovery of
angiogenic factors is their utility as either predictive or
diagnostic biomarkers of preeclampsia. Many studies
have highlighted the association of preeclampsia with
an abnormal pattern of circulating maternal proangio-
genic and antiangiogenic factors that has disrupted the
proper angiogenic balance at various points of gesta-
tion (PlGF, sEng, and sFlt-1).9,3740 Using stored
serum specimen derived from the landmark CPEP
(Calcium for Preeclampsia Prevention) trial, Levine
et al22 found that the mean sEng levels of women with
preterm and term preeclampsia were both signicantly
higher than in healthy control pregnancies. Longitudi-
nal case-control studies have shown higher levels of
sFlt-1 and lower levels PlGF, and in some cases higher
levels of sFlt-1/PlGF ratios many weeks preceding
manifestation of the disease versus levels in normal
pregnant controls.37,39,41 A large-scale study that uti-
lized an automated platform to measure angiogenic
factors in patients at 20 to 36 weeks of gestation
showed that both sFlt-1 and PlGF were found to have
B. Jim and S.A. Karumanchi
sensitivities of 96%, while sFlt-1 showed a 96%
specicity and PlGF a 95% specicity for preeclamp-
sia.42 Tsiakkas et al43 reported that a combination of
maternal factors and angiogenic biomarkers (sFlt-1
and PlGF) during the third trimester could predict
nearly all cases of preterm preeclampsia and half of
those with term preeclampsia with only a 5% false
positive rate.43 A recent meta-analysis of 20 studies
demonstrated a pooled diagnostic sensitivity of sFlt-1/
PlGF to be 0.78 and specicity to be 0.84, with an
area under the curve of 0.88.44 In subgroup analyses,
the diagnostic value of sFlt-1/PlGF for early-onset
preeclampsia (o 34 weeks) was highest with a pooled
diagnostic odds ratio of 241 and area under the curve
of 0.98. Angiogenic factors also have the ability to
stratify women who are at risk for developing pre-
eclampsia. In these women, an sFlt-1/PlGF ratio Z
85, or an angiogenic form of preeclampsia, can
predict adverse maternal or fetal outcomes occurring
within 2 weeks of presentation (e.g., end organ
damage, prematurity, small for gestational age, need
for neonatal intensive care unit care).45 Conversely, a
low sFlt-1/PlGF ratio (o 85), or nonangiogenic form
of preeclampsia, is characterized by either no or very
little risk for preeclampsia-related adverse outcomes,
other than iatrogenic prematurity.46
Furthermore, it is also important that we have a
diagnostic marker to discriminate preeclampsia from
other diagnoses with overlapping signs such as chronic
hypertension and chronic kidney disease. In a cohort of
hypertensive pregnant women, sFlt-1, sEng, and the
sFlt-1/PlGF ratio were found to be signicantly higher
whereas PlGF was signicantly lower in women with
superimposed preeclampsia.47 Also, as compared with
women with chronic kidney disease, preeclamptic
patients demonstrated higher sFlt-1, lower PlGF,
and a higher sFlt-1/PlGF ratio.48 Masuyama et al49
similarly showed that sFlt-1 levels in pregnancies
with superimposed preeclampsia were signicantly
increased and PlGF signicantly decreased when
compared with women with proteinuria without
hypertension.49
Despite these studies, it must be emphasized to
practicing physicians that these biomarkers are not
Food and Drug Administration approved and therefore
not available for clinical use. Standardization of these
assays across the various automated platforms and
prospective studies that demonstrate clinical utility
are currently underway.
FETAL COMPLICATIONS
More information has now been gleaned from the
effect of preeclampsia on fetal complications. Bron-
chopulmonary dysplasia (BPD), for example, is a well-
recognized complication of prematurity. Because an
Pathogenesis and treatment of preeclampsia
appropriate angiogenic state is necessary for normal
pulmonary vascular development and airway branch-
ing, an antiangiogenic state such as preeclampsia may
additionally predispose infants to BPD. Indeed, infants
who were born to mothers with preeclampsia and fetal
growth restriction have a signicantly higher odds ratio
of having BPD.50,51 Similarly, the incidence of BPD in
preterm infants born to preeclamptic women was
signicantly higher than in preterm infants born to
normotensive women (38.5% versus 19.5%).52 To dem-
onstrate pathogenicity, sFlt-1-injected Sprague-Dawley
rats at 20 days of gestation (near term) produced
newborn pups with reduced alveolar number and
pulmonary vessel density.53 This further resulted in
right and left ventricular hypertrophy and increased
apoptosis in endothelial and mesenchymal cells in the
newborn lungs.53
Preeclampsia can also predispose the offspring of
affected mothers to cardiovascular disease in adult-
hood. Children who were born to a preeclamptic
mother demonstrated an approximately 30% higher
pulmonary arterial pressure as compared with children
born to mothers without preeclampsia.54 Thus, pree-
clampsia appears to leave a permanent defect in the
systemic and pulmonary circulation of the offspring,
which, when stressed, may lead to cardiovascular
disease later in life.
THERAPEUTIC STRATEGIES
Based on the knowledge of angiogenic disturbance in
preeclampsia, strategies to either promote angiogenic
factors or block antiangiogenic factors may be feasible.
Animal studies have shown benecial results of
replenishing with VEGF or PlGF, which are naturally
occurring ligands for sFlt-1. Administration of VEGF
121 has alleviated symptoms of preeclampsia (blood
pressure, proteinuria, glomerular endotheliosis), and
reversed many of genes are that up- or downregulated
by sFlt-1 in a pregnant rat model of preeclampsia.55
Similar results were found in another pregnant rat
model of reduced uterine perfusion pressure (RUPP) in
which blood pressure, glomerular ltrate rate, and
endothelial function were all improved. 56 The coad-
ministration of adenovirus and VEGF in an sFlt-1
induced model of preeclampsia can reduce free sFlt-1
in the plasma by more than 70% and rescue endothelial
dysfunction.57 A recent study using PlGF to rescue the
RUPP mouse model of preeclampsia showed that it
abolished the derangements of decreased glomerular
ltration rate and increased blood pressure, though
there was no mention of proteinuria.58 Because PlGF
demonstrates specic afnity to Flt-1 (VEGF receptor
1 [VEGFR-1]) in contrast to VEGF, which binds to
both Flt-1 (VEGFR-1) and Flk-1 (VEGFR-2) and
may cause undesirable side effects such as edema,
389
the authors conclude that PlGF is the preferred rescue
agent.58 Another approach would be to use molecules
that upregulate proangiogenic factors. As statins have
been shown to prevent the signs of preeclampsia in a
mouse model by inducing PlGF expression,59 both its
safety and efcacy are currently being tested in
humans. The Pravastatin for Prevention of Preeclamp-
sia trial is being tested by the Eunice Kennedy Shriver
National Institute of Child Health and Human Devel-
opment to evaluate the pharmacokinetics and safety
prole of statins in pregnancy (NCT01717586).60
The StAmP (Statins to Ameliorate early onset Pree-
clampsia) trial, a double-blind, randomized, placebo-
controlled trial, is underway in the United Kingdom to
establish whether pravastatin reduces antiangiogenic
factors in preeclampsia.61 Yet another novel approach
is to inhibit sFlt-1 upstream. Ouabain, which belongs
to the cardiac glycoside family, was found to be
effective by inhibiting hypoxia-inducible factors
(hypoxia inducible factor 1-alpha) protein expression
in the placenta and was able to reduce the mean arterial
pressure in the RUPP rat model of placental ische-
mia.62 There are likely additional such candidates that
have yet to be discovered and tested for safety in
human pregnancy.
The idea of removing antiangiogenic factors has led
to 2 pilot studies of extracorporeal removal. The rst
study used a negatively charged dextran sulfate cellu-
lose column to adsorb sFlt-1 and was tested in a total
of 5 women who experienced severe, early preeclamp-
sia. After each apheresis treatment, the women expe-
rienced a dose-dependent decrease in circulating sFlt-1
levels, decrease in proteinuria, and stabilization of
blood pressure.63 Pregnancy was ultimately prolonged
between 15 and 23 days in these women without
adverse effects to the mother or fetus. In the second
pilot trial where the apheresis device was rened to
rst separate plasma from whole blood before passing
through a plasma-specic dextran sulfate column,
pregnancy was continued from 2 to 21 days depending
on whether women were treated once or multiple
times.64 There was, for the most part, a dose-
dependent reduction in both sFlt-1 and urine protein
to creatinine ratio. The major side effect was hypo-
tension, which was easily treated by withholding
antihypertensive agents and saline hydration. At this
point, we await a randomized control trial to validate
these ndings.
PREVENTION OF PREECLAMPSIA
Numerous preventive measures such as calcium and
antioxidants have been tried and studied, some even in
well-designed, large, randomized designed trials; how-
ever, many of the trials have been largely disappoint-
ing. The results are summarized in Table 2.
390 B. Jim and S.A. Karumanchi

Table 2. Interventions for Prevention of Preeclampsia

Intervention Evidence Benefits Comments
66
Low-salt diet Multicenter RCT None No difference in hospitalization or obstetric outcomes
(N 361)
Diuretic use67 Meta-analysis of 9 RCTs None Higher incidence of adverse events including nausea
(N 7,000) and vomiting
May aggravate the reninangiotensin system
Calcium Systematic review of 13 Small to moderate Greatest benefit in women with low dietary calcium
supplementation72 studies (N 15,730) intake and women at high risk of preeclampsia
Vitamin C and E Multicenter RCT None Therapy slightly increased rate of low-birthweight
supplementation involving 2,410 babies
women76
Multicenter RCT of None No benefit to therapy
1,877 women77
Multicenter RCT of None Study performed in women of low nutritional status
1,365 women79
Aspirin83 Meta-analysis of 34 Small Routinely recommended in high-risk women; must be
RCTs involving started before 16 weeks of gestation
11,348 women
Heparin \LMWH Meta-analysis of 4 RCTs Moderate benefit in women Potentially useful for prevention of recurrent placenta-
involving 324 with prior placental mediated pregnancy complications in women with a
women87 disease history of adverse pregnancy outcomes
Meta-analysis of 6 RCTs
involving 848
women88

LMWH, low-molecular-weight heparin; RCT, randomized control trial; UFH, unfractionated heparin.
Reprinted with permission from Bramham et al.126

Low-Salt Diet/Diuretic Use
Though the concept of utilizing a low-salt diet with or
without diuretics is tempting due to the presence of
hypertension and edema in preeclampsia, the evidence
is against it. A large historical review found no
convincing evidence that salt restriction helps to
prevent preeclampsia,65 followed by a randomized
control trial of a low-salt diet (r 50 mmol sodium/d)
versus normal diet also not showing a difference in
diastolic blood pressure, admissions for hypertension,
or obstetric outcomes.66 In terms of diuretic use, a
meta-analysis of 9 randomized trials showed that the
administration of diuretics, though decreased incidence
of edema and hypertension, did not decrease the
incidence of preeclampsia.67 Thus, salt restriction and
diuretic use are not recommended.
Calcium Supplementation
The idea behind calcium supplementation stemmed from
epidemiologic data that showed an inverse relationship
between calcium intake and maternal blood pressure as
well as preeclampsia.68 This led to promising animal
studies followed by 10 randomized human trials. The
biggest ones that exceeded 1,000 healthy nulliparous
women essentially showed that there was no signicant
difference in the incidence of preeclampsia in women
who received calcium or placebo; only the subgroup of
women with probable calcium deciency appeared to
benet. One large randomized control trial that did show
a reduction in hypertensive disorders in patients who
received 2 g of elemental calcium versus placebo (odds
ratio, 0.63; 95 condence interval [CI], 0.44-0.90)69 was
conducted in countries with low calcium intake. Thus,
an important follow-up study the CPEP trial ensued in
the United States. This trial, which randomized 4,589
nulliparous patients to receive 2 g of calcium versus
placebo, however, did not demonstrate any signicant
differences in the incidence of preeclampsia or high
blood pressure measurements.70 Focusing on women
with low calcium intake, a complementary study con-
ducted by the World Health Organization randomized
more than 8,000 patients to receive either 1.5 g of
calcium or placebo.71 Though there was no signicant
difference in the rate of preeclampsia, there was a
reduction in the severity of maternal morbidity and
neonatal mortality. The most recent Cochrane Review
by Hofmeyr et al72 essentially found that calcium
supplementation (4 1 g/day) appears to reduce the risk
of severe hypertensive disorders, especially in the
subgroup with low calcium intake, but recognize that
the positive results may be overestimated due to small-
study effects or publication bias.
Antioxidants
The pathophysiology of preeclampsia, in part, has been
thought to be caused by an imbalance between oxidant
Pathogenesis and treatment of preeclampsia
and antioxidant activity. The source of antioxidant
activity appears to be the placenta, which harbors a
functional NADPH (nicotinamide adenine dinucleotide
phosphate) oxidase, the superoxide-producing enzyme.
Women with early onset of preeclampsia have been
found to have higher superoxide production as com-
pared to those with late-onset disease.73 As the anti-
oxidant vitamin E is known to inhibit NADPH oxidase
activation and the inammatory response, it is thought
to have potential in preventing preeclampsia. Vitamin
C also has known synergism with vitamin E; thus,
combining the 2 appeared reasonable.74 However, this
hypothesis has not been substantiated by several well-
conducted randomized, placebo-controlled trials.7578
A subsequent study by the World Health Organization,
which randomized 1,365 patients to either daily 1,000
mg vitamin C plus 400 international units of vitamin E
versus placebo, also found no difference in preeclamp-
sia or other maternal or fetal outcomes.79 The largest
study thus far, which enrolled 2,410 women between
14 and 22 weeks of gestation, again showed no
difference in the rate of preeclampsia, but instead
found an increased number of low-birthweight babies
in the treatment arm.76 In addition, hypertensive
complications were found to be signicantly higher
in the treatment group in the randomized trial con-
ducted by Rumbold et al.77 Given the mounting
negative evidence, supplementation with vitamins C
and E is not recommended to prevent preeclampsia.
Antithrombotic Agents
The theory behind using antithrombotic agents origi-
nates from the idea that preeclampsia is a state of
vasospasm, endothelial dysfunction, and activated
coagulation system. There also appears to be enhanced
platelet activation with thromboxane production. Thus,
some of the factors may be alleviated by the use of
antithrombotic agents. The most widely studied antith-
rombotic agent is aspirin. In low doses ranging from 50
to 150 mg aspirin can inhibit platelet thromboxane A2
biosynthesis without effecting too much change in
prostacyclin production.80 An earlier, randomized,
placebo-controlled study that consisted of more than
1,200 patients in each group showed that women who
were at high risk to develop preeclampsia did not
reduce their incidence with low-dose aspirin use.81
Subsequently, a meta-analysis from the Paris Collabo-
rative Group that studied 32,217 women from 31
randomized trials found a relative risk (RR) of devel-
oping preeclampsia to be 0.90 (95% CI, 0.84-0.97),
thus concluding that their reduction in outcome is
modest.82 Other outcomes, such as delivering before
34 weeks and having a pregnancy with a serious
adverse outcome, also carried an RR reduction of
0.90 (CI, 0.83-0.98) and 0.90 (CI, 0.85-0.96),
391
respectively. A later meta-analysis by Bujold et al83
showed that aspirin signicantly prevented the inci-
dence of preeclampsia and intrauterine growth restric-
tion (IUGR) if administered prior to 16 weeks of
gestation (RR, 0.47; 95% CI, 0.34-0.65) and (RR,
0.44; 95% CI, 0.30-0.65), respectively.83 Administra-
tion after 16 weeks, however, rendered the prevention
ineffective for preeclampsia (RR, 0.81; 95% CI, 0.63-
1.03)
or IUGR (RR, 0.98; 95% CI, 0.87-1.10). All in all,
it is agreed that the numbers needed to treat are
large to see positive results, and thus many large
practice groups such as the American Congress of
Obstetricians and Gynecologists recommend use of
aspirin only for high-risk individuals.84 A large,
randomized, placebo-controlled trial will use angio-
genic markers (PlGF) and other maternal factors
to identify high-risk individuals early in pregnancy
(11 to 13 weeks) and test the role of aspirin in
preventing early-onset preeclampsia and other adverse
outcomes.85
Given the high incidence of placental thrombotic lesions
seen with severe preeclampsia, the addition of low-
molecular-weight-heparin (LMWH) has been studied as
prophylaxis for recurrent disease. This application seems
particular apt for women with inherited thrombophilias.
Early on, small case-controlled studies showed that
LMWH signicantly reduced the risk of recurrence of
adverse outcomes, with odds ratios ranging from 0.05 to
0.30.86 A Cochrane meta-analysis that studied antithrom-
botic therapy, either alone or in combination with other
agents, demonstrated a reduction in the risk of preeclamp-
sia and eclampsia in the antithrombotic group versus
placebo or no treatment; however, there was no signicant
difference in perinatal mortality or preterm birth of less
than 34 weeks of gestation.87 This was followed by a more
recent meta-analysis of 6 randomized controlled trials
consisting of 848 women that showed a signicant
reduction in the composite outcome of preeclampsia, small
for gestation age, placental abruption, or pregnancy less of
less than 20 weeks (RR, of 0.52 with 95% CI, 0.32-0.86;
P .01).88 However, the outcome of live birth rate among
women with recurrent miscarriages does not seem to be
improved.89 Given the encouraging but not denitive data,
while weighing the side effects, the decision to treat has to
be individualized to those with a history of severe obstetric
outcomes with pathologic evidence of abnormal placenta-
tion. In the absence of placental histology, clinical
surrogates such as poor fetal growth, history of preeclamp-
sia with IUGR, placental abruption, or stillbirth can be
used to determine candidacy for prophylaxis.
PREVENTION AND TREATMENT OF ECLAMPSIA
The exact pathogenesis of eclamptic seizures is still
unclear, though it is believed related to vasospasm with
392
ischemia and hypertensive encephalopathy. The use of
magnesium sulfate was rst used to treat tetany in the
early 1900s before it was tried in eclamptic patients.
Though effective, the mechanism of action remains
unknown. Its use was called into question by leading
neurologists and put to the test in randomized con-
trolled trials against the prevailing anticonvulsants of
their time. Five randomized trials compared magne-
sium sulfate with anticonvulsants for women with
various pregnancy hypertensive disorders.9093 The
largest of which was conducted by Lucas et al93 in
which the authors studied over 2,000 women with gesta-
tional hypertension and randomized them to receive either
intramuscular magnesium sulfate or an intravenous/oral
phenytoin formulation. The difference in seizure incidence
was 0% versus 0.8% (P .004) in favor of magnesium
sulfate.93 In the same year, another international, multi-
center, randomized trial performed by the Eclampsia
Collaborative Group recruited 1,687 women comparing
with the standard anticonvulsant regimen and found that
women allocated to the magnesium sulfate arm had a 52%
lower risk of recurrent seizures than did those in the
diazepam arm; magnesium sulfate was also found to have
a 67% lower risk of recurrent convulsion as compared with
the phenytoin arm.94 Maternal mortality has also been
shown to be decreased with magnesium sulfate use.95 Side
effects of magnesium, however, range from minor symp-
toms of intense ushing, nausea, vomiting, and muscle
weakness to the major effect of respiratory depression.95,96
Thus it is generally believed that magnesium sulfate is the
drug of choice in eclampsia prevention. Proper dosing and
monitoring is imperative especially in patients with
impaired renal function.
FUTURE HEALTH OUTCOMES
The belief that preeclampsia is a self-limited condition
while all symptoms will dissipate on delivery of the
placenta is no longer held true. There is increasing
epidemiological data that shows signicant long-term
cardiovascular, metabolic, kidney problems, and even
death that may arise decades after preeclampsia (Table 3).
Risk of Chronic Hypertension
Ample evidence indicates that hypertension during
pregnancy increases the risk of future hypertension.
A meta-analysis of more than 3 million women showed
that the RR for hypertension was 3.70 (95% CI, 2.70-
5.05) after 14.1 weighted mean years of follow-up.97
The large registry-based Danish cohort study compris-
ing more than 500,000 singleton deliveries also
showed that a history of mild preeclampsia increased
the risk of chronic hypertension 3.61-fold (95% CI,
3.43-3.80).98 Others have shown that women who
experienced 2 episodes of preeclampsia were 10 times
B. Jim and S.A. Karumanchi
more likely to use blood pressure medication at follow-
up.99
Risk of Cardiovascular Disease and Stroke
The increased risk of future cardiovascular disease and
stroke in women with a history of preeclampsia has
also been conrmed by multiple epidemiologic studies.
Bellamy et als97 meta-analysis showed that the RRs
for ischemic heart disease and stroke are 2.16 (95% CI,
1.86-2.52) after 11.7 years and 1.81 (95% CI, 1.45-
2.27) after 10.4 years, respectively. Cardiovascular
disease surrogates such as the coronary artery calci-
cation score and left ventricular mass were both found
to be signicantly higher in women with a history of
preeclampsia as compared with women with a healthy
pregnancy more than 30 years after the affected
pregnancies, though the duration and frequency of
hypertension were higher in the preeclampsia
groups.100,101 Additional cardiovascular risks such as
cerebrovascular disease, peripheral arterial disease, and
cardiovascular mortality were found to be doubled,102
while death from stroke for women with preeclampsia/
eclampsia was also increased.103 The prognosis of
women after coronary artery revascularization is also
inuenced by the type of placental disease they had.
For women who have undergone coronary revascula-
rization, a history of placental infarction or abruption
was associated with a higher risk of death (adjusted
hazard ratio [HR], 3.09; 95% CI, 1.23-7.74) and
(adjusted HR, 2.79; 95% CI, 1.31-5.96) respectively,
as compared with women with a history of preeclamp-
sia (adjusted HR, 1.61; 95% CI, 1.00-2.58).104 This
effect is compounded when women experience 2 or
more placental maternal syndromes (adjusted HR,
4.31; 95% CI, 1.71-10.89).
Risk of Renal Disease
The impact of preeclampsia on future kidney health
was not evident until recently. Early on, however,
small studies showed that the mean urinary albumin
excretion rate was signicantly higher in women 3 to
5 years after delivery as compared with normal con-
trols,105 which was conrmed by later, larger systemic
reviews106; however, serum creatinine and estimated
glomerular ltration rate were not signicantly differ-
ent at the end of the 7-year follow-up, and hence it was
believed that there was no lasting impact on kidney
health. However, this assumption was contradicted by
a large Norwegian registry database that showed that
the RR of developing end-stage renal disease (ESRD)
was 4.7 (95% CI, 3.6-6.1) with the risk increasing to
15.5 (95% CI, 7.8-30.8) if 2 or 3 pregnancies were
complicated by preeclampsia.107 It must be kept in
mind that although the RR may seem substantial, the
Pathogenesis and treatment of preeclampsia 393

Table 3. Long-Term Outcomes After Preeclampsia

Outcome
Chronic hypertension
Cardiovascular disease
Stroke
End-stage renal disease
Metabolic disorders
Evidence Effect on Risk
97
Meta-analysis of 3,488,160 women with 14.1-year follow-up RR 3.70
(95% CI, 2.70- 5.05)
Registry-based cohort study of 500,000 women over 29 years98 AR 3.61
(95% CI, 3.43-3.80)
Meta-analysis of 3,488,160 women with 11.7-year follow-up97 RR 2.16
(95% CI, 1.86-2.52)
Observational study of 115 women with persistent hypertension AR  2
over 5-10 years127
Meta-analysis of 3,488,160 women with 10.4-year follow-up97 RR 1.81
(95% CI, 1.45-2.27)
Meta-analysis of 116,175 women102 RR 2.03
(95% CI, 1.54-2.67)
Norwegian registry database of 570,675 women followed AR 3.7/100,000 women/y
over 29 years107
 Single pregnancy complicated by preeclampsia RR 4.7
 2-3 pregnancies complicated by preeclampsia (95% CI, 3.6-6.1)
RR 15.5
(95% CI, 7.8-30.8)
Cohort study of 26,000 women over 11 years108 aHR 14.0
(95% CI, 9.43-20.7)
Type 2 diabetes mellitus: registry-based cohort of 500,000 women 3.12-fold (range) increase
over 29 years98
Hypothyroidism: nested case-control study during pregnancy and TSH increased 2.42
population-based follow-up study after pregnancy times above baseline
over 5 years109
Retrospective cohort study of 889 women over 14 years110 aOR 2.11
(95% CI, 1.00-4.47)
 Metabolic syndrome aOR 1.78
 Hyperinsulinemia (95% CI, 1.13-2.81)

Mortality Prospective study of 14,403 women112 aHR 2.14

(95% CI, 1.29-3.57)
Retrospective study of 670,000 women over 8 years113 RR 3.7
(95% CI, 1.1-12.1)

aHR, adjusted hazard ratio; aOR, adjusted odds ratio; AR, absolute risk; CI, confidence interval; RR, relative risk; TSH, thyroid-
stimulating hormone.
Reprinted with permission from Bramham et al.126

absolute rate of ESRD was only 3.7 per 100,000
women per year. This nding was also conrmed in
a Taiwanese cohort of more than 26,000 patients in
which women with a history of preeclampsia or
eclampsia had an adjusted HR of 14.0 (95% CI,
9.43-20.7) for the development of ESRD as compared
with women with no hypertensive disorder based on
International Classication of Diseases-Ninth Revision
codes.108 It must be kept in mind that the Norwegian
and the Taiwanese studies are based on registry and
coding data, respectively, hence they cannot control for
pre-existing hypertension or renal disease.
Risk of Metabolic Disorders
In addition to vascular disease, preeclampsia portends
derangements in the metabolic and endocrine systems
as well. A Denmark registry cohort study found a
3.12-fold increase of diabetes mellitus after gestational
hypertension and a 3.68-fold increase after severe
preeclampsia.98 The CPEP trial discovered that thyroid
stimulating hormone increased 2.42 times above base-
line and that free triiodothyronine decreased more so
than control patients.109 The prevalence of metabolic
syndrome was found to be 2-fold higher in women
with a history of preeclampsia as compared with
women with a history of small for gestational age
babies, even after adjusting for confounding factors
such as hyperinsulinemia and insulin resistance.110
When women with early-onset preeclampsia, late-
onset preeclampsia, and gestational hypertension were
compared, those with the early-onset preeclampsia had
signicantly higher fasting blood glucose, insulin,
triglycerides, and total cholesterol as early as 3 months
postpartum.111 In other words, common modiable
cardiovascular risk factors may be detected within the
394
rst year of the postpartum period, which offers an
opportunity for early prevention strategies.
Risk of Death
The risk of death is particularly increased in women
who experienced early, severe, preterm preeclampsia.
A large, prospective study of 14,403 women from the
Kaiser Permanente Health System in California found
that preeclampsia was independently associated with
cardiovascular disease death (mutually adjusted HR,
2.14; 95% CI, 1.29-3.57).112 The risk was notably
higher in women who experienced preeclampsia by 34
weeks of gestation (HR, 9.54; 95% CI, 4.50-20.25). In
a study of all-cause mortality of more than 670,000
women who experienced singleton deliveries it was
found that women with preeclampsia had a signi-
cantly higher rate of maternal death compared with
women without preeclampsia (risk ratio, 3.7; 95% CI,
1.1-12.1).113 Again, early-onset preeclampsia showed a
higher rate of maternal mortality as compared with
those with late-onset preeclampsia (42.1 versus 11.2
per 100,000 singleton deliveries). The authors also
discovered that early-onset preeclampsia conferred a
higher risk of end organ damage in terms of the
cardiovascular, respiratory, central nervous, renal, and
hepatic systems.113 Hence, the risk of disease appears
to be related to the severity of the pregnancy-related
hypertensive disease and gestational age at onset.
SUMMARY
In the last decade, we have improved, if not trans-
formed, our understanding of pathogenesis of pree-
clampsia to the extent that new treatment and
predictive markers are in sight. However, as with all
promising bench research, it must be translated to the
bedside, which should be prioritized, especially in
terms of government funding. Concern for hyperten-
sion disorders of pregnancy are gaining attention as
potential mothers delay their childbearing years which
increase their risks for these disorders. Prevention and
treatment measures remain very limited. With the
increasing epidemiologic data of the persistent vascular
effects of preeclampsia after delivery, both patients and
physicians need to be aware so that proper surveillance
and treatment can commence.
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