ACKD

Preeclampsia for the Nephrologist: Current

Understanding in Diagnosis, Management,
and Long-term Outcomes
Divya Bajpai

Preeclampsia is a multisystem progressive disorder of pregnancy that can be potentially catastrophic for the mother and the
fetus. It involves complex perturbations of the kidney and systemic physiology, along with long-term effects on vascular and
kidney health. Thus, the nephrologist plays a key role in the peripartum and long-term management of preeclampsia. Recent
translational research has improved our understanding of its pathophysiology, and there is hope for novel therapies. In this re-
view, we discuss the evolution of diagnostic criteria and dilemmas in the diagnosis of hypertensive disorders in pregnancy. We
summarize the advances in the pathogenesis and prediction of preeclampsia. We describe the management and prevention of
preeclampsia focusing specially on the forthcoming strategies from the nephrologist’s perspective. We address the evidence
regarding long-term outcomes for the mother and the child. We end with exploring areas warranting future research.
Q 2020 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Preeclampsia, Pregnancy, Hypertension, Angiogenic biomarkers, Outcomes

T o accommodate and nurture the growing fetus, a

mother exhibits dramatic changes in systemic hemo-
dynamics, establishing a new delicate equilibrium that
can be tipped by even the slightest disturbance. One of
the best examples of this tipping over is preeclampsia. Pre-
eclampsia is a multisystem progressive disorder character-
ized by de novo hypertension and proteinuria presenting in
the latter half of pregnancy and resolving after delivery. In
a 2013 systematic review,1 the global incidence of pre-
eclampsia was 4.6% with a wide variation across countries
(range: 2.7%–8.2%). Worldwide, preeclampsia/eclampsia
is associated with 10% to 15% of maternal deaths.2 In the
United States, the case-fatality rate of preeclampsia/
eclampsia was 6.4 per 10,000 cases at delivery.3 Preeclamp-
sia is associated with intrauterine growth retardation,
oligohydramnios, and bronchopulmonary dysplasia
in the neonate. It also remains the leading cause of indi-
cated preterm deliveries, contributing to perinatal
morbidity and mortality.4 This review focusses on the ne-
phrologist’s perspective on current understanding and
challenges in diagnosis, pathogenesis, management, and
long-term outcomes for the mother with preeclampsia
and her child.
THE EVOLUTION OF DEFINITION AND
CLASSIFICATION
There is a growing understanding that preeclampsia is an
umbrella term that encompasses a spectrum of patients
with varying severity and heterogenous presentations.
From the Department of Nephrology, Seth G.S.M.C & K.E.M. Hospital,
Mumbai.
Financial Disclosure: The author declares that she has no relevant financial
interests.
Address correspondence to Divya Bajpai, MD, DM, Flat no 101, CO quarter
building no 2. K.E.M. Hospital campus, Seth G.S.M.C & K.E.M. Hospital,
Parel, Mumbai 400012. E-mail: divyaa24@gmail.com
Ó 2020 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2020.05.001
This has led to an evolution in the way we define pre-
eclampsia. The former definitions were more rigid and
used stringent criteria for blood pressure and proteinuria.
While they were better suited for research, they were less
sensitive in clinical practice. Newer definitions focus
more on the threatening clinical features such as
end-organ damage. The severity is now better defined by
features correlating with the outcomes. According to the
latest definition by the American College of Obstetricians
and Gynecologists5 Task Force (ACOG, 2013), proteinuria
is no longer an essential criterion for the diagnosis of pre-
eclampsia (Table 1). They define preeclampsia as presence
of systolic blood pressure $140 mm Hg or diastolic blood
pressure $90 mm Hg on at least 2 occasions at least 4 hours
apart after 20 weeks of gestation in a previously normoten-
sive patient and the new onset of either proteinuria or
other end-organ damage as listed in Table 1. Proteinuria
is defined as 24-hour urine protein $0.3 g or urine
protein-creatinine ratio $ 0.3 (mg/mg) in a random
urine specimen or $21 on dipstick. If systolic blood pres-
sure is $160 mm Hg or diastolic blood pressure is
$110 mm Hg, then the diagnosis can be confirmed with
a second reading within minutes, and it points toward se-
vere disease. The term “severe preeclampsia” is now better
known as “preeclampsia with severe features” to empha-
size it as a part of the same spectrum. The 2002 ACOG
guidelines6 included the presence of proteinuria ($5 gm/
24 hours), oliguria (,500 mL/24 hours), and fetal growth
restriction as diagnostic features of severe disease. The
2013 guidelines have removed these because the degree
of proteinuria and oliguria does not correlate well with
the outcome. Also, the presence or absence of preeclamp-
sia does not dictate the management of fetal growth re-
striction. However, uteroplacental dysfunction is a part
of diagnostic criteria given by other societies (Table 1).
Blood Pressure Measurements in Pregnancy
It is important to remember that most of these guidelines
are based on blood pressure measurement using a mer-
cury sphygmomanometer, which is still the gold standard
in pregnancy. However, as mercury devices are phasing

540 Adv Chronic Kidney Dis. 2020;27(6):540-550

 Current Understanding in Preeclampsia 541

out because of occupational hazards, automated devices The distinction between preexisting/chronic hyperten-
gain popularity. One additional benefit of automated de- sion and preeclampsia can become arduous when pre-
vices is that pregnant women can use them at home. It is pregnancy blood pressure readings are not available.
important to note that automated devices may underesti- Pregnancy leads to a physiologic decline in blood pressure
mate blood pressure in preeclampsia by an average of after 6 weeks of gestation. Clinicians examining the
5 mm Hg8 and can have wide intraindividual varia- women for the first time can misinterpret this decline as
tions.9-11 Hence, we recommend the use of devices that normal blood pressure in women with preexisting hyper-
are specifically validated in preeclampsia12-14 (eg, tension. Any blood pressure rise thereafter can appear de
Microlife WatchBP Home, Microlife 3BTO-A, and Omron novo, leading to the wrong diagnosis of preeclampsia.
T9P) and for cases of borderline elevated values to Here, the presence of nephrotic range proteinuria and
recheck with auscultation. high serum uric acid levels favor the diagnosis of pre-
eclampsia over chronic hypertension. Women with
Ambulatory Blood Pressure Monitoring in Pregnancy chronic hypertension can also develop superimposed pre-
There is evidence suggesting that pregnant women eclampsia, which is defined as de novo proteinuria and/or
tolerate ambulatory blood pressure monitoring (ABPM) significant end-organ dysfunction, after 20 weeks of
reasonably well.15 However, it will not be practical or gestation in a woman with chronic hypertension. For
cost-effective to subject every pregnant woman to women with both preexisting hypertension and protein-
ABPM. Normal cutoffs for ABPM have been defined for uria, superimposed preeclampsia is defined by acute
various stages of gestation tolerated by pregnant worsening of hypertension/resistant hypertension in
women.16 It is noteworthy that these values are higher the last half of pregnancy or development of signs/symp-
than conventional blood pressure readings during preg- toms of the severe end of the disease spectrum. This is a
nancy. Also, ABPM shows a tricky diagnosis in women
greater night time fall in CLINICAL SUMMARY with underlying chronic
blood pressure in pregnant kidney disease (CKD) as
women than nonpregnant
Preeclampsia is a systemic disorder comprised of both hypertension and pro-
counterparts.16 It is well es- hypertension and end organ damage with heterogenous teinuria are the hallmarks
tablished that the absence of presentations. of CKD itself. Also, there is
nocturnal blood pressure dip an overlap in the risk factors

It is imperative to distinguish preeclampsia from
and nocturnal hypertension for preeclampsia and CKD
preexisting hypertension or kidney disease, as their
is present in preeclampsia management and complications differ.
(Table 2). Table 3 summa-
and is associated with poor rizes the features which
outcomes. ABPM readings
Defective placentation causes placental ischemia and help distinguish between
correlate with adverse preg- oxidative stress. This leads to an angiogenic imbalance superimposed preeclamp-
nancy outcomes in pre- triggering systemic endothelial dysfunction and end- sia and worsening of under-
organ damage. This persists for a long time leading to
eclampsia.17,18 However, lying kidney disease.
long-term consequences in the mother and the child.
there is no conclusive evi- Preeclamptic women with
dence suggesting that ABPM
The angiogenic molecules can aid the diagnosis of severe disease can present
is superior to conventional preeclampsia in clinically obscure cases and form the with end-organ damage
home blood pressure mea- basis of several novel experimental therapies. including acute kidney
surements in predicting preg- injury, hemolysis, elevated
nancy outcomes. ABPM has a liver enzymes, and thrombo-
definite role in the diagnosis of white coat hypertension in cytopenia (HELLP). It is important to distinguish them from
pregnant women and differentiating it from essential hy- thrombotic microangiopathies (TMAs: hemolytic uremic
pertension in early pregnancy which has more sinister out- syndrome [HUS] and thrombotic thrombocytopenic pur-
comes.19 Another important and yet neglected indication pura [TTP]) as their management differs significantly. In
of ABPM is the screening of preeclamptic women post- contrast to HELLP, TMAs have a milder elevation of trans-
partum who are at higher risk of chronic hypertension aminases, a higher percentage of schistocytes on peripheral
and adverse cardiovascular events.20 These women may smear, marked elevation of lactate dehydrogenase (often
have elevated awake and sleep blood pressure readings, .1000 IU/L), severe platelet consumption, and more severe
which might not be apparent on conventional screening. kidney involvement (often patients of HUS require dialysis).
The derangement of coagulation parameters (prothrombin
DIAGNOSTIC DILEMMAS IN THE SPECTRUM time, activated partial thromboplastin time) which can be
In the severe end of this spectrum is eclampsia defined seen in severe preeclampsia is absent in TMA. TTP can
by the development of grand mal seizures in a patient also present with fever, which is not a feature of preeclamp-
with preeclampsia (after excluding other possible neuro- sia and is diagnosed by severe ADAMTS13 deficiency (ac-
logical conditions).5 Another end of this spectrum is tivity , 10%). TTP can also present early in pregnancy;
gestational hypertension. Gestational hypertension, the preeclampsia occurs after 20 weeks of gestation. Patients
most common cause of hypertension in pregnancy, is a with HUS however present later in pregnancy, and it is com-
temporary diagnosis whose fate is decided by its further mon for them to have an uneventful pregnancy course and
course21,22 (Fig 1). present postpartum.

Adv Chronic Kidney Dis. 2020;27(6):540-550

542
Table 1. Diagnostic Criteria From Various Societies
Society
American College of Obstetricians and
Gynecologists (ACOG) 20135
International Society for Study of
Hypertension in Pregnancy (ISSHP)
20187
Bajpai
Diagnostic Criteria for Preeclampsia Blood Pressure Targets
Systolic blood pressure $ 140 mm Hg or Start treatment at 160/110 mm Hg.
diastolic blood pressure $ 90 mm Hg on at Target blood pressure 120-160/80-
least 2 occasions at least 4 h apart after 20 wk 105 mm Hg for hypertensive women.
of gestation in a previously normotensive
patient AND the new onset of 1 or more of the
following
a. Proteinuria $0.3 g in a 24-h urine specimen or
protein/creatinine ratio $0.3 (mg/mg) (30 mg/
mmol) in a random urine specimen or
dipstick $21 if a quantitative measurement is
unavailable
b. Platelet count , 100,000/mL
c. Serum creatinine . 1.1 mg/dL (97.2 micro-
mols/L) or doubling of the creatinine con-
centration in the absence of other renal
diseases
d. Liver transaminases at least twice the upper
limit of the normal concentrations for the
local laboratory
e. Pulmonary edema
f. Cerebral or visual symptoms (for example,
new-onset and persistent headaches not
accounted for by alternative diagnoses and
not responding to usual doses of analgesics;
blurred vision, flashing lights or sparks,
scotomata)
Preeclampsia with severe features: systolic
blood pressure $160 mm Hg or diastolic blood
pressure $110 mm Hg and proteinuria (with or
without signs and symptoms of significant
end-organ dysfunction) OR systolic blood
pressure $140 mm Hg or diastolic blood
pressure $90 mm Hg (with or without pro-
teinuria) and one or more of the following
signs and symptoms of significant end-organ
dysfunction. (one or more out of b, c, d, e, f)
Preeclampsia is gestational hypertension Start treatment at 140/90 mm Hg in clinic
accompanied by one or more of the following or office (or $135/85 mm Hg at home)
new-onset conditions at or after 20-wk Target 110-140/85 mm Hg in the office
gestation:
a. Proteinuria
b. Other maternal organ dysfunction including:
- Acute kidney injury (AKI) (creatinine
$90 mmol/L; 1 mg/dL)
- Liver involvement (elevated transami-
nases: alanine aminotransferase or aspar-
tate aminotransferase . 40 IU/L) with or
without right upper quadrant or epigastric
abdominal pain)
- Neurological complications (examples
include eclampsia, altered mental status,
blindness, stroke, clonus, severe head-
aches, persistent visual scotomata)
- Hematological complications (thrombocy-
topenia—platelet count below 150,000/mL,
disseminated intravascular coagulation,
hemolysis)
c. Uteroplacental dysfunction (such as fetal
growth restriction, abnormal umbilical artery
Doppler waveform analysis, or stillbirth)
(Continued )
Adv Chronic Kidney Dis. 2020;27(6):540-550
 Current Understanding in Preeclampsia 543

Table 1. Diagnostic Criteria From Various Societies (Continued )

Society
National Institute for Clinical Excellence
(NICE) 2019 (https://www.nice.org.
uk/guidance/ng133)
Society of Obstetric Medicine of
Australia and New Zealand
(SOMANZ) 201411
Diagnostic Criteria for Preeclampsia Blood Pressure Targets
Same as the previous row Start treatment at .140/90 mm Hg. Target
blood pressure ,130/85 mm Hg
Multisystem disorder unique to human Treatment of moderate hypertension
pregnancy characterized by hypertension and (140-160/90-100 mm Hg) should be
one/more of based on local practice. Above these
a. Significant proteinuria—a spot urine protein/ levels, treatment should be considered
creatinine ratio $ 30 mg/mmol or serum or mandatory.
plasma creatinine . 90 mmol/L or oliguria
, 80 mL/4 hr
b. Thrombocytopenia , 100,000/mL or hemoly-
sis or disseminated intravascular coagulation
c. Raised serum transaminases or severe
epigastric and/or right upper quadrant pain.
d. Convulsions (eclampsia) or reflexia with
sustained clonus persistent or new headache
or persistent visual disturbances or stroke
e. Pulmonary edema
f. Fetal growth restriction

Atypical Presentations molar pregnancy, preeclampsia can begin before 20 weeks

Occasionally, the onset of proteinuria and hypertension is
not simultaneous. Few women can present with isolated
gestational proteinuria, which may progress to preeclamp-
sia at term or postpartum.25 Sometimes the onset of pre-
eclampsia can be delayed for up to 2 days postpartum,
known as delayed onset postpartum preeclampsia. It
most commonly presents with headache.26 We should
train every woman to recognize signs and symptoms of
preeclampsia before discharge. Rarely in women with a
of gestation.
PATHOGENESIS
In the past decade, there have been many advances in our
understanding of the pathogenesis of preeclampsia. The
presence of preeclampsia in molar pregnancies testifies
that the placenta, and not the fetus, is necessary for its
development. We now know that abnormal placentation
is cardinal to the development of preeclampsia. In healthy

Figure 1. Diagnosis and course of gestational HTN. BP, blood pressure; HTN, hypertension.

Adv Chronic Kidney Dis. 2020;27(6):540-550

544 Bajpai

Table 2. Preconceptional Risk Factors for Preeclampsia
Risk factors Chronic hypertension*
common to chronic Chronic kidney disease*
kidney disease Diabetes mellitus*
Autoimmune disease* such as
systemic lupus erythematosus,
antiphospholipid syndrome, obesity
Age . 40 y
Obstructive sleep apnea
Vascular disease
Mother small for gestational age
Maternal low birth weight/prematurity
Risk factors unique to Preeclampsia in a previous
pregnancy pregnancy*
Multifetal gestation*
Nulliparity
Family history of preeclampsia
Age , 18 y
Hydrops fetalis
Trisomy 13
Fetal growth restriction, abruptio
placentae, fetal demise in a previous
pregnancy
Partner-related factors such as new
partner, fatherhood of preeclamptic
pregnancy, limited sperm exposure
In vitro fertilization
Long interpregnancy interval
Factors reducing the Maternal smoking
risk Prolonged sexual cohabitation
*Factors with the highest relative risk.23,24
pregnancy, the terminal branches of uterine arteries (the
spiral arteries) lose muscular walls and extend up to the
myometrium. This helps them transform into large capac-
itance vessels with low resistance. This pseudovasculogen-
esis facilitates flow of enormous amount of blood to the
placenta. In preeclampsia, this transformation fails to
occur, resulting in a high-resistance placental vasculature
hypoperfusion and ischemia. This is the first stage of pre-
eclampsia, known as the stage of abnormal placentation.
There are immunological, genetic, and environmental fac-
tors that contribute to this placental dysfunction (Fig 2).
Placental ischemia and oxidative stress lead to widespread
maternal endothelial injuries and increased capillary
permeability.27 This stage of systemic vascular injury and
its effects on end organs comprise the second stage of pre-
eclampsia, also known as the stage of maternal syndrome.
This is mediated by an imbalance in angiogenic factors.
Diseased placenta releases antiangiogenic factors such as
soluble fms-like tyrosine kinase 1 (sFLT-1) and soluble en-
doglin (sEng). sFLT-1 Is a circulating antagonist to vascular
endothelial growth factor (VEGF) and placental growth
factor (PlGF); it binds to VEGF and PlGF and prevents
their interaction with endogenous receptors, thus antago-
nizing their proangiogenic biologic activity. Placental hyp-
oxia and oxidative stress appear to be the most important
triggers for the secretion of sFLT-1, as shown by the
increased expression of hypoxia-inducible transcription
factors in preeclampsia. This rise in antiangiogenic factors
and a decline in proangiogenic factors lead to maternal
systemic endothelial dysfunction, which causes a cascade
of downstream effects culminating in end-organ damage
characteristics of preeclampsia (Fig 2).
What Are the Clinical Implications of Angiogenic
Markers?
It is now certain that women with preeclampsia have high
levels of sFLT-1 and sEng and decreased levels of VEGF
and PlGF. These abnormalities precede the onset of the
clinical syndrome, resolve postpartum, and correlate
with disease severity. Therefore, they have been evaluated
as biomarkers for early detection and prognostication of
preeclampsia.27 Measurement of sFLT-1-PlGF ratio ap-
pears to be useful in ruling out preeclampsia in women
with suspected diagnosis. In a prospective cohort of 550
women,28 an sFLT-1-PlGF ratio # 38 ruled out preeclamp-
sia with a negative predictive value of 99.3% (97.9%,
99.9%) with 80% sensitivity and 78.3% specificity. In
another prospective study of 616 women,29 an sFLT-1-
PlGF ratio $ 85 predicted adverse maternal and fetal out-
comes within 2 weeks of presentation. Furthermore, these
can be crucial diagnostic markers to discriminate between
preeclampsia and other conditions having similar signs
and symptoms such as CKD or lupus nephritis.30 They
also aid the diagnosis of superimposed preeclampsia in
patients with such comorbidities31 (Table 3). Although
useful in later stages of pregnancy, these biomarkers
were not useful for the prediction of preeclampsia in early
pregnancy. In a systematic review, serum levels of PlGF,
VEGF, sFLT-1, or sEng did not predict preeclampsia before

Table 3. Differences Between Superimposed Preeclampsia and Worsening of Kidney Disease

Superimposed Preeclampsia in Kidney Disease
Quick progression of proteinuria to nephrotic range
Classical symptoms of preeclampsia (visual disturbances,
headache, epigastric pain, hyperreflexia)
Investigations suggestive of preeclampsia (hemolysis, raised
liver enzymes, thrombocytopenia)
High serum uric acid
Deranged angiogenic markers (high sFLT-1, sEng,
low PlGF, VEGF)
Resolves 12 wk postpartum
Worsening of Kidney Disease in Pregnancy
Gradual worsening of proteinuria. Usually subnephrotic; however,
nephrotic range proteinuria can occur in lupus flares
Uncommon
Uncommon but can occur in lupus
Uncommon till kidney function (glomerular filtration rate) drops too low
Absent
Persists 12 wk postpartum

PlGF, placental growth factor; sEng, soluble endoglin; sFLT, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor.

Adv Chronic Kidney Dis. 2020;27(6):540-550

 Current Understanding in Preeclampsia 545

Figure 2. Pathogenesis of preeclampsia. HTN, hypertension; BMI, body mass index; SNP, single nucleotide polymorphism;
sFLT, soluble fms-like tyrosine kinase-1; sEng, soluble endoglin; VEGF, vascular endothelial growth factor; PlGF, placental
growth factor; HIF, hypoxia inducible factor; HLA, human leukocyte antigen; NK, natural killer; AT1, angiotensin 1; AKI, acute
kidney injury; PRESS, posterior reversible encephalopathy syndrome.

30 weeks of gestation.32 Another systematic review33 in MANAGEMENT

2018 testing the role of sFLT-1-PlGF ratio for prediction
of preeclampsia showed a pooled sensitivity of 80% (95%
confidence interval [CI]: 0.68, 0.88), specificity 92% (95%
CI: 0.87, 0.96), positive likelihood ratio 10.5 (95% CI: 6.2,
18.0), and a negative likelihood ratio 0.22 (95% CI: 0.13,
0.35). The authors noted that all the women were at least
20 weeks of gestation, and these markers do not change
significantly until the later stages of pregnancy.33 It is
important to emphasize that these biomarkers are not yet
Food and Drug Administration approved and will require
standardization across the globe before they are available
for clinical use.
Risk Prediction Models
Evidence suggests that no test can individually predict the
risk of preeclampsia in early pregnancy. Investigators have
tried combining specific clinical characteristics, Doppler
ultrasound findings, and maternal biomarkers in logistic
regression analysis to create risk-prediction models, for
example, Fetal Medicine Foundation model (https://
fetalmedicine.org/research/assess/preeclampsia/first-
trimester). These have a detection rate of 75% to 92% and a
false positive rate of 10%.34 As these algorithms continue
to evolve, clinicians can use them to motivate the high-
risk women to address the modifiable risk factors and train
them about home blood pressure measurements and iden-
tifying signs and symptoms of preeclampsia. There is no
consensus on the frequency of their antenatal office visits
and investigations.
Advances in our understanding of the pathophysiology
have not yet translated into successful therapies. Only
definitive treatment of preeclampsia is the timely delivery
of the fetus and the placenta. Preeclampsia with severe fea-
tures is an indication of urgent delivery regardless of
gestational age. Occasionally, gestational age is less than
34 weeks. Prolonged antepartum care can be given at a ter-
tiary center only when the maternal and fetal condition is
stable. Women with preeclampsia without severe features
are best delivered at 37 weeks.
Novel Therapeutic Strategies in Preeclampsia
Researchers are in search of novel strategies to restore the
angiogenic imbalance and prolong gestation. Infusion of
VEGF121, which is a ligand for sFLT-1, decreased blood pres-
sure and improved glomerular filtration rate in rodent
models of preeclampsia.35,36 The downside of VEGF121 is
its nonspecific binding to both FLT-1(VEGFR-1) and FLK-
1(fetal liver kinase-1 also known as VEGFR-2) and side ef-
fects such as capillary leak and edema. PlGF has affinity
only to FLT-1 and has shown promise in primate models.37
Table 4 summarizes other therapies for preeclampsia which
are under investigation. A major setback with these therapies
is the potential risk of exposure to the fetus. We can overcome
this hazard by direct removal of angiogenic molecules using
apheresis. Apheresis is known to be safe in pregnant women.
In a pilot study, et al used a plasma-specific dextran sulfate
column to remove circulating sFLT-1 in 11 pregnant
women.44 It led to a decline in proteinuria and prolongation

Adv Chronic Kidney Dis. 2020;27(6):540-550

546 Bajpai

Table 4. Novel Strategies for the Management of Preeclampsia

Therapy Remark
VEGF121 Decreased blood pressure and improved kidney perfusion in rodents.35,36
PlGF Effective in primates, no adverse events such as edema or vascular permeability.37
Relaxin A pregnancy-specific naturally occurring proangiogenic molecule reduced blood pressure and
improved uterine perfusion in rodents.38
RNA interference molecules RNA silencing molecules to stop the production of specific sFLT-1 proteins. More cost-effective
than recombinant proteins.39 This can be beneficial in resource-deficient settings.
Sildenafil Phosphodiesterase 5 inhibitor, enhances NO production by increased cGMP signaling. Shown
benefit in a small RCT.40 However, STRIDER trial41 was terminated because of adverse fetal
outcomes.
Ouabain Inhibits HIF1 and HIF2, blocked sFLT1 production, and reduced hypertension in rodent models.42
Metformin and proton pump Shown to reduce antiangiogenic factors in vitro.43 Combination is found to be more effective than
inhibitors (esomeprazole) either drug alone.
Statins Stimulation of HO-1 expression causes enhanced NO synthase and decreased sFLT1. In a RCT
from England, (StAmP trial), pravastatin did not decrease sFLT-1 after a diagnosis of early onset
preeclampsia.45
Apheresis Plasma-specific dextran sulfate columns can remove antiangiogenic molecules.44 Adsorption
columns using monoclonal antibodies to sFLT-1 are under development.

cGMP, cyclic guanosine monophosphate; HIF, hypoxia inducible factor; HO-1, heme oxygenase-1; NO, nitric oxide; PlGF, placental growth
factor; RCT, randomized controlled trial; sEng, soluble endoglin; sFLT, soluble fms-like tyrosine kinase-1; STRIDER, Sildenafil TheRapy in
dismal prognosis early onset fetal growth restriction; VEGF, vascular endothelial growth factor.

of pregnancy by 8-15 days. This approach awaits validation
in randomized controlled trials.44
Antihypertensive Therapy
Lowering blood pressure does not affect the course of pre-
eclampsia because the basis of the maternal syndrome in
preeclampsia is placental ischemia (Fig 2). According to a
Cochrane review46 (24 trials, 2815 women), the treatment
of mild hypertension did not prevent perinatal outcomes,
but it decreased by half the incidence of development of se-
vere hypertension (relative risk [RR] 0.5; 95% CI, 0.41, 0.61;
number needed to treat ¼ 10; range: 8 to 13). Aggressive
blood pressure control in women with mild hypertension
can compromise fetal perfusion in the presence of already
compromised placental circulation. In contrast, severe hy-
pertension warrants urgent treatment to prevent maternal
complications (for example, stroke, heart failure). With these
considerations, various societies have recommended blood
pressure ranges for initiating treatment and target blood
pressure goals (Table 1). For acute management of severe
hypertension, intravenous labetalol and hydralazine are
the preferred drugs, and nimodipine, diazoxide, and ketan-
serin are best avoided.47 Refractory patients are benefitted
by infusion of nicardipine, esmolol, nitroprusside, or nitro-
glycerin. Immediate-release oral nifedipine can be used
cautiously only when intravenous access is not available.48
Stable patients can take oral therapy with labetalol, methyl-
dopa, nifedipine, and hydralazine. This can be especially
helpful in resource-limited settings. In a randomized trial
from India,49 pregnant women with severe hypertension
(systolic blood pressure $ 160 mm Hg or diastolic blood
pressure $ 110 mm Hg) were effectively managed with
either oral methyldopa, nifedipine retard, or labetalol.
Nifedipine retard was found superior in controlling blood
pressure within 6 hours with no adverse outcomes.49 In
every woman with preeclampsia, clinicians should closely
monitor blood pressure for at least 72 hours postpartum
and then at 7-10 days and should alter therapy accordingly.
Seizure Prophylaxis
Magnesium sulfate is indicated for the prevention and treat-
ment of eclampsia. All preeclampsia patients with severe
features warrant prophylactic use of magnesium sulfate.
In Cochrane reviews of randomized trials50,51 involving
eclamptic women, magnesium sulfate was safer and more
effective than phenytoin, diazepam, or anticonvulsants. Cli-
nicians should remember that seizure prophylaxis does not
prevent the development of other complications related to
preeclampsia. The use of magnesium sulfate in preeclamptic
women without severe disease is less clear, and the ACOG
task force recommends individualizing the decision based
on risk-benefit trade-off in each woman.5 One important
consideration in women with decreased glomerular filtra-
tion rate is the accumulation of magnesium and the risk of
toxicity.5 Patients with severe renal impairment should get
magnesium sulfate at a loading dose of 4-6 gm loading
dose over 30 minutes, followed by infusion of 1 gm/hour
for 24 hours after delivery. Magnesium levels should be
frequently monitored, and before every dose, clinician
should actively look for the clinical signs of magnesium
toxicity in these patients.5
PREVENTION OF PREECLAMPSIA
Researchers have unsuccessfully evaluated various mo-
dalities for prevention of preeclampsia (vitamin C and E
supplementation, salt restriction, diuretics, anticoagula-
tion, fish oil supplements, nitric acid donors).
Only the following interventions are helpful in the pre-
vention of preeclampsia:

Low-dose aspirin: Preeclampsia is a state of activation of
the coagulation system with platelet activation and
increased thromboxane production. In low doses

Adv Chronic Kidney Dis. 2020;27(6):540-550

 Current Understanding in Preeclampsia
(50 mg to 150 mg), aspirin inhibits platelet thromboxane
A2 synthesis while keeping prostacyclin synthesis intact.
Also, aspirin can reduce maternal inflammation, which
acts as a trigger for endothelial dysfunction. In a metaa-
nalysis of 74 trials with 40,249 women (2019),52 there
was a reduction in risk of preeclampsia (RR, 0.82; 0.77,
0.88), preterm birth (RR, 0.91; 0.87, 0.95), small for gesta-
tional age infants (0.84; 0.76, 0.92), fetal/neonatal death
(RR, 0.85; 0.76, 0.95), and overall serious adverse out-
comes (RR, 0.90; 0.85, 0.96). This benefit was maximum
in high-risk women. United States Preventive Services
Task Force53 recommends low-dose aspirin started
before 16 weeks of gestation in women at high risk of
developing preeclampsia (Table 2). Some clinicians prefer
starting aspirin at $12 weeks as the pathophysiological
changes of preeclampsia begin early in pregnancy.
However, there is no consistent evidence till date about
the benefit of early initiation of aspirin before 16 weeks.

Calcium supplementation: Epidemiologic data show an
inverse relationship between calcium intake and
maternal hypertension.54 In a recent multicenter ran-
domized trial of 1300 high-risk women, calcium supple-
mentation did not reduce the risk of recurrent
preeclampsia.55 In 2018 Cochrane review, supplemental
calcium (.1 g/day) reduced the risk of severe hyperten-
sive disorders in pregnancy, particularly for women
with a low-calcium diet. Thus, in women with low cal-
cium intake, the World Health Organization recom-
mends 1.5 g to 2 g of calcium supplementation/day,
particularly those at a higher risk of developing hyper-
tension.

Weight reduction: In obese women, preconception
weight loss decreases the risk of preeclampsia and other
adverse outcomes.56 Also, interpregnancy weight loss
reduced the risk of recurrent preeclampsia.57 Hence-
forth, we should encourage all women to maintain a
healthy preconception weight.
LONG-TERM OUTCOMES OF PREECLAMPSIA
It will be flawed to consider preeclampsia as a pregnancy-
limited condition, which completely resolves after deliv-
ery. There is ample evidence to suggest that there are
significant long-term outcomes that may arise decades af-
ter delivery (Table 5). It is uncertain that whether these out-
comes are a direct consequence of endothelial dysfunction,
which persists for a long time after delivery in preeclamp-
sia, or these women are more predisposed to develop
end-organ damage because of common risk factors (eg, hy-
pertension, CKD, obesity, and so on). Experimental studies
in mice suggest that preeclampsia leads to enrichment of
proteins associated with vascular disease, atherosclerosis,
and inflammatory response that persists for a long time
postpartum.58 This supports the notion that preeclampsia
leads to persistent vascular damage rather than only
unmasking the underlying predisposition.
Cardiovascular Disease
Multiple systematic reviews of controlled studies have
illustrated the risk of future cardiovascular disease
Adv Chronic Kidney Dis. 2020;27(6):540-550
547
(CVD) in women with preeclampsia. Women with early-
onset preeclampsia, recurrent preeclampsia, and preterm
birth are at the highest risk.59 American Heart Association
now recognizes preeclampsia as a major risk factor for the
development of CVD.60 Preeclampsia is also a risk factor
for cardiomyopathy which can occur postpartum or later;
however, the absolute risk appears small (14.6 to 17.3
cases/100,000 person-years).61 Pathogenesis of CVD years
later can result from endothelial dysfunction, sympathetic
overactivity, inflammation, insulin resistance, and dyslipi-
demia, which may persist years after delivery.62,63 Aware-
ness about the CVD risk will motivate women to reduce
modifiable risk factors such as obesity, smoking, and dys-
lipidemia. At present, there is no evidence to guide the
type of CVD screening required in this population, and
every clinician should individualize it based on a woman’s
risk profile.
Diabetes Mellitus
Women with preeclampsia or gestational hypertension are
at increased risk of developing diabetes. This risk is even
higher in women with gestational diabetes with pre-
eclampsia (Table 5). Insulin resistance and inflammation
associated with preeclampsia may mediate this risk. These
are partially modifiable risk factors; however, there is not
enough evidence for regular screening for diabetes in
this population.
Chronic Kidney Disease
Women with preeclampsia are at an increased risk of
developing CKD, especially within 5 years postpartum.69
There is also a small absolute risk of developing end-
stage kidney disease in the future (1% within 20 years).70
It is important to note that most of the evidence is registry
based, which is uncontrolled for preexisting hypertension
or kidney disease. As with CVD, the risk factors for CKD
and preeclampsia overlap, and it is also possible that these
women might have underlying subclinical kidney
dysfunction before pregnancy.
Long-Term Outcomes in the Child
Children born to mothers with preeclampsia are at higher
risk of developing hypertension as documented in a sys-
tematic review, including 53,029 individuals.72 We attri-
bute these associations to common genetics, an
angiogenic milieu in utero, and environmental exposures
later in life. Also, offspring born of preeclamptic pregnan-
cies are at risk of having a higher body mass index later in
life.73,74 Placental insufficiency if severe can give rise to
fetal growth restriction and low nephron dosing.75,76
This predisposes to future risk of hypertension and kidney
dysfunction. Observational studies have found an associa-
tion between maternal preeclampsia and autism spectrum
disorder in the offspring.77,78 Neonates are at a higher risk
of developing bronchopulmonary dysplasia. Exposure to
amniotic sFLT-1 can hamper pulmonary angiogenesis.79
They may be at a higher risk of pulmonary hypertension,
which may continue beyond the teenage years.85 Current
data are inadequate to recommend screening of all the
548 Bajpai

Table 5. Evidence Supporting Long-Term Maternal Outcomes in Preeclampsia

Outcome Evidence
Cardiovascular disease Systematic review. 22 studies, .6.4 million
women, .258,000 with preeclampsia64
Systematic review, 15 studies with 116,175
women with preeclampsia 65
Systematic review, 3,488,160 women66
Stroke Systematic review. 22 studies, .6.4 million
women, .258,000 with preeclampsia 64
Vascular dementia Registry-based cohort, 1,178,005 women84
Chronic hypertension Systematic review. 22 studies, .6.4 million
women, .258,000 with preeclampsia 64
Diabetes mellitus Retrospective cohort study, n ¼ 1,010,06867
Registry-based cohort, 500,000 women68
End-stage kidney disease Registry-based data, 570,675 women70
Retrospective cohort study with controls, 26,651
women with preeclampsia 71
Hypothyroidism Nested case-control study during pregnancy and
population-based follow-up study after
pregnancy80
Metabolic syndrome Retrospective cohort study, 889 women81
Mortality Prospective cohort study, 14,403 women82
Retrospective cohort study, 670,000 women83
Year Risk
2017 Heart failure: RR, 4.19; 95% CI, 2.09-8.38
Coronary artery disease: RR, 2.50; 95% CI,
1.43-4.37
Death from CVD: RR, 2.21; 95% CI, 1.83-2.66
2008 CVD: RR, 2.03; 95% CI, 1.54-2.67
Peripheral vascular disease: RR, 1.87; 95% CI,
0.94-3.73
CV mortality: RR, 2.29; 95% CI, 1.73-3.04
2007 CVD: RR, 2.16; 95% CI, 1.86-2.52
2017 RR, 1.81; 95% CI, 1.29-2.55
2018 HR, 3.46; 95% CI, 1.97-6.10
2017 RR, 3.70; 95% CI, 2.70-5.05
2013 HR for preeclampsia/gestational hypertension,
15.75; CI, 14.52-17.07
HR for preeclampsia/gestational
hypertension 1 gestational diabetes, 18.49; 95%
CI, 17.12-19.96
2009 Risk increased by 3.12-fold (range: 2.63 to 3.70)
after gestational hypertension
3.68-fold (range: 3.04 to 4.46) after severe
preeclampsia
2008 RR (single pregnancy), 4.7; 95% CI, 3.6-6.1
RR (recurrent pregnancy), 15.5; 95% CI, 7.8-30.8
2013 HR, 2.72; 95% CI, 1.76-4.22 after controlling for
hypertension and diabetes
2009 2.42 times rise in predelivery cases as compared
to 1.48 times rise in controls.
2015 aOR, 2.11; 95% CI, 1.00-4.47
2010 aHR, 2.14; 95% CI, 1.29-3.57
2014 RR, 3.7; 95% CI, 1.1-12.1

aHR, adjusted hazard ratio; aOR, adjusted odds ratio; CI, confidence interval; CVD, cardiovascular disease; RR, relative risk.

offsprings of the preeclamptic mothers. Nevertheless, cli- REFERENCES

nicians should inform parents about potential future risks.
Future Considerations
Since the earliest description of preeclampsia by Francois
Mauriceau in 1637,86 there have been considerable ad-
vances in our understanding of the pathogenesis of pre-
eclampsia. This has led to an expansion of diagnostic
criteria to better account for the systemic nature of the dis-
ease. Future therapies for preeclampsia will focus more on
the correction of angiogenic imbalance and restoring the
systemic endothelial homeostasis. As worldwide mothers
delay their child-bearing years, it becomes a priority to
bring these strategies from bench to bedside. The develop-
ment of newer risk-prediction models incorporating the
pathogenic biomarkers will enable us in early prediction
of at-risk women, who can then be prioritized for preven-
tive measures. Emerging evidence points toward the long-
term hazards of persistent vascular dysfunction in mothers
and the offspring. We should validate these associations in
large prospective interventional studies. There is a need to
explore optimum screening protocols and targeted thera-
pies for this population.
1. Abalos E, Cuesta C, Grosso AL, et al. Global and regional estimates
of preeclampsia and eclampsia: a systematic review. Eur J Obstet Gy-
necol Reprod Biol. 2013;170(1):1-7.
2. Duley L. The global impact of pre-eclampsia and eclampsia. Semin
Perinatol. 2009;33(3):130-137.
3. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from
preeclampsia and eclampsia. Obstet Gynecol. 2001;97(4):533-538.
4. Sibai BM. Preeclampsia as a cause of preterm and late preterm (near-
term) births. Semin Perinatol. 2006;30(1):16-19.
5. ACOG practice bulletin No. 202: gestational hypertension and pre-
eclampsia. Obstet Gynecol. 2019;133(1):e1-e25.
6. ACOG Committee on Obstetric Practice. ACOG practice bulletin.
Diagnosis and management of preeclampsia and eclampsia. Num-
ber 33, January 2002. American College of Obstetricians and Gyne-
cologists. Int J Gynaecol Obstet. 2002;77(1):67-75.
7. Brown M, Magee L, Kenny L, et al. Hypertensive disorders of preg-
nancy: ISSHP Classification, Diagnosis, and Management Recom-
mendations for International Practice. Hypertension. 2018;72(1):24-43.
8. Villar J, Say L, Shennan A, et al. Methodological and technical issues
related to the diagnosis, screening, prevention, and treatment of pre-
eclampsia and eclampsia. Int J Gynaecol Obstet. 2004;85(Suppl 1):S28-S41.
9. Gupta M, Shennan AH, Halligan A, Taylor DJ, de Swiet M. Accu-
racy of oscillometric blood pressure monitoring in pregnancy and
pre-eclampsia. BJOG. 1997;104(3):350-355.

Adv Chronic Kidney Dis. 2020;27(6):540-550

 Current Understanding in Preeclampsia
10. Lo C, Taylor RS, Gamble G, McCowan L, North RA. Use of auto-
mated home blood pressure monitoring in pregnancy: is it safe?
[see comment]. Am J Obstet Gynecol. 2002;187(5):1321-1328.
11. Bello NA, Woolley JJ, Cleary KL, et al. Accuracy of blood pressure
measurement devices in pregnancy: a systematic review of valida-
tion studies. Hypertension. 2018;71(2):326-335.
12. Chung Y, de Greeff A, Shennan A. Validation, and compliance of a
home monitoring device in pregnancy: microlife WatchBP home.
Hypertension Pregnancy. 2009;28(3):348-359.
13. Reinders A, Cuckson AC, Lee JT, Shennan AH. An accurate auto-
mated blood pressure device for use in pregnancy and pre-
eclampsia: the Microlife 3BTO-A. BJOG. 2005;112(7):915-920.
14. Brown MA, Roberts L, Davis G, Mangos G. Can we use the Omron
T9P automated blood pressure monitor in pregnancy? Hypertension
Pregnancy. 2011;30(2):188-193.
15. Walker SP, Permezel MJ, Brennecke SP, Tuttle LK, Higgins JR. Pa-
tient satisfaction with the SpaceLabs 90207 ambulatory blood pres-
sure monitor in pregnancy. Hypertens Pregnancy. 2004;23(3):295-301.
16. Brown MA, Robinson A, Bowyer L, et al. Ambulatory blood pres-
sure monitoring in pregnancy: what is normal? Am J Obstet Gynecol.
1998;178(4):836-842.
17. Halligan AWF, Shennan A, Lambert PC, Bell SC, Taylor DJ, de
Swiet M. Automated blood pressure measurement as a predictor of
proteinuric pre-eclampsia. Br J Obstet Gynaecol. 1997;104(5):559-562.
18. Peek MSA, Halligan A, Lambert PC, Taylor DJ, deSwiet M. Hyperten-
sion in Pregnancy: which method of blood pressure measurement is
most predictive of outcome? Obstet Gynecol. 1996;88(6):1030-1033.
19. Brown MA, Mangos G, Davis G, Homer C. The natural history of
white coat hypertension during pregnancy. BJOG. 2005;112(5):
601-606.
20. Mangos GJ, Spaan JJ, Pirabhahar S, Brown MA. Markers of cardio-
vascular disease risk after hypertension in pregnancy. J Hypertens.
2012;30(2):351-358.
21. Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hyper-
tension become pre-eclampsia? Br J Obstet Gynaecol. 1998;105(11):
1177-1184.
22. Barton JR, O’brien JM, Bergauer NK, et al. Mild gestational hyper-
tension remote from term: progression and outcome. Am J Obstet
Gynecol. 2001;184(5):979-983.
23. Bartsch E, Medcalf KE, Park AL, et al. Clinical risk factors for pre-
eclampsia determined in early pregnancy: systematic review and
meta-analysis of large cohort studies. BMJ. 2016;353:i1753.
24. Roberts JM, Redman CWG, Global Pregnancy Collaboration. Global
Pregnancy Collaboration symposium: prepregnancy and very early
pregnancy antecedents of adverse pregnancy outcomes: overview
and recommendations. Placenta. 2017;60:103-109.
25. Shinar S, Asher-Landsberg J, Schwartz A, et al. Isolated proteinuria
is a risk factor for pre-eclampsia: a retrospective analysis of the
maternal and neonatal outcomes in women presenting with isolated
gestational proteinuria. J Perinatol. 2016;36(1):25-29.
26. Redman EK, Hauspurg A, Hubel CA, et al. Clinical course, associ-
ated factors, and blood pressure profile of delayed-onset post-
partum preeclampsia. Obstet Gynecol. 2019;134(5):995-1001.
27. Phipps EA, Thadhani R, Benzing T, et al. Pre-eclampsia: pathogen-
esis, novel diagnostics, and therapies. Nat Rev Nephrol. 2019;15(5):
275-289.
28. Zeisler H, Llurba E, Chantraine F, et al. Predictive value of the sFlt-
1:PlGF ratio in women with suspected preeclampsia. N Engl J Med.
2016;374(1):13-22.
29. Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the
risk of adverse outcomes in women with suspected preeclampsia.
Circulation. 2012;125(7):911-919.
30. Lea~nos-Miranda A, Campos-Galicia I, Berumen-Lechuga MG, et al.
Circulating angiogenic factors and the risk of preeclampsia in sys-
temic lupus erythematosus pregnancies. J Rheumatol. 2015;42(7):
1141-1149.
Adv Chronic Kidney Dis. 2020;27(6):540-550
549
31. Perni U, Sison C, Sharma V, et al. Angiogenic factors in superimposed
preeclampsia: a longitudinal study of women with chronic hyperten-
sion during pregnancy. Hypertension. 2012 Mar;59(3):740-746.
32. Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, et al. Accuracy
of circulating placental growth factor, vascular endothelial growth
factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in
the prediction of pre-eclampsia: a systematic review and meta-anal-
ysis. BJOG. 2012;119(7):778-787.
33. Agrawal S, Cerdeira AS, Redman C, Vatish M. Meta-analysis
and systematic review to assess the role of soluble FMS-like
tyrosine kinase-1 and placenta growth factor ratio in prediction
of preeclampsia: the SaPPPhirE study. Hypertension. 2018;71(2):
306-316.
34. Mosimann B, Amylidi-Mohr SK, Surbek D, Raio L. First trimester
screening for preeclampsia - a systematic review. Hypertens Preg-
nancy. 2020;39(1):1-11.
35. Gilbert JS, Verzwyvelt J, Colson D, Arany M, Karumanchi SA,
Granger JP. Recombinant vascular endothelial growth factor 121
infusion lowers blood pressure and improves renal function in
rats with placental ischemia induced hypertension. Hypertension.
2010;55(2):380-385.
36. Siddiqui AH, Irani RA, Zhang Y, et al. Recombinant vascular endo-
thelial growth factor 121 attenuates autoantibody-induced features
of pre-eclampsia in pregnant mice. Am J Hypertens. 2011;24(5):
606-612.
37. Makris A, Yeung KR, Lim SM, et al. Placental growth factor reduces
blood pressure in a uteroplacental ischemia model of preeclampsia
in nonhuman primates. Hypertension. 2016;67(6):1263-1272.
38. Santiago-Font JA, Amaral LM, Faulkner J, et al. Serelaxin improves
the pathophysiology of placental ischemia in the reduced uterine
perfusion pressure rat model of preeclampsia. Am J Physiol Regul In-
tegr Comp Physiol. 2016;311(6):R1158-R1163.
39. Turanov A, Lo A, Hassler M, et al. RNAi modulation of placental
sFLT1 for the treatment of preeclampsia. Nat Biotechnol. 2018;36:
1164-1173.
40. Trapani A Jr, Gonçalves LF, Trapani TF, Vieira S, Pires M, Pires MM.
Perinatal and hemodynamic evaluation of sildenafil citrate for pre-
eclampsia treatment: a randomized controlled trial. Obstet Gynecol.
2016;128(2):253-259.
41. Pels A, Kenny LC, Alfirevic Z, et al. STRIDER (Sildenafil TheRapy in
dismal prognosis early onset fetal growth restriction): an interna-
tional consortium of randomised placebocontrolled trials. BMC
Pregnancy Childbirth. 2017;17(1):440.
42. Rana S, Rajakumar A, Geahchan C, et al. Ouabain inhibits placental
sFlt1 production by repressing HSP27-dependent HIF1a pathway.
FASEB J. 2014;28(10):4324-4334.
43. Kaitu’u-Lino TJ, Brownfoot FC, Beard S, et al. Combining metformin
and esomeprazole is additive in reducing sFlt-1 secretion and
decreasing endothelial dysfunction — implications for treating pre-
eclampsia. PLOS ONE. 2018;13(2):e0188845.
44. Thadhani R, Hagmann H, Schaarschmidt W, et al. Removal of solu-
ble fms-like tyrosine kinase-1 by dextran sulfate apheresis in pre-
eclampsia. J Am Soc Nephrol. 2016;27(3):903-913.
45. Ahmed A, Williams DJ, Cheed V, et al. Pravastatin for early-onset
pre-eclampsia: a randomised, blinded, placebo-controlled trial.
BJOG. 2020;127(4):478-488.
46. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihyperten-
sive drug therapy for mild to moderate hypertension during preg-
nancy. Cochrane Database Syst Rev. 2007;(1):CD002252.
47. Duley L, Meher S, Jones L. Drugs for treatment of very high blood
pressure during pregnancy. Cochrane Database Syst Rev. 2013:
CD001449.
48. American College of Obstetricians and Gynecologists. Emergent
therapy for acute-onset, severe hypertension during pregnancy
and the postpartum period. ACOG Committee Opinion No 767.
Obstet Gynecol. 2019;133(2):e174-e180.
550
49. Easterling T, Mundle S, Bracken H, et al. Oral antihypertensive reg-
imens (nifedipine retard, labetalol, and methyldopa) for manage-
ment of severe hypertension in pregnancy: an open-label,
randomised controlled trial. Lancet. 2019;394(10203):1011-1021.
50. Duley L, Gulmezoglu AM. Magnesium for eclampsia. Cochrane
Database Syst Rev. 2001;(1):CD002960.
51. Duley L, Henderson-Smart D. Magnesium sulphate versus phenytoin
for eclampsia. Cochrane Database Syst Rev. 2003;(4):CD000128.
52. Duley L, Meher S, Hunter KE, Seidler AL, Askie LM. Antiplatelet
agents for preventing pre-eclampsia and its complications. Cochrane
Database Syst Rev. 2019;2019(10):CD004659.
53. LeFevre ML. U.S. Preventive Services Task Force. Low-dose aspirin
use for the prevention of morbidity and mortality from preeclamp-
sia: U.S. Preventive Services Task Force recommendation statement.
Ann Intern Med. 2014;161(11):819-826.
54. Belizan JM, Villar J, Repke J. The relationship between calcium
intake and pregnancy-induced hypertension: up-to-date evidence.
Am J Obstet Gynecol. 1988;158(4):898-902.
55. Hofmeyr GJ, Betr an AP, Singata-Madliki M, et al. Prepregnancy and
early pregnancy calcium supplementation among women at high
risk of pre-eclampsia: a multicentre, double-blind, randomised,
placebo-controlled trial. Lancet. 2019;393(10169):330-339.
56. Maggard MA, Yermilov I, Li Z, et al. Pregnancy and fertility following
bariatric surgery: a systematic review. JAMA. 2008;300(19):2286-2296.
57. Mostello D, Jen Chang J, Allen J, Luehr L, Shyken J, Leet T. Recur-
rent preeclampsia: the effect of weight change between pregnancies.
Obstet Gynecol. 2010;116(3):667-672.
58. Bytautiene E, Bulayeva N, Bhat G, Li L, Rosenblatt KP, Saade GR.
Long-term alterations in maternal plasma proteome after sFlt1-
induced preeclampsia in mice. Am J Obstet Gynecol. 2013;208(5).
388.e1–e10.
59. Theilen LH. Pre-eclampsia and cardiovascular risk: comparing ap-
ples with apples. BJOG. 2018;125(13):1655.
60. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines
for the prevention of cardiovascular disease in women–2011 update:
a guideline from the American Heart Association [published correc-
tion appears in J Am Coll Cardiol. 2012 May 1;59(18):1663]. J Am Coll
Cardiol. 2011;57(12):1404-1423.
61. Behrens I, Basit S, Lykke JA, et al. Association between hypertensive
disorders of pregnancy and later risk of cardiomyopathy. JAMA.
2016;315(10):1026-1033.
62. Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH,
McLaughlin MK. Impairment of endothelial function in women
with a history of preeclampsia: an indicator of cardiovascular risk.
Am J Physiol Heart Circ Physiol. 2004;286(4):H1389-H1393.
63. Yinon Y, Kingdom JC, Odutayo A, et al. Vascular dysfunction
in women with a history of preeclampsia and intrauterine growth re-
striction: insights into future vascular risk. Circulation. 2010;122(18):
1846-1853.
64. Wu P, Haththotuwa R, Kwok CS, et al. Preeclampsia and future car-
diovascular health: a systematic review and meta-analysis. Circ Car-
diovasc Qual Outcomes. 2017;10(2):e003497.
65. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Car-
diovascular sequelae of preeclampsia/eclampsia: a systematic re-
view and meta-analyses. Am Heart J. 2008;156(5):918-930.
66. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and
risk of cardiovascular disease and cancer in later life: systematic re-
view and meta-analysis. BMJ. 2007;335(7627):974.
67. Feig DS, Shah BR, Lipscombe LL, et al. Preeclampsia as a risk factor
for diabetes: a population-based cohort study. PLoS Med. 2013;10(4):
e1001425.
Bajpai
68. Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW,
Paidas MJ. Hypertensive pregnancy disorders and subsequent car-
diovascular morbidity and type 2 diabetes mellitus in the mother.
Hypertension. 2009;53(6):944-951.
69. Kristensen JH, Basit S, Wohlfahrt J, Damholt MB, Boyd HA. Pre-
eclampsia and risk of later kidney disease: nationwide cohort study.
BMJ. 2019;365:l1516.
70. Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Pre-
eclampsia and the risk of end-stage renal disease. N Engl J Med.
2008;359(8):800-809.
71. Wang IK, Muo CH, Chang YC, et al. Association between hyperten-
sive disorders during pregnancy and end-stage renal disease: a
population-based study. CMAJ. 2013;185(3):207-213.
72. Andraweera PH, Lassi ZS. Cardiovascular risk factors in offspring
of preeclamptic pregnancies-systematic review and meta-analysis.
J Pediatr. 2019;208:104-113.e6.
73. Alsnes IV, Vatten LJ, Fraser A, et al. Hypertension in pregnancy and
offspring cardiovascular risk in young adulthood: prospective and
sibling studies in the HUNT study (Nord-Trøndelag health study)
in Norway. Hypertension. 2017;69(04):591-598.
74. Fraser A, Nelson SM, Macdonald-Wallis C, Sattar N, Lawlor DA.
Hypertensive disorders of pregnancy and cardiometabolic health
in adolescent offspring. Hypertension. 2013;62(03):614-620.
75. Wlodek ME, Westcott K, Siebel AL, Owens JA, Moritz KM.
Growth restriction before or after birth reduces nephron number
and increases blood pressure in male rats. Kidney Int. 2008;74(02):
187-195.
76. Wlodek ME, Mibus A, Tan A, Siebel AL, Owens JA, Moritz KM.
Normal lactational environment restores nephron endowment and
prevents hypertension after placental restriction in the rat. J Am
Soc Nephrol. 2007;18(6):1688-1696.
77. Dachew BA, Mamun A, Maravilla JC, Alati R. Pre-eclampsia and the
risk of autism-spectrum disorder in offspring: meta-analysis. Br J
Psychiatry. 2018;212(3):142-147.
78. Xu RT, Chang QX, Wang QQ, et al. Association between hyperten-
sive disorders of pregnancy and risk of autism in offspring: a sys-
tematic review and meta-analysis of observational studies.
Oncotarget. 2017;9(1):1291-1301.
79. Wallace B, Peisl A, Seedorf G, et al. Anti-sFlt-1 therapy preserves
lung alveolar and vascular growth in antenatal models of broncho-
pulmonary dysplasia. Am J Respir Crit Care Med. 2018;197(6):
776-787.
80. Levine RJ, Vatten LJ, Horowitz GL, et al. Pre-eclampsia, soluble fms-
like tyrosine kinase 1, and the risk of reduced thyroid function: nested
case-control and population based study. BMJ. 2009;339:b4336.
81. Al-Nasiry S, Ghossein-Doha C, Polman SE, et al. Metabolic syndrome
after pregnancies complicated by pre-eclampsia or small-for-gesta-
tional-age: a retrospective cohort. BJOG. 2015;122(13):1818-1823.
82. Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and car-
diovascular disease death: prospective evidence from the child health
and development studies cohort. Hypertension. 2010;56(1):166-171.
83. Lisonkova S, Sabr Y, Mayer C, Young C, Skoll A, Joseph KS.
Maternal morbidity associated with early-onset and late-onset pre-
eclampsia. Obstet Gynecol. 2014;124(4):771-781.
84. Basit S, Wohlfahrt J, Boyd HA. Pre-eclampsia and risk of dementia
later in life: nationwide cohort study. BMJ. 2018;363:k4109.
85. Jayet PY, Rimoldi SF, Stuber T, et al. Pulmonary and systemic
vascular dysfunction in young offspring of mothers with preeclamp-
sia. Circulation. 2010;122(5):488-494.
86. Bell MJ. A historical overview of preeclampsia-eclampsia. J Obstet
Gynecol Neonatal Nurs. 2010;39(5):510-518.
Adv Chronic Kidney Dis. 2020;27(6):540-550