ACKD

Hypertensive Disorders of Pregnancy

Virginia Dines and Andrea Kattah

Hypertensive disorders of pregnancy are increasing in incidence and are major causes of maternal morbidity and mortality both
in the United States and worldwide. An understanding of these diseases is essential for the practicing nephrologist, as preex-
isting kidney disease is an important risk factor. In addition, the development of hypertensive disorders of pregnancy has impor-
tant implications for long-term risk of kidney disease and cardiovascular disease. The definition and diagnostic criteria has
changed in recent years as our understanding of the disease entity has progressed. Currently, proteinuria is no longer a neces-
sary diagnostic feature of preeclampsia. Preeclampsia and gestational hypertension may develop through multiple different
mechanisms. Current research suggests contributions of both placental factors and maternal factors contribute to the disease
and represent different phenotypic presentations of preeclampsia.
Q 2020 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Preeclampsia, Gestational hypertension, Hypertensive pregnancy disorders, Pregnancy, Chronic kidney disease

H ypertensive disorders in pregnancy, which include

gestational hypertension, chronic hypertension, pre-
eclampsia, eclampsia, and preeclampsia superimposed
on chronic hypertension, are a major cause of maternal
morbidity and mortality.1 Preeclampsia can present in se-
vere forms and may affect multiple organ systems. Severe
preeclampsia is defined by several factors, including the
severity of blood pressure (BP) elevation, presence of
neurologic symptoms, pulmonary edema, acute kidney
injury, thrombocytopenia, and evidence of liver dysfunc-
tion. Hypertensive disorders of pregnancy have signifi-
cant implications for the fetus as well, such as
intrauterine growth restriction and preterm birth.2
Preeclampsia is estimated to complicate 3-6% of preg-
nancies3 and gestational hypertension complicates 5-10%
of pregnancies worldwide.4 Hypertensive disorders of
pregnancy can have important effects on maternal health
in the prenatal and immediate perinatal period but also
are associated with long-term significant maternal health
risks.1,3 An understanding of the pathogenesis, manage-
ment, and the associated long-term risks is essential for
the practicing nephrologist.
EPIDEMIOLOGY
Hypertensive disorders of pregnancy are an important
cause of maternal morbidity and mortality both in the
United States and worldwide. The World Health Organi-
zation identifies hypertensive disorders of pregnancy as
a leading cause of maternal death.5 Hypertensive disor-
ders of pregnancy made up 16.1% of deaths in developed
countries and 25.7% of deaths in Latin America and the
Caribbean.5 In the United States, rates of hypertensive dis-
orders of pregnancy are increasing, with an increase in the
rate of both gestational hypertension and preeclampsia
from 1987 to 2004.6 During this time period, the age-
adjusted incidence of gestational hypertension per 1000
births increased from 10.7 to 30.6. In addition, the age-
adjusted incidence rate of preeclampsia was noted to
increase from 23.6 to 29.4. The rates increased across US re-
gions and maternal age groups; however, younger women
(age , 25 years) and women delivering in the southern
United States were at the greatest risk.6 The authors noted
the increased risk for women in the southern United States
is potentially due to both obesity and racial disparities, as a
larger proportion of the population of the southern United
States is African American relative to other regions. Afri-
can Americans have been shown to have increased risk
of preeclampsia, independent of other known risk factors.7
Data from the Center for Disease Control showed that in
the United States, from 2011 to 2013, non-Hispanic black
women were 3.4 times more likely to die of a pregnancy-
related complication than non-Hispanic white women.
Hypertensive disorders of pregnancy accounted for 7.4%
of deaths during this time period.8
To better understand the changes in prevalence rates of
preeclampsia, a US-based age-period-cohort study evalu-
ated the associations between maternal age, smoking,
obesity, and the changes in prevalence rates.3 The study
found that overall rates of preeclampsia increased from
3.4% in 1980 to 3.8% in 2010, with increasing rates of severe
cases across all age groups.3 Etiology of the increasing
rates of preeclampsia is likely multifactorial but at least
partially related to increasing prevalence of obesity,
advanced maternal age, chronic kidney disease (CKD)
and chronic hypertension.9
Chronic hypertension occurs in 1-15% of women of child-
bearing age, with incidence increasing with increased age.
In 2004, self-reported data indicated that 1.7% of pregnan-
cies were complicated by pre-existing hypertension, which
represented a 50% increase from estimated rates in 1998.
As chronic hypertension rates increase, rates of superim-
posed preeclampsia also increase. Women with chronic
hypertension have a 20-25% risk of developing superim-
posed preeclampsia.3
Similar to other hypertensive disorders of pregnancy,
gestational hypertension rates have also increased, with
30.6 of 1000 pregnancies complicated by gestational hyper-
tension in 2004. Women with gestational hypertension are
twice as likely to develop complications of pregnancy rela-
tive to women with normotensive pregnancies. These
From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester,
Minnesota
Financial Disclosure: See Acknowledgment(s) on page 538.
Address correspondence to Andrea Kattah, MD, 200 First Street SW, Ro-
chester, MN, 55905. E-mail: Kattah.andrea@mayo.edu
Ó 2020 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2020.05.006

Adv Chronic Kidney Dis. 2020;27(6):531-539 531

532 Dines and Kattah

women are at additional increased risk if they are later cations of these newer diagnostic criteria for preeclampsia
diagnosed with pre-eclampsia3; 15-25% of women diag- have been studied in multiple retrospective cohort studies.
nosed with gestational hypertension are subsequently Khan et. al investigated a cohort of 66,946 singleton preg-
diagnosed with preeclampsia during their pregnancy.10 nancies and compared the incidence rates of preeclampsia
by the older ACOG and ISSHP definitions with the inci-
DEFINITIONS dence rates based on the revised definitions.13 Based on
Hypertensive disorders of pregnancy were first classified data availability, this study did not include evidence of
in 1972 by the American College of Obstetrics and Gyne- placental dysfunction or neurological complications.
cology (ACOG) into 4 categories: preeclampsia- Despite this, there was an increase in incidence rates of pre-
eclampsia, chronic hypertension, chronic hypertension eclampsia from 2.8% using the older ISSHP criteria to 3.4%
with superimposed preeclampsia, and gestational hyper- using the newer ISSHP criteria and 3.0% using the newer
tension. These main categories have remained consistent, ACOG criteria. Both the ACOG and ISSHP have recom-
although the diagnostic criteria have been modified as mended against classifying preeclampsia as mild owing
our understanding of hypertensive disorders of pregnancy to the rapidly evolving and progressive nature of pre-
has expanded.2 eclampsia.2,12 The ACOG has continued to include a defi-
In 2013, the ACOG released an updated report and exec- nition of severe preeclampsia (Table 1).
utive summary on hypertensive disorders of pregnancy, The Full Preeclampsia Integrated Estimate of Risk model
which reflects the most updated definitions of hyperten- for predicting adverse maternal outcomes in severe pre-
sive disorders of pregnancy. Preeclampsia is diagnosed eclampsia has been important in informing current diag-
by the presence of BP greater than or equal to 140 mm nostic criteria.14 Developed from a multicenter
Hg systolic or 90 mm Hg diastolic, on two occasions, after prospective study investigating women admitted with
20 weeks gestational age. preeclampsia, the criteria in
Along with hypertension, CLINICAL SUMMARY the Full Preeclampsia Inte-
preeclampsia also requires grated Estimate of Risk
the presence of proteinuria
Hypertensive disorders of pregnancy are increasing in study included not only hy-
(defined as 300 mg or more incidence and are a significant cause or maternal pertension greater than or
of protein in 24 hours or a morbidity and mortality in the United States and equal to 140/90 mm Hg and
protein/creatinine ratio of at worldwide. proteinuria, but also hyper-
least 0.3 g/g Cr), thrombocy- tension in the setting of hy-

Both maternal and placental factors can lead to
topenia, kidney insufficiency preeclampsia, and the pathogenesis may determine the
peruricemia or hemolysis,
(defined as serum creatinine phenotype of disease presentation and the risk of adverse elevated liver enzymes, and
of 1.1 mg/dL or greater or a outcomes. low platelets (HELLP) syn-
doubling of serum creati- drome without hypertension
nine), impaired liver func-
Patients with underlying kidney disease, previous kidney or proteinuria. The study
donation, or kidney transplant are at increased risk of
tion, pulmonary edema, or found the independent pre-
developing hypertensive disorders of pregnancy.
cerebral or visual symptoms. dictors of adverse maternal
Proteinuria is no longer a
Women who develop hypertensive disorders of pregnancy outcomes were gestational
requirement for the diag- are at increased risk of long-term health effects including age, chest pain, shortness of
nosis of preeclampsia, if end-stage kidney disease and cardiovascular disease. breath, oxygen saturation,
other severe features are pre- platelet count, creatinine,
sent (Table 1).2 and elevated aspartate trans-
In 2014 and 2018, the International Society for Hyperten- aminases. Notably, BP was not found to be an independent
sion in Pregnancy (ISSHP) also revised their diagnostic predictor of adverse maternal outcomes. The authors sug-
criteria for preeclampsia.11 Similar to the revised ACOG gest this could be because of the availability of antihyper-
definitions, proteinuria was no necessary for diagnosis in tensive agents to treat BPs and modify this risk factor.14 BP
the presence of other severe features. The ISSHP criteria elevation to greater than or equal to 160/110 mm Hg re-
also expanded on ACOG criteria by including platelet count mains a criterion for severe preeclampsia by the ACOG
of less than or equal to 150,000 platelets per microliter (as definition.1,2 The Full Preeclampsia Integrated Estimate
opposed to 100,000 platelets per microliter) as the threshold of Risk model has been subsequently validated externally
for thrombocytopenia and adding evidence of uteroplacen- across multiple cohorts in other high-income countries.15
11
tal dysfunction as a criterion for diagnosis (Table 1). Recognition of severe features remains important as
One factor in the elimination of proteinuria as a neces- ACOG recommends delivery if presentation at 34 weeks
sary criterion for the diagnosis of preeclampsia stems gestational age or later. Before 34 weeks, delivery may
from the understanding that nonproteinuric preeclampsia also be indicated depending on the clinical scenario.1
2,11,12
is a different phenotype of the same disease process. Despite revisions in diagnostic criteria, several diag-
It is now widely accepted that preeclampsia is a multi- nostic challenges and controversies remain in hyperten-
system disease that has significant variability in presenta- sive disorders of pregnancy. Cerebral symptoms such as
tion.2,11,12 In addition, there was concern regarding false headache may be subjective and nonspecific.1 The presen-
negative rates for proteinuria and delayed diagnosis of tation of hypertension and proteinuria may represent pre-
this rapidly evolving, life-threatening disease.12 The impli- eclampsia; however, other diagnoses such as hemolytic

Adv Chronic Kidney Dis. 2020;27(6):531-539

Adv Chronic Kidney Dis. 2020;27(6):531-539
Table 1. Diagnostic Criteria for Hypertensive Disorders of Pregnancy as per American College of Obstetrics and Gynecology 2013 Guidelines2 and the International Society for
the Study of Hypertension in Pregnancy 2018 Guidelines10
Disorder
Gestational hypertension
Chronic hypertension
Preeclampsia-eclampsia
Preeclampsia superimposed
on chronic hypertension
SBP, systolic blood pressure; DBP, diastolic blood pressure; Cr, creatinine; IUGR, intrauterine growth restriction.
Point in Gestation Blood Pressure
After 20 wk SBP $ 140 mm Hg or DBP
$ 90 mm Hg greater
than 4 h apart on at
least 2 occasions
Before pregnancy or 20 wk SBP $ 140 mm Hg or DBP
$ 90 mm Hg greater
than 4 h apart on at
least 2 occasions
OR
Normal blood pressure in
the presence of
antihypertensive therapy
After 20 wk SBP $ 140 mm Hg or DBP
$ 90 mm Hg greater
than 4 h apart on at
least 2 occasions
OR
SBP $ 160 mm Hg or DBP
$ 110 mm Hg on 2
occasions in a shorter
time interval (minutes)
After 20 wk Worsening blood
pressure or need for
additional
antihypertensive
therapy.
American College of Obstetrics
and Gynecology 2013
Absence of proteinuria or other
severe features (see below).
Absent or stable proteinuria and
no other severe features
Proteinuria (.300 mg/24 h,
protein/Cr ratio . 0.3 g/g Cr or
11 dipstick)
OR any severe features:
SBP $160 mm Hg or DBP
$110 mm Hg
Platelets , 100,000/mL
Elevated liver enzymes or
severe epigastric pain
Acute kidney injury
(Cr . 1.1 mg/dL or doubling of
baseline serum Cr)
Pulmonary edema
New neurologic or visual
disturbance
Any of the severe features
listed previously.
In women with proteinuria
predating pregnancy, a
significant and sustained
increase in proteinuria may
indicate the presence of
superimposed preeclampsia.
International Society for the
Study of Hypertension in
Pregnancy 2018
Same
Same. Recommend use of
ambulatory BP and home
monitoring to confirm the
diagnosis of new
hypertension in pregnancy.
Hypertension in Pregnancy
Proteinuria (.11 or 30 mg/dL on
automated dipstick, followed
by protein/Cr ratio . 0.3 g/g
Cr)
OR any severe features:
Acute kidney injury (Cr . 1 mg/
dL)
Elevated liver enzymes with or
without epigastric pain
Neurologic disturbance
Hematologic complications:
(Platelets , 150,000/mL,
disseminated intravascular
coagulation, or hemolysis)
Uteroplacental dysfunction
(IUGR)
Any of the severe features
aforementioned, with the
exception that IUGR can be
part of chronic hypertension
and therefore cannot be used
as a diagnostic criterion for
superimposed preeclampsia.
533
534 Dines and Kattah
uremic syndrome, thrombotic thrombocytopenic purpura,
or kidney parenchymal disease, such as glomerulone-
phritis, should be considered. This is especially true in
women presenting early in pregnancy when induction
and delivery would lead to significant fetal mortality and
morbidity.1
PATHOGENESIS
Our understanding of the pathogenesis of hypertensive
disorders of pregnancy has largely stemmed from research
in preeclampsia. Preeclampsia has become increasingly
recognized as a syndrome rather than a specific disease
state, with multiple potential pathways of pathogenesis
(Fig 1).16 Placental development has been an area of inves-
tigation, as the placenta is necessary for the development
of preeclampsia. It is thought that preeclampsia can be
divided into placental vs maternal phenotypes (Table 2).
Placental preeclampsia is caused by the development of
an abnormal placenta interacting with normal maternal
substrate, whereas maternal preeclampsia is thought to
be secondary to pre-existing abnormal maternal vascula-
ture interacting with a normal placenta.17 In reality, there
is significant overlap of these phenotypes, but it is a useful
construct for thinking about the pathogenesis of disease.
Preeclampsia can also be divided into early onset (before
34 weeks gestational age) and late onset preeclampsia (on
or after 34 weeks gestational age), as the timing of disease
onset is associated with different clinical outcomes. Early
onset preeclampsia is thought to be secondary to abnormal
placentation and is more often associated with adverse
fetal and maternal outcomes, such as low birth weight
Maternal Factors
• Age
• Race
• Parity
• Hypertension
• Obesity
• Sleep apnea
• Insulin Resistance/Diabetes
• Chronic Kidney Disease
• Autoimmune disease
• Gene cs
Physiologic Changes of
Pregnancy
• Increased coagulability
• Complement Ac va on
• Inflamma on
• T-Helper 2 cell polariza on
Preeclampsia
Figure 1. Contributing factors to the development of preeclampsia.
and severe preeclampsia. Conversely, later onset pre-
eclampsia occurs in patients with a normal placenta and
tends to result in less severe disease and more favorable
outcomes.18 We will explore the placental and maternal
contributions in the following paragraphs to understand
the complex pathogenesis of this disease.
PLACENTAL CONTRIBUTION TO DISEASE
In normal placental development, extravillous fetal cyto-
trophoblasts invade the placental bed and spiral arteries,
leading to arterial dilation and remodeling. In preeclamp-
sia, there is abnormal trophoblast invasion and incomplete
remodeling of these arteries, leading to perfusion abnor-
malities, which damage placental tissue, leading to an
imbalance in proangiogenic and antiangiogenic factors
that lead to systemic endothelial dysfunction and pre-
eclampsia.16,17,18 Vascular endothelial growth factor
(VEGF) is an angiogenic factor with a role in regulation
of BP, maintenance of the glomerular filtration barrier,
and an essential signaling molecule for placental angio-
genesis.16,19 Several studies have shown the role of an
imbalance in VEGF and other angiogenic and antiangio-
genic factors as a major cause of preeclampsia.16 Soluble
fms-like tyrosine kinase receptor-1 (sFlt-1) is a soluble re-
ceptor for VEGF, which is released from the placenta in
response to ischemia, and has been shown to be elevated
in certain patients with preeclampsia.16,20 Increased
sFlt-1 binds to VEGF and thus decreases VEGF availability
for normal placental development.16 Exogenous adminis-
tration of sFlt-1 in animal studies induces hypertension
and glomerular endotheliosis via antagonism of VEGF.20
Placental Factors
• Placental ischemia
• Imbalance of angiogenic
factors
• Failure of spiral artery
forma on
• Mul ple gesta on
Adv Chronic Kidney Dis. 2020;27(6):531-539
 Hypertension in Pregnancy
Table 2. The Maternal and Placental Phenotype Paradigm
Onset (Gestational
Phenotype weeks) Underlying Etiology
Placental ,34 Abnormal placentation
Maternal .34 Underlying endothelial
dysfunction
sFlt, soluble fms-like tyrosine kinase; PLGF, placental growth factor.
Placental growth factor (PLGF) is a proangiogenic
growth factor that is expressed by placental trophoblasts.21
In comparing women with preeclampsia and normoten-
sive control patients, patients with preeclampsia have
been shown to have significantly lower PLGF and higher
sflt-1.21 The ratio of sFlt-1/PLGF is a promising biomarker
for the rule out of preeclampsia in the short term,22 though
is not yet widely available in clinical practice. These bio-
markers may also play a role in differentiating glomerulo-
nephritis or worsening CKD from preeclampsia, a difficult
clinical diagnostic dilemma.23 In a prospective study of
women with suspected preeclampsia, a cutoff value for
the ratio of sFlt-1/PLGF of 38 was found to be highly predic-
tive of the presence of preeclampsia with a positive predic-
tive value of 36.7%, compared with 20% for clinical factors
alone.24 However, these angiogenic markers may only
identify a subset of women with preeclampsia. The differ-
ences in PLGF and sFlt-1 levels are most notable in patients
with preterm preeclampsia relative to patients with later-
onset preeclampsia, consistent with the placental vs
maternal paradigm (Table 2).21 In a cross-sectional study
of women with preeclampsia and normotensive pregnan-
cies, investigators found a reduction in the PLGF level
was seen from 15 to 25 weeks gestational age for women
who developed preeclampsia, whereas elevated sflt-1
levels were notable from 25.1 weeks gestational age to
term. There was a subset of women who had low PLGF
throughout gestation, as well. The differences in levels of
biochemical markers were present before evident clinical
features of preeclampsia, but the biologic variability still
limits the routine use of these markers in practice at this
time.21 In addition, there are other important mechanisms
to be considered in the pathogenesis of this disease.
The presence of endotheliosis on kidney biopsy, as well
as proteinuria in preeclampsia, has led to interest in podo-
cyte dysfunction as a potential mechanism in preeclamp-
sia. The degree of proteinuria is associated with degree
of podocyturia25 and may be an important mechanism in
the development of proteinuria.26 Podocyturia may also
have an important role in diagnosis of preeclampsia or
HELLP syndrome as measured by the presence of
podocin-positive cells in the urine.25 Women with pre-
eclampsia may continue to shed podocytes in the post-
partum period, which may reflect ongoing kidney injury.22
MATERNAL CONTRIBUTION TO DISEASE
Preeclampsia that develops because of significant maternal
disease and risk factors is a well-recognized phenomenon.
Adv Chronic Kidney Dis. 2020;27(6):531-539
535
Angiogenic Uterine Artery
Markers Doppler Fetal Outcomes
Markedly elevated Abnormal Fetal growth restriction and
sFlt-1/PLGF ratio poor neonatal outcomes
Mildly elevated Normal Growth restriction rare and
sFlt-1/PLGF ratio better neonatal outcomes
This is thought to occur due to underlying maternal
endothelial dysfunction, such as in women with preexist-
ing hypertension or obesity. The physiological changes of
pregnancy cause an exacerbation of underlying maternal
endothelial dysfunction, leading to preeclampsia.16
The role of maternal immunity has been increasingly
recognized as having an important role in pathogenesis
of preeclampsia. Paternal alloantigens are present on
trophoblast cells, and abnormal maternal immune toler-
ance to these alloantigens may affect placental develop-
ment. Several immune cells have also been found to be
abnormal in preeclampsia relative to normal pregnancy,
including helper T cells, regulatory T cells, regulatory B
cells, dendritic cells, and natural killer cells. In addition,
the complement system may have an important role in
pathogenesis of preeclampsia.27
In normal pregnancy, there is an increase in T helper 2
(TH2) cell activity, termed TH2 polarization, and a decrease
in TH1 cell activity; however in preeclampsia, there is more
abundant TH1 activity, leading to increased proinflamma-
tory cytokines. Mesenchymal stem cells have been shown
to have an important role in TH2 polarization as well as
other important effects such as decreased tumor necrosis
factor-alpha and increased interleukin-10, with overall
effect of proangiogenesis and anti-inflammatory effects.28
Suvakov28et. al. examined mesenchymal stem cells har-
vested from adipose tissue from patients with preeclampsia
and with normotensive pregnancies and found that women
with preeclampsia had fewer live viable mesenchymal
stem cells, more senescent cells, and less angiogenic poten-
tial. Importantly, exposure of the preeclampsia mesen-
chymal stem cells with senolytic agent dasatinib led to a
decrease in the number of senescent cells and increased
angiogenic markers and potential. These findings suggest
that stem cell activity may have a role in pathogenesis of
preeclampsia and thus may provide an opportunity for
the development of future treatment options.
Abnormalities in complement activity may also have a
role in pathogenesis of preeclampsia. Elevated levels of
C3a, C5a, and Bb have been identified early in pregnancy
in patients who later develop preeclampsia. C5a has been
reported to be associated with increased BP and arterial
stiffness and trophoblast dysfunction.27 There is evidence
of terminal complement pathway activation in the serum
and urine of women with preeclampsia,29,30 and eculizu-
mab, a complement C5a inhibitor, has been used in a few
women with HELLP syndrome, though data are
limited.31,32 Genetic studies have not identified a specific
536 Dines and Kattah
genetic mutation in the complement system in women
with preeclampsia.33
The pathogenesis of gestational hypertension is an area
of active interest. Current evidence suggests that pre-
eclampsia and gestational hypertension are distinct clin-
ical entities. Approximately 15% of women initially
diagnosed with gestational hypertension will go on to
develop preeclampsia.34 Women at high risk for progress-
ing to preeclampsia include women who develop hyper-
tension at an earlier gestational age (,34 weeks) and
women who have abnormal angiogenic markers.35
RISK FACTORS
There are several well-established risk factors for hyper-
tensive disorders of pregnancy (Fig 1). Patients with un-
derlying chronic medical conditions, including chronic
hypertension, pregestational diabetes, gestational dia-
betes, lupus, thrombophilia, obesity, and sleep apnea are
known to be at increased risk.1 In addition, having a previ-
ous pregnancy affected by preeclampsia, a multifetal
gestation, or pregnancy via reproductive technology are
also known risk factors. Nulliparity has also been shown
to be a risk factor, as has older maternal age (.35 years).1
Particularly relevant to the practicing nephrologist is the
increased risk of hypertensive disorders of pregnancy after
kidney donation. This risk is likely due to reduced
nephron number in the setting of normal physiologic
changes of pregnancy. A study by Garg et. al evaluated
the risk of pregnancy complications in living kidney do-
nors.36 The study included 85 kidney donors and 510 non-
donor control patients. Within the cohort, there were a
total of 919 pregnancies, 131 in donors, and 788 in nondo-
nors. The kidney donors had an increased risk of gesta-
tional hypertension or preeclampsia relative to control
patients, with an odds ratio of 2.4 (95% confidence interval
[CI]: 1.2-5.0; p ¼ 0.01). Absolute risk was 11% in the donor
patients vs 5% in the nondonor patients. This increased
risk of hypertensive disorders of pregnancy should be dis-
cussed with potential living donors of childbearing age.
Women who have received kidney transplants are also at
high risk for developing preeclampsia. A recent meta-
analysis of pregnancy outcomes in kidney transplant re-
cipients found that 21.5% of pregnancies were complicated
by preeclampsia and 24.1% were complicated by
pregnancy-induced hypertension.37
Previous kidney diseases, including both CKD and a his-
tory of resolved AKI, have been established as risk factors
for hypertensive disorders of pregnancy. A retrospective
study of pregnancy outcomes found that there was a sig-
nificant increased risk of preeclampsia associated with a
history of resolved acute kidney injury, with an odds ratio
of 2.9 (95% CI: 1.9-4.4).38
CKD is one of several chronic diseases that can increase
the risk of preeclampsia and gestational hypertension. In
a large meta-analysis, there was a significant increase in
risk of preeclampsia with CKD, with an odds ratio of
10.36 (95% CI: 6.28-19.1; p , 0.01).39 The risk of preeclamp-
sia in women with CKD is strongly associated with pre-
pregnancy glomerular filtration rate (GFR). Nearly 50%
of women with serum Cr . 1.4 mg/dL will develop pre-
eclampsia in pregnancy.40 An Italian study from 2007
analyzed the maternal outcomes in women with nondia-
betic kidney disease and an estimated GFR (eGFR) ,
60 mL/min/1.73 m2 before pregnancy (n ¼ 49) and approx-
imately half had hypertension (54%) in pregnancy.41 One
remaining question is whether women with CKD have
more deterioration in kidney function with pregnancy
if preeclampsia develops. A 2010 study addressed this
question by evaluating women with biopsy-proven
kidney disease before pregnancy, and comparing the risk
of end-stage kidney disease (ESKD) in women with and
without preeclampsia.42 They found no significant in-
crease in the risk of ESKD after preeclamptic pregnancy,
though there was limited power. Preterm birth, however,
was associated with an increased relative risk of ESKD in
women with CKD (RR 2.4, 95% CI: 1.2-4.6).42
There are groups of women with kidney disease that are
particularly high risk of developing preeclampsia. Women
with systemic lupus erythematosus, especially those with
lupus nephritis, are at high risk for preeclampsia. A 2010
meta-analysis found that 7.6% of pregnancies in women
with systemic lupus erythematosus were complicated by
preeclampsia and that prior nephritis was significantly
associated with preeclampsia and hypertension in meta-
regression analysis.43 Women with type 1 diabetes and
diabetic nephropathy are also at high risk, with approxi-
mately 50% developing preeclampsia and the majority
requiring intensification of antihypertensive regimens in
pregnancy.44
Although these risk factors have been established and are
important considerations in patient management, it is also
important to consider that many cases of hypertensive dis-
orders of pregnancy occur in otherwise healthy patients
without identifiable risk factors.1
PREVENTION AND TREATMENT
Currently, the only evidence-based recommendation for
the prevention of preeclampsia is the use of low-dose
aspirin beginning late in the first trimester for women at
high risk.2 This includes women with a previous history
of preterm preeclampsia or multiple pregnancies with pre-
eclampsia, and those with hypertension, CKD, and kidney
transplants.
There is currently no treatment for preeclampsia, other
than delivery. The decision to deliver takes into consider-
ation gestational age, presence of severe features, and intra-
uterine growth restriction. Management of superimposed
preeclampsia is similar to management of preeclampsia.
The 2013 ACOG guidelines do not recommend the use of
antihypertensive medications for women with new onset
gestational hypertension or preeclampsia if systolic BP
is , 160 or diastolic BP is , 100 mm Hg owing to concern
that excessive treatment may reduce placental perfusion
and cause growth restriction.45 The Control of Hypertension
in Pregnancy Study of women with chronic hypertension in
pregnancy found that tight vs less tight control (diastolic BP
of 85 mm Hg vs 100 mm Hg) did not cause any adverse fetal
events but did prevent severe range BPs.46 This study was
reassuring and may set the stage for future guidelines. It is
recommended that women with underlying chronic
Adv Chronic Kidney Dis. 2020;27(6):531-539
 Hypertension in Pregnancy 537

hypertension have frequent monitoring and be placed on
prophylactic aspirin late in the first trimester.2 Table 3
shows the preferred agents for use in the treatment of hyper-
tension in pregnancy and potential side effects. Preferred
agents for use include methyldopa, labetalol, hydralazine,
nifedipine, and thiazide diuretics. All agents are category
C by the Food and Drug Administration, except thiazides
which are considered category B. All have some risks and
potential side effects. Methyldopa and labetalol have been
most consistently demonstrated to be safe and efficacious
in pregnancy. Thiazides are particularly useful for patients
with chronic hypertension, underlying CKD, and conges-
tive heart failure. Caution must be taken to avoid volume
contraction and electrolyte abnormalities.47 Medication ad-
justments may need to be made during pregnancy, particu-
larly midpregnancy as BP typically decreases.
LONG-TERM EFFECTS OF HYPERTENSIVE
DISORDERS OF PREGNANCY
Although hypertensive disorders of pregnancy typically
resolve after delivery or the early postpartum period, there
is growing evidence of long-term health risks associated
with hypertensive disorders of pregnancy. Preeclampsia
has been associated with adverse kidney outcomes including
albuminuria and ESKD.48-52 Rates of albuminuria may be
elevated in patients with hypertensive disorders of
pregnancy in the months and years after pregnancy.49,51
The estimated relative risk of developing ESKD after a first
pregnancy with preeclampsia was found to be 4.7 (95% CI:
3.6-6.1) by Vikse et. al.48 This risk was increased for patients
with multiple pregnancies affected by preeclampsia and for
pregnancies where preeclampsia resulted in preterm deliv-
ery or the birth of a low-birth-weight infant.48 It remains un-
known whether the increased risk of ESKD is due to
common risk factors for both preeclampsia and kidney dis-
ease.52 The imbalance in angiogenic and antiangiogenic fac-
tors observed in the pathogenesis of preeclampsia may also
have a role in progression of CKD later in life.48 Podocyturia
could also impact the risk of future kidney disease.15 Pre-
eclampsia could also represent a clinically apparent exacer-
bation of subclinical kidney disease that was present before
pregnancy.48,52

Table 3. Antihypertensive Therapy With Associated Risks and Benefits in Pregnancy

US Federal Drug
Medication Category Administration
and Agents Benefits Risks Risk Category*
Central Agents
Preferred Methyldopa Proven safety and efficacy Neurodepressant side effects B/C in injectable form
Alternative Clonidine Efficacy similar to methyldopa Unproven safety C
Beta blockers
Preferred Labetalol Safety and efficacy similar to Fetal bradycardia, neonatal C
methyldopa. May be used for hypoglycemia, decreased
hypertensive urgency. uteroplacental flow
Contraindicated Atenolol None compared with Labetalol Intrauterine growth retardation D
Calcium channel
blockers
Preferred Nifedipine Lowers blood pressure without Fetal distress, profound C
affecting umbilical artery flow hypotension with magnesium
Alternative Verapamil Similar efficacy to other oral Untested safety profile, risk of C
agents interaction with magnesium
Direct vasodilators
Preferred Hydralazine Most efficacious oral agent Maternal neuropathy, drug- C
induced lupus, neonatal
thrombocytopenia and lupus
Alternative Nitroprusside Effective in severe hypertension Cyanide and thiocyanate C
toxicity
Diuretics
Preferred Thiazide Useful in chronic hypertension, Volume contraction, electrolyte B
kidney failure, congestive abnormalities
heart failure
Contraindicated Spironolactone None Possible fetal antiandrogen C
effects
RAAS blockade
Contraindicated ACE inhibitors/ARBs None Associated with congenital D
heart and kidney defects
Contraindicated Aliskiren None Oligohydramnios and other D
defects associated with RAAS
blockade in the fetus

ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers; RAAS, renin-angiotensin-aldosterone system.
*Food and Drug Administration categories. A, controlled human studies show no risk; B, no evidence of risk in studies; C, risk cannot be ruled
out; D, positive evidence of risk. Adapted from Kattah et al, 2013.47

Adv Chronic Kidney Dis. 2020;27(6):531-539

538 Dines and Kattah
Studies have investigated the risk of declining kidney
function after a pregnancy complicated by hypertensive dis-
orders of pregnancy with differing results. The Prevention
of Renal and Vascular End-Stage Diseases cohort did not
find an increased risk of CKD in patients who previously re-
ported a diagnosis of a hypertensive disorder of pregnancy.
The study did show marginally lower eGFR and more rapid
decline in eGFR in women with hypertensive disorders of
pregnancy; however, the authors suggested this was due
to higher rates of hypertension and use of renin-
angiotensin system blockers in this population.50
The American Heart Association,53 ACOG,54 and the
American Stroke Association55 have all included hyper-
tensive disorders of pregnancy as risk factors for future
cardiovascular disease and make recommendations for
follow-up and screening. Women with recurrent pre-
eclampsia are at particularly high risk. A recent meta-
analysis by Covella56et al, found that the number of
women needed to follow up after a preeclamptic preg-
nancy to detect 1 adverse event was 310 for ESKD, but
only 4 for albuminuria, though no screening guidelines
exist from the kidney perspective. Given the increased
risk of long-term adverse outcomes for patients who
have had a hypertensive disorder of pregnancy, close
follow-up may be warranted. General nephrologists and
practitioners should be familiar with these disorders and
the potential long-term adverse effects to best counsel
and manage at risk patients.
CONCLUSION
Hypertensive disorders of pregnancy represent a significant
cause of maternal morbidity and mortality with potential
long-term health effects for patients and their infants. Recent
research has revealed multiple potential pathogenic mecha-
nisms of hypertensive disorders of pregnancy, which may
lead to advances in diagnosis and treatment of these dis-
eases. Nephrologists have a key role in counseling at-risk
patients and providing consultation for complex cases and
long-term care for affected patients.
ACKNOWLEDGMENTS
Dr. Kattah is supported by the Catalyst Award through the
Department of Internal Medicine, Mayo Clinic, Rochester, MN.
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