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Curr Hypertens Rep. Author manuscript; available in PMC 2018 April 25.
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Published in final edited form as:

Curr Hypertens Rep. 2017 August ; 19(8): 61. doi:10.1007/s11906-017-0757-7.

Pathophysiology and Current Clinical Management of

Preeclampsia
Lorena M. Amaral1, Kedra Wallace2, Michelle Owens2, and Babbette LaMarca1,3
1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson,
MS, USA
2Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson,
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MS, USA
3Department of Pharmacology, Center for Excellence in Renal and Cardiovascular Research,
University of Mississippi Medical Center, Jackson, MS 39216, USA

Abstract
Preeclampsia is characterized by blood pressure greater than 140/90 mmHg in the second half of
pregnancy. This disease is a major contributor to preterm and low birth weight babies. The early
delivery of the baby, which becomes necessary for maintaining maternal well-being, makes pre-
eclampsia the leading cause for preterm labor and infant mortality and morbidity. Currently, there
is no cure for this pregnancy disorder. The current clinical management of PE is hydralazine with
labetalol and magnesium sulfate to slow disease progression and prevent maternal seizure, and
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hopefully prolong the pregnancy. This review will highlight factors implicated in the
pathophysiology of preeclampsia and current treatments for the management of this disease.

Keywords
Preeclampsia; Placental ischemia; Inflammation; Endothelial dysfunction

Introduction
Preeclampsia (PE) is a pregnancy specific multisystem hypertensive disorder that is a major
contributor to maternal, neonatal morbidity and mortality. PE is responsible for an estimated
50,000–60,000 pregnancy-related deaths per year worldwide [1••, 2–6]. This disease is
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associated with new-onset hypertension in the second half of pregnancy and is often
associated with proteinuria. Complications such as eclampsia, hemorrhagic stroke,
hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), renal failure and
pulmonary edema may be associated with PE.

Correspondence to: Babbette LaMarca.

Compliance with Ethical Standards
Conflict of Interest The authors declare no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects
performed by any of the authors.
 Amaral et al. Page 2

Although the underlying pathophysiology of PE is not completely understood, hallmark

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characteristics of this disease include increased uterine artery resistance index (UARI),
chronic immune activation, intrauterine fetal growth restriction (IUGR), increased
inflammatory cytokines, maternal endothelial dysfunction, decreased vasodilators, and other
systemic disturbances (Fig. 1) [7–14]. Importantly, the only resolve for PE is delivery of
placenta, leaving this disease one of the leading causes of preterm birth.

Pathophysiology of Preeclampsia
The inappropriate vascular remodeling and a hypoperfused placenta, which result from the
shallow cytotrophoblast migration toward the uterine spiral arterioles, have been
characterized as an important initiating events in PE [15•]. The placenta becomes ischemic
which leads to the release of factors that are associated with maternal vascular endothelial
dysfunction [11, 12, 15•, 16–18]. Endothelial dysfunction has been a common phenotype of
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PE and it is characterized by vasoconstriction and reduced blood flow to organs.

Furthermore, preexisting conditions such as diabetes and obesity contribute to factors
released from the ischemic placenta. In addition, an increase in immune cells and
inflammatory cytokines are related to endothelial dysfunction during PE [9, 19–21].
Importantly, hallmarks such as endothelin-1 (ET-1), anti-angiogenic factor sFlt-1, agonistic
autoantibodies to the angiotensin II type I receptor (AT1-AA) and decreased nitric oxide
(NO) have been shown to play an important role in the development of PE [22–26, 27••].

Endothelial Dysfunction Is a Common Thread that Could Contribute to

Pathology of PE
During PE, the mechanisms responsible for systemic maternal vascular dysfunction are still
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not fully understood. However, anti-angiogenic factors such as sFlt-1 or soluble vascular
endothelial growth factor receptor 1 have been associated with decreased renal function and
hypertension during pregnancy. Circulating sFlt-1 levels and placental sFlt-1 mRNA are
higher in women who have preeclampsia compared to normal pregnant women [25]. Also,
animal data have demonstrated that sFlt-1 induces PE-like syndrome, which was associated
with increased ET-1 and decreased NO and resulting in endothelial dysfunction [23•].
Previous studies have demonstrated that ET-1 is increased in PE and some studies report a
positive correlation between ET-1 and the severity of symptoms. NO is required vascular
alterations during normal pregnancy to support the increased blood volume [28]. NO
deficiency has been shown to impair the vasorelaxation in human and animal models of PE
[29–31] and increased NO bioavailability could contribute to improve maternal and fetal
outcomes.
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Chronic Inflammation Contributes to Endothelial Dysfunction and to the

Pathology of PE
During a normal pregnancy, there is a careful balance between TH1 and TH2 immune cells
and their respective immune responses. However in PE, this balance is disrupted and there is
a shift toward a TH1 response leading to a chronic immune environment similar to that

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experienced by individuals with autoimmune diseases [19, 20, 32]. The increase in TH1
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immune cells and cytokines increases the B cell production of autoantibodies to the
angiotensin II (Ang II) type 1 receptor (AT1-AA) [26, 27•, 33], increases ET-1 and sFlt-1
expression [34, 35] and increases oxidative stress [36–38], all of which contribute to the
pathophysiology of PE and ultimately the development of hypertension during pregnancy.

What is becoming more apparent is that despite the unknown etiology of PE, women with
obesity or a high body mass index (BMI: >30 kg/m2) [39, 40], chronic hypertension,
diabetes and systemic lupus erythematosus (SLE) prior to pregnancy are more susceptible to
the development of PE [41, 42]. As obesity represents a chronic state of low-grade
inflammation, is a risk factor for PE [39, 43, 44]. In addition to the systemic inflammation
that is associated with obesity, a study by Aye et al. [45] has shown that as body mass index
increases so does placental activation of inflammatory pathways. Placentas from obese
women have also been shown to be lipotoxic and have increased oxidative stress [46, 47].
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Women with chronic hypertension who develop PE, superimposed-PE (SI-PE), have a
different immune profile compared to PE women [48]. Though women with chronic
hypertension and SI-PE have evidence of chronic inflammation, the ratio of sFlt-1/PlGF
does not reach the levels of severity as they do in women with just PE. The sFlt-1/PlGF ratio
in late pregnancy is not as severe as that experienced by women with PE suggesting that the
inflammatory pathway triggered in PE might be different compared to that of hypertension
alone since an additive effect has not been reported.

Women with type 1 diabetes (T1D), type 2 diabetes (T2D) or gestational diabetes (GD) are
all at an increased risk of developing PE. Approximately 15–20% of pregnant women with
T1D [49–51], 10–14% of pregnant women with T2D [51, 52] will develop PE and women
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with GD have an odds ratio = 1.3 (95% confidence interval 1.2, 1.4) of developing PE [53].
Both T1D and T2D are associated with chronic low-grade inflammation [54], which along
with the fact that women with PE tend to be insulin resistant prior to pregnancy could stand
as one reason why women with diabetes are more susceptible to PE [55]. Women with GD
have an immune profile similar to that of women with PE, as there is evidence of endothelial
dysfunction [56], angiogenic imbalance [57] and an increase in oxidative stress [58]. As PE
is associated with insulin resistance as well as immune dysregulation, it is less clear as to
whether there is a common etiological pathway between GD and PE.

SLE is an autoimmune disease that predominantly affects women in their childbearing years
and is associated with immune alteration, specifically a reduction in Treg cells. Over 20% of
pregnant women with SLE have pregnancies complicated with PE [59, 60]. For women with
lupus nephritis, kidney inflammation due to SLE, who become pregnant, the decrease in
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Tregs, which are needed for a successful pregnancy puts them at an increased risk for PE
[61–64]. SLE is also associated with antiphospholipid antibodies (aPLs) which is associated
with PE, preterm birth and intrauterine growth restriction (IUGR) [65, 66]. As all of these
abovementioned disorders have an underlying theme of chronic inflammation, it can be
suggested that when a pathological inflammatory insult is superimposed onto the pro-
inflammatory state of pregnancy, more severe complications of pregnancy, such as PE may
develop [21].

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Preeclampsia Affects Not Only the Mother but Also the Offspring
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As delivery of the placenta is the only effective treatment for PE, babies born to women with
PE often suffer from intrauterine growth restriction and preterm birth along with some of the
associated neonatal comorbidities (i.e., respiratory distress syndrome, intraventricular
hemorrhage) and increased fetal pro-inflammatory profiles [67•]. In addition to this, these
children are more susceptible to neurodevelopmental and behavioral problems as well as
cardiovascular diseases as they age [68•]. All of which suggest that we still need to further
our understanding of the complex relationship between the ischemic placenta, maternal
inflammation and fetal programming.

Clinical Management of PE
The focus of clinical management of preeclampsia are prevention of maternal morbidity by
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aggressive treatment of hypertensive emergency, maternal seizure prevention in severe pre-

eclampsia, and limiting injury to the fetus. These three principles are carried out through the
administration of medications and with the application of fetal surveillance to assess fetal
status. If treatment fails to correct severe maternal hypertension or if there is evidence of
non-reassuring fetal status, delivery is warranted.

Recognition and management of persistently elevated (greater than 15 min in duration)

severe hypertension is necessary to prevent maternal and fetal morbidity and mortality [1••].
This is accomplished through aggressive treatment of SBP ≥ 160 mmHg and/or DBP ≥ 105
mmHg. Labetalol (a beta-blocker) and/or hydralazine (a vasodilator) are considered first-line
therapy for acute hypertensive emergency and are administered intravenously as a bolus.
Immediate-release oral nifedipine, a calcium channel blocker, may also be used as first-line
therapy, especially when intravenous access is not available [69]. The goal of treatment is to
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lower maternal blood pressure 15–25%, with a goal SBP of 140–150 mmHg and DBP of
90–100 mmHg (Fig. 2). Care is taken to avoid excessive lowering of blood pressure, as this
may further decrease placental perfusion and potentiate negative effects on fetal status.
When severe PE develops prior to 34 weeks gestation in the otherwise stable patient,
conservative inpatient management may be considered. In the event of progressive severe
disease or HELLP syndrome, delivery is indicated. Plasma exchange and steroid therapy
have also been used in the care of women with recalcitrant severe preeclampsia and
unremitting HELLP syndrome with favorable results [70••].

Prophylaxis against maternal seizures (eclampsia) is achieved by the use of magnesium

sulfate [63]. Magnesium sulfate is administered either as an intravenous bolus or
intramuscular injection. While magnesium sulfate may have the favorable effect of lowering
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maternal blood pressure, it has been shown to be superior to other anticonvulsants in the
prevention of eclamptic seizures and is considered first-line therapy. However, when
magnesium sulfate is either contraindicated or unavailable, traditional anticonvulsants may
be used.

Fetal assessment is determined based on gestational age and maternal status. In more acute
settings, continuous fetal monitoring is used in an effort to assess for signs of intrauterine

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hypoxia. After maternal stabilization, other mechanisms of fetal assessment (biophysical

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profiles, fetal non-stress tests, fetal umbilical artery Doppler assessments) may be used. If
fetal assessments are non-reassuring, delivery is warranted.

Conclusion
Preeclampsia is a multisystem disorder which is characterized by hypertension and end-
organ dysfunction. It is a source of significant maternal and fetal morbidity and mortality
worldwide. While our understanding of the pathophysiology of pre-eclampsia has grown
significantly in the past decades, greater understanding of the complex relationship between
placental ischemia, maternal inflammation, and fetal programming is needed.

The only known cure for preeclampsia is delivery of the placenta, which often results in
premature delivery of the fetus, exposing the newborn to the immediate risks of prematurity
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as well as additional risks for metabolic disturbances and chronic diseases across the
lifespan of the child. Preeclampsia has also been shown to increase the risk for
cardiovascular disease and overall mortality in those women affected by the disease.

Aggressive management of persistent severe maternal hypertension, seizure prophylaxis

with magnesium sulfate, and assessment of fetal well-being are the hallmarks of clinical
management. When administered timely and appropriately, these interventions have been
shown to decrease maternal and fetal morbidity and mortality [71].

Acknowledgments
This work was funded by the NIH grants HL105324 and HD067541-06.
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Fig. 1.
Placental ischemia leads to release of factors that play a role to pathophysiology of
preeclampsia. Abbreviations: TH1 T helper cells type 1, TH2 T helper cells type 2, AT1-AA
autoantibodies to angiotensin II type 1 receptor, ET-1 endothelin 1, sFlt-1 soluble vascular
endothelial growth factor receptor 1, NO nitric oxide, IUGR uterine growth restriction
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Fig. 2.
Management of onset hypertension in pregnancy. Abbreviations: PE preeclampsia, HELLP
hemolysis, elevated liver enzymes, and low platelet count, IV intravenous, PO orally
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