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Available online at

ScienceDirect
www.sciencedirect.com

Review

Preeclampsia: Pathophysiology and management

R. Nirupamaa , S. Divyashreeb , P. Janhavib , S.P. Muthukumarb , P.V. Ravindrab,*
a
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, United States
b
Department of Biochemistry, CSIR-CFTRI, Mysuru, 570020, India

A R T I C L E I N F O A B S T R A C T

Article history: Preeclampsia is a pregnancy-related multisystem disorder, frequently encountered pregnancy-related

Received 28 August 2020 medical complications next to gestational diabetes mellitus. It is the onset of hypertension during
Received in revised form 25 October 2020 pregnancy. The preeclampsia can be of two types, placental or maternal preeclampsia. Among these two
Accepted 3 November 2020
types former, i.e., placental preeclampsia is more severe than the latter. According to the recent survey by
Available online xxx
National Health Portal of India, the incidence of preeclampsia is about 8–10 % among pregnant women.
Though our understanding of preeclampsia has improved in recent years, the development and
Keywords:
interpretation of the clinical tests remain difficult for preeclampsia. Hence, we have made an attempt to
Preeclampsia
Hypertension
understand the pathophysiology, associated conditions/consequences, treatment and management/
Pregnancy complication prevention of the condition in this review.
Placenta © 2020 Published by Elsevier Masson SAS.
Angiogenic-antiangiogenic factors

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Definition of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Abnormal placentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Placental hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Nitric oxide synthesis pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Angiogenic- antiangiogenic balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Angiotensin –II type-1 receptor agonistic autoantibodies (AT1-AA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Inflammatory response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Clinical representation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Management of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Introduction pregnancy-related medical complications next to gestational

diabetes mellitus. Preeclampsia is one of the leading causes of
Preeclampsia is a pregnancy-related multisystem disorder, maternal mortality and morbidity, neonatal and fetal mortality,
whose pathophysiology is unknown. Preeclampsia is also referred and preterm birth. It is estimated that in developing countries,
as a disease of placenta since it is triggered by placental preeclampsia accounts for 15 % of maternal deaths every year [1]. It
insufficiency. It is one of the most frequently encountered is the 3rd leading cause of maternal mortality in the United States
(US) [2]. The studies show that about 10 % of perinatal death is due
to pregnancy complicated by preeclampsia [3]. Neonatal or fetal
* Corresponding author. death is mostly due to preterm delivery, placental abruption, and/
E-mail address: raviravindra1@gmail.com (P.V. Ravindra). or intrauterine death.

http://dx.doi.org/10.1016/j.jogoh.2020.101975
2468-7847/© 2020 Published by Elsevier Masson SAS.

Please cite this article as: R. Nirupama, S. Divyashree, P. Janhavi et al., Preeclampsia: Pathophysiology and management, J Gynecol Obstet Hum
Reprod, https://doi.org/10.1016/j.jogoh.2020.101975
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Definition of preeclampsia
It is defined as the onset of hypertension during pregnancy
(according to International Society for the Study of Hypertension in
Pregnancy (ISSHP) in 2014), which is characterized by a persistent
high systolic/ diastolic blood pressure of  140/90 mm Hg as well
as proteinuria of  300 mg/ 24 h after 20 weeks of gestation in
women with normal blood pressure previously. According to new
guidelines (2013) by the American Congress of Obstetricians and
Gynaecologists (ACOG), preeclampsia may or may not be
accompanied by proteinuria. Preeclampsia is associated with
maternal organ dysfunction such as acute renal insufficiency, liver,
neurological or hematological complications, uteroplacental dys-
function, fetal growth restriction/ intrauterine growth restriction,
and intrauterine death. Preeclampsia affects both mother and
fetus. A proper intrauterine environment is required for the
adequate development of the fetus. Any changes in the placenta
affect normal growth and development of the fetus. On the
maternal side, preeclampsia causes renal failure, HELLP syndrome
(Hemolysis, Elevated Liver enzymes and Low Platelets), liver
failure, and cerebral oedema with seizures - a severe variant of
preeclampsia. Fetal complications include stillbirth, iatrogenic
prematurity, fetal growth restriction/ intrauterine growth restric-
tion, oligohydramnios, and increased risk of perinatal death [4].
One of the complications of preeclampsia is eclampsia which
accounts for about 2% of preeclamptic pregnancies and 1–4 % of
pregnancies [3]. Eclampsia is defined as a convulsion associated
with preeclampsia found without pre-existing neurological
condition. It is characterized by severe headaches, blurred vision
that might be accompanied with or without hypertension, edema
and proteinuria. The preeclamptic women with seizures are
diagnosed as eclamptic. It is considered as a neurological
complication of preeclampsia.
Fig. 1. The schematic representation of angiogenesis in normal and preeclamptic pregnant mothers.
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Preeclampsia can be broadly categorized into 2 subtypes, viz.
early-onset (placental) and Late-onset (maternal) preeclampsia.
Both appear to have distinguished etiology and phenotypes. Early
reports [5,6] suggests that placental preeclampsia is more severe
than maternal preeclampsia. This may be because, as there is no
increase in the syncytiotrophoblast microparticles in maternal
preeclampsia compared to placental preeclampsia [7]. Placental
preeclampsia is characterized by abnormal placentation due to
placental hypoxia. Placental hypoxia causes decreased placental
growth factor (PlGF). This might be due to reduced expression of
PlGF protein or decreased binding to its receptor. The latter might
be contributed by the increased sFlt-1 levels, a decoy receptor for
VEGF which binds to PlGF and VEGF receptors and thereby blocking
their angiogenic function. This alters the angiogenic and anti-
angiogenic balance that changes the blood flow to the developing
embryo. Placental preeclampsia is associated with the alteration in
the physiologic transformation of spiral arteries in cytotropho-
blast, thereby causing resistance to blood flow in the uterine
arteries [8–10]. Maternal preeclampsia arises due to the interac-
tion between a healthy placenta and maternal factors that would
ultimately cause microvascular damage. This might be due to
maternal endothelial dysfunction. Since maternal preeclampsia
occurs later in the gestation period, this can be managed
expectantly until 37 weeks of gestation [11]. The maternal
preeclampsia occurs at the later stages of pregnancy, hence there
is truly little or no change in the arterial conversion and thus the
placental perfusion is maintained.
Several risk factors are associated with preeclampsia which
include previous chronic hypertension, diabetes mellitus, renal
disease, obesity [12], short stature, nutritional deficiencies,
gestational hypertension [13] in previous pregnancies, heredity,
autoimmune disorders (systemic lupus erythematosus & anti-
phospholipid antibody syndrome), hydatidiform mole, multiple
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pregnancies and fetal macrosomia [14–17], nulliparity, advanced
maternal age, high BMI and assisted reproduction.
Pathophysiology
Though our understanding of preeclampsia has improved in
recent years, the development and interpretation of the clinical
tests remain difficult for preeclampsia. Evidence suggests that
proper screening would be beneficial in managing preeclampsia.
Pathophysiology of preeclampsia includes abnormal placentation,
abnormal spiral artery remodeling, placental insufficiency, and
endothelial dysfunction.
Abnormal placentation
The defective placenta is attributed to the development of
preeclampsia. Examination of the preeclamptic placenta reveals
numerous placental infarcts and arterial sclerosis. This is
accompanied by placental hypoperfusion due to altered tropho-
blast invasion and, thus, placental ischemia. During a healthy
pregnancy, the extravillous cytotrophoblast of fetal origin invades
the spiral arteries in the deciduas and myometrium. These spiral
arteries then lose their endothelial nature and transform
themselves from high resistance vessels into large vessels capable
of providing adequate placental perfusion to supply nourishment
to the developing fetus. This spiral remodeling is disrupted in
preeclamptic condition. Due to impaired spiral artery remodeling,
the placenta is deprived of oxygen, which leads to a condition
called placental ischemia. This favors the production of antiangio-
genic factors into maternal circulation that contributes to
endothelial damage. A lot of previous studies have shown that
increased levels of antiangiogenic factors like tyrosine kinase-1
(sFlt-1) [18,19] and soluble endoglin (sEng) [20] released by the
placenta into the maternal circulation during preeclampsia
contributes to endothelial dysfunction and thus cause proteinuria.
In addition to placental hypoperfusion and ischemia, studies also
reveal the presence of atherosis, vascular lesion including fibrin
deposition, intimal thickening, necrosis, atherosclerosis, and
placental infarcts. Cytotrophoblast invasion also depends on the
expression of adhesion molecules. Abnormal expression of
adhesion molecules by cytotrophoblasts in preeclamptic placental
is reported by several studies [21]. All this evidence suggests the
occurrence of abnormal placentation during preeclampsia. Fur-
ther, Fig. 1 represents the schematic representation of angiogenesis
in normal and preeclamptic pregnancy.
Placental hypoxia
It is a condition that occurs due to abnormal spiral artery
remodeling during preeclampsia. This appears to be the leading
cause of placental insufficiency. Placental hypoxia is shown to
upregulate the expression of sFlt-1 protein in trophoblast culture
from the first trimester placentas [22]. Placental hypoxia induces
Hypoxia Inducible Factor - 1α (HIF- 1α). During normal pregnancy,
which relatively has low oxygen concentration during the first
trimester, HIF- 1α is produced, which is vasculogenic. HIF - 1α
under normoxia is rapidly targeted for proteasomal degradation.
However, during placental hypoxia, there is a variation in the
production of HIF - 1α because of which sFlt-1 expression is
upregulated. sFlt-1 being antiangiogenic causes endothelial
damage during preeclampsia. Besides, during placental hypoxia,
another target for HIF- 1α, TGF- β3 is also increased. This blocks the
trophoblast invasion [23] and cytotrophoblast proliferation [24–
26]. 2-methoxy estradiol, a natural metabolite of estradiol, has
been demonstrated to suppress placental hypoxia by blocking HIF-
1α expression [27]. This metabolite is elevated during 3rd trimester
in a natural pregnancy. A study conducted by Kanasaki et al. [27]
has demonstrated that the addition of 2 methoxy estradiol
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improved preeclamptic like features in COMT knockout pregnant
mice [27]. These studies indicate the involvement of placental
hypoxia in preeclamptic pathophysiology.
Oxidative stress
As discussed above, defective spiral artery remodeling and
abnormal cytotrophoblast invasion in preeclampsia are responsi-
ble for placental hypoperfusion and ischemia. This favors a high
level of oxidative stress. During normal pregnancy, the placenta
undergoes a state of oxidative stress due to increased mitochon-
drial activity in the placenta that leads to the production of excess
reactive oxygen species (ROS) [28,29]. However, during pre-
eclampsia, this effect is enhanced due to abnormal placentation.
Several studies have reported high levels of lipid peroxides in
preeclamptic women compared to normal pregnant women
[30,31]. Several essential antioxidants such as vitamins C, A & E,
glutathione levels, and iron-binding capacity are lowered in
preeclamptic women. ROS is found to be increased in the
preeclamptic placenta, especially in and around the blood vessel.
Dechend et al. [32] demonstrated the correlation between
increased ROS production and increased activity of NADPH
oxidase. He showed that VSMCs and trophoblasts were stimulated
with AT1-AA isolated from preeclamptic women increased ROS
production NADPH oxidase components p22, p47 and p67 phox
protein expression.
Nitric oxide synthesis pathway
Placental hypoxia and ischemia have found to be triggering
factors for reduced nitric oxide synthesis. Nitric oxide (NO) is
synthesized from L-arginine by endothelial nitric oxide synthase
(eNOS) in vascular endothelial cells. NO is a potent vasodilator that
helps in the relaxation of spiral arteries, thus reducing vascular
resistance. Several animal studies have shown enhanced produc-
tion and responsiveness to NO in reproductive tissues in normal
pregnancy. However, NO synthesis is reduced during preeclampsia,
which causes vasoconstriction. It is also a contributing factor for
altered spiral artery remodeling that is seen during preeclampsia.
Reduction in NO synthesis appears to be associated with several
uteroplacental changes like decreased uterine artery diameter,
spiral artery length, and uteroplacental blood flow [33]. These
studies suggest the critical role of NO synthesis in spiral artery
remodeling and uteroplacental blood flow during normal preg-
nancy.
Angiogenic- antiangiogenic balance
Angiogenic factors play a significant role in the development of
preeclampsia. A well-developed vasculogenesis and angiogenesis
in the placenta is a prerequisite for the proper development of the
fetus. Alterations in the angiogenic factors will certainly affect the
vasculature. A large body of studies supports the angiogenic
imbalance in the development of the preeclamptic condition.
Vascular endothelial growth factor (VEGF), placental growth factor
(PIGF), β- fibroblast growth factor (β-FGF), TGF-β, and angiopoie-
tins are some of the angiogenic proteins known to influence the
vasculogenesis and angiogenesis. These angiogenic factors bring
about the changes in the vasculature by binding to their receptors.
Thus angiogenic proteins with their receptors Flt-1/ VEGFR-1,
VEGFR-2, Tie-1, and Tie-2 are found to be essential for normal
vascular development. A few previous studies have demonstrated
the role of VEGF and its isoforms in pregnancy. VEGF is a cytokine
synthesized by cytotrophoblast during pregnancy. Any alteration
in the expression and function of VEGF, its receptor and isoforms
will have an adverse effect on the endothelium. Free bioactive
VEGF levels are reported to be decreased significantly in
preeclampsia [34–36], whereas sFlt-1 is found to be significantly
elevated in preeclamptic subjects. sFlt-1 acts as a decoy receptor
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that binds with free VEGF and disrupts its normal signaling
pathway. This finding is confirmed by several studies that have
shown altered VEGF signaling in preeclampsia [37–39].
VEGF and its receptors are highly expressed by invasive
cytotrophoblast in the first trimester of pregnancy for proper
vascular development of the placenta. However, several human
studies have shown altered expression of VEGF, PlGF, and VEGFR-1
in preeclamptic condition [40]. PlGF has structural homology to
VEGF and is a potent angiogenic protein. PlGF is mainly secreted by
syncytiotrophoblast of the placenta, which is also required for
vasculogenesis throughout embryonic development during nor-
mal pregnancy. However, preeclampsia is found to be associated
with decreased PlGF levels. In fact, a reduction in PlGF is noticed
quite early in women who are destined to develop preeclampsia,
whereas sFlt-1levels are elevated in the preeclamptic state
[18,41,42]. sFlt-1 binds to both VEGF and PlGF in preeclampsia
and prevents them from binding to endogenous receptors [43].
sFlt-1, when injected into mice, developed significant hypertension
and proteinuria like preeclamptic condition [44] and similar
results were also reported by Maynard and his colleagues where
they overexpressed sFlt-1 in rats using viral vectors [39]. Thus, sFlt-
1 appears to be the central mediator for preeclampsia. Several
investigators have opined that sFlt-1 elevation in maternal
circulation precedes the onset of clinical preeclampsia
[18,45,46]. sFlt-1 administration in vivo produces vasoconstriction
and endothelial dysfunction.
Another important antiangiogenic factor found to be involved
in preeclampsia is sEndoglin (sEng). This angiogenic protein is a
cell surface receptor for TGF- β. sEng have antiangiogenic
properties [47–49]. Endoglin, also referred as CD105, is a
membrane-bound protein which binds with TGF-β1 and TGF-
β3. This protein is found significantly in syncytiotrophoblasts,
proliferating endothelial cells, hematopoietic stem cells, and
stromal cells. This activates the endothelial nitric oxide synthesis
[17]. However, sENG is a decoy receptor for TGF- β, which binds and
blocks endoglin action.
In circulation, both sFlt-1 and sEng bind to their receptors and
blocks the action of pro-angiogenic factors such as VEGF, PlGF, and
TGF – β. Thus, it is clear from existing evidence that the expression
of angiogenic factors during placental development is essential for
the uteroplacental circulation and embryonic development
[50,51].
Another antiangiogenic splice variant of VEGF –A, VEGF165b
appears to play a significant role in the pathogenesis of
preeclampsia. [52] showed a positive correlation between the
VEGF angiogenic forms and their antiangiogenic splice variants in
the healthy placenta and negative correlation of the same in the
preeclamptic placenta. The role of this novel splice variant of VEGF
is still under research. Based on the levels of these splice variants,
they have demonstrated the angiogenic and antiangiogenic
imbalance in preeclampsia.
Angiotensin –II type-1 receptor agonistic autoantibodies (AT1-AA)
Studies have shown a link between the production of
autoantibodies and the development of preeclampsia. Numerous
studies have reported angiotensin receptor against autoanti-
bodies that bind to and activate AT1 angiotensin receptor [53,54].
Wallukat et al. [53] first reported these antibodies, in preeclamp-
tic women. During normal pregnancy, although Ang-II levels are
high, women are refractory to its vasopressor effects. A previous
study [55] showed that normal pregnant women require twice
the concentration of Ang-II during pregnancy to experience the
vasomotor response of the same. It is speculated that the reason
behind this is might be due to increased production of
progesterone and prostacyclin, which decreases Ang-II sensitivi-
ty [56].
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J Gynecol Obstet Hum Reprod xxx (xxxx) xxx
In preeclampsia, the presence of AT-1 AA increases vascular
sensitivity of the placenta to Ang-II and other vasoconstrictive
agents [57]. This hypersensitivity is secondary to the production of
AT1-AA that binds and activates the Ang-II receptor [53], thus
reducing cytotrophoblast invasion. This action of AT1-AA is
executed via the production of high levels of sFlt-1. The production
of sFlt-1 by AT1-AA increases by 2–5 fold when compared to
normal pregnancy (normal pregnancy [39,40,58]. Another vital
function of AT-1AA in inducing preeclampsia is via increasing
expression of Plasminogen Activator Inhibitor-1 (PAI-1) levels
[59,60]. PAI-1 inhibits Urokinase- like plasminogen activator (uPA),
resulting in decreased synthesis of plasmin. This leads to reduced
extracellular matrix digestion and thereby causing shallow
trophoblast invasion in the placenta.
During normal pregnancy, the trophoblast invasion and spiral
artery remodeling are assisted by immune cells like macrophages,
dendritic cells, and natural killer cells (NK cells) which infiltrate
the deciduas and congregate around the trophoblast cells allowing
them to reach endothelium [61–63]. Improper trophoblast
invasion in preeclampsia and placental ischemia due to inappro-
priate spiral artery remodeling both contribute to the immune
imbalance that is typically seen in the preeclamptic condition.
Thus, existing evidence shows that an altered immune response
also contributes significantly to the development of preeclampsia.
Inflammatory response
Inflammatory responses are nonspecific and can be elicited by
any tissue injury. Immune response elicits an inflammatory
response. Altered immune response initiates the inflammation
in preeclampsia. During normal pregnancy, there is increased
innate immunity. Cells of innate immunity like monocytes and
granulocytes are increased, whereas NK cells and dendritic cells
are decreased. In contrast to this, there is an elevation in the
production of NK cells and dendritic cells during preeclampsia
because of the altered immune response. This initiates inflamma-
tory pathways similar to those seen in autoimmune diseases [64–
66]. Proinflammatory cytokines like Interferon- g, TNF- α and IL- 1,
2, 6, 8, 15, 16 & 18 are significantly elevated [67], on the other hand,
anti-inflammatory cytokines are reduced in the maternal circula-
tion of preeclamptic women. This imbalance leads to chronic
inflammation and further complicates the pregnancy. In addition,
Toll-Like Receptor – 4 (TLR-4) is found to be associated with
preeclampsia and HELLP syndrome [68]. In the vascular endothe-
lium, TNF-α and IL-6 contribute endothelial dysfunction and is
characterized by increased production of adhesion molecules
[69,70]. TNF-α also activates endothelial cells and produces
significantly high levels of a potent vasoconstrictor endothelin-1
[71,72].
Clinical representation
Clinical representation of preeclampsia is very difficult.
Preeclampsia is asymptomatic in the first 2 trimesters of
pregnancy as the symptoms are highly variable. Preeclampsia
often remain obscure to identify and hence it could be dangerous. It
is a heterogenous multisystem disorder that can be diagnosed only
during routine antenatal visits. The early signs are high blood
pressure, which is characterized by a systolic blood pressure of 
140 mm Hg and diastolic blood pressure of  90 mm Hg and
proteinuria of  300 mg/24 h. Besides, swelling of legs occurs due
to edema. However, edema cannot be considered as a diagnostic
triad for preeclampsia as it is nonspecific since pregnant women
without preeclampsia also develop edema towards the end of
pregnancy. The other symptoms include headache, rapid weight
gain, abdominal pain, changes in reflexes, dizziness, excessive
vomiting and nausea, visual changes. In severe cases, right upper
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quadrant pain from acute liver injury, hemolysis, and seizures due
to eclampsia may occur if not treated immediately. Eclamptic
seizures complicate around 2% of preeclampsia. These seizures
might also occur about 48 h to one month after delivery. Fetal and
neonatal complications include premature delivery, iatrogenic
prematurity, fetal growth restriction, oligohydramnios, and
perinatal death. These complications occur due to placental
insufficiency, abnormal placentation, and abnormal uteroplacental
blood flow.
Management of preeclampsia
Despite extensive research on preeclampsia till date, there is no
treatment for preeclampsia except delivery. Currently, several
clinical tests are suggested to confirm preeclampsia. These include
blood tests comprised of liver function tests, kidney function tests
and also platelet count, urine analysis measuring amount of
protein in urine for 24 h and also to measure the ratio of protein to
creatinine, non stress test or biophysical profile which is a test to
check baby heart rate when baby moves, ultrasound to measure
baby's breathing and volume of amniotic fluid in the uterus and
fetal ultrasound to monitor baby's growth and fetal weight.
Though our understanding on the pathophysiology of pre-
eclampsia has improved over the past 10 years, there is still no
accurate diagnostic tool or biomarkers for screening and diagnos-
ing preeclampsia in the early stages of gestation. Preeclampsia is a
major cause of maternal and fetal mortality and morbidity and has
an adverse effect on mothers after pregnancy. Clinical data
suggests that early detection, monitoring, and management are
beneficial for preeclampsia. Currently, there is no screening or
diagnostic test for preeclampsia. Management decisions should
balance maternal risks for continued delivery and fetal risks in
association with preterm delivery. The decision depends on the
gestational age at diagnosis time and severity of preeclampsia.
For severe preeclamptic women, the treatment includes both
for the control of hypertension and the prevention of eclampsia.
Mother is subjected to both laboratory tests and ultrasound testing
to monitor the severity of the disease. International guidelines
strongly recommend administration of antihypertensive drugs for
severe hypertension and preeclampsia. This treatment benefits the
mother from undergoing severe complications like cerebral
hemorrhage and eclampsia. These medications include methyldo-
pa, hydralazine, β- blockers and nifedipine, and acetylsalicylic acid.
Vasodilators have been tried to prevent preeclampsia and prolong
pregnancy in women with preeclampsia. Methyldopa is recom-
mended as the first line of treatment. It is an α2- adrenergic
receptor agonist. It inhibits vasoconstriction. It is the most
frequently used because of its beneficial effect. It does not affect
maternal uterine artery Doppler pulsatility and decreases systemic
vascular resistance. However, it is advised to avoid this drug in
women with a prior history of depression because of the induction
of postnatal depression.
Several studies have also indicated the usage of aspirin and low
molecular weight heparin to prevent preeclampsia [73,74].
However, there is no standard dosage prescribed for the
administration of aspirin. Repeated doses of nifedipine, intrave-
nous hydralazine, or labetalol every 15 30 min is effective in
bringing blood pressure under control in 80 % of women [75–78].
Corticosteroid therapy is also prescribed in the treatment of
HELLP syndrome and to prevent respiratory distress syndrome in
preeclamptic pregnancy [79]. Though corticosteroid therapy did
not significantly associated with maternal mortality and morbidi-
ty, the corticosteroid therapy improved platelet count and reduced
blood transfusion rate and ICU admission, as reported by Mao and
Chen [79]. The most widely used corticosteroid, betamethasone,
accelerate fetal lung maturity (Amorim et al., 1999).
5
J Gynecol Obstet Hum Reprod xxx (xxxx) xxx
Administration of betamethasone at a dosage of 2 injections of
12 mg 24 h apart reduced the risk of neonatal mortality, hyaline
membrane disease, and intraventricular hemorrhage [80].
Magnesium sulfate is also used as a part of therapeutic strategies
to treat preeclampsia. Magnesium sulfate is given intravenously to
prevent seizures in women with preeclampsia. This is given along
with corticosteroids. Magnesium sulfate prolongs the pregnancy up
to 2 days [81]. Thus, it is given in combination with corticosteroids so
that it speeds up baby’s lung maturation.
All complications of preeclampsia can also occur during the
postnatal period, especially during the first 48 h. Labetalol and
hydralazine are prescribed to treat severe hypertension during the
post natal period. In addition, calcium supplementation at a dosage
of 1.5 g/day is recommended by the WHO throughout pregnancy.
Statins that stimulate the heme oxygenase-1 expression also
prescribed to prevent early-onset preeclampsia [82]. Studies show
that pregnant women with high sFlt-1:PlGF ratio are at risk of
hypertensive disorder. Though there are very less scientific
evidence on the usage of these molecules to manage preeclampsia,
these studies shows a promising therapeutic strategies for the
management of preeclampsia. Further studies are required
regarding their mechanism of action to use standardize the dose
during preeclampsia.
Following delivery, the patients must be followed at least for 72
h. Hemodynamic and laboratory monitoring include frequent
blood pressure monitoring, diuresis, signs of seizures including
headaches, tinnitus, and brisk tendon reflexes. Further, clinical
tests like blood count, liver function tests, and kidney function
tests are monitored for a few days to a month.
Prevention
Preeclampsia is more challenging to manage than prevention. A
lot of evidence is available regarding the risk factors for
preeclampsia; however, interpretation is complicated. There are
numerous factors, including a family history of preeclampsia,
immunologic factors, genetic factors, nulliparity, high BMI,
increased maternal age, congenital anomalies, a hydatidiform
mole, chronic hypertension, kidney disease, diabetes, insulin
resistance, stress, etc.
The screening of preeclampsia is very difficult as it is
asymptomatic. Reliable and accurate biomarkers would be
essential to predict the occurrence of preeclampsia in 3rd
trimester. Imaging tests like uterine artery Doppler ultrasound
allows only for predicting only one-third of preeclamptic cases
[39]. Since there is no single test available that can predict
preeclampsia, combination of tests is used to assess the
preeclampsia condition. The most frequently used biomarkers
for preeclampsia are sFlt-1, PlGF, endoglin, and VEGF. Increased
levels of sFlt-1 and sEng combined with decreased levels of PlGF
during 1st trimester are found to be associated with the occurrence
of preeclampsia. Studies show that the relationship between sFlt-
1/PlGF is regarded as a promising index of the imbalance between
angiogenic and antiangiogenic factors [18,83–85].
Conclusion
Preeclampsia is a pregnancy-related heterogeneous disease
whose etiology is not entirely understood. How angiogenic
imbalance occurs, what causes abnormal spiral artery remodel-
ing, abnormal placentation, and placental insufficiency? and
their molecular mechanism behind the development of pre-
eclampsia remains unknown. Preeclampsia poses a significant
risk for both mother and fetus. The only solution for
preeclampsia is delivery. However, preterm delivery is associ-
ated with several complications.
G Model
JOGOH-101975; No. of Pages 7
R. Nirupama, S. Divyashree, P. Janhavi et al.
Angiogenic factors appear to play a significant role in the
establishment of a proper intrauterine environment for the growth
of the fetus. A minuscule change in this environment will have an
adverse effect on both mother and fetus. Recent studies have
identified several biomarkers that will aid in the early diagnosis of
this dangerous disease. Screening for these biomarkers would
prove beneficial to prevent pregnancy-related complications.
Future studies should aim at investigating the molecular mecha-
nisms behind the altered angiogenesis and developing a novel and
reliable biomarkers for early screening of this disease.
Funding
The corresponding author wishes to thank the Department of
Biotechnology (DBT), Govt. of India and Science and Engineering
and Research Board (SERB), Department of Science and Technolo-
gy, New Delhi, India for providing the financial support in the form
of Ramalingaswamy Fellowship and extramural grant respectively.
Declaration of Competing Interest
We declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported
Acknowledgements
The authors are grateful to the Director, CSIR-CFTRI, Mysuru for
providing the required facilities for this study.
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