Non-obstetric complications in preeclampsia

Abstract

Preeclampsia is a multisystem disorder of pregnancy that remains a leading cause of maternal and foetal morbidity and mortality. It is still an underestimated risk factor for future cardiovascular, cerebrovascular, and kidney disease, developing often in the perimenopausal period of a woman's life. It remains unclear whether preeclampsia is an individual risk factor for future cardiovascular, cerebrovascular, and renal events or an early marker of women with high-risk profiles for these diseases. Risk factors for cardiovascular disorders and preeclampsia are very similar and include the following: obesity, dyslipidaemia, insulin resistance, pro-inflammatory and hypercoagulable state, and endothelial dysfunction. Thus, the pregnancy can only be a trigger for cardiovascular alterations that manifest in development of preeclampsia. On the other hand, there is strong evidence that changes in cardiovascular, endothelial, and metabolic systems occurring in the course of preeclampsia may not fully recover after delivery and can be a cause of future disease, especially in the presence of other metabolic risk factors regarding, for example, perimenopause. In this review the authors present current knowledge about short- and long-term maternal consequences of preeclampsia, such as: cardiovascular disease, cerebrovascular incidents (posterior reversible encephalopathy and stroke), kidney injury (including the risk of end-stage renal disease), liver failure, and coagulopathy (thrombocytopenia and disseminated intravascular coagulation).

Full text

99
Corresponding author:
Katarzyna Pankiewicz, Department of Obstetrics and Gynaecology, Institute of Mother and Child,
17a Kasprzaka St., 01-211 Warsaw, Poland, e-mail: katarzynahak@wp.pl
Review papeR
DOI: https://doi.org/10.5114/pm.2019.85785
Menopause Rev 2019; 18(2): 99-109
Introduction
Preeclampsia is considered to affect about 5-8%
of all pregnancies. It is defined in accordance with the
European Society of Cardiology (ESC) guidelines on
the management of cardiovascular diseases during
pregnancy 2018 as hypertension (blood pressure
≥140/90mm Hg) developing after 20 weeks’ gestation
accompanied by anew-onset of significant proteinuria
(> 0.3 g/24 h) [1]. In other definitions – American College
of Gynaecologists and Obstetricians (ACOG) anew-onset
proteinuria is not necessary to diagnose preeclampsia –
instead, hypertension can be accompanied by one of the
following: signs of liver or renal dysfunction, cerebro-
vascular or cardiovascular incidents, and foetal growth
restriction (FGR). Early-onset preeclampsia is defined as
disease developing before 34 weeks’ gestation, whereas
late-onset preeclampsia is defined as disease developing
at or after 34 weeks’ gestation [2].
Pathophysiology of preeclampsia
The underlying mechanism for preeclampsia is
thought to be impaired placentation due to inadequate
Non-obstetric complications in preeclampsia
Katarzyna Pankiewicz1, Ewa Szczerba2, Tomasz Maciejewski1, Anna Fijałkowska2
1Department of Obstetrics and Gynaecology, Institute of Mother and Child, Warsaw, Poland
2Department of Cardiology, Institute of Mother and Child, Warsaw, Poland
Abstract
Preeclampsia is amultisystem disorder of pregnancy that remains aleading cause of maternal and foetal
morbidity and mortality. It is still an underestimated risk factor for future cardiovascular, cerebrovascular, and
kidney disease, developing often in the perimenopausal period of awoman’s life. It remains unclear whether
preeclampsia is an individual risk factor for future cardiovascular, cerebrovascular, and renal events or an early
marker of women with high-risk profiles for these diseases. Risk factors for cardiovascular disorders and preec-
lampsia are very similar and include the following: obesity, dyslipidaemia, insulin resistance, pro-inflammatory
and hypercoagulable state, and endothelial dysfunction. Thus, the pregnancy can only be atrigger for cardiovas-
cular alterations that manifest in development of preeclampsia. On the other hand, there is strong evidence that
changes in cardiovascular, endothelial, and metabolic systems occurring in the course of preeclampsia may not
fully recover after delivery and can be acause of future disease, especially in the presence of other metabolic
risk factors regarding, for example, perimenopause. In this review the authors present current knowledge about
short- and long-term maternal consequences of preeclampsia, such as: cardiovascular disease, cerebrovascular
incidents (posterior reversible encephalopathy and stroke), kidney injury (including the risk of end-stage renal
disease), liver failure, and coagulopathy (thrombocytopenia and disseminated intravascular coagulation).
Key words: preeclampsia, cardiovascular disease, stroke, kidney disease, coagulopathy.
trophoblastic invasion of the maternal spiral arteries.
On the basis of recent studies, preeclampsia is consid-
ered as atwo-stage disorder. The first stage is reduced
placental perfusion due to failed remodelling of the ma-
ternal vessels. It results in the imbalance between pro-
angiogenic and antiangiogenic factors, aconsequence
of which is endothelial damage leading to the second
stage: development of acute maternal syndrome with
systemic multiorgan dysfunction [3].
Apart from antiangiogenic state, which seems to be
one of the most important factors, there are alot of oth-
er pathogenetic mechanisms implicated in preeclamp-
sia, including: oxidative stress, the presence of type-1
angiotensin II receptor (AT1) autoantibodies, platelet and
thrombin activation, and intravascular inflammation [3].
An antiangiogenic state in preeclampsia manifests as
an overexpression of soluble fms-like tyrosine kinase 1
(sFlt-1), which is asoluble form of type-1 receptor for
vascular endothelial growth factor (VEGF). sFlt-1 binds
VEGF and placental growth factor (PlGF) and causes de-
fective angiogenesis and endothelial dysfunction. VEGF
and PlGF are very important for the maintenance of en-
dothelial cell function, especially in fenestrated endo-
thelium, which is found in the brain, liver, and glomer-
Submitted: 18.01.2019
Accepted: 9.05.2019

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uli. In preeclampsia maternal plasma concentrations of
sFlt-1 are significantly increased, even prior to clinical
diagnosis of disease, whereas levels of VEGF and PlGF
are significantly decreased [3].
A second antiangiogenic factor implicated in the
pathogenesis of preeclampsia is soluble endoglin (sEng),
acell-surface co-receptor of TGF-β (tumour growth fac-
tor β) that induces migration and proliferation of en-
dothelial cells. Maternal plasma concentrations of sEng
in preeclampsia are also significantly higher than in
healthy controls. Oxidative stress and anti-AT1 autoan-
tibodies can stimulate placental production of antian-
giogenic factors and additionally contribute to impaired
placentation and development of preeclampsia [3].
The pathophysiology of preeclampsia is summarised
in Figure 1.
Screening of preeclampsia
Knowledge about the mechanisms responsible for
the development of disease led to the introduction into
clinical practice screening methods of preeclampsia. This
screening is performed in the first trimester, during rou-
tine 11-13-week ultrasound examination, and includes
Doppler evaluation of blood flow in uterine arteries and
measurement of maternal plasma concentrations of sev-
eral factors, such as PlGF, sFlt-1, sEng, and PAPP-A.
The combination of maternal risk factors (history of
preeclampsia, multiple pregnancy, obesity, black race), ultra-
sound indices, and biochemical measurements can reach
apositive predictive value for developing preeclampsia later
in pregnancy even at the level of about 96%. Patients with
high risk of preeclampsia can receive acetylsalicylic acid
prophylaxis, which can reduce that risk. This is, however, not
clinically relevant to low-risk women [4].
Epidemiology and complications
in preeclampsia
In developed countries preeclampsia is aleading cause
of maternal and foetal morbidity and mortality. It is re-
sponsible for about 16-18% of maternal perinatal deaths
and up to 40% of foetal and neonatal deaths.
The most common complications occurring in the
course of preeclampsia are: preterm delivery, foetal growth
restriction (FGR), intrauterine foetal death (IUFD), and HELLP
syndrome with high risk of liver rupture and eclampsia.
Avery serious problem is the onset of severe maternal
multiorgan dysfunction, including: heart failure, peripar-
tum cardiomyopathy, pulmonary oedema, disseminated
intravascular coagulation (DIC), cerebrovascular inci-
dents (posterior reversible encephalopathy syndrome and
stroke), acute renal failure, and liver failure.
All these complications (see Table 1) can cast along
shadow on maternal health in the future, years after de-
livery [1, 2].
Cardiovascular short- and long-term
complications in preeclampsia
The most common cardiovascular complications
associated with preeclampsia are: heart failure, peri-
partum cardiomyopathy, pulmonary oedema, and in-
creased cardiovascular risk in future life [5].
Heart adaptation during pregnancy
During normal pregnancy, the cardiovascular sys-
tem undergoes alot of haemodynamic changes in or-
der to support the developing foetal-placental unit.
Total peripheral resistance decreases and consequent-
ly blood pressure falls, with the greatest decrease in the
second trimester (between 16 and 20 weeks). Cardiac out-
put increases by 30-50% during the first two trimesters
and plateaus after 20 weeks of gestation. It is achieved by
an increase in heart rate (10 bpm on average) and a50%
rise in plasma volume. These changes are accompanied
by atransient left ventricle (LV) eccentric hypertrophy as
acompensatory mechanism of volume overload. All these
changes fully recover postpartum. However, pregnant
women can complain about easy fatigue, dyspnoea, exer-
cise intolerance, and oedema. These symptoms are quite
common during pregnancy, but they may mask the pres-
ence of underlying LV dysfunction [6].
Fig. 1. Pathophysiology of preeclampsia
Eclampsia
Genetic factors Immunological factors
Inadequate trophoblast invasion into maternal spiral arteries
Reduced placental blood flow and hypoxia
Endothelial dysfunction
Increased total
vascular resistance
Multiorgan dysfunction
Hypertension
Oxidative
stress
AT1
antibodies
Proinflammatory
cytokines
Antiangiogenic
state aFlt-1, sEng
STBM
Heart failure,
pulmonary
oedema Proteinuria
HELLP
syndrome

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Hypertension – current treatment options
Hypertension is an essential part of preeclampsia
and contributes to development of other complica-
tions, such as heart failure, renal dysfunction, or cere-
bral injury.
Drug treatment of severe hypertension in pregnancy is
required and beneficial, whereas treatment of less severe
hypertension is controversial. Although it might be bene-
ficial for mothers with hypertension to reduce their blood
pressure (BP), alower BP may impair uteroplacental per-
fusion and foetal growth. The benefits and risks of anti-
hypertensive therapy for mild to moderate hypertension
(defined as systolic blood pressure SBP of 140-169 mm
Hg and diastolic blood pressure [DBP] of 90-109 mm Hg)
are still discussed.
Current ESH/ESC guidelines recommend initiation
of drug treatment at BP of 140/90 mm Hg in women
with gestational hypertension, pre-existing hyperten-
sion with superimposed preeclampsia, or hypertension
with subclinical organ damage or symptoms at any
time during pregnancy. In any other circumstances drug
treatment is recommended if SBP ≥ 150 mm Hg or DBP
≥ 95 mm Hg [1].
In contrast, ACOG guidelines recommend, for wom-
en with mild gestational hypertension or preeclampsia
with apersistent BP of less than 160 mm Hg systolic or
110 mm Hg diastolic, that antihypertensive drugs
should not be administered [2].
Acute-onset, severe systolic (≥ 160 mm Hg) or di-
astolic (≥ 110 mg) hypertension that is persistent for
15 minutes or more is considered as an emergency
and demands immediate treatment, because it can
cause central nervous system injury. It is very import-
ant to remember that the goal is not to normalise BP,
but to achieve arange 140-150/90-100 mm Hg in or-
der to prevent repeated, prolonged exposure to severe
systolic hypertension, with subsequent loss of cerebral
vasculature autoregulation and at the same time not
to cause obstetric complications related to decreased
uteroplacental blood flow, such as placental abruption
or immediate foetal deterioration leading to IUFD [1, 2].
Heart failure during preeclampsia and the
postpartum period
In women who develop preeclampsia, inadequate
trophoblast invasion into maternal spiral arteries leads
to impaired transformation of maternal vessels and
uteroplacental circulation remains high-resistant with
lower blood flow. An antiangiogenic state cause general
vasoconstriction. In contrast to normal pregnancy, total
vascular resistance and vascular stiffness in patients
with preeclampsia are increased and cause apressure
overload of the maternal heart, which leads to LV re-
modelling and diastolic dysfunction [7].
A typical finding in women with preeclampsia is
mild-to-moderate isolated LV diastolic dysfunction ac-
companied by LV concentric hypertrophy. LV remodel-
ling is asymmetrical, involving predominantly the basal
anteroseptum and is aresponse to the increased sys-
temic afterload in order to minimise myocardial oxygen
demand and preserve LV function [6].
Diastolic function abnormalities may also play asig-
nificant role in the pathogenesis of pulmonary oedema.
It is alife-threatening condition, developing mainly in
the early post-partum period in the setting of haemo-
dynamic changes and fluid resorption. In a recently
published study pulmonary oedema occurred in 9.5%
of patients with severe preeclampsia [5].
Global systolic function is preserved in the majori-
ty of women with preeclampsia. However, acute heart
failure with reduced ejection fraction may also occur,
especially as a result of hypovolaemia from haemor-
rhage, intracerebral haemorrhage, or the adverse effect
of pharmacological agents. Arare cause of acute heart
failure in preeclampsia is myocardial infarction related
to spontaneous coronary artery dissection [5-7].
Several studies assessing the relationship between
signs of impaired placentation (e.g. altered uterine ar-
teries Doppler indices), cardiovascular profile, and de-
velopment of preeclampsia revealed that women with
both placental insufficiency and LV dysfunction were
more likely to develop preeclampsia than those with
placental insufficiency but normal LV function. It shows
that the ability of the maternal cardiovascular system
to adapt to placental dysfunction plays an important
role in the development of preeclampsia [7].
Table 1. Most common obstetric and non-obstetric complica-
tions in preeclampsia.
Obstetric complications
in preeclampsia
Non-obstetric complications
in preeclampsia
Intrauterine growth restriction
(IUGR)
Heart failure
Intrauterine foetal death (IUFD) Peripartum cardiomyopathy
Preterm delivery Pulmonary oedema
HELLP syndrome Future risk of cardiovascular
disease
Eclampsia Posterior reversible
encephalopathy syndrome
Stroke
Renal failure
Acute kidney injury
Future risk of end-stage renal
disease
Liver failure
Hepatic rupture
Coagulopathy (i.a.
thrombocytopaenia and DIC)

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Peripartum cardiomyopathy
Peripartum cardiomyopathy (PPCM) is defined by
the European Society of Cardiology as cardiomyopathy
with reduced ejection fraction (< 45%) presenting to-
wards the end of pregnancy or in the first four months
postpartum in a woman without previously known
structural heart disease [8].
A recent meta-analysis of 22 studies with almost
1000 cases of PPCM revealed the presence of pre-
eclampsia in 22% of patients [8].
However, there are controversies in the definition
of PPCM, and some researchers state that heart fail-
ure in the course of any hypertensive disorder during
pregnancy cannot be included in the definition of PPCM
– they call it hypertensive heart failure of pregnancy
(HHFP) [9].
On the other hand, it was recently suggested that
PPCM may be associated with increased placental pro-
duction of sFlt-1, as in preeclampsia. Serum sFlt-1 level
is increased not only in women with preeclampsia, but
also in patients suffering from PPCM without any hyper-
tensive disorder (up to 10-fold higher than in the control
group). In normal pregnancies sFlt-1 serum levels return
to normal values within 48-72 hours after delivery. In
patients developing PPCM postpartum sFlt-1 levels are
still elevated four to six weeks after delivery, especially in
women with preeclampsia [10].
Future cardiovascular risk
The syndrome of preeclampsia is now recognised as
a risk factor for future cardiovascular disease. Epide-
miological studies revealed that preeclampsia is associ-
ated with four-fold increased risk of heart failure, two-
fold increased risk of coronary artery disease, two-fold
increased risk of stroke, and two-fold increased risk of
cardiovascular death later in life [11, 12] (Table 2).
It still remains unclear whether preeclampsia is an
individual risk factor for future cardiovascular events or
an early marker of women with high-risk profiles for
cardiovascular disease. Risk factors for cardiovascular
disorders and preeclampsia are very similar and in-
clude: obesity, dyslipidaemia, insulin resistance, pro-in-
flammatory and hypercoagulable state, and endothelial
dysfunction. Thus, the pregnancy can only be atrigger
for cardiovascular alterations that manifest in the de-
velopment of preeclampsia.
On the other hand, there is strong evidence that
changes in cardiovascular, endothelial, and metabolic
systems occurring in the course of preeclampsia may not
fully recover after delivery and can be acause of future
disease. Melchiorre et al. found that one year postpartum
70% of women with early-onset preeclampsia presented
stage B (asymptomatic) heart failure and 40% developed
hypertension within one or two years after delivery. It
was quite different in the group of women with late-on-
set preeclampsia – only 24% presented stage B heart
failure one year postpartum [7, 13].
In the study performed by Irgens et al. on aNorwe-
gian cohort, with 13 years of follow-up, preeclampsia
was associated with significantly higher risk of car-
diovascular-related death. The highest association in-
volved early-onset preeclampsia with preterm birth,
whereas women with term preeclampsia had only
aslight increase in cardiovascular-related death but no
significant increase in stroke [14].
The study called CHAMPS, published in 2005, con-
sisting of acohort of 1 million women with maternal
placental syndromes (preeclampsia, gestational hyper-
tension, placental abruption, and FGR) followed for an
average 8.7 years revealed additionally that women
with pregnancies complicated by FGR or stillbirth had
the highest risk of cardiovascular disease. It means that
even typical obstetric complications in preeclampsia are
related to elevated cardiovascular risk, and pregnancy
can be found as akind of “stress test” for the heart and
the whole cardiovascular system [15].
For all these reasons, since 2011 the American
Heart Association has included hypertensive disorders
of pregnancy to major risks factors for cardiovascular
diseases and recommends that obstetricians refer their
patients to primary care physicians or cardiologists be-
cause they need adequate follow-up [16].
ESC in the 2016 European Guidelines on cardiovas-
cular disease prevention in clinical practice suggests
that in women with history of preeclampsia and/or ges-
tational hypertension periodic screening for hyperten-
sion and diabetes mellitus should be performed [17].
Also, the ACOG recommends yearly assessment of
BP, lipids, fasting blood glucose, and body mass index for
women with medical history of preeclampsia who gave
Table 2. Future risk of cardiovascular, cerebrovascular, and
kidney disease in women with preeclampsia [11, 12, 31-33]
Event Study/
meta-analysis
Risk
Heart failure Wu et al. RR 4.19 (95% CI 2.09-8.38)
Coronary heart
disease
Wu et al.
Berks et al.
RR 2.50 (95% CI 1.43-4.37)
RR 1.89 (IQR 1.76-1.98)
Cardiovascular
disease death
Wu et al.RR 2.21 (95% CI 1.83-2.66)
Stroke Wu et al.
Berks et al.
RR 1.81 (95% CI 1.29-2.55)
RR 1.55 (IQR 1.40-1.71)
Microalbuminuria McDonald et al.RR 4.31 (95% CI 2.7-6.89)
End-stage renal
disease
Vikse et al.
Dai et al.
RR 4.7 (95% CI 3.6-6.1)
PE in 1st pregnancy
RR 15.5 (95% CI 7.8-30.8)
PE during 2nd or 3rd
pregnancies
HR 4.7 (95% CI 3.6-6.0)

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birth preterm (less than 37 weeks’ gestation) or who
have amedical history of recurrent preeclampsia [2].
Cardiovascular risk in the offspring of preeclamptic
women
Concerning cardiovascular complications in pre-
eclampsia, it should be mentioned that there is also ev-
idence of increased cardiovascular risk in the offspring
of preeclamptic mothers. Multiple studies have shown
a correlation between maternal pregnancy hyperten-
sive disorders and the development of hypertension in
their children [11].
However, it is not clear if this relationship is caused
by a direct effect, a familial aggregation of risk, or is
confounded by its association with intrauterine growth
restriction. Ameta-analysis of case-control and cohort
studies on the effect of maternal hypertension on off-
spring demonstrated an increase in systolic and diastol-
ic blood pressure among children of preeclamptic wom-
en compared to normotensive women. The differences
were observed even after adjusting for gestational age
and birth weight, in both males and females. On the
other hand, after adjustment for maternal body mass
and blood pressure, the difference in SBP was largely
attenuated [18, 19]. It may suggest the influence of ma-
ternal, familiar, and genetic factors on blood pressure of
the offspring and needs further research. Furthermore,
there is also strong evidence for increased risk of de-
veloping preeclampsia in daughters and sisters of pre-
eclamptic women [20].
Shared environmental and genetic factors of famil-
iar aggregation pose achallenge to future studies ex-
amining cardiovascular risk in the offspring of women
with preeclampsia.
Future work
It is important to notice that the risk of cardiovas-
cular diseases is influenced by many factors appearing
throughout life and there is alarge time gap between
pregnancy and development of cardiovascular disease
in women. Therefore, there is a need for further re-
search that can explain this connection. Most avail-
able studies in this area are based on national medical
registries and thus have aretrospective nature; there
are also differences in definitions of gestational hy-
pertension and preeclampsia and also in follow-up
time. That makes these studies open to bias. Only
well-planned prospective research with standardised
definitions including patients with similar risk factor
profiles can add valuable weight to the body of evi-
dence in this area.
Cerebrovascular complications
in preeclampsia
Neurological complications with aclose relationship
to preeclampsia are: posterior reversible encephalopa-
thy syndrome (PRES) and stroke.
Nervous system in normal pregnancy
and preeclampsia
The nervous system undergoes numerous physio-
logical adaptations during pregnancy. Most of all, they
are aconsequence of changes in other systems – mark-
edly increased hormone levels, hypercoagulability, and
cardiovascular modifications.
Substantial changes in maternal haemodynamics,
together with alterations in coagulation profile, lead to
cerebral endothelial permeability and pressure adapta-
tions. The middle cerebral artery (MCA) perfusion pres-
sure increases steadily during gestation and returns
to nonpregnant values in the puerperium. Oestrogen
lowers the seizure threshold by downregulating expres-
sion of GABA in the brain, whereas progesterone and
its metabolites exert the opposite effect. Several animal
studies indicate that the abrupt withdrawal of proges-
terone can be followed by increased seizure suscepti-
bility. However, the relationship between progesterone
and eclampsia has not been studied [21].
During normal pregnancy increased sympathetic
nervous activity (SNA) can be observed. It is signifi-
cantly higher during preeclampsia, and it is proposed
that over-activation of the SNA contributes to altered
uteroplacental vascular tone and perfusion leading to
placental ischaemic events and exaggerated responses
to soluble placenta ischaemic factors [21].
Posterior reversible encephalopathy syndrome
PRES was first described in 1996 by Hinchey et al.
and is characterised by arange of clinical symptoms,
such as headache, seizures, visual disturbances, and
other focal neurological deficits accompanied by va-
sogenic cerebral oedema observed in magnetic res-
onance imaging (MRI) or computed tomography (CT),
predominantly in the posterior regions [22].
There are two leading theories regarding the patho-
physiology of PRES. First is elevation of blood pres-
sure levels above the upper brain autoregulatory lim-
it, leading to cerebral hypertension, vascular leakage,
and vasogenic oedema. Normally, in healthy people,
cerebral blood flow autoregulation is efficient between
50 and 150 mm Hg. Conditions like arterial hyperten-
sion or acute fluctuations of blood pressure may lead
to increased vulnerability of the cerebral circulation and
predispose to ischaemia. The second theory is endothe-
lial dysfunction caused by circulating toxins: exogenic

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(chemotherapy agents, immunosuppression) and en-
dogenic (preeclampsia, sepsis, autoimmune diseases).
In this theory blood pressure elevations are asequel of
primary endothelial damage [22].
The exact prevalence of PRES in women with pre-
eclampsia/eclampsia is difficult to estimate because of
the small number of studies concerning it. In one retro-
spective study PRES was found in more than 90% of ec-
lamptic and in about 20% of preeclamptic women with
neurological symptoms [23].
It is important to note that there may be differences in
patterns of PRES associated with preeclampsia and PRES
associated with other conditions. Liman et al. showed in
their retrospective study that patients with preeclampsia/
eclampsia had a significantly higher presence of head-
aches and significantly lower prevalence of altered mental
status than nonpregnant women. However, there were no
differences in the frequency of seizures or visual distur-
bances between the groups [22-24].
PRES is considered to be areversible syndrome, be-
cause clinical signs and symptoms regress in the major-
ity of patients. The prognosis is mainly determined by
underlying pathology, and some neurological sequelae
(e.g. epilepsy, cognitive difficulties related to memory
and concentration) may persist. In long-term follow-up
cerebral white matter lesions (WMLs) are diagnosed
significantly more often in formerly preeclamptic/ec-
lamptic women than in age-matched controls with un-
complicated pregnancy [24].
It seems that PRES in preeclampsia is associated
with aless severe course of disease, but it still remains
detrimental for young women demanding adequate di-
agnosis and treatment to prevent its long-term conse-
quences [22].
Stroke
Stroke is defined as alocal or global alteration in ce-
rebral function lasting over 24 hours and is adevastat-
ing diagnosis because it can result in long-term disability
and death.
The prevalence of stroke during pregnancy and post-
partum is estimated at 34 per 100,000 deliveries and is
still increasing. In the United States the rate of pregnan-
cy-associated stroke rose from 45% (in the years 1994-
1995) to 83% (in the years 2005-2006). The mortality
rate is 1.4 per 100,000 deliveries [25].
The frequencies of ischaemic and haemorrhagic
stroke during pregnancy have been reported as similar.
However, there are also studies that have concluded that
ischaemic stroke due to cerebral sinus thrombosis is the
most common type of stroke during pregnancy and pu-
erperium [26].
The most important risk factors for pregnancy-as-
sociated stroke are: hypertensive disorders during preg-
nancy, chronic hypertension, pregestational diabetes,
caesarean delivery, heart disease, thrombophilia, and
migraine headaches. Too et al. estimated that the risk
of postpartum stroke within 60 days after delivery was
41.7 per 100,000 deliveries for patients with hyperten-
sive disorders of pregnancy, 59.6 per 100,000 deliveries
for patients with chronic hypertension without superim-
posed preeclampsia, and 21.7 per 100,000 deliveries for
patients without either condition [25].
In the course of severe preeclampsia/eclampsia the
most common type of stroke is haemorrhagic stroke as
a result of severe hypertension. In the study conduct-
ed by Martin et al. (only with women affected by pre-
eclampsia/eclampsia) the prevalence of haemorrhagic
stroke was 89% [27]. However, there are available stud-
ies reporting an increased risk of ischaemic stroke in pre-
eclampsia as well [25].
The clinical presentation in stroke associated with
preeclampsia/eclampsia is quite different than in stroke
due to other reasons. The most common symptoms
of stroke in this group of pregnant women are: severe
headache, impairment of consciousness and elevated
systolic blood pressure. Some studies have confirmed
that an acute increase in systolic blood pressure (SBP) is
the most important risk factor for haemorrhagic stroke in
preeclampsia. Despite the fact that the majority of inter-
national guidelines emphasise DBP as aprimary deter-
minant of intervention, women with severe preeclamp-
sia and high isolated SBP should be immediately treated
with antihypertensive therapy because of avery high risk
for haemorrhagic stroke [25].
Recent studies suggest an 80% increased risk of
stroke in patients with preeclampsia compared to wom-
en with uncomplicated pregnancy. What is very import-
ant - preeclampsia increases also (by about 55-60%) the
risk of future non-pregnancy-related stroke [22] (Table 2).
Future work
Several factors including modern lifestyle, environ-
ment, and postponing the age of childbearing lead to
increasing incidence of neurological pregnancy com-
plications, such as stroke. There is a need for further
research in this area, which aims to work out effective
and detailed preventive strategies for these patients.
Renal dysfunction and preeclampsia
The most common renal complications related to
preeclampsia include: renal failure, acute kidney injury,
and future risk of end-stage renal disease.
Renal function during uncomplicated pregnancy
Renal function undergoes alot of physiological chang-
es during pregnancy. The overall size of the human kidney

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105
increases due to arise in renal vascular and interstitial
volume. In more than 80% of normal pregnancies adila-
tion of the renal pelvises can be observed, due to external
compression of the ureter, as well as hormonal changes
related to progesterone [28].
Renal perfusion increases during normal pregnan-
cy because of increased cardiac output, and it leads to
arise in glomerular filtration rate (GFR) – about 40-60%
in the second half of pregnancy. Serum creatinine falls
during normal pregnancy to anormal range of 0.4-0.8
mg/dl. A serum creatinine of 1 mg/dl (considered as
normal in nonpregnant women) can represent a re-
nal impairment in pregnant women. Protein excretion
during normal pregnancy increases, but does not ex-
ceed 300 mg per day [28].
Renal function during preeclampsia
During preeclampsia functional changes in renal hae-
modynamics are quite different. The GFR in women with
preeclampsia is significantly lower than in healthy controls.
It is related to typical histopathological changes including
fibrin deposition, endothelial swelling, and loss of capillary
space. These changes, called “glomerular endotheliosis”
(aterm introduced by Spargo in 1976), are pathognomonic
for preeclampsia, which is considered as the most common
glomerular disease worldwide. Nevertheless, in the majori-
ty of patients with preeclampsia glomerular changes disap-
pear within eight weeks of delivery [28].
During normal pregnancy changes in renin-angio-
tensin-aldosterone system (RAAS) are also observed,
including elevated angiotensin II (ang-II) levels and de-
creased sensitivity to it. In contrast, during preeclamp-
sia decreased components of the RAAS and decreased
sensitivity to ang-II have been reported. It is probably
related to increased placental ang-II type 1 receptor
(AT1R) expression and circulating AT1R autoantibodies.
Moreover, circulating AT1R antibodies and ang-II are ca-
pable of inducing sFlt-1 production by AT1R activation.
It means they can be responsible for placental sFlt-1
up-regulation in preeclampsia [29].
Acute kidney injury in preeclampsia
In rare cases, preeclampsia can lead also to renal
cortical necrosis or acute tubular necrosis and is one
of the main causes of acute renal failure in pregnancy.
Acute kidney injury (AKI) is defined as an increase in
serum creatinine level in patients without chronic kidney
disease and manifests most of all as oliguria or anuria.
In a Chinese cohort study the incidence of AKI during
pregnancy and puerperium was 0.81%. Preeclampsia
and postpartum haemorrhage were the main cause of it.
About 17% of patients with preeclampsia/eclampsia and
60% of women with HELLP syndrome were diagnosed
with AKI. The mortality rate among pregnant women
with AKI was 4.08%, but the major causes of death were
amniotic fluid embolism and postpartum haemorrhage,
whereas the maternal outcome of AKI related to pre-
eclampsia was relatively good [30].
Future risk of end-stage renal disease
As mentioned before, after preeclampsia, complete
renal recovery takes place in the majority of cases. How-
ever, there is strong evidence for increased risk of mi-
croalbuminuria and end-stage renal disease in future life
after pregnancy complicated by preeclampsia (Table 2).
A recent meta-analysis revealed that 31% of pre-
eclamptic women had microalbuminuria after seven
years postpartum compared to 7% of women with
uncomplicated pregnancy. The risk of developing mi-
croalbuminuria was increased four-fold after mild pre-
eclampsia and eight-fold after severe preeclampsia [31].
End-stage renal disease (ESRD) is chronic renal fail-
ure requiring long-term dialysis or renal transplantation.
In a cohort of 570,433 women, in a study performed
by Vikse et al., preeclampsia in the first pregnancy was
associated with a relative risk (RR) of ESRD of 4.7. If
women also had preeclampsia during subsequent preg-
nancies the RR of ESRD was 15.5 [32].
In the Chinese cohort of 13,633 women with hyper-
tensive disorders of pregnancy (HDPs) in the follow-up
period of nine years on average, 0.34% of women de-
veloped ESRD compared to 0.02% of women with un-
complicated pregnancy. The risk of ESRD in women with
HDPs was 4-15-times higher than in healthy controls,
and it was even higher in women who had apreterm
birth or low birth weight child. The risk was highest in
women with history of preeclampsia superimposed on
chronic hypertension (hazard ratio 44.72) [33].
Future work
Several factors may explain the increased risk of mi-
croalbuminuria and ESRD in women with preeclampsia:
shared risk factors of preeclampsia and kidney disease,
undetected hypertension or microalbuminuria before
pregnancy, and the impact of preeclampsia itself on
kidney function with incomplete recovery after glomer-
ular endotheliosis. Similarly as for future cardiovascular
risk, there is aneed for well-designed prospective stud-
ies that might help to explain this connection.
Liver failure and preeclampsia
The most important liver abnormalities with a close
relationship to preeclampsia are liver failure and hepatic
rupture.

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Liver function during normal pregnancy
During normal pregnancy many physiological and
hormonal changes occur, and some of them are also
related to liver function.
Despite the rise in cardiac output, blood flow to the
liver remains constant. The liver in not enlarged and im-
palpable. Due to compression of the inferior vena cava
by the enlarging uterus small, clinically insignificant
oesophageal varices can occur in up to 50% of preg-
nancies during the late second and third trimester [34].
Biochemical liver function tests are also altered
during pregnancy. Amild increase in alkaline phospha-
tase (due to placental isoenzyme) and amild decrease
in serum albumin levels (due to increased plasma vol-
ume and haemodilution) can be observed. Urea, hae-
moglobin levels, and prothrombin time remain un-
changed or slightly decreased due to haemodilution.
Elevations in transaminases, bilirubin, or prothrombin
time are abnormal and require further diagnostics. Liver
function test abnormalities occur in about 3% of preg-
nancies [34].
Liver dysfunction during preeclampsia
Preeclampsia/eclampsia and HELLP syndrome are
the main cause of hepatic dysfunction during pregnan-
cy. Abnormal biochemical liver tests occur in about 20-
30% of these patients [34].
In the study performed by Suresh et al. the over-
all incidence of hepatic dysfunction during pregnancy
was 3.2% and the most common causes of it were: pre-
eclampsia (1.8%), eclampsia (0.6%), HELLP syndrome
(0.24%), viral infection (0.19%), hyperemesis grav-
idarum (0.14%), ICP (0.13%), and chronic liver disease
(0.03%). Liver dysfunction was also related to prema-
ture deliveries, low birth weight babies, and increased
maternal and foetal mortality [35].
Liver dysfunction during preeclampsia is related
(as in involvement of other organs) to endothelial dys-
function, which leads to hepatic microcirculatory dete-
rioration and hepatocellular necrosis. Liver biopsies in
women with HELLP syndrome have shown thrombotic
microangiopathy [36].
There is also evidence of the contribution of sFlt-1
in the development of liver dysfunction in preeclamp-
sia. SFlt-1 antagonises VEGF, whereas VEGF increases
the expression of endothelial nitric oxide synthase
(eNOS) and activates it. Raised sFlt-1 production during
preeclampsia and therefore the lack of eNOS synergis-
tically induce liver dysfunction and thrombocytopae-
nia, which was confirmed in animal models. The exact
mechanism of liver injury is unknown, but some studies
demonstrated also that placenta-derived CD95 ligand
(Fas) causes damage in hepatocytes and leads to their
apoptosis in women with HELLP syndrome [37].
Hepatic rupture
One of the most important hepatic complications
related to hypertensive disorders of pregnancy is he-
patic haemorrhage and liver rupture.
It is avery rare but life-threatening complication
with very high maternal and perinatal mortality rates
(39% and 42%, respectively). The incidence of liver
rupture in pregnancy is estimated on 1 per 67,000
deliveries and 1 per 2000 patients with preeclamp-
sia or HELLP syndrome. Additional risk factors in this
group of patients are: multiparity, age > 40 years, and
gestational age > 32 weeks. The pathophysiology has
been attributed to vasoconstriction due to increased
levels and sensitivity to circulating vasopressors,
such as endothelin and angiotensin II, leading to
ischaemia, necrosis, and finally rupture [38].
Liver rupture during pregnancy may occur not only
because of hypertensive disorders, but also due to coex-
isting hepatic pathologies – adenomas, haemangiomas,
malignancies, and coagulation disorders. However, they
are rather casuistic [38].
Escobar Vidarte et al. in their literature review
reported 35 cases of pregnancy hepatic haemor-
rhage: 28 (80%) of them caused by HELLP syndrome,
three (8.5%) caused by preeclampsia and HELLP syn-
drome, and four (11.4%) by preeclampsia without
HELLP syndrome [38].
Clinical presentation of hepatic haemorrhage in-
cludes epigastric right upper-quadrant pain, hypovo-
lemic shock, and cardiovascular collapse. In the vast
majority of patients (approximately 90%) abdominal
pain is the first symptom, and it should always raise
suspicion. Computed tomography or magnetic res-
onance imaging is the investigation of choice. Pa-
tients with liver rupture require urgent laparotomy,
because only surgery significantly reduces maternal
mortality [39].
Future work
Hepatic rupture is rare, but it is connected to high
mortality rate, and there is still alack of detailed preven-
tion strategies to avoid this complication. There is also
aneed for further research estimating potential relation-
ship between preeclampsia and liver abnormalities in
future life, years after delivery.
Coagulopathy and preeclampsia
Nankali et al. in their cohort of 349 severe preeclamp-
sia cases presented coagulopathy as the most frequent
maternal complication (10.6% of patients). The most
common coagulopathies in preeclampsia are thrombo-
cytopaenia and DIC [40].

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Coagulation-fibrinolytic system during normal
pregnancy and preeclampsia
Pregnancy is recognised as aprocoagulant state be-
cause of an increase in concentration of fibrinogen and
other clotting factors together with areduction of levels
of natural anticoagulants, such as protein S and C [41].
During preeclampsia the coagulation-fibrinolytic
system is seriously affected by maternal inflammatory
reactions and immune dysfunction. Increase in blood
clotting is crucial for pregnant women to reduce post-
partum haemorrhage. When the balance between co-
agulation and fibrinolysis is altered, as in preeclamp-
sia, the blood flow of the placenta and other organs is
blocked by microthrombosis. In comparison to normal
pregnancy, significantly higher levels of tissue factor,
fibrinogen, and von Willebrand factor and significant-
ly lower levels of anticoagulation factors, such as anti-
thrombin and tissue factor pathway inhibitor 2 (TFPI2),
are observed in women with preeclampsia. Thus, pre-
eclampsia is sometimes called a“super-hypercoagula-
ble state” [42].
D-dimer in pregnancy
D-dimer is a specific degradative product coming
from hydrolysis of the fibrin monomer and thus serves
as an indirect marker for thrombosis and fibrinolytic ac-
tivity, widely used in the diagnosis of venous thrombo-
embolism (VTE).
In normal pregnancy, however, the maternal D-dimer
concentration increases progressively from concep-
tion to delivery, and for this reason the D-dimer test
has no use in ruling out VTE with standard cut-off of
0.5 mg/l. Kline et al. established amean D-dimer con-
centration in normal pregnancy of 0.579 mg/l in the
first trimester, 0.832 mg/l in the second trimester, and
1.159 mg/l in the third trimester. The mean rise in the
maternal D-dimer concentration from preconception to
the third trimester was 0.69 mg/l [43].
In the recent study (published in 2018) plasma
D-Dimer levels were measured during the three trimes-
ters of pregnancy to establish trimester-specific reference
ranges. D-Dimer levels increased progressively during
pregnancy with the highest values in the third trimester,
when in 99% of women included in the study they were
above the conventional cut-off point (500 μg/l) [44].
It is also important to note that in women with
preeclampsia D-dimer concentrations are additionally
significantly higher than in healthy pregnant controls,
especially in severe early-onset preeclampsia. In wom-
en with preeclampsia D-dimer is considered to involve
in the dynamic balance between plasminogen activa-
tors (t-PA and uPA) and plasminogen inhibitor (PAI-1).
However, according to new guidelines, D-dimer plasma
concentration should not be routinely measured during
pregnancy because of the lack of reliable norms and
possible confusion in diagnostics [45].
Thrombocytopaenia during preeclampsia
Thrombocytopaenia is defined as aplatelet count
below 150,000/μl and is the second most common ab-
normality of complete blood count in pregnancy (beside
anaemia) with aprevalence of 6.6 to 11.6% in the third
trimester [41].
Preeclampsia and HELLP syndrome are responsible
for 15-22% of all cases of thrombocytopaenia in preg-
nancy. On the other hand, thrombocytopaenia is diag-
nosed in 30-50% of women with preeclampsia and is
even one of the diagnostic criteria of severe preeclamp-
sia and HELLP syndrome [46].
There is asignificant association between severity
of thrombocytopaenia and maternal morbidity. If the
platelet count is in the range of 100-150,000/μl, the
rate of maternal complications is 40%. For the range of
50-100,000/μl it is 54%, and for platelet count below
50,000/μl it is 64%. Fortunately, fewer than 5% of pre-
eclamptic women develop severe thrombocytopaenia
with platelet count below 50,000/μl [46].
Thrombocytopaenia that develops during pre-
eclampsia or HELLP syndrome is related to excessive
platelet activation due to endothelial dysfunction
and proinflammatory cytokines, does not cause neo-
natal thrombocytopaenia, and usually normalises in
6-11days postpartum [46].
Disseminated intravascular coagulation syndrome
and preeclampsia
DIC is a thrombo-haemorrhagic condition second-
ary to underlying clinical pathologies characterised by
activation of intravascular coagulation accompanied by
secondary fibrinolysis.
Several pregnancy complications may lead to DIC,
including: preeclampsia and HELLP syndrome, placental
abruption, intrauterine foetal death, amniotic fluid em-
bolism, placenta accreta, and acute fatty liver of preg-
nancy [47].
Preeclampsia and HELLP syndrome are leading
causes of DIC in developing countries, whereas in de-
veloped countries they are placental abruption and
postpartum haemorrhage. DIC is reported in 12-14%
of preeclamptic women. However, it has been suggest-
ed that in the majority of cases these women also had
HELLP syndrome, and the prevalence of DIC in women
with preeclampsia only is rare [42].
There are several mechanisms of developing DIC in
patients with preeclampsia and HELLP syndrome: con-
sumption coagulopathy (because of strong association
of HELLP and placental abruption), hepatic injury (de-

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108
creased production of clotting factors), and systemic
maternal inflammatory response (characteristic for pre-
eclampsia) [42].
Significantly increased circulating pro-inflammatory
cytokines during preeclampsia can lead to exaggerat-
ed expression of tissue factor by leukocytes and endo-
thelial cells. There is strong evidence that tissue factor
plasma levels are markedly higher in women with pre-
eclampsia compared with healthy controls [42].
There is also asuggestion that in women who de-
velop DIC associated with HELLP syndrome there is an
inherit imbalance between coagulation factors, anti-co-
agulation proteins, and reduced fibrinolysis. This state
was defined by de Boer et al. as “compensated DIC”,
which can easily developed into real DIC in the presence
of other risk factors. Women with HELLP syndrome
should be closely followed for the development of DIC,
because this coagulopathy is associated with the high-
est risk of maternal and foetal mortality [48].
Future work
Coagulopathies during preeclampsia are well-de-
scribed but remain asignificant cause of maternal mor-
bidity and mortality. Therefore, researchers and clini-
cians should maximise their efforts for early diagnosis
and appropriate therapy in these group of preeclampsia
complications.
Conclusions
Preeclampsia is amultisystem disorder of pregnan-
cy that remains aleading cause of maternal and foetal
mortality. It is still an underestimated risk factor for fu-
ture cardiovascular, cerebrovascular, and kidney diseas-
es. There is aneed for early screening of preeclampsia
and effective prophylaxis to prevent the most severe
complications related to increased risk of maternal
death and disability. On the other hand, women with
pregnancy complicated by preeclampsia should also be
covered by avery watchful follow-up, many years after
pregnancy, because of rising cardiovascular disease-re-
lated mortality in adult women, especially those aged
35-45 years.
Disclosure
The authors report no conflict of interest.
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