HORMONES 2015, 14(2):211-

223

Review

Pregnancy-Induced hypertension
Evangelia Kintraki,1 Sophia Papakatsika,2 George Kotronis,2
Dimitrios G. Goulis,1 Vasilios Kotsis2
1
Unit of Reproductve Endocrinology and Unit of Human Reproducton, First Department of Obstetrics and
Gynecology,
2
Third Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

AbstrAct
pregnancy-induced hypertension (pIh) complicates 6-10% of pregnancies. It is defined as
systolic blood pressure (sbp) >140 mmhg and diastolic blood pressure (dbp) >90 mmhg. It
is classified as mild (sbp 140-149 and dbp 90-99 mmhg), moderate (sbp 150-159 and dbp
100-
109 mmHg) and severe (SBP ≥160 and DBP ≥110 mmHg). PIH refers to one of four
conditions: a) pre-existing hypertension, b) gestational hypertension and preeclampsia (pe), c)
pre-existing hypertension plus superimposed gestational hypertension with proteinuria and d)
unclassifiable hypertension. pIh is a major cause of maternal, fetal and newborn morbidity
and mortality. women with pIh are at a greater risk of abruptio placentae,
cerebrovascular events, organ failure and disseminated intravascular coagulation. fetuses of
these mothers are at greater risk of intrauterine growth retardation, prematurity and
intrauterine death. ambulatory blood pressure monitoring over a period of 24 h seems to
have a role in predicting deterioration from gestational hypertension to pe. antiplatelet
drugs have moderate benefits when used for prevention of pe. treatment of pIh depends
on blood pressure levels, gestational age, pres- ence of symptoms and associated risk
factors. non-drug management is recommended when sbp ranges between 140-149 mmhg
or dbp between 90-99 mmhg. blood pressure thresholds for drug management in
pregnancy vary between different health organizations. according to 2013 esh/esc
guidelines, antihypertensive treatment is recommended in pregnancy when blood pressure
levels are ≥150/95 mmHg. Initiation of antihypertensive treatment at values
≥140/90 mmHg is recommended in women with a) gestational hypertension, with or without
proteinuria, b) pre-existing hypertension with the superimposition of gestational
hypertension or c) hypertension with asymptomatic organ damage or symptoms at any time
during preg- nancy. methyldopa is the drug of choice in pregnancy. atenolol and
metoprolol appear to be safe and effective in late pregnancy, while labetalol has an efficacy
comparable to methyldopa. angiotensin-converting enzyme (ace) inhibitors and
angiotensin II antagonists are contrain- dicated in pregnancy due to their association with
increased risk of fetopathy.
key words: Antihypertensive treatment, Gestational hypertension, Methyldopa, Pre-eclampsia,
Pregnancy-induced hypertension

Address for correspondence:

Assistant Prof. Vasilios Kotsis, Third Department of Internal Medicine, “Papageorgiou” General Hospital, Ring Road, 54601 Nea
Efkarpia, Thessaloniki, Greece, Tel.: +2310 693131, Fax: +2310 991510, E-mail: vkotsis@auth.gr
Received: 22-05-2014, Accepted: 10-02-2015
212 E. KINTIRAKI ET AL

IntroductIon
Definition and classification
Pregnancy-induced hypertension (PIH) complicates
about 6-10% of pregnancies.1 It is defined as
systolic blood pressure (SBP) >140 mmHg and
diastolic blood pressure (DBP) >90 mmHg. It is
classified as mild (SBP 140-149 and DBP 90-99
mmHg), moderate (SBP 150-159 and DBP 100-109
mmHg) and severe (SBP ≥160 and DBP ≥110
mmHg).2
According to the Canadian Hypertension
Society, PIH refers to one of four conditions: a)
pre-existing hypertension, b) gestational
hypertension and PE, c) pre-existing hypertension
plus superimposed gesta- tional hypertension with
proteinuria and d) unclas- sifiable hypertension, as
is shown in Table 1.3
Epidemiology
An epidemiological study in the USA over the
pe- riod 1995-2004 showed that gestational
hypertension and PE were the most commonly
diagnosed hyper- tensive conditions in pregnancy,
whereas pre-existing hypertension was much rarer.4
Studies from Europe revealed a prevalence of
preeclampsia at 2.3-3%.5,6
Complications
According to the WHO, PIH is one of the main
causes of maternal, fetal and neonatal mortality and
morbidity.1 It is the most common cause of
maternal death in Europe.7 In a retrospective study
over the period 2000-2009 in a tertiary center in
India, PIH was the third cause of maternal death. In
a similar study, over the period 1996-2009 in Henan
Province, China, PIH was the second cause of
maternal death. One tenth of maternal deaths in
Africa and one quarter in Latin America are due to
PIH-associated complica-
table 1. PIH classification3,151,152
Pre-existing hypertension (1-5%)
Gestational hypertension and preeclampsia (PE, 2-8%)
Pre-existing hypertension plus superimposed gestational
hypertension with proteinuria (previously known as chronic
hypertension with superimposed preeclampsia)
Unclassifiable hypertension
HORMONES 2015, 14(2):213-
223
tions. Another study showed that the most com-
1,8,9
mon cause of mortality in cases of preeclampsia
was haemolysis, elevated liver enzymes and low
platelet count (HELLP) or partial HELLP syndrome
(83.3%). Haemorrhagic stroke and pulmonary
edema have been reported as the most common
causes of death in patients with eclampsia,
accounting for as many as 60% of all eclampsia-
related deaths.10
Other maternal short-term complications include
central nervous system dysfunction, hepatocellular
injury, thrombocytopenia, acute disseminated intravas-
cular coagulation (DIC), oliguria, pulmonary
edema, cerebrovascular events and placental
abruption.11-14
In one study of 4,188 women with preeclampsia the
incidence of one or more systemic complications
was
6%. Haematologic complications were most
common and the incidence of placental abruption
was 2.8%.15
PIH-associated complications are more frequent
in early-onset (< gestational week 32) compared to
late-onset PE.16 A comparative study showed that
women with PE and superimposed PE have the
same rates of perinatal complications. By contrast,
women with superimposed PE had a significantly
higher risk of intervention-related complications,
such as deliv- ery at < gestational week 34,
caesarean delivery and neonatal intensive care unit
admission.17
Fetal/neonatal short-term complications include
intrauterine growth restriction (IUGR), small for
gestational age (SGA) neonate, low birth weight
neonate, preterm birth, intrauterine and perinatal
death.18,19 In one study of 17,933 stillbirths, 9.2%
were by pregnancies complicated by hypertensive
disorders of pregnancy.20 One study from Greece
revealed increased neonatal adverse outcomes in in-
fants of preeclamptic women as compared to those
of
<20th gestational week, persists more than 42 days postpartum,
+/- proteinuria
>20th gestational week, resolves within 42 days postpartum,
+/- significant proteinuria, poor organ perfusion
>20th gestational week, further worsening of blood pressure
and protein excretion, up to 3 g/24 h
>20th gestational week, +/- systemic manifestations,
214 E. KINTIRAKI ET AL
reassessment is necessary at or after 42 d
postpartum
Pregnancy-Induced hypertension 213
 214 E. KINTIRAKI ET AL
normotensive women. 21
ability and mental risk for PE.34-36 Anti-phospholipid
A retrospective study disorders in later Maternal age >30 syndrome (APS), an
showed that hospital- life.27-31 years and increased autoimmune condition
based continuous body mass index characterized by
R
prenatal care reduced (BMI) were found to recurrent thrombosis,
i
the risk of pre-term be positively is widely recognized as
s
delivery and impaired correlated to risk for a risk factor for several
k
fetal growth in PIH in Arab women.37 obstetric
pregnancies Increased pre- complications,
f
complicated by PE.22 a pregnancy BMI was including PIH.
Concerning long- c also a risk factor for Approximately one
term health risk, t PE in twin pregnan- third of women with
several studies o cies.38 In addition, APS will develop
demonstrated that r above-average weight PE.42,43
women with PIH are s gain during pregnancy Two recent meta-
at greater risk of other Hypertension, was positively analyses concluded
medical conditions, collagen vascular correlated to PE that low maternal
such as hyperten- sion, disease, obe- sity, risk.36 vitamin D
cardiovascular disease, black race, insulin Personal and family concentrations are
diabetes mellitus and resistance, diabetes history of PE are associated with
kidney disease in later mellitus, gestational considered significant increased risk of
life.23,24 One study of diabetes, increased risk factors for PE in PE. 44,45

3,593 women with serum testosterone pregnancy.39-41

preeclampsia during concentrations and physIoLoGy:
their first singleton thrombophilia are cardIovascuLa
pregnancy pointed to a considered risk factors r chanGes
positive association of for PIH.32,33 durInG
hyper- tensive diseases A recent preGnancy
of pregnancy with epidemiological study
diseases related to Significant
showed that Black and cardiovascular and
hypertension in later some Hispanic women
life.25 haemodynamic
had markedly increased changes occur early in
The risk of diabetes risk for all pregnancy in order to
in later life was 2-fold hypertensive disorders provide enough blood
higher in women with in pregnancy for the embryo and
PE or gestational compared to non- maintain normal fetal
hypertension com- Hispanic white intrauterine growth.
pared with women women, while Asian Such changes include
without them.26 Long- women were at in- creased maternal
term health risk seems decreased risk. The plasma volume,
to be increased among same study disclosed a cardiac output and
the offspring of positive correlation heart rate, and
pregnancies between pre- decreased maternal
complicated by PIH. pregnancy weight and systemic vascular
These conditions risk of PIH, whereas resistance and arterial
include higher blood parity and smoking blood pressure.46
pressure in childhood were protective for PE
and adult- hood and a development.4 The The expansion of
tendency towards data for parity are maternal plasma
impaired lipid profile, conflicting, as both volume is due to
a nulliparity and stimulation of the
2-fold higher stroke multiparity seems to renin-angiotensin-
risk, lower cognitive predispose to higher aldosterone system. As
 Pregnancy-Induced hypertension 215
a compensatory a multi- factorial
mechanism, disease. Many theories
vasodilator synthesis have been developed
is increased in order to about its pathogenesis.
maintain normoten- Their common
sion.47 Such characteristic is the
vasodilators include central role of the
the kallikrein-kinin placenta. The
system, prostacyclin, modified theory of the
nitric oxide and “two-stage model”
vascular-en- dothelial suggests that
growth factor abnormal
(VEGF).48-50
In addition to the
functional adaptation
of the ma- ternal
cardiovascular system,
structural changes also
occur during
pregnancy. This
adaptive remodelling
results in cardiac
hypertrophy that
enables the heart to
cope with the
increased demands of
gestation. This
hypertrophy is
reversible and is not
associated with long-
term cardiovascular
dysfunction.51
In summary,
haemodynamic
changes during preg-
nancy include a
reduction of systolic,
diastolic and mean
arterial blood pressure
in the second trimester
followed by a slight
increase in the third, a
reduction of total
vascular resistance,
especially in the
second trimester, and
an increase of cardiac
output.52

pathophysIoLoGy
PIH and especially
PE is considered to be
216 E. KINTIRAKI ET AL
Pregnancy-Induced hypertension 217
placental implantation, misbal- ance between angiogenesis and in PE and the sFlt-
vascularization or antioxidant and pre- promote vascular 1/PlGF ratio has been
function together with oxidant factors and dysfunction. sFlt-1 proposed as an
the contribution of increased production binds to VEGF and additional diagnostic
maternal factors can of ROS results in PlGF, and sEng or predictive tool for
lead to PE.53 Factors vascular endothelium impairs binding of PE.72-74
that have been dysfunction in women TGF-β1 to its A meta-analysis
implicated in PE with PE.60 One study receptor, blocking showed increased
pathophysiology are showed that women their actions.68,69 Both concentrations of
cardiovascular with early-onset of them are expressed placental and maternal
maladap- tation and severe preeclampsia by normal placenta.70,71 sFlt1 and sEng and
vasoconstriction, have increased NK cell Many studies have decreased
genetic predisposition, function related to amplified the theory of concentrations of
immunologic cytokine production.61 the misbalance of PIGF in pregnancies
intolerance between circulating angiogenic which devel- oped PE.
Angiogenic factors, VEGF was lower,
feto-placental and factors
such as VEGF family though not
maternal tissue,
members (VEGF, significantly different,
platelet activation and
PIGF), angiopoietins between the women
vascular en- dothelial
and their receptors, are who developed PE and
dysfunction.54
thought to be those who did not.75
Moreover, coexisting
significant for the
metabolic factors can Several studies have
regulation of placental
contribute to shown an increased risk
growth and vascular
endothelial of PIH and PE in
development.62
dysfunction, and pregnancies with
Angiopoietin 1 binds
hyperlipidaemia and positive familial
to Tie receptors,
insulin resistance have history of PE.76,77 The
whereas angiopoietin
been associated with latter implies a genetic
2 acts as an
preeclampsia.55-57 predisposition. Many
antagonistic ligand.63
Immune factors, Impaired expression of single nucleotide
such as auto- demonstrated polymorphisms
antibodies, oxida- tive decreased VEGF levels (SNPs) in candidate
stress and natural in the umbilical cord genes of clotting
factors, vascular
killer (NK)-cell from pregnancies
growth factors,
abnormalities, cause complicated by
vasoactive proteins,
placental dysfunction hypertension as
oxidative stress related
and impaired placental compared to normal
factors, immunoactive
perfusion. The latter pregnancies.66 The
mediators and
acts as a stimulus of angiopoietin
components of the
placental release of 1/angiopoietin 2 ratio
renin-angiotension-
anti-angiogenic and was found significantly
aldodterone system
inflammatory media- lower in women who
have been associated
tors that eventually developed
with PE
cause endothelial preeclampsia than in
development.78,79
dysfunction and organ normal pregnant
damage.58 Increased women.67
numbers of activated f
Anti-angiogenic o
monocytes and
factors, such as sFlt1 L
macrophages have
[soluble Flt1 (fms-like L
been described in the
tyrosine kinase 1)] and o
endometrium of
soluble endoglin w
women with PE.59 A
(sEng), inhibit -
 218 E. KINTIRAKI ET AL
u gestational weeks 28-
p 30 and 32-
34. Cardiotocography
The assessment of
is suggested if fetal
women with pregnacies
activity is abnormal.
compli- cated by PIH
Fetal follow-up is also
includes clinical
recommended for
follow-up, serological
cases of mild or
investigation and fetal
moderate gestational
ultrasound
hypertension. For
evaluation.80,81 The
cases with severe
type and frequency of
gestational
follow-up depends on
hypertension or PE,
the kind and severity
fetal ultrasound,
of the hypertensive
amniotic fluid volume
disorder.
assessment and
Clinical follow-up umbilical Doppler
includes blood pressure velocimetry is
measure- ments using recommended to be
mercury performed not more
sphygmomanometry frequently than every
(Korotkoff phase V), two weeks.
in the sitting position, Cardiotocography is
and evaluation of any recommended if
signs or symptoms abnormal
indicative of clinical
detero- riation.82
Biochemical and urine
tests include urine
dipstick, urinalysis for
proteinuria, if urine
dipstick has >1+, full
blood count
(haematocrit,
haemoglobin,
platelets), liver
enzymes, serum urea,
creatinine, eloctrolytes
and serum uric acid.
Similarly, frequency of
fetal monitoring
depends on the type of
hyperten- sive
disorder. In
pregnancies
complicated by
chronic hypertension,
fetal ultrasound,
amniotic fluid volume
assessment and
umbilical artery
Doppler velocimetry
are recommended at
Pregnancy-Induced hypertension 219
 220 E. KINTIRAKI ET AL
fetal activity, vaginal detection of that group cases of PIH had group. 99,100
Other
bleeding or of women with WCH conflicting results. RCTs resulted in
deterioration of the who are going to Prospective controlled better pregnancy
pre-existing condition develop PE is studies of metoprolol- outcome in the treated
is observed.83 important for hydralazine, groups. In contrast to
pregnancy outcome. nifedipine and the above findings,
Non-invasive
ABPM contributes to labetalol-methyldopa atenolol and labetalol
ambulatory blood
the achievement of treatment administered prevented proteinuria
pressure monitor- ing
both the above goals, to pregnant women in the treatment group
(ABPM) seems to be a
in parallel with the with mild PIH, as compared to the
useful tool for the
evaluation of unclassifiable control group.101-103
diag- nosis,
treatment hypertension or mild RCTs with
differential diagnosis
efficacy.84,89,91,92 PE showed no methyldopa pointed to
and follow-up of PIH.
It contributes to significant better pregnancy
identification of cases t improvement of outcome in cases of
with white-coat r pregnancy outcome as mild PIH and mild PE
hypertension (WCH), e compared to the non- with regard to mid-
prediction of PE, a treated group.95-98 pregnancy abortions
prognosis in late t Labetalol had no effect and progres- sion to
pregnancy and m on development of severe PE,
treatment e proteinuria in a trial of respectively. 104,105

modification.84-88 n 114 women with PIH Another trial of

t and nifedipine had no methyldopa in mild
WCH refers to effect on PIH demonstrated a
elevated blood Treatment of PIH
PE-related significant
pressure measure- depends on blood
hypocalciuria as prolongation of
ments when “in clinic”, pressure levels, compared to the pregnancy, by about
while “out of clinic” gestational age, control
presence of symptoms 10.3 days, with no
measure- ments are
and associated risk adverse effect on birth
normal. WCH in
factors. weight.106 An RCT of
pregnancy is a
100 pregnant women
frequent and benign Mild with mild PIH who
condition with good to were treated either
prognosis and no mod with methyldopa or
apparent need for erate labetalol and 50
antihypertensive hype controls confirmed the
treatment. Despite that, rtens
positive effect of
a small proportion of ion
antihypertensive treat-
patients with WCH in Data for the ment on pregnancy
early pregnancy will treatment of mild to outcome. Maternal
develop PE later in moderate PIH are
pregnancy.89,90 outcomes that were
controversial, making significantly improved
Consequently, it is it difficult to formulate
essential to by the
clear antihypertensive
differentiate WCH recommendations.80,81,9
from PIH, thus 3,94
treatment were
avoiding exposing progression to severe
these women to the Randomized PIH, proteinuria,
possible adverse controlled trials hospitalization before
effects of (RCTs) that com- term and delivery by
antihypertensive pared pharmaceutical caesarean section,
treatment as well as treatments with whereas fetal/neonatal
unnecessary caesarean placebo or no outcomes were SGA,
sections. In addition, treatment in mild preterm birth and
 Pregnancy-Induced hypertension 221
admission to neonatal antihypertensive
unit.107 treatment in cases of
mild to moderate PIH
Early treatment
concluded that greater
with clonidine plus
decrease of blood
hydralazine compared
pressure was
to the non-treatment
associated with fetal
group prevented pre-
growth restriction. The
mature delivery in
drugs that were used in
primigravid diagnosed
the RCTs of this
with mild PIH
meta-regression
(<170/110 mmHg).108
analysis were a-
Treatment with
methyldopa, beta-
nifedipine in cases of
blockers, thiazides,
mild PE had a positive
ketanserin,
effect on renal
hydralazine, calcium-
function with
channel blockers and
significant reduction
clonidine. Birth
of urea, creati- nine
weights of newborns
and 24 h urine protein
of the mothers who
in the treatment
took antihypertensive
group. 109
therapy during
Isradipine treatment
pregnancy were lower
was found to have no
adverse affect on
maternal kidney or
liver function or blood
flow in the umbilical
artery.110
Regarding neonatal
glucose
concentrations, there
was no significant
difference between
mothers who received
either isradipine,
atenolol or low
sodium diet (control
group).111 As far as
fetal growth is con-
cerned, atenolol and
labetalol treatment in
mild PIH and mild PE,
respectively, were
associated with fetal
growth restriction,
whereas early
antihypertensive
treatment with
oxprenolol had no
such effect.112-115 A
meta-analysis of the
effect of oral
222 E. KINTIRAKI ET AL
Pregnancy-Induced hypertension
than those of the non-
treated/placebo group.
Decrease in mean
arterial pressure of 10
mmHg was associated
with a 145 g decrease
in mean birth weight,
as found in a post-hoc
analysis.116
RCTs of
methyldopa treatment
during pregnancy had
smaller head
circumference in the
treatment group at
birth, 2 months, 6
months and 4 years of
age as compared to
control groups.117-121 In
contrast, an RCT with
nifedipine treatment in
cases of mild to
moderate PIH
exhibited no
difference between the
treatment and control
groups as far as
development and
health status at 18
months of age were
concerned.122
The ratio of
maternal-fetal benefit
to risk for fetal
adverse effects, such
as low birth weight,
need to be further
evaluated.116,123,124 A
Cochrane systematic
review on the control
of blood pressure in
mild to moderate PIH
did not reach
conclusive results due
to insufficient data.125
In general, non-
pharmacological
treatment is sug-
gested for pregnant
women with mild to
moderate PIH that do
223
not fulfil the criteria mmHg (Table 2).
for pharmacologic h Initiation of
treatment. According y antihypertensive treat-
to the WHO, lifestyle p ment at lower levels
modifi- cation, such as e (≥140/90 mmHg) is
strict bed rest and salt r suggested for women
restriction, are not t with a) gestational
e
recommended in PIH hypertension with or
n
or PE.1 Compliance without proteinuria, b)
s
with the i pre-existing
recommendations for o hypertension with the
the pre-pregnancy n superimposition of
BMI- dependent gestational
Blood pressure
indicated weight gain hypertension or c)
thresholds for drug
is essential due to the hypertension with
treatment initia- tion in
fact that both obesity asymptomatic organ
PIH vary between
and gestational weight damage or symptoms
different health
gain are risk factors at any time during
organizations.
for PIH, PE or pregnancy.127
According to the 2013
eclampsia.34,36,126
European Society of The aim of
Strict follow-up and
Hyperten- sion antihypertensive
early diagnosis of
(ESH)/European treatment is to prevent
progression to a more
Society of Cardiology complications, such as
severe condition is
(ESC) guidelines, maternal cerebral
necessary.
antihypertensive haemor- rhage and
Women at high risk treatment in pregnancy eclampsia, and allow
of PE are is recommended when prolongation of preg-
recommended to blood pressure levels nancy. According to
receive 75 mg aspirin are ≥150/95 the National Institute
and calcium of Clinical Excellence
supplements daily, (NICE) guideline for
especially when dietary “management of
calcium intake is low. hypertensive disorders
Vitamins C, E, D are during pregnancy
not recommended for 2010”, the therapeutic
PE prevention due to goal in severe PIH is a
insufficient data.1,127 gradual decrease of
Magnesium sulphate blood pressure to
(MgSO4) is <150/100 mmHg.128
recommended for Methyldopa is
eclampsia prevention considered the drug of
in women with severe choice in pregnancy
PE or as a due to its effectiveness
supplementary and long safety record.
treatment mo- dality in Labetalol can be given
eclampsia.1 intravenously in emer-
gency cases. Calcium
S
channel blockers
e
(CCB), such as
v
e nifedipine per os or
r isradipine IV, are
e effective and have no
 224 E. KINTIRAKI ET AL
major teratogenic risk. h s
A potential synergism y h i
with MgSO4 that may p y o
e p n
induce hypotension r ,
e
must be taken into t r
consideration. e t o
Atenolol and n e r
s n c)
metoprolol appear to
i s hype
be safe and effective in o i rtens
late pregnancy. Hy- n o ion
dralazine is no longer , n with
the parenteral drug of asym
choice in emergency w w ptom
cases due to perinatal i i atic
t t orga
adverse effects and
h h n
slower therapeutic
t dam
response. 129-132
A o h age
Cochrane review about r e or
the use of diuretics for sym
prevention of PE and w s ptom
its complications i u s at
disclosed no t p any
h e time
significant difference
o r durin
in pregnancy u i g
outcomes between the t m preg
treated group and the p nanc
placebo or no-drug p o y
groups.133 r s
Angiotensin- o i
t t
e i
i o
table 2. ESH/ESC 2013 n
n
guidelines for hypertension in
pregnancy127 u
r o
antihypertensive treatment i f
>160/110 mm Hg a
+ , g
≥150/95 mm Hg e
(if persistent) o s
+ r t
≥140/90 mm + b a
+ ) t
i
a)
p o
g
r n
e
e a
s
- l
t
a e
t x h
i i y
o s p
n t e
a i r
l n t
g e
n
Pregnancy-Induced hypertension 225
 226 E. KINTIRAKI ET AL
converting enzyme and ARBs during central sympatholytic parison of labetalol to
inhibitors (ACEIs) and pregnancy compared effect mediated via hydralazine,
angiotensin II receptor to controls.137 stimulation of sero- methyldopa and
blockers (ARBs) are tonin 5HT1A receptors nicardipine. Labetalol
Several RCTs
contraindicated in in the central nervous was associated with
compared different
pregnancy due to their system. It reduces marginally less
antihypertensive drugs
association with an blood pressure by hypotension and
in pregnancy. A
increased risk of decreasing peripheral caesarian section rate
Cochrane systematic
fetopathy.134-136 vascular resistance.140 compared to
review included 24
Women who are Studies comparing diazoxide. MgSO4 had
RCTs that compared at
treated with an ACE or hydralazine to urapidil a higher risk of
least two anti-
ARB before provided insufficient persistent high blood
hypertensive drugs.138
conception should be data. One prospective pressure, of maternal
The review did not
advised to avoid study of 100 women respiratory distress
come to a clear
exposure to these with severe PIH and of postpartum
conclusion due to
drugs during showed that urapidil haemorrhage but a
insufficient data.
pregnancy by was effective in 80% lower risk of
Hydralazine as
replacing them with a of cases.141 eclampsia compared to
compared to
different nimodipine. Isosorbide
nifedipine and Data were also
antihypertensive drug was associated with
isradipine was seen to insufficient as
as soon as pregnancy lower frequency of
be less effective as regards the com-
is confirmed.128
regards persistent high caesarian section than
Studies of pregnant
blood pressure. No MgSO4.
women who received
difference was
the above classes of An RCT of 200
detected between hy-
drugs and animal pregnant women who
dralazine and
experimental studies were treated with
prostacyclin.
showed increased risk hydralazine IV or
Ketanserin is a
of fetal hypotension, labetalol for severe
selective S2-
decreased glo- merular PIH re- sulted in a
serotoninergic
perfusion pressure, significantly higher
antagonist exerting
impaired renal tubular rate of palpitations and
alpha-1 receptor
development, reduced maternal tachycardia in
antagonistic action,
fetal urine output or the hydralazine-treated
especially with higher
complete anuria and group and higher rate
doses of the drug. It
oligohydramnios, limb of hypotension and
inhibits the
contractures, pul- bradycardia in the
vasoconstriction and
monary hypoplasia, labetalol-treated
platelet aggregation
cranio-facial group.142 Another
induced by
deformation and smaller (n=16) trial of
serotonin.139
impaired ossification, hydralazine or
intrauterine growth Hydralazine was labetalol in acute
restriction and associated with lower severe PIH revealed
decreased placental risk for per- sistent the high effectiveness
and umbilical high blood pressure as of both drugs, with no
perfusion. compared to ketanserin effect of either of them
Epidemiological but with increased rate on fetal Doppler.143 In
studies demonstrated of adverse effects. contrast, the group that
an increased risk of Urapidil is an alpha-1 received hydralazine
congenital receptor antagonist had a significant
malformations among with agonistic action increase in uterine
neonates of mothers at serotonin 5-HT1A arteries resistance.
who received ACEIs receptors. It also has a Hydralazine IV as
 Pregnancy-Induced hypertension 227
compared to mini compared the
bolus diazoxide effectiveness of oral
resulted in a nifedipine and
significantly higher intravenous labetalol
rate of persistent in pregnant women
hypertension.144 with gestational
The latter was also hypertension and BP
observed in a trial of ≥160/110 mmHg. No
hydralazine IV or significant difference
nifedipine per os in in BP decrease was
hypertensive crisis. found between the two
Another smaller study groups.149 Intravenous
of dihydralazine and nitroglycerin, oral
urapidil found no methyldopa or oral
difference as regards clonidine can be used
effectiveness between as second line
the two drugs.145 treatment.148
Treatment with Magnesium sulfate
nitroglycerine IV plus can be used in
plasma volume combination with an
expansion and MgSO4 antihypertensive agent
as compared to
sublingual nifedipine
plus plasma volume
expansion and MgSO4
showed no difference
in effectiveness or
maternal and fetal-
neonatal adverse
effects.146 Finally, a
double-blind RCT of
nifedipine per os versus
labetalol IV resulted in
no significant
difference in the time
needed to achieve the
therapeutic goal or the
overall efficacy
between the two
drugs. 147

Acute severe
hypertension in
pregnancy is consid-
ered a medical
emergency and
requires hospitaliza-
tion. Labetalol,
hydralazine and
nifedipine are used as
first line treatment.148
A double-blind
randomized trial
228 E. KINTIRAKI ET AL

table 3. Treatment of severe hypertension (Modified by SOGC Clinical Practice Guideline 2014)148
anti-hypertensive dosage onset duration comments
agent
Labetalol 20 mg IV, repeat 20 to 80 mg IV q 30 min, 5 min 4h Contra indications:
or 1 to 2 mg/min, max 300 mg (then switch to asthma, cardiac failure
oral)
Nifedipine 5 to 10 mg capsule to be swallowed or bitten, every 30 min 5-10 min 6h
Hydralazine 5 mg IV, repeat 5 to10 mg IV every 30 min, or 5 min Ιncreased risk of
0.5 maternal hypotension
to 10 mg/hr IV, to a maximum of 20 mg IV (or 30 mg
Pregnancy-Induced hypertension 229
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