Treatment of arterial hypertension in pregnancy

Archives of Perinatal Medicine 13(2), 7-16, 2007
ORIGINAL PAPER
Treatment of arterial hypertension in pregnancy
LUDWINA SZCZEPANIAK-CHICHEŁ1, GRZEGORZ H. BRĘBOROWICZ2, ANDRZEJ TYKARSKI1
Abstract
Arterial hypertension is a problem in 7-10% of pregnant women and is related to increased mortality and risk of complications in perinatal
period for both, a mother and a child. In the treatment of pregnancy hypertension there are still no agreed and widely approved standards
to be followed. Influence of the therapy on both, the pregnant and the fetus, altogether with a lack of large randomized trials lead to conclusion
that the optimal solution is a cooperation based on the sum of the experience of gynaecologist, obstetrician, neonatologist and specialists in
hypertension. The treatment of hypertension in pregnancy differs in both, pharmacological and non-pharmacological regimens, from the
standards established for non-pregnant patients. Weight reduction and increased physical activity are not recommended for women with
hypertension who become pregnant. In mild to moderate pregnancy hypertension the non-pharmacological treatment can be enough, providing
that sufficient control of the state of both, the mother and the child, is granted. Nevertheless, in case of moderate to severe hypertension
pharmacotherapy is indicated and beneficial. Antihypertensives accepted in the management of pregnancy hypertension are alpha-methyldope,
labetalol, $-blockers, calcium channel blockers and hydralazine. Among them only alpha-methyldope can be used safely during the whole period
of pregnancy, which has been confirmed by the long-term clinical observations. In the latest guidelines ESH/ESC from 2007 hydralazine is
no longer considered as one of the first line drugs in management of hypertension in pregnancy because of increased risk of perinatal
complications reported lately.
Key words: arterial hypertension, pregnancy, treatment
Arterial hypertension is a problem in 7-10% of pregnancies and is a reason for increased risk of perinatal complications including death of a mother or a child [21, 22, 39]. The
level of blood pressure during pregnancy has a direct influence on the clinical status of the pregnant women and the
fetus. Preterm delivery is a problem in 33% of women with
mild hypertension, in comparison to 62-70% in women with
severe form of the disease. Intrauterine growth restriction
(IUGR) is present respectively in 11% and 40% of those populations [21]. Among various forms of pregnancy hypertension
preeclampsia and eclampsia are responsible for most of the
serious complications of elevated blood pressure. In USA 15%
of mortality rate in pregnant women is caused by hypertension and its complications, second cause of death after pulmonary embolism in this population [22].
Management of hypertension is controversial mainly due
to lack of widely accepted standards of treatment in this specific clinical situation. Diversity of proposed classifications,
values of blood pressure considered as an indication for treatment, hypotensive drug regimens regarded as optimal are the
result of the objective causes (overlap of the pathogenetic factors typical for hypertension and those connected with pregnancy itself, different priorities distribution when taking into
consideration the outcome of the mother and the fetus, lack
of large, randomized trials because of ethical issues) but also
stem from different points of view presented by specialists
taking part – gynecologist, obstetrician, perinatologist and
hypertensiologist. A harmonious and efficient cooperation
between them can be highly beneficial for both mother and a
child facing a threat of hypertension and its complications.
Blood pressure profile in the course of pregnancy
Regardless from presence or absence of arterial hypertension before gestation, in women with normal pregnancy
1
2
there is a drop in peripheral resistance due to increased
activity of local vasoactive substances such as prostacycline
and nitric oxide. As a result, value of systolic blood pressure
(SBP) decreases 4-6 mm Hg and value of diastolic blood pressure (DBP) – 8-15 mm Hg in the first trimester. Both reach
their lowest values around 22-24 week of gestation and then
rise gradually to pre-pregnancy level or even higher, at term.
Immediately after delivery blood pressure falls down and rises
once more in the first 4-5 days of the postpartum period and
afterwards gradually goes back to normal non-pregnant level
[24]. Except from fall in peripheral resistance during pregnancy, there is also a rise in heart rate (10-15 heart beats/min)
and increase in the intravascular volume – reason for a term
“hyperkinetic circulation” for the haemodynamics of the cardiovascular system of a pregnant woman [30].
Measurement of blood pressure in pregnancy
Changes of blood pressure with the advancement of pregnancy suggest that values considered as normal should be
different than those in the general population. Nevertheless,
the arterial hypertension in gravidity is recognized when SBP
$ 140 mm Hg or DBP $ 90 mm Hg at least twice with the
minimum 6 hours’ break between the two measurements
[22].
The recommended device for the blood pressure measurement is a mercury sphygmomanometer with the length
and width of the cuff adjusted to the circumference of the patient’s arm. The measurement should be performed after at
least 10 minutes of rest, in the sitting or left lateral position
with the cuff at the level of the heart.
The diastolic value of the blood pressure is considered to
be more important predictive factor for the outcome of both,
the mother and the child, than the systolic one. According to
the recommendations of the European Society of Hyperten-
Department of Hypertensiology, Angiology and Internal Diseases, Medical University in Poznań, Poland
Department of Perinatology and Gynaecology, Medical University in Poznań, Poland
L. Szczepaniak-Chicheł, G. H. Bręborowicz, A. Tykarski
sion and European Society of Cardiology the diagnostic investigation and therapeutic decisions should be based on the
value of DBP assessed in the V phase of Korotkoff [13]. In
typical for pregnancy hyperkinetic circulation the appearance
of the V phase may even reach the 0 point – than the DBP
should be assessed already in the IV, when auscultation over
the brachial artery reveals abrupt muffling of the sound [24].
In recent ESH/ESC guidelines the assessment of blood
pressure in pregnant women by automatic 24-hours blood
pressure measurement (ABPM) has been shown to be
superior to conventional measurements in predicting proteinuria, risk of preterm delivery, infant weight at birth and in
general outcome of pregnancy [13].
Classification of arterial hypertension in pregnancy
There are almost as many classifications of arterial hypertension in pregnancy as scientific societies struggling with the
subject. There is a problem with differentiation between chronic hypertension which antedates the pregnancy and hypertension induced by gravidity itself. Frequently, lack of data
concerning values of blood pressure before conception and in
the first trimester leads to the situation when proper recognition is possible only retrospectively.
Classification of arterial hypertension in pregnancy according to ESH/ESC, 2007 [13]:
C Pre-existing hypertension (chronic hypertension in pregnancy) – hypertension which antedates pregnancy or develops before 20th week of gestation and in most cases
persists for more than 42 days post partum; may be associated with proteinuria; is present in 1-5% pregnancies
[18]. The problem of chronic hypertension in pregnancy
will probably increase due to tendency among women to
postpone pregnancy until later period of life while the
incidence of primary arterial hypertension with age is
raising. Among women aged 18 to 29 the pre-existing
hypertension is present in 0,6-2% of them and in comparison in population aged 30-39 years old it affects 4,622,3% of pregnant women [21].
C Gestational hypertension (pregnancy induced hypertension) – develops after 20th week of gestation and in most
cases resolves within 42 days post partum, with or without accompanying proteinuria; affects 6-17% healthy
before pregnancy primigravid women and 2-4% of multipara [21].
– Preeclampsia – gestational hypertension with proteinuria > 0,5 g/day; affects 2-7% healthy primigravid
women, 14% of twin pregnancies and 18% of patients
with preclampsia in previous gravidity [35].
– Eclampsia – appearance of seizures in the course of
preeclampsia (with no sign of other possible explanation such as epilepsia or intracranial hemorrhage).
C Pre-existing hypertension with superimposed preeclampsia (pre-existing hypertension plus superimposed gestational hypertension with proteinuria) – pre-existing hypertension with further increase of BP and appearing or
worsening of proteinuria > 3 g/day in 24-hour urine collection after 20th week of gestation; hypertension does
not recede after 42 days from delivery. 10-25% women
with pre-existing hypertension is going to have superimposed preeclampsia [21]. Risk is higher if there is a co-
existence of kidney failure, when hypertension is present
for at least 4 years or was present in previous pregnancy
[22].
C Antenatally unclassifiable hypertension – hypertension
with or without systemic manifestation, first recorded
after 20 weeks of gestation, re-assessment is necessary
at or after 42 days post partum.
Main differences among scientific societies in definitions
and criteria for recognition of arterial hypertension in pregnancy are presented in table 1.
Simple differentiation between hypertensive disorders in
pregnancy, based on presence of proteinuria and the time of
onset of hypertension, which might be useful for everyday
clinical practice is presented in figure 1.
Management of arterial hypertension in pregnancy
Every pregnant women or planning to become one
should have checked her blood pressure regularly. Performing the measurement before 20th week of pregnancy is crucial for the early recognition of the form of pregnancy hypertension and has its clinical, therapeutic and prognostic implications for the mother and the fetus. The aim of the management of hypertension in pregnancy is to diminish the risk
which follows for both of them.
P r e s e n c e o f p r o t e in u r i a
8
+
Pre-existing
hypertension
with superimposed
preeclampsia
Preeclampsia
Pre-existing
hypertension
Gestational
hypertension
20 weeks
40 weeks
Time when elevated BP emerged during pregnancy
Fig. 1. Arterial hypertension in pregnancy
In case of recognition of hypertension for the first time
during pregnancy in previously healthy woman or not diagnosed before, an admission to the hospital unit for a short
period of time is recommended to implement the diagnostic
procedures for differentiation between primary and secondary
hypertension and assessment of the form of pregnancy hypertension as well as the proper management according to achieved results.
Special attention should be paid if risk factors of preeclampsia listed in table 3 are present. Pre-eclampsia is more
than hypertension – it is a systemic syndrome where the
function of the heart, kidneys, liver, central nervous system
and coagulation system is influenced. Preeclampsia is the
outcome we want to avoid. Several of its non-hypertensive
complications can be life-threatening even when blood pres
sure elevations are quite mild. For clinical management, pre-
Treatment of arterial hypertension in pregnancy
9
Table 1. Definition and criteria for recognition of arterial hypertension in pregnancy (acc. to Helewa and co-authors [15]; modified)
Definition
/criteria
Arterial
hypertension
[mm Hg]
Severe
hypertension
[mm Hg]
PTNT*2003
ESC/ESH2007
SBP $ 140 and
(or)
DBP $ 90
SBP $ 140
and (or)
DBP $ 90
SBP $ 170
and (or)
DBP $ 110
Korotkoff
sounds
Significant
proteinuria
(24-h urine
collection)
Time after
delivery for
recognition
of gestational AH
SBP $ 150
or DBP $ 95
NHLBI-WG
2003
SBP $ 140
and (or)
DBP $ 90
–
V
(IV only if V at the
level of 0 mm Hg)
$ 3 g/24h
> 500 mg/24h;
> 300 mg/l;
$2+
(dipstick test)
mg/24h
42 days
12 weeks
42 days
–
$ 300
NHBPEP-WG
2000
ISSH
2000
CHS
1997
ACOG1996
SBP $ 140
or DBP $ 90
DBP $ 90
DBP $ 90
DBP $ 90
or SBP $ 140
DBP $ 110
or SBP $ 160
DBP $ 110
DBP $ 110
DBP $ 110
SBP $ 160-180
V
IV
IV
–
$ 3 g/24h
$ 3 g/24h
> 5 g/24h
–
42 days
–
$ 0,3 g/24h
or
$1+
(dipstick test)
12 weeks
*PTNT – Polish Society of Arterial Hypertension (Polskie Towarzystwo Nadciśnienia Tętniczego) [39]; ESH/ESC – European Society of Hypertension
/European Society of Cardiology [13]; NHLBI-WG – National Heart, Lung, and Blood Institute Working Group (USA) [32]; NHBPEP-WG – National High Blood
Pressure Education Program Working Group (USA) [22]; ISSH – International Society for Study of Hypertension; CHS – Canadian Hypertension Society [15];
ACOG – American College of Obstetricians and Gynecologists; SBP – systolic blood pressure; DBP – diastolic blood pressure, AH – arterial hypertension
Table 2. Laboratory tests recommended for the assessment of the hypertensive disorders in pregnancy [13, 15, 22, 39, 42]
Laboratory test
Purpose and conclusions
Dipstick test for proteinuria has significant false-positive and false-negative rates. If dipstick results are positive
Urinalysis
(> 1), 24-h urine collection is needed to confirm proteinuria. Negative dipstick results do not rule out proteinuria, especially if DBP > 90 mm Hg.
Proteinuria
Standard to quantify proteinuria. If in excess of 2 g/day, very close monitoring is warranted. If in excess of
(24-h urine collection) 3 g/day, delivery should be considered.
Serum albumin
Assessment of the liver function, can be the indicator of the protein leakage at the microvascular level.
Hemoglobin
Hemoconcentration supports diagnosis of gestational hypertension with or without proteinuria.
and hematocrit
It indicates severity. Levels may be low in very severe cases because of hemolysis.
Low levels < 100 000 × 109/l may suggest consumption in the microvasculature. Levels correspond to severity
Platelet count
and are predictive of recovery rate in post-partum period, especially for women with HELLP syndrome.
Serum AST, ALT
Elevated levels suggest hepatic involvement. Increasing levels suggest worsening severity.
Elevated levels are associated with hemolysis and hepatic involvement. May reflect severity and may predict
Serum LDH
potential for recovery post partum, especially for women with HELLP syndrome.
Serum uric acid
Elevated levels aid in differential diagnosis of gestational hypertension and may reflect severity.
Levels drop in pregnancy. Elevated levels suggest increasing severity of hypertension; assessment of 24-h
Serum creatinine
creatinine clearance may be necessary.
eclampsia should be overdiagnosed to prevent maternal and
perinatal morbidity and mortality – primarily through timing
of delivery.
Early baseline sonogram, repeated thereafter with accurate dating and assessment of fetal growth, performing nonstress test or biophysical profile are methods of the fetal
assessment in pregnancy, also in women with arterial hypertension. Abnormal uterine artery Doppler together with fetal
arterial and venous Doppler ultrasonography seems to be
useful predictive factor for development of preeclampsia and
further perinatal outcome.
Laboratory tests for monitoring hypertension in pregnancy
Adverse influence of hypertension and its complications
on the clinical state of the mother and a child is visible in the
laboratory assessment of the kidney and liver function and
also in the coagulation status. Laboratory tests summarized in
table 2 are helpful in the differentiation between hypertension
and other pathological disorders as well as in recognition of
the form of hypertension itself, are the indicators of complications and ease the clinical decisions concerning management
of the hypertensive state.
L. Szczepaniak-Chicheł, G. H. Bręborowicz, A. Tykarski
10
Table 3. Risk factors for development of arterial hypertension
in pregnancy and preeclampsia [7, 8, 24-26]
MATERNAL, non-changeable
age < 18 or > 40 years old
low socioeconomic status
previous preeclampsia
primigravidity
multigravidity
family history of preeclampsia
low birth weight of the mother
black race, or Spanish nationality
FETAL
hydatid mole
hydrops fetalis
chromosomal anomalies
PATERNAL
primipaternity
limited sperm exposure
MATERNAL, co-morbidities
increased BMI (body mass index)
diabetes
increased insulin resistance
chronic hypertension
smoking
hyperlipidaemia
hyperhomocysteinemia
renal disease (even without significant impairment)
frequent urinary tract infections
rheumatoid disorders
thrombophilia
antiphospholipid syndrome
increased level of testosterone
ANTYHYPERTENSIVES*
AT, rec. blockers
ACE-I
as a continuation of treatment
diuretics
β-blockers
Ca channel blockers
labetalol
hydralazine
α-metyldope
I trimester
II trimester
III trimester
labour
definitely contraindicated
recommended with some exceptions
relatively contraindicated, increased risk
recommended
* - there is no class effect (just preparations with proven safety)
Fig. 2. Treatment of hypertension according to the time of gestation
Several attempts has been made to estimate which one of
the laboratory tests has the best predictive value for the risk
of developing preeclampsia. It has been noticed that coexistence of raised blood pressure values (> 140/90 mm Hg) with
decreased serum renin activity and increased serum uric acid
results in 86% risk of preeclampsia. If just one or two of the
mentioned are present the risk is 40 or 62% consecutively [21].
Nonpharmacological treatment of hypertension in pregnancy
Pregnancy changes most of the rules for the nonpharmacological management of hypertension. In opposite to nonpregnant patients increased physical activity and restrictions
in diet in order to gain lower body mass are not recommended
during gestation [13, 20, 22].
Possible and safe methods of nonpharmacological management in pregnancy are as follows:
C restriction of physical activity – both at work and at home;
C bed rest in left lateral position;
C light diet, rich in vitamins, microelements and proteins;
C smoking cessation;
C prohibition on alcohol consumption.
There are no proves that restriction of physical activity
and prolonged bed rest have a significant influence on the
number of complications for the mother and the fetus in pregnancy hypertension [18], [35].
Restriction of salt in diet is not recommended [13]. Women with natrium-sensitive hypertension before pregnancy
and significant, beneficial effect of such intervention on values
of blood pressure in the past can be an exception.
Treatment of arterial hypertension in pregnancy
Loosing weight in pregnancy is contraindicated, even
though obesity is a risk factor of preeclampsia, because during
pregnancy it can be harmful for the fetus development (lower
birth weight, worse neonatal outcome) [33], [39].
Similarly, increased physical activity during pregnancy is
not indicated for the sake of a child [35].
Nonpharmacological management should be recommended for all women with hypertension in pregnancy. Decision
whether it is enough or should the pharmacological therapy be
added to it depends on the level of blood pressure, week of
gestation and presence of risk factors for development of the
preeclamptic state.
Prevention of the preeclamptic state
– possible interventions
Data concerning the role of calcium suplementation in
prophylaxis of preeclampsia are divergent [23]. Recent metaanalysis has shown the reduction in the incidence of severe
hypertension and the risk of preeclampsia, followed by the
reduction in maternal and fetal mortality and morbidity
especially in women at high risk of preeclampsia or with
deficiency of this element in diet [2]. Proper ingestion of
calcium (2 g/day) in well-balanced diet is advisable regardless
of whether gravida has a hypertension or not [2], [22].
Role of the acetylosalicylic acid administered in small
doses (75-150 mg/day) has already been established in prevention of preeclampsia and is beneficial especially in women
with increased risk of this disease [13, 39]. In women at high
risk, aspirin reduces the incidence of preeclampsia (RR = 0.85;
95%CI 0.78-0.92) also the risk of preterm birth before 37th
week of gestation (RR = 0.92; 95%CI 0.88-0.97) and mortality
among children (RR = 0.86; 95%CI 0.75-0.98) [19]. Compared
with placebo, aspirin diminishes the risk of preeclampsia in
about 15%, the risk of preterm birth in 8% and perinatal mortality in 14%, with no increase in prevalence of significant bleeding [21]. Small but beneficial effect of the administration of
aspirin in high risk group was confirmed by the metaanalysis
of Coomarasamy and co-authors [6]. It should be implemented
after 12 weeks of gestation (if earlier, there is an increased
risk of miscarriage according to data on the use of non-steroid
anti-inflammatory drugs) and continued up to delivery.
Up to date, there are no proves from randomized studies
and metaanalyses for protective effect of zinc, potassium, magnesium, L-arginine or vitamins (D, E, C, β-carotene) supplementation. Similarly, there are insufficient data to draw reliable conclusions for fish oils, evening primrose oil, administration of glyceryl trinitrate or ozagrel hydrochloride. They are
not recommended in prevention of preeclampsia [13, 37].
Pharmacological treatment of hypertension in pregnancy
Choice of the antihypertensive agent
All antihypertensive drugs are capable of crossing the placenta into the cardiovascular system of the child. That is why
lack of adverse effects for the fetus is crucial for the choice of
the hypotensive treatment. In pregnancy only those drugs
which proved to be safe for the child can be used, there is no
class effect while choosing the medication. Otherwise with
adverse effects – if there is a negative reaction for one drug
only – the whole group is regarded distrusted. The choice of
11
treatment is also dependent on the doctor’s experience with
the drug and the gestation period (Fig. 2.). In case of preexisting hypertension the treatment regimen should be
changed after conception regarding its influence on the fetus
development. Angiotensin converting enzyme inhibitors or
angiotensin II type 1 receptor blockers should be withdrawn
immediately [13, 15, 22, 32, 39].
Available data do not allow to decide undoubtedly which
treatment regimen is the best in mild and moderate pregnancy
hypertension [18]. Generally, it is established that the first
line treatment should be the alpha-methyldope – a drug which
is safe for the child through the whole period of pregnancy and
has a low incidence of adverse effects for the mother. The
other possibility is labetalol – effective in lowering even high
values of blood pressure. The second choice drug should be
the calcium channel blockers or beta-blockers. After all hydralazine can be given as a part of polytherapy. In clinical practice
the treatment of hypertension in pregnancy is often started
with alpha-methyldope an in case of insufficient blood pressure
control the drugs from other groups are added gradually.
In case of severe hypertension when rapid lowering of
blood pressure is needed intravenously administered labetalol,
orally given nifedypine or alpha-methyldope are preferred.
Dihydralazine and sodium nitroprusside should be avoided
because of increased risk of child side effects with such management. Lowering of high blood pressure should be done with
caution – rapid decrease may result in hypoperfusion of the
uterus and placenta as well as hypoperfusion of the internal
organs and central nervous system of the pregnant woman.
Ideal antihypertensive drug should lower the blood pressure to the desired level quickly, with no side effects, but in
a controllable manner, should not influence the heart rate, and
have beneficial effect on the constriction of the utero-placental
vessels.
Groups of antihypertensive drugs
and their application during pregnancy
Alpha-methyldope – is centrally acting α-agonist, acts primarily in the central nervous system, but also stimulates α-2
receptors peripherally and decreases arterial pressure by influence on the sympathetic tone. It does not affect the renal
blood flow (can be used in case of kidney failure) and the
utero-placental circulation (hemodynamics of the fetal cardiovascular system is not affected). It is an antihypertensive drug
of the first choice in case of pregnancy, safe in every trimester, which has been established by the 7,5 years of observation of 195 children from pregnancies with such pharmacological intervention with no adverse outcome on their development [21]. Addition of diuretic in a small dose can be helpful to overcome the problem of resistance to alpha-methyldope, as a solution to overhydratation which is an underlying
cause of this phenomenon. Alpha-methyldope should be
avoided in case of pheochromocytoma because it can change
the results of the catecholamine tests [24].
Labetalol – a combined α2- and β-blocker, diminishes the
peripheral resistance with mild effect on cardiac output. It is
more effective than alpha-methyldope, commonly used in case
of moderate to severe hypertension [21]. It is given mainly in
the III trimester and during the labour. Transient mild hypotension and bradycardia rarely requiring intervention may occur
L. Szczepaniak-Chicheł, G. H. Bręborowicz, A. Tykarski
12
Table 4. Orally administered antihypertensives in pregnancy (acc. to Montan [19] – modified)
Antihypertensive drugs
Centrally acting
α-methyldope
Adrenergic receptor blockers
β-blockers
atenolol
metoprolol
α, β-blockers
labetalol
Calcium channel blockers
nifedypine
felodypine
Vasodilatator
hydralazine
Daily dose
Frequency
250-500 mg
3-4 × day
25-50 mg
25-50 mg
2 × day
2-3 × day
100-200 mg
2-3 × day
5-10 mg
2,5 mg
3 × day
2 × day
25-50 mg
3 × day
Adverse effects for the mother
Somnolence, vertigo, headaches, nightmares, depression,
hypotension, Parkinson-like symptoms when overdosed,
allergic reactions
Bradycardia, atrio-ventricular conduction impairment, fainting, bronchospasm, Raynaud syndrome, worsening of
the peripheral vessel perfusion when with atherosclerosis
Peripheral oedema, headaches, flushing, vertigo, paresthesia, muscle weakness, gingival hypertrophy, tachycardia
and hypotension when overdosed
Peripheral oedema, tachycardia, lupoid-like syndrome
Table 5. Antihypertensive drugs used in severe hypertension in pregnancy (acc. to Montan [19] – modified)
Antihypertensive drugs
Dose
Nifedypine
10-20 mg sl. or orally, repeat after 20-30 min., then 10-20 mg every 3-6h until 1 mg/kg m.c. (max. dose = 50 mg/h;
120 mg/day)
Labetalol
20 mg iv. in bolus, or 20-80 mg every 20-30min. or iv. 0,5 mg/min. (max. dose = 220 mg/h; 2,4 g/day)
Hydralazine
2,5-5 mg iv., repeat after 15-20min. or i.v. 0,5-10 mg/h (max. dose = 20 mg/h)
Nitroglicerine
i.v. 5 μg/min., increase every 3-5 min. up to max. 100 μg/min.
Diazoxide
30-75 mg i.v. every 30 min.
Sodium nitroprusside 0,25 μg/kg/min., max. 5 μg/kg/min. Not longer than 4 h – danger of intoxication with cyjanide
in babies born by the mothers treated with labetalol [18]. There
are suggestions that in women with preeclampsia labetalol given
intravenously during general anesthesia may diminish the tachycardia and hypertensive reaction to intubation [18].
-blockers such as metoprolol may be used as a monotherapy in mild and moderate hypertension, except from the
I trimester because of increased risk of bradycardia of the
fetus and intrauterine growth restriction (IUGR) (12 studies;
n = 1346; RR = 1.36; 95%CI 1.02-1.82) probably due to decreased heart rate or increased peripheral resistance [17].
Later in pregnancy they are as safe and efficient as alphamethyldope.
Beta
Beta-blockers decrease the risk of severe hyper-
tension (11 studies;
n = 1128; RR = 0.37; 95%CI 0.26-0.53),
the need for additional antihypertensive drugs (7 studies;
n = 856; RR = 0.44; 95%CI 0.31-0.62) and frequency of hospitalizations [17].
From among calcium channel blockers most frequently
used in management of mild and moderate hypertension is
nifedypine [21]. Form of 10 mg tablets with prolonged action
appeared to be better than short-acting capsules, even in case
of severe, suddenly rising (> 170/110 mm Hg) hypertension
with need for urgent action, because of lower rate of hypotension as a result of the intervention [3]. This group of drugs
can also be given sublingually (8 mg s.l.) or intravenously in
case of severe hypertension with even better antihypertensive
effect than management with hydralazine (5-10 mg i.v.) [19].
Nifedypine acts fast – within 10-20 minutes from oral administration. Given together with magnesium sulphate requires special attention because of highly increased risk of hypo-
tension – dangerous for the central nervous system and the
utero-placental circulation [18].
Other frequently used calcium channel blocker is nicardypine. Comparison of labetalol with this drug revealed similar
hypotensive effect (20% decrease in BP) with slightly better
results and increased rate of mild tachycardia in the calcium
channel blocker group [19].
Felodypine is another, newer calcium channel blocker
used in pregnancy, which has a selective effect on the vascular
smooth muscle cells and decreases blood pressure with insignificant influence on the heart [21].
Calcium channel antagonists should not be used in the I
trimester because of data suggesting that they can increase
the number of fetal anomalies and should be used with caution
whenever given together with magnesium sulphate, as highly
increasing the risk of severe hypotension as an adverse effect
[16].
Non-dihydropirydine calcium channel antagonist – verapamil is also effective and safe in management of hypertension
in pregnancy. It is useful in maintenance treatment when may
prevent the tachycardia caused by β-mimetics together with
relaxation of the uterus muscular tissue [26].
Hydralazine is an arterial direct vasodilatator used usually
in polytherapy in the treatment of severe chronic and gestational hypertension, also in eclampsia, preeclampsia and in the
hypertension during the postpartum period. Hydralazine can
be given parenterally or orally. Recent recommendations
ESH/ESC 2007 do not mention dihydralazine anymore as
a drug of the first choice in the management of hypertension
Treatment of arterial hypertension in pregnancy
in pregnancy [13]. It is due to increased frequency of perinatal
adverse effects when given parenteraly. Results of metaanalysis from previous studies suggest that treatment with hydralazine compared with labetalol or nifedypine is responsible for
increased incidence of hypotension (13 studies; RR = 3.29;
95%CI 1.50-7.23) and oliguria in pregnant patients (3 studies;
RR = 4.0; 95%CI 1.22-12.50), increased risk of premature
placental ablation (5 studies; RR = 4.17; 95%CI 1.19-14.28),
necessity for cesarean section (14 studies; RR = 1.30; 95%CI
1.08-1.59) and lower score in the Apgar scale in the first minute of the newborn’s life (3 studies; RR = 2.70; 95%CI 1.275.88). Compared with labetalol only the frequency of newborns’ bradycardia was lower in the hydralazine group
(RD = !0.24; 95%CI !0.42 to !0.06) [16]. There are data suggesting that hydralazine given during pregnancy for a longer
period of time may induce lupoid-like syndrome and thrombocytopenia in the newborn. Also other adverse effects of hydralazine like nausea, vomiting or headache in pregnant woman
may be misleading – they suggest worsening of the clinical
state of the patient due to hypertension itself, even with the
transformation of preeclampsia into eclampsia. Even though,
hydralazine is still used and useful in clinical practice mainly
because of wide and of many years standing experience of the
gynecologists and obstetricians with this drug.
Diuretics can be used as an antihypertensives only if given as a continuation of the preconceptional treatment lasting
before pregnancy for a longer period of time [26]. Metaanalysis of Collins and co-workers encompassing over 7000 patients treated with diuretics did not reveal any significant risk
for pregnancy period [5]. Nevertheless, because of the theoretical premises implementation of antihypertensive treatment with diuretic for the first time during pregnancy is not
considered to be accurate. Decrease of intravascular volume,
already diminished in gestational hypertension, with further
impairment of the utero-placental blood flow may lead to
intrauterine growth restriction [31]. Diuretics are indicated in
pregnancy only in specific situations such as severe heart
failure, pulmonary oedema [39] or oliguria [13].
Angiotensine converting enzyme inhibitors (ACE-I) and
angiotensine II receptor type 1 blockers (ARB) are contraindicated during pregnancy and lactation because of possible adverse effect on the child’s health such as: intrauterine growth
restriction, hypoplasia of the lungs, oligohydramnios, kidney
failure (temporary in case of the newborn after telmisartan
therapy; permanent after ACE-I therapy of chronic hypertension in the mother in II and III trimester) and increased
perinatal mortality (5 death cases) [4, 14, 19, 31, 39].
Sodium nitroprusside – dilatation of the vessels, both
veins and arteries is responsible for antihypertensive action.
The drug is nowadays gradually withdrawn from the market,
in pregnancy was used rarely, only in hypertensive crisis when
other possibilities failed, always under control of the cyjanide
levels in the blood serum and not longer than for 4 hours
(danger of the intoxication of the fetus) [19].
Management of pre-existing arterial hypertension in
pregnancy
There is a lack of unanimity between recommendations
of different scientific societies concerning the level of blood
pressure at which pharmacological treatment should be
13
implemented in pre-existing hypertension. There is a wide
spectrum of views on the subject – from treatment of every
patent with BP > 140/90 mm Hg [39], to regarding as the indication for intervention only the severe form of hypertension
($ 180/110 mm Hg) [15].
It seems rational to take into account not only the values
of BP but also the form of hypertension in pregnancy, number
and severity of risk factors, data from the history of the patient, present state of the mother and a child and possible
side effects of the therapy [13]. Antihypertensive treatment
is indicated and beneficial in severe form of hypertension
(according to European recommendations the cut-off point is
at 170/110 mm Hg [13], and according to North American –
at 160/110 mm Hg [32]). In mild and moderate forms of hypertension necessity of treatment in pregnancy is controversial.
In mild pre-existing hypertension without proteinuria
antihypertensive treatment do not diminish the number of
complications (superimposed preeclampsia, preterm delivery,
preterm placenta detachment and mortality) [14]. According
to data from metaanalysis of Magee and co-authors pharmacotherapy of mild pre-existing hypertension decreases the prevalence of severe forms of hypertension (> 160/100 mm Hg),
but with no significant effect on its complications for the mother and a child. None of the antihypertensives seemed to be
more effective or beneficial in this analysis [18]. Similarly,
metaanalysis of 40 studies (3797 women) concerning mild
and moderate hypertension showed the reduction in prevalence of severe form of hypertension (17 studies, 2155
women; RR = 0.52 (95% CI 0.41-0.64; NNT = 9-17)) with no
reduction in prevalence of preeclampsia (19 studies, 2402
women; RR = 0.99 (95%CI 0.84-1.18), neonatal mortality (23
studies, 2727 women; RR = 0.71 (95%CI 0.46-1.09)), preterm
delivery rate (12 studies, 1738 women; RR = 0.98 (95%CI
0.85-1.13)) or intrauterine growth restriction (17 studies,
2159 women; RR = 1.13 (95%CI 0.91-1.42)). Also none of the
antihypertensive agents seemed to be better than the others [1].
Harm for the mother’s cardiovascular long-term outcome
is insignificant when dealing with relatively short, 9-month
period without appropriate hypotensive treatment. On the
contrary – the harm for the baby connected with adverse
effects of treatment and iatrogenic hypotension is huge [33].
Based on data given above it is advised to diminish or
even withdraw the antihypertensive pharmacological treatment in women with mild pre-existing hypertension without
superimposed proteinuria, especially in the I trimester when
the BP values might be even lower than those before conception [7]. Further management in this group is based on BP
monitoring and assessment of the clinical state of the mother
and a child. In women with complicated, long-lasting hypertension treated with three or more drugs before pregnancy it
is advised to modify therapy without withdrawal if antihypertensives are necessary to maintain blood pressure within the
norm [34]. Values above 160/100 mm Hg are indication for
treatment intensification.
The metaanalysis performed by Duley and co-workers
was aimed at the assessment of the efficacy and safety of
different antihypertensives. It included 20 studies with overall
number of 1637 women with severe hypertension. It revealed
that diazoxide and ketanserine should not be used anymore
L. Szczepaniak-Chicheł, G. H. Bręborowicz, A. Tykarski
14
because of episodes of severe hypotension requiring treatment in case of the first one and a lack of appropriate hypotensive effect in comparison to hydralazine for the other.
Authors of the metaanalysis conclude that the choice between
available antihypertensives, except from the two mentioned
above, should be based on the individual clinical experience,
because there is no proof that any of them is better or worse
than the rest [10].
Management of gestational hypertension
or antenatally unclassificable hypertension
In women with gestational hypertension or hypertension
unclassified before delivery with values of BP < 150/ 100 mm
Hg non-pharmacological treatment is enough. In case of
higher BP additional pharmacotherapy should be considered.
Proteinuria, target organ involvement, symptomatic hypertension, history of gestational hypertension in previous
pregnancies indicate that pharmacotherapy should be implemented earlier – when BP is $ 140/90 mm Hg, similarly as it
is for the pre-existing hypertension in pregnancy [35].
Management of preeclamsia
Coexistence of proteinuria > 500 mg/day with arterial
hypertension which appeared in pregnancy after 20 week of
gestation is called preeclampsia. In some cases such symptoms like headache, blurred vision, stomachache, incorrect
values of laboratory findings instead of proteinuria can also be
a signal of the worsening of the clinical state.
Increase in the SBP $ 30 mm Hg or DBP $ 15 mm Hg,
peripheral oedema and increase in body mass are no longer
considered to be the diagnostic criteria of preeclamptic state
but if present also demand more careful clinical observation
[13, 24, 39].
Preeclampsia is responsible for 15% of preterm deliveries, which are the main cause of increased neonatal mortality, especially in countries with low socio-economic status
[25]. Still, even in highly equipped centers preeclampsia and
its complications remains a serious problem. Preeclampsia
can be mild or severe [26].
Diagnostic criteria for mild form of preeclampsia:
C BP > 140/90 mm Hg in at least two measurements;
C proteinuria > 500 mg /24 h.
Diagnostic criteria for severe form of preeclampsia:
C SBP $ 160 mm Hg or DBP $ 110 mm Hg;
C proteinuria $ 2,0 g (+2 or +3 in the dipstick test) – without coexisting urine tract infection, no history of proteinuria before pregnancy;
C serum creatinine > 1,2 mg/dl;
C PLT < 100 000/mm and/or microangiopathic hemolytic
anemia (with increased serum LDH);
C serum uric acid > 3,6 mg/dl;
C ARO < 4 ng/ml/h;
C increased serum ALT and/or AST;
C persistent headache, blurred vision or other neurological
symptoms;
C persistent stomachache, nausea, vomiting.
th
3
In case of mild preeclampsia bed-rest, avoiding physical
activity and stress are recommended with regular assessment
of the BP values and the clinical state of the mother and
a child even as an ambulatory management if the patients
compliance is proper [35].
In case of severe preeclampsia hospitalization is necessary. Usually the state of the pregnant woman gradually deteriorates and the final solution is induction of the delivery.
Through the optimal antihypertensive and anticonvulsant
therapy it is possible to postpone this moment until the child
is ready to be born [30]. In case of preterm induction of the
delivery between 33-34 week of gestation it is advisable to
accelerate the maturation of the surfactant by administration
of glicocorticosteroids 48 hours before delivery – if the state
of the mother and the fetus is stable enough to prolong the
pregnancy for two more days [28, 35].
Management of eclampsia
Eclampsia may appear in pregnancy (38-53%), during
delivery (18-36%), and also in the postpartum period (1144%), usually in the first 48 hours. Most of the cases (91%)
appear in the first 28 weeks of pregnancy, only in 7,5% of
women between 21-27 week and in 1,5 % cases before 21
week [37].
Except from early recognition of preeclampsia there are
no other prodromal symptoms and signs of forthcoming eclampsia, although there are some attempts to use the values
of blood pressure within the intracranial vessels assessed by
ultrasound methods as a predictive ones [19].
Treatment of eclampsia is based on the anticonvulsant
therapy with optimal antihypertensive treatment to lower the
values of blood pressure to the safe level of SBP 140-160 mm
Hg and DBP 90-110 mm Hg. Antihypertensive drugs used in
severe hypertension in eclampsia are mainly labetalol, dihydralazine and nifedypine (Table 5) [30].
Preferred anticonvulsant drug in prevention and treatment of seizures in eclampsia according to surveys and metaanalises is magnesium sulphate [9], [35], [38]. In order to
stop the seizures and prevent the recurrent ones it is recommended to inject 3-6 g (30-60 ml of 10% MgSO solution)
slowly intravenously (during 5-20 minutes) with following
infusion of 1-2 g/h. 10% of those women will have recurrent
attacks – it is possible to give once more 2 g of magnesium
sulphate solution in injection lasting for 3-5 minutes. Maximal
daily dose of magnesium sulphate is 20-24 g. Other anticonvulsants used in clinical practice are fenytoine (iv. infusion
50 mg/min.) and diazepam (5-10 mg iv., afterwards 20 mg im.
every 6 hours) [37].
st
4
HELLP syndrome (haemolysis, elevated liver enzyme
levels and low platelet count)
Coincidence of haemolysis, elevated liver enzyme levels
and low platelet count in pregnant women is called HELLP
syndrome [40]. It seems to be the multi-organ manifestation
of severe preeclampsia or eclampsia, although 15% of women
with this syndrome have normal values of blood pressure with
no proteinuria [36].
HELLP syndrome is a severe state with high mortality
rate and complications such as: pulmonary oedema, DIC,
ARDS, acute kidney failure, sepsis, liver failure or liver haemorhage, stroke, premature detachment of the placenta, and
all possible aftermaths for the child of the premature birth
[18, 27, 29, 36].
Treatment of arterial hypertension in pregnancy
Treatment of arterial hypertension during lactation
According to available data, all antihypertensive drugs appear in the milk of a breast-feeding mothers [41]. Data on
safety of antihypertensive treatment during lactation are scarce, there are no long-term observations. It seems that alphamethyldope and hydralazine are safe for the child, and in case
when β-blockers are indicated propranolol, labetalol, atenolol
or metoprolol can be administered [26]. There are no data
concerning safety of nifedipine [26]. Diuretics may reduce
milk volume and suppress lactation, ACE-I and angiotensine
receptor blockers damage kidney function of the newborn –
those groups of antihypertensives are contraindicated [22].
To summarize – it is recommended for breast-feeding mothers with hypertension to continue the therapy with drugs
considered to be safe during pregnancy.
As it is underlined in the recent ESH/ESC guidelines
women with previous gestational hypertension seem to be at
increased risk for cardiovascular disease in later life. It may
depend on relative hiperandrogenic state and further
alterations in endothelial function, carbohydrates and lipid
metabolism which have been shown in otherwise healthy
women with history of gestational hypertension [13].
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J
L. Szczepaniak-Chicheł
Department of Hypertensiology, Angiology
and Internal Diseases
Medical University in Poznań
61-848 Poznań, ul. Długa 1/2, Poland