MEDICINE
REVIEW ARTICLE
The Diagnosis and Treatment of
Hypertensive Disorders of Pregnancy
New Findings for Antenatal and Inpatient Care
Werner Rath, Thorsten Fischer
SUMMARY
Background: Hypertensive disorders of pregnancy (HDP)
are among the leading causes of maternal and fetal mor-
bidity and mortality. New guidelines and findings from
clinical trials must be taken into account so that the diag-
nosis and treatment of HDP can be optimized.
Methods: Current guidelines, Cochrane reviews, metaanal-
yses, and randomized, controlled trials were retrieved by a
search in PubMed and the Cochrane Library for reports
published from 2006 to March 2009. These publications
were then analyzed and evaluated for their evidence levels
(EL).
Results and Conclusions: Aside from hypertension and
proteinuria, the definition of preeclampsia (PE) should also
take organ dysfunction into account. Important aspects of
antenatal care include the following: the early recognition
of risk factors, measurement of the uterine arteries in the
1st and 2nd trimesters with Doppler ultrasonography (A
diagnostic tool which is now well established), prophylac-
tic oral administration of 100 mg of acetylsalicylic acid
daily from the beginning of pregnancy, particularly in high-
risk patients (EL I++), and appropriate measurement of
blood pressure and urinary protein. Patients should be
hospitalized whenever indicated. Therapeutic goals are
adequate treatment of hypertension, as well as seizure
prophylaxis with magnesium sulphate in severe pre-
eclampsia to prevent maternal cerebrovascular compli-
cations (EL I++). If delivery is indicated, it should be per-
formed, regardless of the gestational age (EL IV). Careful
monitoring during the puerperium and a general medical
review six weeks after delivery are essential. Women with
preeclampsia have a significantly elevated long-term risk
of developing cardiovascular diseases in later life (EL I++).
Key words: pregnancy, maternal mortality, obstetrics, pre-
vention, treatment
Cite this as: Dtsch Arztebl Int 2009; 106(45): 733–8
DOI: 10.3238/artebl.2009.0733
Gynäkologie und Geburtshilfe, Medizinische Fakultät des Universitätsklinikum
Aachen (RWTH): Prof. Dr. med. Rath
Frauenklinik, Krankenhaus Landshut-Achdorf mit Perinatalzentrum Nieder-
bayern und Mammazentrum Landshut: Prof. Dr. med. Fischer
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2009; 106(45): 733–8
orldwide, hypertensive disorders of pregnan-
W cy (HDP) account for more than 50 000
maternal deaths per year. With an incidence of 12%
to 18%, HDP are the second commonest cause of
antenatal and postnatal deaths in industrialized coun-
tries, as well as being implicated in 20% to 25% of
perinatal mortality (1, e1). Of greatest importance is
preeclampsia, characterized by hypertension,
proteinuria and/or organ dysfunction, which compli-
cates between 2% and 5% of all pregnancies. (1).
Severe consequences of preeclampsia include
eclampsia with tonic-clonic seizures (0.03% to 0.1%
of all pregnancies) (2) as well as HELLP syndrome
(Hemolysis, Elevated Liver enzymes, Low Platelet
count) with right upper quadrant pain as the cardinal
clinical symptom (0.17% to 0.8% of all live births)
(e2).
The overwhelming weight of new knowledge
relating to HDP created a need for a new appraisal of
the literature, with the goal of improving diagnosis
and treatment.
A literature review was undertaken including
Association of the Scientific Medical Societies in
Germany (AWMF) guideline 015/018 (3), random-
ized controlled trials and meta-analyses extracted
from PubMed and Cochrane reviews. This included
consideration of evidence levels and covered the
period 2006–03/2009.
Clinical presentations
Hypertension
The criteria for diagnosis of HDP is as follows: two
readings, showing a systolic blood pressure of
≥140mm Hg and/or a diastolic blood pressure of
≥90mm Hg, taken over a period of 4 to 6 hours after
20 weeks gestation, in a woman who was normoten-
sive prior to pregnancy (4, e3). Contrary to previous
findings, the Korotkov phase V (disappearance of
the blood flow murmur) is the correct means of
measuring diastolic blood pressure in pregnancy. If
the diastolic pressure according to this means is zero
(up to 15%), then the Korotkov sound IV (the quiet-
ening of the blood flow murmur) should be used
(evidence level [EL] I+) (4, e3). If “white-coat” hy-
pertension is suspected (10% to 15%), or in cases of
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MEDICINE
one-off elevated blood pressure readings, either a 24
hour blood pressure reading should be obtained or
self-monitoring undertaken at home (3). The use of
the sphygmomanometer remains the gold standard
for measuring blood pressure (4, e3). Oscillometric
devices for measuring blood pressure has, however,
been validated recently in pregnancy.
It should be noted that in 10% to 15% of cases of
eclampsia and 12% to 18% of HELLP syndrome the
blood pressure is normal (EL III) (e4).
Proteinuria
A urinary total protein of ≥300mg in 24 hours is con-
sidered pathological (1). Urine dipstick testing is an
integral component of antenatal care. If a dipstick in-
dicates ≥ 1+ of protein, a 24 hour collection should
be assayed (1, 3). When compared with a 24 hour
urine collection, the sensitivity of dipstick testing for
proteinuria is only 61%, with a specificity of 97%
(6). The role of the protein:creatinine ratio is contro-
versial (7) and therefore the 24 hour urine collection
remains the gold standard investigation (EL II) (3).
All pregnant women who develop de novo hyperten-
sion should have a 24 hour urine collection for pro-
tein (EL II+) (6). The severity of proteinuria does not
correlate with maternal morbidity, and taken in iso-
lation should not be considered an indication for
delivery (7). In up to 34% (e5) of eclampsia and 5%
to 15% of HELLP syndrome (7, e4) there may be no
proteinuria.
Classification
The population of hypertensive pregnant women can
be subdivided into the following:
● Gestational hypertension
● Preeclampsia
● Chronic hypertension
● Superimposed preeclampsia.
Up to 22% of chronic hypertensives may develop
superimposed preeclampsia with impaired prognosis
(8), and up to 50% of gestational hypertensives can
progress to preeclampsia (5, e6). In these patients in-
creased antenatal care is mandatory.
Defining preeclampsia by multi organ dysfunction
In addition to the standard definition, preeclampsia
can be diagnosed when, in the absence of proteinuria,
one or more of the following are present:
● Deterioration of renal function: serum creati-
nine greater than 0.9g/L or oliguria <500mL/
day
● Liver involvement: severe epigastric pain and/
or elevated transaminases
● Pulmonary edema (severe preeclampsia)
● Hematological involvement: thrombocytope-
nia, hemolysis, disseminated intravascular
coagulation (DIC)
● Neurological involvement: severe headache,
persistent visual disturbance, hyperreflexia.
● Intrauterine growth restriction.
734
These symptoms/complications reflect the most
common systemic dysfunctions of severe pre-
eclampsia. Severe preeclampsia is diagnosed in the
presence of blood pressure ≥160/110mm Hg and/or
proteinuria ≥5g/24 hours (4, e3, e7).
Risk factors
Pre-existing cardiovascular, renal or autoimmune
disease should have already been diagnosed precon-
ceptually and appropriate medications for a planned
pregnancy prescribed. Of utmost clinical importance
is the assessment of risk factors at the antenatal
booking visit.
Most pertinent are:
● HDP in previous pregnancies
● Body mass index >30
● Pre-existing diabetes
● Renal disease or chronic hypertension
● Maternal age >40 years
● Family history (9).
The relevance of inherited thrombophilia in the
development of preeclampsia is unclear. Routine
antenatal thrombophilia screening is not recom-
mended. According to a recent US guideline, anti-
phospholipid antibodies should be determined in
patients with a previous history of severe or recurrent
preeclampsia/HELLP syndrome < 34 weeks’ gestation
or intrauterine growth restriction (IUGR) (EL II-) (e8).
A recent consensus paper recommends investigating
inherited and aquired thrombophilias in these cases
(EL IV) (e9).
When counselling women the risk of recurrence of
preeclampsia and especially HELLP syndrome is
important. An early cohort study (10) gives the abso-
lute risk of preeclampsia recurring as 14.7%
(EL II++). The recurrence risk of preeclampsia de-
pends on the time of manifestation of preeclampsia in
previous pregnancies (≤28 weeks, ≥37 weeks). World-
wide the risk for a recurrence of HELLP syndrome is
between 2.1% and 19% (11). One German study
gave it as 12.8% (EL III) (e10).
The most frequent pregnancy-associated risk factors
for developing preeclampsia are: “bilateral notch”
(diagnosed by uterine artery Doppler), multiple preg-
nancies and gestational diabetes mellitus.
Predictive testing
Despite the analysis of more than 100 methods, there
is still no reliable and certain test for predicting HDP
(9). The most useful method is uterine artery
Doppler ultrasonography. If abnormal uterine flow
(specifically the bilateral notch or high resistance
index) is present between weeks 22 and 24, there is a
60% risk of developing preeclampsia and/or IUGR
later in pregnancy. The predictive value of Doppler
ultrasound is particularly high for the development
of severe preeclampsia before 34 weeks and for pre-
eclampsia with IUGR (e11). However, routine
screening of all pregnant women was not recom-
mended (e12); uterine artery Doppler is beneficial as a
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2009; 106(45): 733–8
 MEDICINE

test in pregnant women who are at high risk for BOX 1

preeclampsia (9). According to recent meta-analyses
an increased pulsatility index with notching (after the
16th week) was the best predictor of preeclampsia in
women with established risk factors (positive likeli-
hood ratio: 21.0). This test should therefore be used in
clinical practice (EL I-) (13).
Research is ongoing to determine the relevance of
combinations of maternal risk factors, early bio-
chemical markers (such as placental protein 13) as
well as Doppler results from the first and second
trimester.
Indications for inpatient review
● Hypertension (systolic ≥160, diastolic ≥100mm Hg )
● Manifest pre-eclampsia (see definitions)
● Proteinuria and profound weight gain in the 3rd
trimester (≥1kg per week).
● Impending pre-eclampsia. Prodromal symptoms include
severe headache/epigastric pain, neurological or visual
symptoms

Prevention ● Clinical suspicion of HELLP syndrome: persistent epi-

Meta-analyses and Cochrane reviews suggest no gastric pain.
reduction in the rate of preeclampsia with the follow- ● Hypertension or proteinuira in the presence of other risk
ing therapies: oral magnesium, the antioxidant vit- factors such as:
amins C and E, fish-oils and oral calcium (EL I++) – Pre-existing maternal morbidity (for example dia-
(9, e13–e16). Nor is there any reduction in the risk of betes)
preeclampsia in subsequent pregnancies (EL I++ to – Multiple pregnancy
IV) (14, e17–e18). The oral administration of cal- – Prematurity (<34 weeks)
cium supplements (at least 1g per day) may signifi- – Poor maternal compliance with outpatient surveil-
cantly reduce the risk of preeclampsia particularly in lance
high-risk patients with poor dietary calcium intake
(EL I-) (e19).
● Indications of fetal compromise:
– Suspicious / pathological CTG or
According to a recent Cochrane review, oral
– Suspicious Doppler sonography ( specifically absent
aspirin 75 to 150 mg per day, compared with placebo
or reversed end-diastolic flow in the umbilical ateries)
(before the 16th week), reduces the rate of pre-
– Intrauterine growth restriction (IUGR) (<10th cen-
eclampsia by 17%, neonatal mortality by 14% (EL
tile)
I++) (15); a meta-analysis makes this 10% and 9%
respectively ( EL I++) (16). Low-dose aspirin in-
hibits increased thromboxane production, induced by
preeclampsia, but do not appear to have a significant
effect on vascular prostacyclin production.
According to the above-mentioned Cochrane
review, pregnancies with pre-exisiting risk factors
(particularly severe preeclampsia in previous preg-
nancies) benefit most from aspirin (15). Notwith-
standing controversial studies, aspirin is not recom-
mended after 23 weeks if a pathological Doppler
flow is present (9). Aspirin is not recommended in
cases of manifest preeclampsia or gestational hyper-
tension (3).
In one recent randomized controlled trial looking
at gravid women with risk factors for preeclampsia
(previous preeclampsia/IUGR), the use of prophy-
lactic low molecular weight heparin (dalteparin,
weight adjusted, 4000–6000 IU/day, on or before the
16th to 36th week) lowered the incidence of pre- blood pressure of ≥170mm Hg systolic and/or a
eclampsia from 23.6% to 5.5% (EL I+) (17). diastolic pressure of ≥110 mm Hg. In the case of pre-
existing hypertension or other causes for super-
Indications for inpatient review imposed hypertension (renovascular disease or
Delayed referral for specialist treatment is an area of diabetes for example) a threshold of ≥160/100 mm
increasing medico-legal activity. Specific indications Hg is appropriate ( EL IV) (3, e7). These measures
for inpatient review/monitoring have been published are consistent with national and international guide-
recently (EL IV) (3) (Box 1) lines (5, e7). A clinically useful point to note is that a
rise in systolic blood pressure to ≥160 mm Hg is
Treatment more relevant for the development of stroke in pre-
The initiation of medical treatment should take place eclamptic women than a rise in diastolic pressure to
in hospitals (3). Antihypertensives are indicated at a ≥105 mm Hg. 80% of patients with stroke present

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BOX 2
Indications for immediate delivery
● Fetal indications, e.g., hypoxia (CTG), reversed end
diastolic flow
● Maternal indications ( apply also for HELLP syndrome ):
– After an eclamptic fit
– Severe therapy-refractory hypertension
– Therapy-refractory renal failure
– Pulmonary edema
– Signs of disseminated intravascular coagulation
(DIC) (progressive thrombocytopenia, rapid increase
in d-dimer)
– Persistent, severe epigastric pain
– Impending eclampsia: manifest neurological signs/
symptoms
– Other maternal/fetal complications, e.g., placental
abruption, suspicion of intracerebral hemorrhage,
liver hematoma/rupture.
with a diastolic blood pressure of less than 105mm
Hg (e20). Of those rare patients whose stroke was
primarily associated with pregnancy, 25% to 45%
were in cases of preeclampsia (e21).
The aim of anti-hypertensive therapy is the pre-
vention of maternal cerebrovascular complications.
A reduction in blood pressure is of little benefit to
the fetus. To the contrary, results of meta-analyses
suggest that in cases of mild hypertension (<170/110
mm Hg) long-acting oral antihypertensive agents
such as beta-blockers may lead to IUGR and reduced
birth weights (EL I++) (18, e22).
Alpha methyl-dopa remains the first line anti-
hypertensive agent for long-term control in pregnan-
cy in Germany. There are restricted indications for
Nifedipine and selective beta-1-receptor blockers
(3). ACE inhibitors are contraindicated (3, e23).
According to meta-analyses and Cochrane re-
views (19, e24) the previously favored acute therapy
of intravenous hydralazine is associated with maternal
side effects and an increased rate of fetal compli-
cations (amongst others placental abruption) (EL
736
I++). Oral nifedipine or intravenous urapidil are
therefore recommended although this constitutes an
off-label use of these preparations (3). Abrupt or
deep drops in blood pressure should be avoided.
Target blood pressure should be 140 to 150 mm Hg
systolic and not less than 90 mm Hg diastolic (EL
IV) (3, e25).
Following a Cochrane review and meta-analysis
the first line medication for prophylaxis and treat-
ment of eclamptic convulsions is intravenous mag-
nesium sulphate (EL I++) (20, e26). The application
of intravenous magnesium sulphate in less severe
preeclampsia is the subject of current discussion. In
the MAGPIE trial the incidence of preeclampsia
compared with placebo was reduced by the adminis-
tration of magnesium sulphate from 1.9% to 0.8%
(EL I+) (21). A comprehensive retrospective study
showed no adverse effects (in particular severe
hypotension) from the simultaneous administration
of nifedipine and magnesium sulphate (EL III )
(e27). Previously advocated plasma-expansion treat-
ment in preeclampsia with hydroxy-ethyl starch
(grounded in theoretical rheological principles) has
been shown to have no management benefits (e28).
Furthermore, a randomized control trial did not show
any improvement in neonatal outcomes (EL I+) (22).
In preeclampsia fluid restriction of 80 to 100 mL per
hour is mandatory (due to the risk of pulmonary
edema).
Special considerations for HELLP syndrome
According to the current literature the treatment and
indications for delivery in HELLP syndrome are the
same as in severe preeclampsia (3). In addition to the
routine application of betamethasone for fetal lung
maturation (indicated <34 weeks) there is evidence
from randomized controlled trials, that glucocorticoids
which do not cross the placenta (such as prednisolone
or dexamethazone) induce clinical and biochemical
remission of HELLP syndrome and prolong pregnan-
cy (EL I+) (11). A Cochrane review of the evidence,
however, suggests there are, as yet, insufficient data
to be certain (e29).
Obstetric interventions and indications
for delivery
To date delivery is the only definite curative treatment
of preeclampsia (3). In cases of mild, therapeutically
well-controlled preeclampsia without evidence of
IUGR or suspicious Doppler findings, an induction
of labour at completed 37 weeks could be considered.
In severe preeclampsia/HELLP syndrome immediate
delivery is required ≥34 weeks. Birth should only take
place once the maternal condition has been stabilized
(3). Patients between 24 and 33+6 weeks should be
managed expectantly in a tertiary perinatal center in
order to reduce neonatal morbidity and mortality. There
should be an assessment of the severity and
dynamics of the disease, of the fetal organ’s maturity
and condition as well as stabilization of the mother.
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There should be facility for emergency caesarean
section around the clock (EL IV) (3).
In order to avoid maternal and fetal complications,
absolute indications for delivery regardless of ges-
tational age are necessary (Box 2) (EL IV) (3, 23). The
results of 11 observational studies looking at severe
preeclampsia showed a prolongation of pregnancy in
48.5% to 62.7% of cases of an average duration of
10.4 days. The rate of severe maternal complications
was 25.1% to 28.4% (23). In severe preeclampsia the
decision to continue a pregnancy before the 24th
week is at the clinician’s individual discretion, but
should be undertaken only after an exhaustive dis-
cussion with the woman. It is worth remembering
that the rate of maternal complications is as high as
65% and the average perinatal mortality is, on aver-
age, 82% (24).
Mode of delivery
If the condition of mother and fetus is stable a
vaginal birth with close medical supervision could
be considered. In severe preeclampsia—dependent
on the urgency of delivery and favorability of the
cervix—induction of labour is an option (success
rate in pregnancies remote from term on average 54%)
(e30). In all other cases caesarean section is indi-
cated (Box 2).
Puerperium
The rate of post-partum HELLP syndrome lies between
7% and 30% (11). Postpartum eclampsia occurs in as
many as 28% of cases (2). Close maternal medical
observation is recommended for at least 48 hours after
birth. If blood pressure is difficult to manage, consul-
tation of an experienced internist is required. Target
blood pressure on discharge should be less than
150/100 mm Hg (3). Weaning is not necessary in most
cases. Follow-up after the puerperium should be with
a specialist or general practitioner and aimed at the
timely detection of hypertension, renal disease, or
cardiovascular complications.
Long-term prognosis
Women with severe preeclampsia have a signifi-
cantly increased risk of developing cardiovascular
disease in later life. According to a recent meta-
analysis (EL I+) (25) the following relative risks
(RR) are given:
● Hypertension—RR 3.7 (average follow up 14
years)
● Ischaemic heart disease—RR 2.16 (11.7 years)
● Stroke—RR 1.81 (10.4 years)
● Maternal death—RR 1.49 (14.5 years).
Referral of affected mothers to their general prac-
titioners for lifestyle changes, risk assessment and
screening for cardiovascular diseases, would be a
valuable goal for future screening programs. The im-
plications of severe maternal preeclampsia for the
future health of the infant is the subject of current,
intensive research.
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2009; 106(45): 733–8
MEDICINE
Conflict of interest statement
The authors declare no conflicts of interest according to the guidelines of
the International Comittee of Medical Journal Editors.
Manuscript submitted on 20 March.2009, revised version accepted on 28
April 2009.
Translated from the original German by Dr E C Prosser-Snelling BA(Hons)
BMBS.
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Corresponding author:
Prof. Dr. med. Werner Rath
Medizinische Fakultät des Universitätsklinikum Aachen (RWTH)
Gynäkologie und Geburtshilfe
Wendlingweg 2
52074 Aachen, Germany
wrath@ukaachen.de
@ For e-references please refer to:
www.aerzteblatt-international.de/ref4509
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2009; 106(45): 733–8

REVIEW ARTICLE
The Diagnosis and Treatment of
Hypertensive Disorders of Pregnancy
New Findings for Antenatal and Inpatient Care
Werner Rath, Thorsten Fischer
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