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Case study
Definitions
Aetiology and risk
factors
Detecting and
monitoring
hypertension in
pregnancy
Managing
pre-eclampsia and
hypertension
The authors
DR ANNEMARIE HENNESSY,
foundation chair of medicine,
University of Western Sydney,
and the Heart Research
Institute, Sydney, NSW.
Pre-eclampsia and
hypertension in pregnancy
DR ANGELA MAKRIS,
renal and obstetric physician,
Liverpool Hospital, Sydney, NSW.
Authors’ case study
SUSAN, 38, presents to her GP with
a plan for another pregnancy with
her new partner. She had had a single
live birth 13 years earlier, as well as
two miscarriages, with her first husband. Her earlier full pregnancy with
her son was complicated by early
delivery at 33 weeks’ gestation, due
to upper abdominal pain, headache,
high BP and proteinuria.
Relevant clinical issues arising
from this case include:
• What was the likely nature of the
pregnancy complication 13 years
earlier?
• What was the likely cause of that
complication?
• What is her risk of a repeat episode
in a new pregnancy, and what can
be done to reduce that risk?
Relevant history
Susan described her first full pregnancy in 1997 as uneventful in the
early stages. She had a pre-preg2
nancy BMI of 23kg/m and her
medical notes reveal no personal
history of hypertension. There was
a positive family history of hypertension on her mother’s side of the
family, including in pregnancy. She
was being seen by her GP for shared
care with her local hospital antenatal clinic, her antenatal tests were
all normal and initially her blood
pressure was low at 110/60mmHg.
Her problems began at about 31
weeks, when her GP noted her BP
to be 130/80. The GP noted that
there was no radiofemoral delay
and no epigastric bruit, and there
was no hyperreflexia or clonus and
no epigastric tenderness, the uterus
was appropriate for 31 weeks’ gestation and there was no uterine tenderness and no proteinuria.
The GP organised review at the
local hospital in the same week
despite the patient having no new
symptoms. Notably there was no
headache, no decrease in appetite
and no upper abdominal pain.
Her BP reading at the local clinic
was 140/90 and she was assessed
for pre-eclampsia. At that time, her
examination was unremarkable, her
urine protein dipstick was negative
and her baby was appropriately
grown for 32 weeks’ gestation (by
fundal height).
She was admitted to day-stay for
assessment of her hypertension and
started on a low dose of methyldopa (250mg tds) under supervision
at the local hospital-based fetomaternal assessment unit. A cardiotocograph was performed, which
was “reassuring” in terms of baseline fetal heart rate and baseline
variability.
Susan’s blood tests showed a creatinine concentration of 30μmol/L
(non-pregnant reference range 6090μmol/L) and uric acid concentration of 0.30mmol/L (0.150.35mmol/L); her LFTs were normal
and her platelet count was 175 ×
109/L. Her BP reading was 140/90
before treatment and settled to
120/80 over the next four hours after
starting methyldopa.
Susan was returned to the care of
her GP and the high-risk clinic, with
a request to have her BP checked
twice a week. She remained well until
33 weeks, when she presented to the
delivery suite with headache and
right upper quadrant pain. She was
noted at this time to have a BP of
170/110 and brisk reflexes with
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clonus. Her cardiotocograph was
normal and her urine had ++++ protein. She had a normal retinal fundal
examination without vessel changes
or haemorrhages.
An urgent caesarean delivery was
organised and Susan was started on
intravenous hydralazine for BP control and magnesium sulfate for
seizure prophylaxis. She delivered a
1050g baby boy. She was transferred
to ICU for 24 hours, but her BP settled to normal over the next six days
and she was discharged on no medications. No further follow-up was
recommended on discharge from the
hospital.
Susan’s miscarriages had preceded
that pregnancy and were at eight and
10 weeks’ gestation. Both pregnancies had been confirmed by ultrasound investigation after a positive
pregnancy test. They were uncomplicated by bleeding or changes in BP.
Susan only had her BP checked
once in the intervening 12-year
period and that was described as
normal. She had no other medical or
surgical issues.
cont’d next page
14 January 2011 | Australian Doctor |
17
HOW TO TREAT
Pre-eclampsia and hypertension in pregnancy
Definitions of hypertension in pregnancy and pre-eclampsia
WHILE prior definitions of
hypertension in pregnancy
had up to 23 classifications
(including peripheral oedema),
we now use a four-category
system relevant to patient risk
while pregnant and in the
immediate- and long-term
post-period (see box below).
Pregnancy-specific diagnoses are gestational hypertension and pre-eclampsia.
Other diagnoses are chronic
hypertension, which includes
essential hypertension and secondary hypertension (eg, renal
disease, endocrine disease,
renovascular disease or coarctation of the aorta [see box:
‘Causes of secondary hypertension identified in pregnancy’, right]), and preeclampsia superimposed on
chronic hypertension.
Hypertension in pregnancy
is defined as a systolic BP of
≥140mmHg or a diastolic BP
≥90mmHg. The blood pressure must be elevated on two
occasions at least four hours
apart. It should be measured
in the right arm, with the
patient sitting in the semirecumbent position, with the
cuff fitted to the bare arm
deflated appropriately slowly.
Too rapid deflation of the cuff
can underestimate the systolic
BP and overestimate the diastolic reading. On the first
assessment the BP should be
measured in both arms to
ensure the readings are similar.
Some of the basic physiological changes of pregnancy
occur very early and result in
a natural decrease in both systolic and diastolic BP. The cardiovascular responses to this
decrease in BP include:
• Activation
of
the
renin–angiotensin system,
and thus sodium and water
retention and increased
blood volume.
• Increased heart rate (sinus
tachycardia up to 120bpm).
• Increased cardiac output.
The increase in blood
volume is further demonstrated by reduced haemoglobin concentration. The
decrease in serum creatinine
concentration seen in normal
pregnancy (<60μmol/L)
reflects the increased glomerular filtration rate due to
increased renal blood flow as
the renovascular resistance is
lowered by the natural pregnancy vasodilators.
The vasodilatory state manifests in several ways, including: BP decreasing from early
pregnancy (6-8 weeks) to 24
weeks’ gestation then increasing slightly towards term; and
BP being intrinsically more
resistant to a ‘stress’ response
than is seen outside pregnancy.
This stress-resistant state
means that any increase in BP
in pregnancy is abnormal and
should therefore be considered
carefully and reviewed regularly. The tendency of chronic
(ie, pre-existing) hypertension
to progress to pre-eclampsia
(17% of patients) is the same
18
Figure 1: Renal biopsy changes in ‘pure’ pre-eclampsia.
Photomicrograph at high power (×80) demonstrating the
unique feature of human pre-eclampsia — endothelial cell
swelling of the renal glomerular endothelial cells. This finding
explains the clinical features of proteinuria, and, when severe,
the reduced renal function manifests as rising serum
creatinine concentration and oliguria.
≥90mmHg occurring after 20
weeks’ gestation and which
normalises by three months
post-partum. There must be
no prior history of hypertension or renal disease for this
diagnosis to be made. A
family history is not relevant
here.
An increase of 25mmHg in
systolic BP, or of 15mmHg in
diastolic BP, should be a cause
for concern and should trigger maternal and fetal monitoring. This is because of the
lower BP seen in a normal
pregnancy compared with the
BP of the non-pregnant state.
Pre-eclampsia
The defining features of preeclampsia are listed in the box
on the opposite page.
Causes of secondary
hypertension identified
in pregnancy
Vascular causes
Coarctation of the aorta
Renal artery stenosis
Endocrine causes
Phaeochromocytoma
Primary aldosteronism
Cushing’s syndrome
Hypothyroidism
Hyperthyroidism
Polycystic ovary syndrome
Hyperparathyroidism
Renal causes
Definitions of
hypertension in
pregnancy
Gestational hypertension
as the risk of white-coat
hypertension progressing to
pre-eclampsia. This indicates
that any increase in BP is
potentially pathological in
pregnancy.
Pre-eclampsia/eclampsia
Chronic hypertension:
• Essential
• Secondary
• White-coat
Pre-eclampsia superimposed
on chronic hypertension
Some of the basic
physiological
changes occur
very early and
result in a natural
decrease in both
systolic and
diastolic blood
pressure.
| Australian Doctor | 14 January 2011
Gestational hypertension
Gestational hypertension is
defined as a systolic BP
≥140mmHg or a diastolic BP
Chronic hypertension
This is defined as an increase
in BP before 20 weeks’ gestation, or persisting beyond
three months post-partum. It
can be essential hypertension,
white-coat hypertension or
secondary hypertension.
As mentioned above, whitecoat hypertension in pregnancy has the same risk pro-
Diabetic nephropathy
Reflux nephropathy
Polycystic kidney disease
Focal sclerosing glomerulosclerosis
IgA disease
Renin-secreting renal
tumours
file of progression to superimposed pre-eclampsia as
chronic hypertension and
should be taken seriously and
monitored carefully. However,
treatment of white-coat hypertension is not usually recommended until the elevation in
BP is sustained above the
guideline limits of 140mmHg
systolic or 90mmHg diastolic.
Secondary hypertension
includes all known causes such
as renal disease (figure 2), diabetes, endocrine disease, renovascular disease or coarctation
of the aorta (see box, left).
Hypertension associated with
the metabolic syndrome, oral
contraceptive pill use or polycystic ovary syndrome also
meets this criterion.
The ‘must-not-miss’ causes
include hypo- and hyperthyroidism, which also have an
impact on the developmental
outcomes for the baby and are
easily correctable. These are
relatively common. The
maternal mortality associated
with phaeochromocytoma is
always worrying, but these
women often have refractory
hypertension and the periodic
symptoms (flushing, tachy-
Figure 2: Renal biopsies of common renal diseases presenting in young women with hypertension and urinary abnormalities (proteinuria
or haematuria).
A: A normal glomerulus.
B: IgA disease causes mesangial expansion and is associated with hypertension and haematuria. Episodes of acute renal failure in
pregnancy can be difficult to distinguish from superimposed pre-eclampsia.
C: Focal sclerosis is demonstrated in the glomerulus on the right. Focal sclerosing glomerulosclerosis (FSGS) usually presents as
proteinuria and hypertension with or without progressive renal failure. These women have a high likelihood of developing superimposed
preeclampsia.
D: PAS stain demonstrating the extent of fibrosis in a focal sclerosis lesion.
E: The globally sclerosed glomerulus in this photomicrograph illustrates advanced FSGS in a woman who had significantly worse
renal failure after pre-eclampsia in her first pregnancy (creatinine 55mmol/L pre-partum and 101mmol/L at three months postpartum).
F: High-grade lupus nephritis with areas of focal necrosis. The glomerulus has a lobular appearance with inflammation and
vasculitis.
A
B
C
D
Segmental
sclerosis
(PAS stain)
Segmental
sclerosis
E
F
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Nuclear ‘dust’
cardia, acute anxiety and
changes in skin colour) commonly associated with catecholamine excess. This is a
very rare cause of hypertension in pregnancy.
Hypertension due to
lifestyle factors such as obesity, illicit drug use (cocaine
and amphetamines) and caffeine intake are not traditionally considered secondary
causes, but attention to
lifestyle in the pre-pregnancy
period can dramatically
reduce the risk of escalating
BP in pregnancy.
Superimposed
pre-eclampsia
Superimposed pre-eclampsia
is defined as chronic hypertension (as above) with the addi-
tional features of pre-eclampsia outlined in the box, right.
The presence of proteinuria
in a patient with renal disease cannot be used to define
pre-eclampsia and the additional features are required.
In the case of SLE with
lupus nephropathy, the diagnosis of superimposed preeclampsia can be more difficult still.
Reliance is needed on
additional clinical features
such as intrauterine growth
restriction and abnormal
LFTs. Cerebral signs can
only be used in the absence
of cerebral lupus, and
platelet counts in the absence
of known antiplatelet
autoantibodies in the underlying disease.
Defining features of pre-eclampsia
Pre-eclampsia is defined as elevation in BP as for gestational hypertension plus one or more of the following:
Renal involvement (figure 1)
• Significant proteinuria: dipstick proteinuria confirmed by a spot
urine protein:creatinine ratio ≥30mg/mmol
• Serum or plasma creatinine ≥ 90μmol/L (normal range 6090μmol/L)
• Oliguria (<0.5mL/kg for three consecutive hours)
Haematological involvement
• Thrombocytopenia (>30% reduction compared with baseline
reading)
• Haemolysis
(Both these indicate disseminated intravascular coagulation)
Liver involvement
• Raised serum transaminase levels (ALT and AST)
• Severe epigastric or right upper-quadrant pain
Neurological involvement
• Convulsions (eclampsia)
• Hyperreflexia with sustained clonus
• Severe headache
• Persistent visual disturbances: photopsia (flashes of light),
scotomata, cortical blindness, retinal vasospasm
• Stroke
Pulmonary oedema
Fetal growth restriction
Placental abruption
In the Australian guidelines for diagnosis:
• Proteinuria is not mandatory to make the clinical diagnosis
• Hyperuricaemia is a common but not diagnostic feature of
pre-eclampsia
• The HELLP syndrome (haemolysis, elevated liver enzyme levels and a
low platelet count) represents a particular presentation of severe preeclampsia, and separating it as a distinct disorder is not helpful
• Peripheral oedema is not a defining feature
Aetiology and risk factors for pre-eclampsia
Aetiology and pathology
THE aetiology and pathology of preeclampsia are not well understood.
Pre-eclampsia is thought to be a twostage disease. Stage one occurs early
in pregnancy when there is a failure
of invasion by the (placental) trophoblasts and inadequate remodelling of the uterine spiral arteries. The
uterine spiral arteries do not adequately invade the inner third of the
myometrium, as is normally the case.
As the pregnancy progresses, this
poor vascular invasion results in placental dysfunction. The dysfunctional
placenta mediates stage two of the
disease, in which the maternal and
fetal signs and symptoms of preeclampsia are seen. The reasons why
the trophoblasts fail to invade the
myometrium adequately are thought
to be many, including immunological
disturbances, vascular disease,
endothelial dysfunction and a thrombotic tendency, to name but a few.
Risk factors
Women with a short duration of
cohabitation with their partner, those
who have used only barrier methods
of contraception, and those who
Table 1: Recurrence rates for pre-eclampsia
Risk factor
Relative risk (95% confidence
interval)
Antiphospholipid antibodies
9.72 (4.34-21.75)
Previous history of pre-eclampsia
7.19 (5.85-8.83)
Pre-exisiting diabetes
3.56 (2.54-4.99)
Multiple pregnancy
2.91 (2.04-4.21)
Nulliparity
2.91 (1.28-6.61)
Family history of pre-eclampsia
2.90 (1.7-4.93)
Elevated BMI (>25kg/m )
2.47 (1.66-3.67)
Maternal age >40 years
1.96 (1.34-2.87)
Diastolic BP > 80mmHg at booking
1.38 (1.01-1.87)
2
have a new partner are generally at
increased risk of pre-eclampsia,
which suggests that immunological
factors are involved. There is an
increased risk with various forms of
assisted reproduction technology and
with the number of fetuses (triplets >
twins > singletons). An inter-pregnancy interval of more than 10 years
also increases the risk, but this may
also reflect the risk associated with a
change in partner that may occur
during that interval.
Pre-eclampsia and miscarriage
are associated in patients with
obstetric lupus syndrome and can
be a manifestation of other thrombophilias. These should be investigated in the settings of:
• Recurrent (three or more) miscarriages.
• Second- or third-trimester pregnancy loss.
• Early severe pre-eclampsia (delivery before 34 weeks of gestation).
Thrombophilic abnormalities
include:
• Non-pregnant protein S and protein C deficiency.
• Antithrombin III deficiency.
• Activated protein C resistance (usually conferred by the factor V
Leiden mutation).
• Hyperhomocystinaemia.
Antiphospholipid syndrome is
defined as multiple miscarriages (three
or more) or second-trimester losses
in the setting of any of the following:
• Abnormal APTT.
• Lupus inhibitor.
• Lupus anticoagulant.
• Positive Russell’s pit viper test.
• The presence of moderate or high
concentration of anticardiolipin
autoantibodies (IgG or IgM).
In some populations, dietary influences such as low calcium intake,
high fat intake and soft drink consumption have been associated with
an increased risk of pre-eclampsia. A
dietary history for calcium and appropriate advice regarding healthy eating
are essential for preventing preeclampsia as well as general wellbeing
during pregnancy.
Recurrent superimposed pre-
eclampsia is more common in
women with underlying renal or
hypertensive disease, autoantibody
diseases or diabetes. Recurrence rates
in women without underlying disease are higher in those with previous
early severe pre-eclampsia without
other cause.
The main risk factors for recurrence of pre-eclampsia are summarised in table 1.
Summary of Susan’s case
Susan’s greatest risk factor is her previous history of early severe preeclampsia, which confers a risk of
recurrence of 18%. Having a new
partner confers a risk of about 10%
for pre-eclampsia (baseline rate 5%
for normal pregnancy). The interpregnancy interval of more than 10
years doubles the risk. However,
thankfully, these risks are not additive. Susan’s diet is replete in calcium, and supplements are not recommended. Her thrombophilia and
anticardiolipin antibody screening
tests were normal. Her BP since her
first pregnancy has been normal.
Her overall risk of pre-eclampsia is
about 18%.
Physical examination for hypertension in pregnancy
PHYSICAL examination
should be undertaken at the
first pregnancy review or as
part of pre-conceptual counselling. The importance of
an accurate physical examination cannot be underestimated in assessing hypertension in pregnancy. In a
woman such as Susan in our
case study, who has a past
history of pre-eclampsia and
is planning another pregnancy, any evidence of
underlying causes for hypertension in pregnancy should
be sought, as well as looking for evidence of endorgan involvement due to
hypertension.
The initial assessment
should include:
• BP in both arms.
• Identification of the apex
beat and heart rate.
• Identification of an S4 or
systolic flow murmur, indicating left ventricular hyper-
trophy or coarctation of the
aorta.
• Feeling for radiofemoral
delay by simultaneously
assessing the femoral and
radial pulses.
• Listening in the epigastrium
for a systolic bruit, indicative of renal artery stenosis.
Assessing urine has become
less universal in regular antenatal practice but is essential
in chronic or potentially
hypertensive women to
exclude the multitude of
glomerular possibilities.
Haematuria exists in 6.7% of
the general Australian population and mostly indicates
thin-membrane disease or
other benign forms of
glomeular abnormality. However, for haematuria in the
presence of additional clinical
features — proteinuria or
hypertension in particular —
a glomerular diagnosis should
be strongly considered.
The systemic features of
vasculitis (rash, abdominal
pain, joint swelling, neuropathy, confusion) should be
obvious. The features of SLE
such as malar rash, arthritis,
enlarged spleen, and rash may
be more subtle. Features of
endocrine conditions would
include purple striae and
proximal muscle wasting in
Cushing’s disease, which may
also be associated with
depression and diabetes. Thyroid disease is best assessed
by thyroid function tests, but
a thyroid examination should
include palpation and auscultation of the gland.
A retinal examination is
essential to identify hypertensive changes (figure 3). Arterial bruits are very uncommon
in people of childbearing age
with hypertension, but a renal
bruit can indicate fibromuscular disease of the renal
arteries in young women.
Figure 3: Retinal changes in pre-eclampsia can represent
malignant hypertension. The early findings of retinal oedema
(the glistening retina) is a subtle change; the dramatic
changes of retinal haemorrhage, papilloedema and retinal
infarction are advanced signs and indicate the need for urgent
delivery, as these changes reflect microvascular injury
elsewhere in the white matter and cerebral cortex.
Although also uncommon,
this a potentially correctable
cause of refractory hypertension associated with severe
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superimposed pre-eclampsia.
If present, consideration can
be given to angioplastic or
surgical correction before a
planned pregnancy.
Biochemical screening is
not a part of routine antenatal care. In hypertensive
women a baseline creatinine
concentration is essential
(Note: the estimated GFR
[eGFR] has not been validated in pregnancy). The
finding of a low serum potassium level can indicate primary hyperaldosteronism,
corticosteroid excess, catecholamine excess or renovascular disease. Assessing
thyroid function can exclude
either hyper or hypothyroidism as a cause of elevated
BP in pregnancy, and a
normal calcium concentration corrected for serum
albumin can exclude hyperparathyroidism from a
parathyroid adenoma as a
cause. Again, these are treatable, reversible causes even if
they are uncommon.
cont’d page 22
14 January 2011 | Australian Doctor |
19
HOW TO TREAT Pre-eclampsia and hypertension in pregnancy
Monitoring
MONITORING for the categories of hypertension in pregnancy should include frequent
urine testing for proteinuria.
This is especially the case with
chronic hypertension, when
BP increases alone become difficult to interpret. Whenever
BP or antihypertensive medication requirements increase,
urine testing, pre-eclampsia
blood tests (platelet count,
LFTs and serum creatinine)
and fetal growth assessment
are required to establish a
diagnosis. Uric acid concentration is useful as a marker
of disease progression,
although this is not diagnostic.
These investigations need to
be repeated as often as
required until delivery to monitor for progression to the
more severe forms of the disease.
Assessing urinary protein
includes screening via a urinary dipstick (figure 4).
Greater accuracy can be
achieved with the use of a
urine-protein:creatinine ratio
(>30mg/mmol) but this
requires a formal laboratory
Figure 4: Dipstick proteinuria indicates pathological proteinuria with a high degree of certainty at
2+ or greater. The diagnostic level of >300mg/day represents + or more in a standard specimen
and may need to be confirmed with a 24-hour urine collection. The picture shows the dipstick
result for a pre-eclamptic patient who had 42g of proteinuria, which resolved after delivery at 34
weeks’ gestation.
test. The ‘gold standard’ of
24-hour urinary protein still
stands, but can be difficult to
interpret due to inaccurate collection (up to 50% of collections) and patient inconvenience. Initial screening of the
urine is essential in early pregnancy hypertension to exclude
underlying renal disease.
Screening for proteinuria at
the time of any change in BP,
at the time of development of
new symptoms, or in the con-
text of intrauterine growth
restriction is an important
adjunct to the diagnostic
workup.
Monitoring for the progression of hypertension in pregnancy usually involves high-
risk obstetric services in association with general practice
shared care and midwifery
support. It would be usual for
the high-risk service to review
a stable woman at least
monthly, then more frequently
if the BP is unstable, and as
the pregnancy advances.
Adjuncts to the clinic-based
assessment can include the use
of day assessment units for
monitoring BP and overall
wellbeing, and occasionally
admission to hospital to assess
24-hour BP patterns and
symptoms.
Given that the definition of
hypertension in pregnancy
requires a demonstration of
sustained high BP, the use of
fetal–maternal or day-stay
assessment units to determine
elevated BP have a proven
benefit in the care of pregnant
women. These units are hospital based and involve assessing
the mother by:
• Regular (half-hourly) BP
checks.
• Urine testing.
• Assessing diagnostic blood
tests (uric acid concentra-
tion, creatinine concentration, LFTs, platelet count
and haemoglobin).
They allow appropriate
fetal monitoring, including
timely fetal ultrasound looking at rates of fetal growth,
wellbeing and amniotic fluid
volume assessment. A cardiotocograph will commonly
be done in this setting. It
involves the mother having 24 hours of monitoring and
review by either a member of
the obstetric team or the renal
and/or obstetric medicine
team.
Summary of Susan’s case
Susan clearly had pre-eclampsia 13 years earlier, with a
complete resolution of the
maternal complications by
three months post-partum.
There was no history of renal
disease and the absence of any
proteinuria (or haematuria) in
the post-partum follow-up
would suggest that underlying
glomerular (renal) disease is
unlikely. Her physical examination did not reveal any
endocrine or vascular causes.
Management of pre-eclampsia risk in pregnancy
THE potential strategies for managing the risk factors for pre-eclampsia
are limited.
Table 2: Low-dose aspirin therapy for prevention of pre-eclampsia
High-risk patients
Low-risk pregnancy
2
500
High-risk patients are women with
several risk factors, as described in
the ‘Causes’ box on page 18 and in
table 1, page 19. The mainstay of
treatment of high-risk patients is preconception counselling. For women
with SLE or obstetric lupus (antiphospholipid syndrome), renal disease or endocrine hypertension, it is
important to carefully manage the
underlying condition with multidisciplinary care throughout pregnancy.
In patients with chronic hypertension, appropriate control of BP
throughout pregnancy is essential.
Management of usual lifestyle issues
is recommended, including a healthy
Normal pregnancy
6
167
Prior severe pre-eclampsia
18
56
Renal disease
30
34
Chronic hypertension
40
25
Diagnosis
Baseline event rate (%)
NNT*
*NNT is the number needed to treat to prevent one case of pre-eclampsia
diet with adequate fruit and vegetables and limits to high-fat food, soft
drinks and high salt intake.
Intermediate-risk patients
The intermediate-risk group should
be considered for low-dose aspirin
therapy to prevent progression to pre-
eclampsia. The vexing question of
whom to treat with aspirin has been
best addressed by a recent metaanalysis of low-dose aspirin to prevent pre-eclampsia.1 Indiscriminant
use in primiparous women is not
supported. However, use of aspirin to
prevent progression to pre-eclamp-
sia in women with chronic hypertension, renal disease and those with a
history of early severe pre-eclampsia
(prior delivery before 34 weeks’ gestation) is supported by this study.
The number needed to treat to prevent one case of pre-eclampsia is 25,
34 and 56 for these groups respectively (table 2).
The greatest benefit in taking
aspirin is afforded if it is started
before 20 weeks’ gestation. Although
the larger trials were free from bleeding complications, in individual
patients common complications of
aspirin such as gastric irritation, gingival bleeding or haemorrhoidal bleeding need to be monitored.
Low-risk patients
For patients at low risk of preeclampsia (no risk factors) there is
limited support for populationbased calcium supplementation for
preventing pre-eclampsia. However,
an individual history of a low-calcium diet should be corrected in
pregnancy by either an increase in
calcium-containing foods or by
supplemental calcium. There is no
clear evidence to suggest that bed
rest prevents pre-eclampsia and its
complications in women with
normal BP, although there is some
evidence to recommend reducing
physical and work activities.
Summary of Susan’s case
In view of her 18% risk, low-dose
aspirin is recommended for prophylaxis from 12 weeks’ to 34
weeks’ gestation in the absence of
any early pregnancy ante-partum
haemorrhage.
Management of hypertension in pregnancy
MANAGEMENT of hypertension in pregnancy is based
on two main strategies: controlling hypertension with
appropriate lifestyle advice
and antihypertensives; and
timing the delivery based on
assessment of progression of
pre-eclampsia and the development of target-organ
effects, such as fetal growth
restriction and maternal
organ involvement. A useful
managment algorithm is
shown in figure 5.
It is not clear
whether tight
blood pressure
control improves
outcomes
compared with
less stringent
blood pressure
control.
Antihypertensives
Hypertension is best managed
by a combination of lifestyle
modification and antihypertensives. The evidence for rest is
not conclusive, but continuation of full-time work or highlevel aerobic exercise in devel-
22
| Australian Doctor | 14 January 2011
oping pre-eclampsia is not recommended. Most trials in this
area in the 1970s and 1980s
included bed rest as part of the
protocol. A meta-analysis of
studies including bed rest alone
confirms that this is not of
proven benefit.2 However, in
the setting of the need for
ongoing and frequent BP monitoring by the obstetric management team, including the
GP, a decrease in work commitments is recommended and
bed rest should be considered
an option.
Hospital admission is often
required when:
• BP is not controlled.
• Biochemistry is abnormal.
• Symptoms occur.
• Fetal compromise is suspected.
The optimal target blood
pressure in pregnancy has not
been established. This is especially the case in a woman
with mild-moderate hypertension. It is not clear whether
tight blood pressure control
improves outcomes compared
with less stringent blood pressure control. The current treatment target is a BP
<140mmHg systolic and
<90mmHg diastolic.
There is strong evidence that
treating severe hypertension in
pregnancy (>170mmHg systolic and/or >110mmHg diastolic) prevents episodes of
extreme hypertension, intracerebral haemorrhage and placental abruption.
Antihypertensive medication
choice is influenced by familiarity with available agents,
and fetal safety. There is no
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formal evidence that one agent
is superior to another. Being
familiar with the agent and its
characteristics is the most
important factor. Either a beta
blocker or a centrally acting
agent is used as first-line therapy. Second-line treatment is
usually a vasodilator, such as
hydralazine, and third-line,
either a beta blocker or centrally acting agent (depending
on what was used as a firstline agent).
Fetal safety is a major concern for the mother and, if this
issue is not adequately
addressed with her, it will
result in reduced compliance.
Several groups of agents have
demonstrable fetal side effects.
ACEIs and ARBs result in fetal
renal tract anomalies and
should be avoided. They have
also been implicated in fetal
skull ossification defects as
well as an increase in the fetal
anomaly rate if used in the first
trimester.
The long-acting, highly
selective beta blockers atenolol
and metoprolol have been
associated with fetal growth
restriction. The newer antihypertensives such as lercanidipine should also be avoided due
to the lack of clinical experience and safety data.
Table 3 provides a summary
of antihypertensive agents in
pregnancy.
Seizure prophylaxis
Anticonvulsant prophylaxis
is reserved for cases of neurological irritability, and
severe hypertension (usually
>170/110mmHg). This
involves the infusion of intravenous undiluted magnesium
sulphate in a dedicated vein
and requires at least hourly
observations for signs of toxicity (most notably, depressed
reflexes). The dose is adjusted
according to the urine output
and level of renal function.
Magnesium is used at the
time of patient stabilisation
before delivery, then for 24
hours post-partum to prevent
seizures. In cases of severe
pre-eclampsia it has been
shown to decrease maternal
mortality.
FORMERLY it was considered that once pre-eclampsia
resolved, maternal cardiovascular risk returned to normal.
It has become apparent that
women who develop preeclampsia later in life have a
significantly increased risk of
developing: hypertension
(odds ratio [OR] 3.7, 95%
confidence interval [CI] 2.75.05), ischaemic heart disease
(OR 2.16, 95% CI 1.86-2.5)
or stroke (OR 2.03, 95% CI
1.64-2.67).
Compared with known
conventional risk factors such
as smoking (relative risk 2.1,
95%CI 1.5-2.9) pre-eclampsia is a significant risk factor.
What is unclear is whether
vigilant monitoring and early
management of known cardiovascular risk factors such
as obesity, smoking, exercise
levels, dietary factors, hypertension, glycaemic monitoring and lipid abnormalities,
will reduce the future maternal cardiovascular risk. Until
evidence is available to guide
clinical practice, women who
have had pre-eclampsia
should be counselled to avoid
smoking, exercise regularly
and maintain a healthy
weight, and should have their
BP measured and urinalysis
assessed yearly. Other cardiovascular assessments should
also be undertaken, such as
fasting glucose and lipids on
a 3-5-yearly basis, depending
on the individual profile.
BP ≥140mmHg systolic or ≥90 mmHg
diastolic
What is the gestation of the patient?
≥20 weeks’ gestation
<20 weeks’ gestation
Secondary cause of hypertension
evident
Assessment must include a urine
analysis
Is there significant proteinuria on
urinalysis?
Yes
No
Seizure (eclampsia)
treatment
Seizures are treated with a
similar protocol to that for
prophylaxis, and preferably
with magnesium sulfate alone.
Ongoing seizure activity,
which is rare on a magnesium
infusion, indicates a possible
structural cause (eg, intracerebral haemorrhage). If benzodiazepines are used as an
adjunct to control seizures,
respiratory suppression is
almost guaranteed. The most
common complication of a
magnesium infusion is pain at
the site of the intravenous cannula.
Prognosis
Figure 5: Treatment of chronic hypertension of <20 weeks’ gestation, and gestational hypertension and pre-eclampsia
after 20 weeks’ gestation.
Yes
Refer for specialist
review or manage as
appropriate
No
Is the booking BP
≥130/80mmHg?
Start an antihypertensive
agent to reduce risk of
superimposed
pre-eclampsia
Counselling
Regular review
Refer for urgent
review
No
Yes
Are there any systemic
symptoms / blood
abnormalities to suggest
pre-eclampsia?
Yes
Chronic
hypertension
likely
No
Start an antihypertensive agent, frequent (twice weekly)
regular review, review by specialist as soon as possible
Several diagnostic possibilities — gestational or chronic
hypertension but may evolve into pre-eclampsia
Pre-eclampsia
Refer for urgent review
After delivery
After delivery the BP does not
immediately normalise, taking
up to six weeks to return to
normal. Thus, after delivery
and on discharge antihypertensives usually need to be
continued. In the weeks after
delivery it is important not to
abruptly stop the antihypertensives but to wean gradually.
Uncommonly the BP can
actually increase after delivery. In this instance the medication dosages will also have
to be increased and titrated to
control the elevated BP.
NSAIDs are contraindicated
in women with hypertension
in the post-partum period, in
which context they have been
shown to exacerbate hypertension. The specific mechanism is not clear but is probably multifactorial, including
reduced renal prostaglandin
synthesis, increased endothelin (a potent vasoconstrictor)
production, as well as
sodium and water retention.
If antihypertensives are still
required at six weeks postpartum, consideration needs
to given to whether the
woman has chronic hypertension rather than pregnancyrelated hypertension. Complete resolution is expected by
three months post-partum for
gestational hypertension and
pre-eclampsia.
The urine analysis also
needs to be rechecked to
ensure the resolution of the
proteinuria and to exclude
the possibility of underlying
renal disease. The proteinuria related to pre-eclampsia
may take up to three months
to completely resolve. Ideally
a urinalysis should be performed at six weeks and in
most cases the proteinuria
Table 3: Antihypertensive choices in pregnancy
Methyldopa
Dosing
Usual
starting dose
Max dose
Side effects
Notes
Mechanism
of action
tds or
qid
250mg
2000mg/
day
Drowsiness,
headache, increased
risk of postnatal
depression, postural
hypotension, liver
dysfunction,
leukopenia,
haemolytic anaemia
Contraindicated in people
Centrally acting
taking monoamine oxidase
anti-adrenergic
inhibitors or lithium, and those
with liver disease or positive
Coomb’s test
Clonidine
qid
75μg
300μg qid
Drowsiness, dry
mouth, dry eyes,
nausea, reduced
fetal heart rate
Avoid stopping suddenly due
to pressor effect
Oxprenolol
tds
40mg
120mg tds
Nightmares
Contraindicated in people
Beta blocker
with asthma.
Avoid in possible
phaechromocytoma, in heart
failure, bradycardia, peripheral
vascular disease, or patients
with Raynaud’s phenomenon
References
1. Duley L, et al.
Antiplatelet agents for
preventing pre-eclampsia
and its complications.
Cochrane Database of
Systematic Reviews 2007;
18 Apr(2):CD004659.2.
2. Meher S, et al. Bed rest
with or without
hospitalisation for
hypertension during
pregnancy. Cochrane
Database of Systematic
Reviews 2005;
(4):CD003514.
Centrally acting
sympathetic
inhibitor
Online resources
• Preeclampsia Research
Laboratories (PEARLS):
www.preeclampsia.org.au
• Australian Action on
Preeclampsia (AAPEC):
www.aapec.org.au
Labetolol
bd/tds
100mg
2.4g/day
(no therapeutic
benefit
above
600mg tds)
Worsening asthma,
cough, nightmares,
bradycardia
Nifedipine
tds
10mg
30mg tds
Headache,
Metabolised through CYT
oedema, palpitations, P450-3A4 —consider
nausea dizziness
interaction with, eg,
phenytoin and cisapride
Hydralazine
qid
12.5mg
50mg qid
Flushing, palpitations, Should be a second- or third- Peripheral vasodilator
headaches, nausea
line agent to minimise side
effects. Can cause
autoimmune lupus
will have completely
resolved or at least should
be considerably reduced at
six weeks post-partum. A
urinalysis before six weeks
Contraindicated in asthmatics. Alpha- and beta
Avoid in possible
blocker
phaechromocytoma, in heart
failure, bradycardia, peripheral
vascular disease or patients
with Raynaud’s phenomenon
is difficult to interpret
because of the ongoing vaginal blood loss.
Similarly, if there were any
residual
biochemical
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Calcium-channel
blocker
changes, such as an elevated
creatinine, LFTs or haematological abnormalities, they
should be repeated about
one week after discharge.
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HOW TO TREAT Pre-eclampsia and hypertension in pregnancy
GP’s contribution
DR RENATA CHAPMAN
Chatswood, NSW
Case study
GAYLE, 32, came to see me
for confirmation of her pregnancy. She had two previous
early miscarriages at six weeks.
This time she was nine weeks
pregnant. She was overweight,
with a BMI of 29 kg/m2, and
had background of mild polycystic ovary syndrome with
axillary acanthosis nigricans
and facial acne. Her routine
examinations included BP of
110/70mmHg and blood and
urine tests, which were
normal.
Gayle returned to me at 28
weeks for review, complaining
of worsening peripheral
oedema and headache. Her BP
was 140/90 and there was +
albumin on the urinary dipstick. I phoned my local hospital and Gayle was seen by the
maternal–fetal medicine assessment unit physician the same
day. She was started on
oxprenolol and low-dose
aspirin.
When I saw her three weeks
later at 31 weeks’ gestation her
BP was well controlled on her
medication but she was feeling sad and emotional. We discussed eventual referral to a
counsellor, and Gayle was
going to consider that option.
She did not attend the routine follow-up but phoned me
five weeks later, complaining
of a sudden-onset upper-quadrant abdominal pain, nausea
and vomiting. When I saw her
that day her BP was 160/100
and she had significant right
abdominal tenderness, bruises
and hyperreflexia. There was
marked albuminuria (+++) on
her urine examination. Her
blood tests performed later in
hospital showed thrombocytopenia and elevated AST and
uric acid levels.
Once in hospital Gayle was
given hydralazine and methyldopa (Aldomet) to control her
BP and was started on IV
magnesium sulfate infusion to
prevent convulsions.
A caesarean section was
performed and a baby boy
delivered. He showed mild
signs of growth retardation
but was in otherwise good
condition, with Apgar scores
9 and 9, at one and five minutes, respectively.
Eight weeks later Gayle
brought her son for vaccination. Her BP had normalised
and she was taking no medications at all. All biochemical
abnormalities had resolved but
Gayle admitted that she did
not feel well — she was very
emotional, crying a lot and
unable to bond well with her
child. Her Edinburgh Postnatal Depression Scale score was
22, indicating depression.
Questions for the author
It seems that pre-eclampsia
and cardiovascular diseases
have similar risk factors.
Depression is now a wellrecognised independent risk
factor for cardiovascular diseases. Could it also be an independent risk factor for preeclampsia?
Depression is not currently
recognised as a risk factor for
pre-eclampsia. A single study
from Finland showed an
increased risk of pre-eclampsia
in women who were identified
as having anxiety or depression at 15-18 weeks’ gestation.1
A subsequent case–control
How to Treat Quiz
study from Peru in 2007
showed a doubling of the odds
for pre-eclampsia.2 It is unclear
whether this is significant in
other cultural settings.
Aspirin and calcium are used
for prevention of pre-eclampsia in pregnant women with a
past history of the condition,
or the presence of risk factors
for it. We know that women
with a history of pre-eclampsia
are at higher risk of developing
hypertension and other cardiovascular diseases in the future.
Would there be a place for
long-term use of aspirin and
calcium in Gayle, who with
her PCOS has additional risk
of developing CVD?
A benefit for the use of calcium for prophylaxis was initially shown in developing
countries, but its usefulness
was not replicated in a largescale trial in the US.3 However,
the meta-analysis of several
smaller trials did show a benefit in pre-eclampsia prevention.4
Use of aspirin and calcium
in the long term as a primary
prevention strategy for CVD
should be the subject of future
randomised controlled trials.
There are no current data to
support their use in the management of pre-eclampsia. The
importance of pre-eclampsia
as an independent risk factor
for CVD is a recent finding
and work needs to be done to
determine which patients
would likely benefit from such
an intervention.
How would this recommendation relate to the recently
published meta-analysis in the
BMJ indicating higher risk of
cardiac events in women
taking calcium supplements?5
This is clearly one of the major
potential detrimental effects of
long-term calcium use and
needs to balanced against any
proven benefit in prevention
of CVD.
Gayle’s son was born with
signs of mild growth retardation. Are there any particular
problems I should be looking
for in children of mothers who
experienced pre-eclampsia?
The Barker hypothesis,
now known as the developmental origins of health and
disease theory, indicates that
growth restriction is a risk
factor for future (later-life)
CVD. In the Raine cohort
from Perth, being born small
was strongly influenced by
the pattern of growth in early
neonatal life and predicted
both BMI and risk of hypertension. Despite these theoretical links, there is no current
recommendation to screen
these children for cardiovascular risk factors in childhood, other than that which
would be undertaken due to
their prematurity.
Is there any evidence of the
benefit of heparin in the management of pre-eclampsia?
Heparin benefit in pregnancy for prevention of preeclampsia is indicated in
women with antiphospholipid
syndrome and other thrombophilias. There is no current recommendation for its global
use in the prevention or treatment of pre-eclampsia.
References
1. Obstetrics and Gynecology
2000; 95:487-90.
2. BMC Women’s Health 2007;
7:15.
3. New England Journal of
Medicine 1997; 337:69-77.
4. Cochrane Database of
Systematic Reviews 2006;
Issue 3, CD001059.
5. BMJ 2010; 341:c3586.
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Pre-eclampsia and hypertension in
pregnancy — 14 January 2011
1. Which TWO of the following are regarded
as relating to elevated blood pressure only
in pregnancy?
a) Gestational hypertension
b) Pre-eclampsia
c) Chronic hypertension
d) Pre-eclampsia superimposed on chronic
hypertension
2. Which TWO statements are correct?
a) Hypertension in pregnancy is defined as a
systolic blood pressure ≥140mmHg or a
diastolic blood pressure ≥90mmHg
b) Too rapid deflation of the cuff can
overestimate the systolic blood pressure and
underestimate the diastolic reading
c) Normally blood pressure decreases from
early pregnancy (6-8 weeks) to 24 weeks’
gestation then increases slightly towards
term
d) In a normal pregnancy, the BP response to
‘stress’ is augmented
3. Which TWO statements are correct?
a) The decrease in the concentrations of
haemoglobin and creatinine in a normal
pregnancy reflect an increase in blood
volume
b) Gestational hypertension occurs within the
first trimester
c) An increase of 25mmHg systolic or 15mmHg
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diastolic from baseline BP should trigger
maternal and fetal monitoring, even if the BP
is <140/90mmHg
d) Proteinuria is mandatory for a diagnosis of
pre-eclampsia in a pregnant patient with
hypertension
4. Which TWO statements are correct
regarding pre-eclampsia?
a) Thrombocytopenia and haemolysis reflect
disseminated intravascular coagulation
b) Peripheral oedema is a defining feature
c) Hyperreflexia, severe headache or visual
disturbances are some of the neurological
manifestations
d) Hyperuricaemia is a common diagnostic
feature
5. Which TWO statements are correct?
a) Chronic hypertension presents after 20
weeks’ gestation
b) Chronic hypertension in pregnancy includes
essential hypertension and secondary
hypertension
c) Hypothyroidism and hyperthyroidism are
correctable causes of hypertension that also
have an impact on developmental outcomes
for the baby
d) White-coat hypertension in pregnancy is
benign and not associated with an increased
risk of pre-eclampsia
6. Which TWO statements are correct?
a) Antenatal urine assessment is essential in
women with chronic hypertension or with risk
factors for hypertension
b) In a hypertensive pregnant woman, a baseline
creatinine concentration is inaccurate and
unhelpful in monitoring renal function
c) Calcium, potassium and thyroid function tests
may identify treatable secondary causes of
hypertension
d) Uric acid concentration is not useful as a
marker of pre-eclampsia disease progression
7. Which THREE statements are correct
regarding monitoring for the development
of pre-eclampsia?
a) An increase in blood pressure should trigger a
platelet count, LFTs and a serum creatinine
test
b) Fetal ultrasound monitors fetal growth rate,
wellbeing and amniotic fluid volume
c) Urine assessment by dipstick is unhelpful
d) Monitoring ideally should involve high-risk
obstetric services at least monthly
8. Which THREE statements are correct?
a) In pre-eclampsia there is placental dysfunction
due to failure of the placental trophoblast to
invade the uterine spiral arteries in the
myometrium normally
b) Definitive treatment of pre-eclampsia is delivery
c) Risk factors for pre-eclampsia include barrier
methods of contraception, a new partner and
multiple-fetus pregnancy
d) High calcium intake is a risk factor for preeclampsia
9. Which TWO statements are correct?
a) Use of aspirin for prophylaxis against preeclampsia is appropriate for women with
prior severe pre-eclampsia, renal disease or
chronic hypertension
b) Aspirin prophylaxis against pre-eclampsia is
appropriate in all primiparous women
c) Aspirin prophylaxis for pre-eclampsia should
be started after 20 weeks’ gestation
d) Continuation of full-time work or high-level
aerobic exercise in women developing preeclampsia is not recommended
10. Which TWO statements are correct?
a) Centrally acting agents or certain beta
blockers are first-line therapy for
hypertension in pregnancy
b) ACEIs or ARBs are second-line therapy for
hypertension in pregnancy
c) Seizure prophylaxis with IV magnesium
sulfate is used where there is neurological
irritability or severe hypertension.
d) Once pre-eclampsia has resolved, the
maternal cardiovascular risk returns to
normal
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fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.
HOW TO TREAT Editor: Dr Giovanna Zingarelli
Co-ordinator: Julian McAllan
Quiz: Dr Giovanna Zingarelli
NEXT WEEK The next How to Treat confronts the anxiety-producing, real or perceived abnormalities in the head shape of an infant or child. The author is Professor David John David, clinical professor of
craniomaxillofacial surgery, University of Adelaide, and head of the Australian craniofacial unit at the Women’s and Children’s Hospital, North Adelaide, SA.
24
| Australian Doctor | 14 January 2011
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