Pregnancy induced hypertension, preeclampsia and eclampsia

Introduction
The term pregnancy induced hypertension (PIH) suggests a disorder of blood pressure
that arises because of the presence of pregnancy. Such a simple view detracts from the
fundamental pathological process that underlies this condition: PIH, pre-eclampsia and its
variants are part of a multisystem disorder that can affect every organ system in the body and
collectively are the second highest cause of direct maternal deaths in the UK.
Although pre-eclampsia is associated with abnormal trophoblast invasion in the first half
of pregnancy, it is not until later in the pregnancy that the clinical syndrome of pre-eclampsia is
seen. The mechanisms by which the abnormal placentation and subsequent impaired placental
perfusion cause the widespread vascular endothelial dysfunction that characterizes pre-eclampsia
are not fully understood.
Pre-eclampsia is defined as hypertension with proteinurial. It is, however, a very
heterogeneous condition such that the timing of onset and the clinical course are unpredictable.
In some, hypertension and proteinuria are the only manifestation, while others may present with
severe renal or liver impairment, and in yet others the most prominent feature might be
intrauterine fetal growth restriction secondary to placental disease.
Eclampsia is a generalized seizure that occurs during pregnancy in association with the
features of pre-eclampsia. In a proportion of women with with eclampsia, however, the features
of pre-eclampsia are notevident at the time of the first seizure. The only cure for these conditions
is delivery.

Definitions
Hypertension in pregnancy is common and affects up to 15% of pregnant women. Hypertension
in pregnancy is calssified into three groups, depending on the timing of onset and the associated
clinical features:

Pre-existing (essential) hypertension (identifies <20 weeks gestations

Pregnancy-induced hypertension (hypertension only, no proteinuria)
Pre-eclampsia (hypertension an proteinuria multisystem involvement).

Hypertension
In normal pregnancy the maternal blood pressure falls slightly during the first trimester,
predominantly as a consequence of reduced system vascular resistance. Maternal blood pressure
continues to fall during the second trimester and reaches a nadir at approximately 22-24 weeks
gestation. Thereafter, maternal blood pressure steadily aincreases during the third trimester to
reach pre-pregnancy levels. Maternal blood pressure falls immediately after delivery of the baby,
but then rises and peaks on the 4th postnatal day.
Maternal blood pressure should be measured in the siting position with an appropriatesized cuff that is palced on the upper arm at the level of the heart (fig.34.1). Phase V Korotkoff
sounds (i.e. disappearance rather than muffling) should be used when measuring the diastolic
blood pressure.

Hypertension in pregnancy is defined as a blood pressure of 140/90 mmHg on two

occasions more than 4 hours apart.

A diastolic blood pressure of 100 mmHg on any one occasion or a systolic blood

pressure of 160 mmHg on any one occasion is also significant hypertension.

A systolic blood pressure of 30 mmHg above the booking systolic blood pressure or a
diastolic blood pressure of 15-25 mmHg above the booking diastolic blood pressure are
alternative and widely used criteria for the diagnosis of hypertension in pregnancy.

Hypertension in pregnancy may be pre-existing or related to pregnancy (PIH or pre-eclampsia).

An increased maternal blood pressure in early pregnancy (before 20 weeks gestation) is usually

due to pre-existing hypertension, most commonly essential hypertension. In a young woman with
pre-existing hypertension, consideration should be given to identify the rare secondary causes of
hypertension such as renal disease, cardiac disease, phaeochromocytoma and endocrine disorders
such as Cushings syndrome. The diagnosis of essential hypertension may be made
retrospectively if the materbal bllodpressure has not returned to normal within 3 months of
delivery of the baby.
PIH and pre-eclampsia rarely occur before 20 weeks gestation unless associated with
trophoblastic disease or fetal triploidy. The hypertension associated with preeclampsia usually
resolves within 6 weeks of delivery.
Proteiunuria
Proteinuria is defined as a urinary protein concentration of more than 300 mg/I, or a urinary
protein excretion of morethan 300 mg in 24 hours. These approximate to 1+ or more on urine
dipstick testing.

Fig.34.1 early detection of pre-eclampsia is important.

(A) Measurement of blood pressure (reproduced with permission).
(B) Testing for urinary protein.
Essential hypertension
Essential hypertension is more common in older women and the prognosis for pregnancy is
generally good; the main risk is from superimposed pre-eclampsia. Women with essential
hypertension are also at increased risk of placental abruption and intrauterine fetal growth
restriction. Some women taking antihypertensive drugs may be able to discontinue their
medication during pregnancy, particularly during the first and second trimesters. Drugs that are
commonly used for the treatment of essential hypertension during pregnancy include
methyldopa, labetalol and nifedipine. Diuretics and angiotension-converting enzyme (ACE)

inhibitors are contraindicated in pregnancy but may be used for the management of hypertension
during the puerperium.
Pregnancy-induced hypertension (PIH), pre-eclampsia and eclampsia
Pathophysiology
Recognized risk factors for PIH and pre-eclampsia are shown in Box 34.1
The precise aetiology and pathophysiology of PIH and pre-eclampsia remain unclear. It is
established, however, that women who develop pre-eclampsia have a genetic or phenotypic
susceptibility and that there are two distinct phases to the conditions development: first there is
inadequate trophoblast invasion during early pregnancy, and secondly, in later pregnancy, there is
reduced placental perfusion and uteroplacental ischemia, which in turn gives rise to the clinical
syndrome.
Box 34.1
Predisposing factors for developing PIH/pre-eclampsia

First pregnancy
Family history mother/sister
Extremes of maternal age
Obesity
Medical factors :
o Pre-exixting hypertension
o Renal disease
o Acquired thrombophilia antiphospolipid antibodies
o Inherited thrombophilia
o Connective tissue diseases (e.g. systemic lupus erythematosus)
o Diabetes mellitus
Obstetric factors :
o Multiple pregnancy
o Previous pre-eclampsia
o Hydatidiform mole
o Triploidy
o Hydrops fetalis (immune and non0immune)
o Inter-pregnancy interval of >10 years

The precise mechanism by which this abnormal placentation causes the multisystem disorder that
characterizes pre-eclampsia is not known. It has been suggested that there is a trigger which
promotes widespread vascular endothelial dysfunction in response to the reduced placental
perfusion. This endothelial dysfunction subsequently causes metabolic changes, an exaggerated
maternal inflammatory response and reduced organ perfusion.
Maternal susceptibility
The evidence for genotypic susceptibility to developing pre-eclampsia is strong. Large
epidemiological studies demonstrate a three-to fivefold increased risk of pre-eclampsia in the
first-degree relatives of affected women. While it is possible that a single maternal gene in some
families may be important, no single gene has been identified. It may be that multiple genes
(maternal, paternal and fetal) interact, and that environmental factors may effect their expression.
Certain phenotypes are also more susceptible. Women with insulin resistance and central
obesity are at increased risk of developing pre-eclampsia, possibly on account of an exaggerated
metabolic response. Those with connective tissue disease, such as systemic lupus erythematosus,
are also at increased risk, possibly because of an exaggerated immune response. In addition,
those with an inherited thrombophilia are more likely to develop pre-eclampsia. These
associations suggest that the pathophysiology of pre-eclampsia involves a significant interaction
between metabolic, immunological and coagulation processes, possibly mediated through
vascular endothelial dysfunction and damage.
Phase 1 abnormal placentation
In normal pregnancy, placentation occurs between 6 and 18 weeks gestation. During
normal placentation development, major structural alterations of the spiral arteries occur,
allowing an increase in blood supply to the placentation. Trophoblast invasion of the maternal
spiral arteries cause the diameter of these arteries to increase approximately five-fold, converting
a high-resistence, low-flow system to one with a low resistance and high flow. In women who
develop pre-eclampsia, adequate trophoblast invasion does not seem to occur, or the
trophoblastinvation is limited to the decidual portions of the vessels. The result is inadequate
placental perfution. This type of abnormal placentation is also associated with intrauterine fetal
growth restriction that occurs independently of pre-eclampsia.

During early pregnancy, trophoblast invasion is regulated ed at the maternal decidual

barrier by the action of the factors expressed wuthin the decidua and on the trophoblast cells.
These regulatory factors include cell adhesion molecules (CAMs) and the extracellular mattix
(ECM), proteinases and their inhibitors, growth factors and cytokines. Abnormalities in any one
of these factors may lead to invasion and subsequent pre-eclamsia.
It has been suggested

that the primery factor in the aetiology of pre-eclampsia is

immunological in origin. Abnormal placentation may be the resulst of material immune rejection
of paternal antigens expressed by the fetus. HLA-G is a class 1B major histocompatibility
antigen that is expressed by extra-villous trophoblast and may protect cells from natural killer
cell lysis. Women who develop pre-eclampsia in first pregnancies and the protective effect of
pairty further support an immunological mechanism for the condition.

Phase 2 endothelial dysfunction

The second phase of pre-eclampsia is characterized by widespread endothelial damage
and dysfunction. Women with pre-eclampsia have increased circulating levels of markers of
endothelial dysfunction. Endothelial damage promotes platelet adhesion and thrombosis, and
disturbs the normal physiological modulation of vascular tone, further amplifying the respons.
The underlying pathophysiology of this second phase of pre-eclampsia is characterized
by an exaggerated maternal systemic inflammatory response, with associated activation of
leucocytes, platelets and coagulation system. Pre-eclampsia is also associated with other markers
of inflammation. Features of oxidative stress and dyslipidemia are also evident and the overall
effect is reduced organ perfusion.
Normal pregnancy is a state of systemic inflammation. In normal pregnancy there is
leuccocytosis and an increase in leucocyte activation. Women with pre-eclampsia appear to have
an excessive inflammatory response to pregnancy. Animal models have demonstrated that the
administration of endotoxin during pregnancy can cause hypertension and proteinuria.
It has been suggested that the exaggerated maternal inflammatory response that is seen in
pre-eclampsia may lead to endothelial dysfunction and damage. Other systemic metabolic

changes that are associated with pre-eclampsia include hypertriglyceridaemia and a significant
increase in free fatty acids. This atherogenic lipid profile may also be a contributor to endothelial
dysfunction in women with pre-eclampsia.
Many of the features of the second phase pre-eclampsia are the result of reduced organ
perfusion caused by vasoconstriction, activation of the coagulation system and reduction of
plasma volume. The resulting organ damage caused by hypoperfusion gives rise to the clinical
features of pre-eclampsia, eclampsia and HELP syndrome (see later) (table 34.1).
Normal pregnancy is associated with an increase in angiotensin II levels. Angiotensin II
is a potent vasoconstrictor. However, during normal pregnancy, despite increased angiotensin II
levels, peripheral vascular resistance falls. This appears to be because normal pregnant women
are resistant to the effects of angiotensin II, a phenomen that seems to be lost in women who
develop PIH and pre-eclampsia. This suggests that abnormalities in the renin-angiotensinaldosterone system may play a role in the pathogenesis of the condition. Women pre-eclampsia
are also more responsive to other vasoconstrictors such as vasopressin and noradrenaline and
appear to be less responsive to vasodilators such as nitric oxide and prostacyclin (PGI2).
In pre-eclampsia, organ perfusion is further compromised by activation of the coagulation
cascade. Altered platelet function is seen in most women with pre-eclampsia. In normal
pregnancy there is increase biosynthesis of eicosanoids, particularry prostacyclin and
thromboxane A2. Prostacyclin is a vasodilator with platelet-inhibitory properties and thromboxane
A2 is a vasoconstrictor with a tendency to promote platelet aggregation. Prostacyclin and
thromboxane A2 usually increase in proportion to one another and consequently there is a net
neutralization, and homeostasis is disrupted due to a relative deficiency of prostacyclin. This
occurs either because of a reduction in prostacyclin synthesis or because of an increased
production of thromboxane A2. This imbalance leads to plateletstimulstion and also
vasoconstriction and hypertension.
In pre-eclampsia, plasma volume is reduced as a consequence of increased capillary
permeability. This further reduces organ perfusion.
Table 34.1

Potential secondary effects of the metabolic, inflammatory endothelial alterations in preeclampsia

CVS

Increased peripheral resistance leading to

hypertension
Increased vascular permeability and reduced
maternal plasma volume
Laryngeal and pulmonary oedema
Glomerular damage leading to proteinuria,

Lungs
Renal

hypoproteinaemia
pressure

which

and
futher

reduced

oncotic

exacerbates

the

hypovolaemia.
May develop acute renal failure cortical
Clotting

necrosis
Hypercoagulability,

with

increased

fibrin

formation and increased fibrinolysis, i.e.

Liver

disseminated intravascular coagulation

HELLP syndrome

CNS

Hepatic rupture
Thrombosis and fibrinoid necrosis of the
cerebral arterioles
Eclampsia

(convulsions),

cerebral

haemorrhage and cerebral oedema

Impaired uteroplacental circulation, potentially

Fetus

leading to FGR, hypoxaemia and intrauterine

death
CVS, cardiovascular system; CNS, central nervous system; FGR, fetal growth restriction.
Linking phase 1 and phase 2
It has been suggested that reduced placental perfusion that is a feature of the first phase of
pre-eclampsia is associated with oxidative stress. Women who develop pre-eclampsia have
reduced levels of the antioxidant ascorbic acid, as well as increased levels of markers of
oxidative stress. Furthermore, women who develop pre-eclampsia have increased cytrophoblast
levels of xanthine oxidase, a superoxide-generating enzyme. The oxidative stress that is

associated with placental hypoperfussion may lead to leucocyte activation and/or cytokinr
production and subsequently the production of free radicals. Oxidative stress may also cause
placental apoptosis and result in the shedding of placental debris into the maternal circulation.
This debris, along with the free radicals produced by osidative stress, may then lead to vascular
endothelial damage that characterizes the maternal syndrome of the second phase of preeclampsia.

Fig.34.2 Uterine artery Doppler notching at 24 weeks is predictive of pre-eclampsia and

intrauterine growth restriction in high-risk mothers.

Screening and detection

Pre-eclampsia is an unpredictable condition and extremely variable in its manner of
presentation. The aim of antenatal screening is to detect pre eclampsia early enough to prevent
disease progression, and hence both maternal and fetal complications, by timely delivery of the
baby.
An important component of routine antenatal care for all pregnant women is directed
towards screening for hypertension and proteinuria. Risk factor for preeclamsia can be identified

at the booking visit. A number of additional screening tests for predicting pre eclampsia have
been proposed, but most are of limited clinical use. Abnormalities of the maternal uterine artery
Doppler waveform between 18 and 24 weeks gestation may identify a group of women at
increased risk of developing severe pre eclampsia that requires preterm delivery (<34 weeks
gestation).
Abnormalities of the maternal uterine artery Doppler waveform appear to be more significant if
they are bilateral and if they are bilateral and if they persist into the third trimester of pregnancy.
In PIH and pre eclampsia there are many non specific symptoms and signs that are
important indicators of
Box 34.2
Symptoms and signs of impending eclampsia
1.
2.
3.
4.
5.
6.
7.
8.

Unusual headaches, typically frontal

Visual disturbances (blurring of vision, diplopia, scotomas or flashes of light)
Restlessness or agitation
Epigastric pain, nausea and vomiting
Sudden severe hypertension and proteinuria
Fluid retention with reduced urine output
Hyperreflexia or ankle clonus
Retinal oedema, haemorrhages or papilloedema

Table 34.2
Investigations is PIH and pre eclampsia

Investigation
FBC
Renal function
Coagulation system
Hepatic system

Finding in pre eclampsia

- Reduced platelets, reduced haemoglobin, haemolysis on blood film
-Reduced urine output
-increased urate, increased urea, increased cretinine
-Prolonged coagulation indices
-elevated alanine transaminase (ALT)
and aspartate transaminase (AST)

FBC,Full Blood Count

Widespread multisystem involvement and these symptomps may herald the onset of severe pre
eclampsia.

Clinical management of hypertension in pregnancy without proteinuria

If the maternal blood pressure is found to be elevated, measurement should be repeated after 1020 minutes if it settles, no further actionis needed; if still elevated, further assessment is required,
ideally at an antenatal day care unit. The woman should be asked about the symptoms of
preeclampsia (headaches, visual disturbance, epigastric pain, oedema), and the fetal size and well
being should be assessed clinically. Ultrasound can be used to assess fetal size, amniotic fluid
volume and fetal umbilical artery Doppler waveform. Serum urate (whice rises with pre
eclampsia), urea and electrolytes (U&Es), liver enzymes and platelets (which fall with pre
eclampsia) should also be checked.
In the absence of severe hypertension (160/110 or above), significant proteinuria or
symptoms of pre-eclampsia, and if the biochemistry and haematology results are normal, then
the woman can usually be managed as an outpatient. She should be seen at least twice weekly,
for blood pressure and urinalysis checks. Serum biochemistry and haematology should also be
repeated at least once a week. The women should be advised to return to hospital if she feels
unwell, or if there is any headache, visual disturbance or epigastric pain.
Treatment of the mother with antihypertensive drugs controls the hypertension but does
not alter the course of pre-eclampsia. Treatment of hypertension may allow prolongation of the
pregnancy and thereby may indirectly improve fetak outcome. Antilhypertensive treatment is
appropriate with consistent recordings of 150/100 or greater.
The only true cure for pre-eclampsia is delivery of the fetus and placenta, but the timing
of this will significantly influence the outcome for both the mother and the baby.

Clinical management of pre-eclampsia

In a womwn with pre-eclampsia, it is important to consider the overall picture rather than make
decisions on the basis of a single parameter. Progression of the diseases is not consistent and
further management should be tailored to the individual women.
Indications for admission to hospital include :

Blood pressure >170/110 mmhg or >140/90 with 2+ proteinuria

Significant symptoms (headaches, visual distrurbance, epigastric pain, oedema)
Abnormal biochemistery or heamatology results

Significant proteinuria
The need for antihypertensive treatment
Signs of fetal compromise.

The aim should be to prolong the pregnancy in order to reduce the risk to the baby, but this must
be balanced against the risks to the mother. The decision to deliver and the method of delivery
are dependent on many factors. There are usually fetal advantages to conservative management
before 34 weeks if the blood pressure, laboratory values and fetal condition are stable.
The principles of management of pre-eclampsia are :

To control the maternal blood pressure. Reduce the diastolic blood pressure to <100

mmHg using labetalol, nifedipine, hydralazine or methyldopa (table 34.3)

To assess maternal fluid balance. Pre-eclampsia isassociated with an increased vascular
permeability and a reduced intravascular compartment. In women with pre-eclampsia,
administering too little fluid risks maternal renal failure and giving too much fluid
maycause pulmonary oedema. Fluid input and urine aoutput should therefore be
monitored. In severe pre-eclampsia the maternal oxygen saturation (SaO2) should also be
monitored, along with serum U&Es, urate, LFTs, haemoglobin, haematocrit, platelets and
coagulation. If there is marked oliguria, central venous pressure monitoring may be

helpful to differentiate intravascular volume depletion from renal impairment.

To prevent seizures (eclampsia). The use of magnesium sulphate in severe pre-eclampsia
halves the risk of subsequent aclampsia, and may reduce the risk of maternal death.
Magnesium sulphate, given to those who have had an eclamptic seizure, also prevents

further seizures.
To consider delivery. The timing of this depends on the maternal condition, the fetal
condition and the gestational age. If preterm delivery is being considered, corticosteroids
should be administered to the mother toreduce the risks associated with prematurity (fig.
34.3).

Management of eclampsia

Eclampsia occurs when there is a

tonic-clonic convulsionin
association with the features of preeclampsia (the word eclampsia
means lightning). In the UK, the
incidence of eclampsia is
4.9/10,000 maternities, with 38%
of eclamptic seizures occurring
anterpartum, 18 % intrapartum and
44% postpartum. Over a third of
eclamptic seizures occur before proteinuria and hypertension have been documented. In the UK,
the maternal mortality associated with eclampsia is 1.8%. with a neonatal death rate of 34/1000.
In lessdeveloped countries, incidences of up to 80/10,000 maternities have been reported, with
maternal death occurring in approximately 10% of cases.
The treatment of eclampsia is outlined in Box 34,3.

Fig.34.3 This baby, born at weeks to a mother with severe pre-eclampsia, weighed 1.6 kg.
(Usual weight at 36 weeks: 2.2-3.3 kg.)

Table 34.3
Drug treatment of hypertension in pregnancy
Drug
Methyldopa (oral)

Action
Central acting

Side-effects
Initial drowsiness

comments
Safe;oral drug of
choice.slow onset of
action.not suitable if

Labetalol

Alpha- and beta-

Postural

history of depression
Widely used in

antagonist

hypotension,tiredness

antenatal setting(oral)
and hypertensive

Hydralazine (oral/i.v.)

Nifedipine (orally/s,

Direct- acting

Parcipitate

crisis (i.v)
Widely used in

vasodilator

hypotension

hypertensive crisis

Calcoium-chanel

Flushing, headaches

(i.v)
Caution interacts

antagonist

with mgSO4. Watch

for precipitous fall in
blood pressure

Prevention
Various preventive stratergie have been employed in women considered to be at risk of
developing pre-eclampsia. The estimated value of these intervention is shown in box 34.4
Box 34.3
Treatment of eclampsia

The patient should be turned onto her left side to avoid aortocaval compression. The

airway should be secured and high-low oxtgen be administered.

Magnesium sulphate (MgSO4) should be administered intravenously to terminate the
seizure and then by intravenous infusion to reduce the chance of further convulsions. The
infusion should be continued for at least 24 hours following delivery or after the last
seizure. MgSO4 can depress neuromuscular transmission and the patient should be
monitored for sign of toxicity. The respiratory rate and patellar reflexes should be
monitored ( reduced patellar reflexes usually precede respiratory depression). If there is
significant respiratory depression, calcium glukonate can be used to reverse the effect of

MgSO4 and consideration given to ventilation.

Urgent delivery is necessary if the seizure has occurred antenatally or intrapartum.
Paralysis and ventilation should be considered if the seizure are prolonged or recurrent.

Box 34.4
Prevention of Pre- eclampsia
Possibly of value

Low-dose aspirin
Calcium supplementation

Not of value

Diet with high protein content

Restriction of salt in diet
Restriction of weight gain
Vitamins C and E
Aspirint inhibits prostaglandin synthesis via cyclooxygenase and the dose of aspirin

required to inhibit thromboxane synthesis is less than that required for prostacyclin inhibition.
Low-dose aspirin should reduce that vasculan and prothrombotic effects of thromboxane A2 in
woman at risk of developing pre-eclampsia. Taking 75% aspirin daily from the firts tremester of
pregnancy leads to a 15% reduction in the incidence of pre-eclamsia. It should be offered to
those woman at high risk of developing pre-eclampsia and should be commenced on or before 12
week gestation.
Calsium supplementation (<1g/day) may olso reduce that risk of hypertension by up to
30% and may reduce the risk of pre-eclampsia by up to 50%. Although calsium supplementation
my reduce the rate of maternal mortality by up to 20%, it has no significant effect on preterm
birth or stillbirth.
The use of antioxidants such as vitamin C and e is not useful for the preventation of preeclampsia. Likewise, restriction of salt intake and limiting weight gain during pregnancy are not
useful in this regard.

HELLP syndrome
Help is the acronym for hemolysis, elevated liver enzymes (particularly transaminases)
and effects up to 12% of those with pre-eclampsia/eclampsia. HELLP syndrome is more
common in multiparous women experiencing pre-eclampsia. Women HELLP syndrome may
present with epigasrtic pain, nausea and vomiting, and right upper quadrant tenderness may be
evident on examination. Aspartate transminase (AST) rises firtst, followed by a rise in lactate
dehydrogenase (LDH). A blood film may show burr cells and polychromasia consistent with
haemolysis, although frank anaemia is uncommon. Platelet tranfusion is only rarely required.
HELLP syndrome is olso associated with acute renal failure and disseminated intravaskular
coagulation (DIC), and there is olso an increased incidence of placental abruption.
The managment of HALLP syndrome is to stabilize the mother, correct any coagulation
disorder, assess fetal well-being and assess the need of delivery. It is generally considered that
delivery is appropriate for moderate or severe cases, but managment my be more concervative
(with close monitoring) if the condition is mild. Vigilance is required for at least 48 hours
postpartum as deterioration in the maternal condition may accur. The risk of recurrence of
HELLP syndrome in subsequent pregnancies is approximately 20%.
Key point

Pre-eclampsia is a multisystem disorder, and is a major cause of maternal and perinatal

morbidity and mortality.

There are two phases; phase 1 is associated with abnormal placentation ang pahe 2 is
characterized by an exaggerated maternal inflammatory response, endothelial dysfuntion

and reduse organ perfusion.

The cure for pre-eclampsia is delivery of the fetus. Antihypertensive therapy does not

fundamentally alter the progress of the condition.

HELLP syndrome is a variant of pre-eclampsia; HELLP is an acronym for haemolysis,
elevated liver enzymes and low platelets.