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Annals of African Medicine Vol.12, No.

2; 2013

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DOI:
10.4103/1596-3519.112395
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Preeclampsia: Areview of the evidence


Page | 75

T. A. Jido, I. A. Yakasai
Department of Obstetrics and Gynaecology, Bayero University/Aminu Kano Teaching Hospital, Kano, Nigeria

Correspondence to: Dr.T. A. Jido, Department of Obstetrics and Gynaecology, Aminu Kano Teaching Hospital,
ZariaRoad, Kano, Nigeria. Email:tukurjido@yahoo.com

Abstract
Preeclampsia is a common complication of pregnancy associated with high maternal and perinatal morbidity
and mortality especially in developing countries. There is considerable progress in the understanding of the
pathophysiology and the management of the diseases, although the aetiology and primary pathology remained
elusive. Integration of current evidence in the clinical management of the condition has witnessed improved maternal
and fetal outcomes in many societies. In developing countries variations in management often not based on current
evidence accounts for comparatively higher morbidity and mortality. This article aims to provide an overview of our
present understanding of preeclampsia help care providers and our managers focus practice and policy to reflect
existing evidence.
Keywords: Evidence, management, preeclampsia

Rsum
La prclampsie est une complication commune des grossesses associes de forts taux de morbidit et mortalit
prinatales, particulirement dans les pays en voie de dveloppement. Des progrs considrables ont t raliss
dans la comprhension de la pathophysiologie et la gestion de cette maladie, bien que ltiologie et la pathologie
primaire en restent encore difficilement cernables. Lintgration des preuves cliniques actuelles dans la gestion de
cette maladie a dmontr une amlioration des rsultats foeto-maternaux dans de nombreuses socits. Toutefois
dans les pays en voie de dveloppement on dnote une morbidit et mortalit comparativement plus hautes - ceci
tant d aux variations et diffrences de gestion de ce problme, gestion peu base sur les rsultats cliniques actuels,
Cet article a pour but de proposer une vue densemble de notre comprhension actuelle de la prclampsie afin
dencourager les prestataires et dirigeants mdicaux adopter une pratique plus cible et prendre les dcisions
qui vont intgrer les rsultats des tests cliniques actuels.
Mots cls: Preuve clinique, gestion, prclampsie

Introduction
Despite lack of complete understanding, preeclampsia
and eclampsia have been recognised and described
many centuries ago. Hippocrates noted that
headaches, convulsions and drowsiness are ominous
signs in association with pregnancy. In his treatise on
gynaecology Varandeous coined the term eclampsia
in 1619.[1] Evidence exist that ancient civilisations
of China, Egypt and India have all recognised and
Annals of African Medicine

described this disease as well as the bleak maternal


and foetal prognosis it portends. Association with
hypertension and proteinuria, the two cardinal features
were noted in mid to late 19thcentury(hypertension)
and the early 20thcentury proteinuria. Delivery was
further identified as the key feature of management
in the 20thcentury. Notwithstanding the extensive
literature and progress in our understanding, these
facts still remains the basis of our management of
preeclampsia and eclampsia.
Vol. 12, April-June, 2013

Jido and Yakasai: Preeclampsia: Areview of the evidence

Page | 76

Hypertension in pregnancy is defined as diastolic


blood pressure(DBP) of 90mmHg or more on
two occasions at least four hours apart or a single
DBP of 110mmHg or more. This may occur in a
patient known to be hypertensive called chronic
hypertension or may arise de novo in an otherwise
normotensive patient often in the second half of
pregnancy in which case it is called pregnancy
induced hypertension or gestational hypertension.
The association of hypertension with significant
protein in the urine constitute preeclampsia.
Significant proteinuria is the presence of 300mg
of protein in the urine collected over24 hours or
30mg/mmol on spot protein:Creatinine ratio. In
semiquantitative assay this correlates with 2+or
more of protein in the urine. When convulsions
occur in the presence of preeclampsia in a patient
with no known seizure disorder the term eclampsia
is ascribed. HELLP syndrome is an acronym for
haemolysis, elevated liver enzymes and low platelets
often seen in association with severe preeclampsia
for which it implies poor prognosis.[2,3]
Ten per cent of all pregnancies are complicated
by hypertension. The incidence of preeclampsia
is 37% in the nulliparous and 13% in the
multiparous.[4] The risk of developing preeclampsia
is 4.1% in the first pregnancy. This however, rises
to 14.7% in the second and 31.9% in the third
pregnancy amongst women with preeclampsia
in all preceding pregnancies. [5] The incidence
of eclampsia on the other hand varies between
developed and developing countries and is in
a way a reflection of the availability, utilisation
and effectiveness of maternity care. In most of
Western Europe and North America the incidence
is 23 per 10000deliveries[6,7] compared to 13 per
1000deliveries in developing countries.[8]

Classification of preeclampsia
The Yorkshire series of severe preeclampsia serve
as a guide for the classification of preeclampsia.[9]
Asimplified version of the inclusion criteria is presented
in Table1. It is important to bear in mind that the
criteria is subjective and events may progress rapidly
such that women should be managed based on careful
assessment rather than a set criteria.
The Cochrane library and the Cochrane register
of controlled trials, PUBMED and Medscape

were searched for relevant metaanalyses,


systematic reviews, randomised controlled trials
and articles as appropriate. Search terms used
include: Preeclampsia, hypertensive disorders of
pregnancy, pregnancy toxaemia, pregnancy induced
hypertension, eclampsia, eclampsia in resource poor
countries.

Aetiology and risk factors


The aetiology of preeclampsia is not known. Various
risk factors have been impugned mostly bordering
on genetic, immunologic factors. Mechanisms
through which these factors cause preeclampsia are
the subjects of many studies and will be considered
in detail under pathophysiology. Risk factors can be
broadly classified into general, pregnancy related
and underlying medical conditions[Tables2 and 3].

Pathophysiology
Although the primary pathology leading to
preeclampsia is still to be defined, complex
pathophysiologic pathways and mechanisms have
been described. These are closely intertwined
and appear to be triggered by the presence of
placental tissue. Women with hydatidiform mole
present with preeclampsia in the absence of fetus.
Placental studies consistently showed aberrant
uterovascular development of the placental bed.
At the core of this is a complete or partial failure
of trophoblastic invasion of the myometrium and
the spiral arteries resulting in muscular vasculature
in the placental bed that is responsive to vasoactive
substances.
This deficiency in trophoblastic invasion is now
known to be as a result of a defective interaction
between trophoblastic cells and uterine natural killer
cells. The same mechanism also releases tumour
necrosis factor alpha(TNF) into the circulation.
Other factors involved in this immunologic
pathway at the level of the placenta are maternal
killer immunoglobulin like receptors and fetal
HLAC molecules.[10] In vitro placental studies
using metallopeptidase ADAM 17 led to increase
production of TNF in preeclamptic placentae
compared to normotensive women.[11] Interactions
between these factors seem to fail in preeclampsia
resulting in deficiency in trophoblastic invasion of
the myometrium and high pressure narrow calibre
vessels.[12]

Table 1: Classification of severity of preeclampsia


Category
Mild
Moderate
severe

Blood pressure
140-149/90-99 mmHg
150-159/100-109 mmHg
160/110 mmHg or more

Proteinuria
0.3 g/24 hrs
0.3 g/24 hrs
1 g/litre

Symptoms
None
None
present

Biochemistry
Normal
Normal
Abnormal

Haematology
Normal
Normal
Abnormal

Symptoms = Severe headache, visual disturbance, nausea, vomting, sudden facial, digital, and pedal swelling, hyperreflexia, ankle clonus.
Biochemistry = ALT >70IU/L and/or AST >70IU/L. Haematology = Platelets less or equal to 100 109/L

Vol. 12, April-June, 2013

Annals of African Medicine

Jido and Yakasai: Preeclampsia: Areview of the evidence

Page | 76

Hypertension in pregnancy is defined as diastolic


blood pressure(DBP) of 90mmHg or more on
two occasions at least four hours apart or a single
DBP of 110mmHg or more. This may occur in a
patient known to be hypertensive called chronic
hypertension or may arise de novo in an otherwise
normotensive patient often in the second half of
pregnancy in which case it is called pregnancy
induced hypertension or gestational hypertension.
The association of hypertension with significant
protein in the urine constitute preeclampsia.
Significant proteinuria is the presence of 300mg
of protein in the urine collected over24 hours or
30mg/mmol on spot protein:Creatinine ratio. In
semiquantitative assay this correlates with 2+or
more of protein in the urine. When convulsions
occur in the presence of preeclampsia in a patient
with no known seizure disorder the term eclampsia
is ascribed. HELLP syndrome is an acronym for
haemolysis, elevated liver enzymes and low platelets
often seen in association with severe preeclampsia
for which it implies poor prognosis.[2,3]
Ten per cent of all pregnancies are complicated
by hypertension. The incidence of preeclampsia
is 37% in the nulliparous and 13% in the
multiparous.[4] The risk of developing preeclampsia
is 4.1% in the first pregnancy. This however, rises
to 14.7% in the second and 31.9% in the third
pregnancy amongst women with preeclampsia
in all preceding pregnancies. [5] The incidence
of eclampsia on the other hand varies between
developed and developing countries and is in
a way a reflection of the availability, utilisation
and effectiveness of maternity care. In most of
Western Europe and North America the incidence
is 23 per 10000deliveries[6,7] compared to 13 per
1000deliveries in developing countries.[8]

Classification of preeclampsia
The Yorkshire series of severe preeclampsia serve
as a guide for the classification of preeclampsia.[9]
Asimplified version of the inclusion criteria is presented
in Table1. It is important to bear in mind that the
criteria is subjective and events may progress rapidly
such that women should be managed based on careful
assessment rather than a set criteria.
The Cochrane library and the Cochrane register
of controlled trials, PUBMED and Medscape

were searched for relevant metaanalyses,


systematic reviews, randomised controlled trials
and articles as appropriate. Search terms used
include: Preeclampsia, hypertensive disorders of
pregnancy, pregnancy toxaemia, pregnancy induced
hypertension, eclampsia, eclampsia in resource poor
countries.

Aetiology and risk factors


The aetiology of preeclampsia is not known. Various
risk factors have been impugned mostly bordering
on genetic, immunologic factors. Mechanisms
through which these factors cause preeclampsia are
the subjects of many studies and will be considered
in detail under pathophysiology. Risk factors can be
broadly classified into general, pregnancy related
and underlying medical conditions[Tables2 and 3].

Pathophysiology
Although the primary pathology leading to
preeclampsia is still to be defined, complex
pathophysiologic pathways and mechanisms have
been described. These are closely intertwined
and appear to be triggered by the presence of
placental tissue. Women with hydatidiform mole
present with preeclampsia in the absence of fetus.
Placental studies consistently showed aberrant
uterovascular development of the placental bed.
At the core of this is a complete or partial failure
of trophoblastic invasion of the myometrium and
the spiral arteries resulting in muscular vasculature
in the placental bed that is responsive to vasoactive
substances.
This deficiency in trophoblastic invasion is now
known to be as a result of a defective interaction
between trophoblastic cells and uterine natural killer
cells. The same mechanism also releases tumour
necrosis factor alpha(TNF) into the circulation.
Other factors involved in this immunologic
pathway at the level of the placenta are maternal
killer immunoglobulin like receptors and fetal
HLAC molecules.[10] In vitro placental studies
using metallopeptidase ADAM 17 led to increase
production of TNF in preeclamptic placentae
compared to normotensive women.[11] Interactions
between these factors seem to fail in preeclampsia
resulting in deficiency in trophoblastic invasion of
the myometrium and high pressure narrow calibre
vessels.[12]

Table 1: Classification of severity of preeclampsia


Category
Mild
Moderate
severe

Blood pressure
140-149/90-99 mmHg
150-159/100-109 mmHg
160/110 mmHg or more

Proteinuria
0.3 g/24 hrs
0.3 g/24 hrs
1 g/litre

Symptoms
None
None
present

Biochemistry
Normal
Normal
Abnormal

Haematology
Normal
Normal
Abnormal

Symptoms = Severe headache, visual disturbance, nausea, vomting, sudden facial, digital, and pedal swelling, hyperreflexia, ankle clonus.
Biochemistry = ALT >70IU/L and/or AST >70IU/L. Haematology = Platelets less or equal to 100 109/L

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Annals of African Medicine

Jido and Yakasai: Preeclampsia: Areview of the evidence

Table 2: General risk factors for preeclampsia


Risk factor
Primigravida
Young maternal age
Maternal age >35 years
Low socioeconomic class
Family history
Multiple pregnancy
Others

Table 3: Medical conditions predisposing to


preeclampsia
Obesity
Chronic hypertension
Renal diseases
Thrombophylia
Gestational diabetes
Vascular and connective tissue diseases
Systemic lupus erythematosus

This in turn leads to microtrauma at the level of the


placenta with release in to the circulation of placental
fragments. These fragments causes systemic
inflammatory reaction, activation of leucocytes and
platelets which further increases the inflammation,
releases free radicals and causes vascular endothelial
damage and vascular dysfunction.[13] Thus defective
trophoblastic invasion causes placental insufficiency,
abnormal fetal growth and placental damage leading
to systemic inflammatory response. [14] This in
turn causes vascular endothelial dysfunction and
damage which clinically manifest as hypertension,
proteinuria and other systemic responses.
Recent molecular studies attributed vascular
endothelial dysfunction in preeclampsia to the
loss of vascular endothelial growth factor(VEGF).
Cancer patients on treatment with VEGF inhibitors
elicit symptoms of preeclampsia like syndrome
in the absence of trophoblast. The mechanism
through which production of VEGF is inhibited in
preeclampsia is mediated through the elevated levels
of fmslike tyrosine kinase 1(sFlt1), a potent VEGF
inhibitor.[1517] Cigarette smokers who are known
to have elevated levels of sFlt1 have incidence of
preeclampsia which is a third lower than general
population. However adverse effects of smoking
like preterm labour, intrauterine growth restriction
and placental abruption more than compensated for
this benefit.[18]
On its own vascular endothelial dysfunction
causes proteinuria, increase capillary permeability
and oedema. Resulting cerebral hypoxia and
oedema leads to eclamptic seizures. In the liver
periportal necrosis and parenchymal damage result
in elevated enzymes and haemolysis. Autopsy
findings in eclamptic patients support the model
Annals of African Medicine

of cerebral oedema, ischaemia, fibrinoid necrosis


and encephalopathy.[1]

Diagnosis and prognosis


The diagnosis and prediction of outcome for mother
and fetus are most of the time taken in a single breath
and will be discussed hand in hand with specific
emphasis on the present evidence.
Page | 77

Proteinuria is a specific feature of preeclampsia and


in the presence of hypertension it is the criterion
standard upon which the diagnosis hinges. It is
a result of characteristic pathological changes in
the glomeruli that are consistent in all patients
with preeclampsia.[19] Here there is swelling of the
glomerulus due to glomerular cellular tuft oedema
which encroaches on the lumen of glomerular
capillaries resulting in ischaemia and increase in
permeability to protein.
Standard urine dipstick is used for screening of
proteinuria. Quantification of protein in 24 hour
urine collection or spot protein:Creatinine ratio
confirms the diagnosis. The degree of proteinuria
and maternal age correlates with adverse maternal
outcome, increase obstetrics interventions and
low birth weight. Intrapartum fetal distress and
recurrent late decelarations are also increased with
rising proteinuria. Similarly massive proteinuria
defined as protein >10 g/24h is associated with
early onset preeclampsia, early gestational age at
delivery, and prematurity.[20] However in terms of
fetal outcome once this is controlled for prematurity
there are no associated adverse events seen with
proteinuria hence it is the prematurity that is the
cause of all adverse events and not the degree of
proteinuria. Arecent systematic review concluded
that the level of proteinuria does not correlate
with maternal and fetal outcome.[21] The national
institute of health and clinical excellence(NICE),
recommend that once proteinuria is diagnosed there
is no benefit in repeating the test.[22] This certainly
seems to fly the face of present clinical practice.
Data from the preeclampsia integrated estimate of
risk study(PIERS) concluded that urine dipstick
test perform as well as protein:Creatinine ratio
and 24urine collection in predicting maternal
outcome[23] with similar cautioned that proteinuria
should not be used in isolation for decision making
in women with preeclampsia.
Preeclamptic toxaemia screen refers to a panel of
blood test carried out once the diagnosis is suspected
with a view to assess the multiorgan nature of
the condition. These include full blood count in
particular platelets count, renal function test, liver
function test and coagulation screen. It is pertinent
Vol. 12, April-June, 2013

Jido and Yakasai: Preeclampsia: Areview of the evidence

to bear in mind that the clinical value of these tests


in assessing maternal fetal outcome or progression
to eclampsia remains very little in the absence of
proteinuria.

Page | 78

Like proteinuria, uric acid is a specific feature of


preeclampsia, but its value in predicting maternal and
fetal outcome remains very tenuous. Asystematic
review involving 2000patients from 23 studies
using a threshold of 360 mol/l or more showed
that the likelihood ratio of disease progression
to eclampsia was 2.1, severe hypertension 1.7,
caesarean section2.4, stillbirth and neonatal
death1.5 and small for gestational age 1.3 leading to
the conclusion that the use of therapeutic measures
such as planning delivery or magnesium sulphate
on this basis is not to be justified.[24]
Similarly serial blood sampling had no predictive
value on disease progression. However, low
platelets count less than 100109/L, raised liver
transaminases and creatinine>110 mcmol/L are
each associated with adverse maternal outcome.[25,26]
The PIERS study enrolled 2008 women with
preeclampsia, 1053 had abnormal liver function test.
The odds of having adverse maternal outcome were
higher in women with any abnormal liver function
test than in those with normal results. Similarly
when results were stratified into quartiles, there
was positive correlation with the higher quartiles
for aspartate and alanine transaminases as well as
lactate dehydrogenase and the lower quartiles for
albumin.[25] However neither change of LFT result
within 48 hrs of admission or from admission to
delivery nor the rate of change was predictive of
adverse outcome.
The odds of abnormal coagulation were increased in
women with platelet count less than 50109/L(OR
7.78, 95% CI 3.3618.03) and 5099109/L(OR
2.69, 95% CI 1.445.01) compared to counts
150109/L. Platelets count less than 100109/L
has good specificity 92% but low sensitivity 22% for
predicting adverse maternal out come and should
therefore not be used in isolation for decision
making in patients with preeclampsia.[26] In the
presence of normal platelets count coagulation
screen does not add any value to these parameters.
A retrospective analysis of 111 preeclamptics
in Sweden shows correlation of diastolic blood
pressure with HELLP syndrome, Oliguria,
eclampsia and placental abruption. Furthermore
the last CEMACH report supports the association
of systolic hypertension with cerebrovascular
haemorrhage.[27]
The PIERS was recently commissioned to
Vol. 12, April-June, 2013

develop a model to identify the risks of fatal or


life threatening complications in women with
preeclampsia admitted to tertiary institutions within
48 hours of admission in Australia, NewZealand
and Canada. The main outcomes are maternal
mortality and other serious complications. Of the
total 2023 women enrolled in the study, 261 had
adverse maternal outcomes (106or 5% within
48 hrs of admission). The predictors of adverse
outcome included: Gestational age at admission,
chest pain or dyspnoea, low oxygen saturation, low
platelet count, creatinine and aspartate transaminase
concentrations.[28]

Treatment
Pharmacological treatment of preeclampsia is
limited to symptomatic control of blood pressure
and seizure prophylaxis. In treating blood pressure
extensive evidence has accumulated over the
years on the safety and efficacy of the blocker
labetalol, presently considered first choice and with
which effective control can be achieved in 80%
of preeclamptic patients.[9,22] Labetalol however is
contraindicated in severe asthma and has tendency
for resistance among AfroCaribbean women.
Alternatives in the form of calcium channel
blocker nifedipine and alpha methyldopa are safe
and effective. There is consistent evidence on the
efficacy of antihypertensives in reducing blood
pressure to a significant level. In preeclampsia this
is not paralleled with improved perinatal outcome.
Maternal morbidity and mortality as well as
gestational age at delivery are improved. Sibai etal.
in a study of 200 primigravidae with mildmoderate
preeclampsia showed that labetalol reduces the
blood pressure, prolonged gestational age at delivery
but no improvement in perinatal outcome.[29]
Commencing antihypertensive treatment in
severe hypertension is an established norm in
clinical practice and it is for this much of the
evidence in improved maternal morbidity and
the gestation at delivery benefits exist.[30,31] The
objective of therapy is DBP 80100mmHg
and SBP less than 150mmHg.[22] Treatment of
moderate hypertension(DBP 100109mmHg,
SBP 150159mmHg) has recently been shown to
reduce progression to severe preeclampsia, reduce
maternal morbidity and prolonged gestational age
at delivery. Perinatal outcome remained the same
after controlling for prematurity with increased risk
of impaired fetal growth.[31] Despite the agreement
on the need for no treatment in mild preeclampsia
in clinical parlance the evidence base for this
recommendation remains sparse.
The tradition that based antihypertensive treatment
in pregnancy on the diastolic blood pressure is
Annals of African Medicine

Jido and Yakasai: Preeclampsia: Areview of the evidence

still prevalent. The centre for maternal and child


enquiries latest report is however instructive that
the most consistent failing in the clinical care for
women with severe preeclampsia is the inadequate
treatment of systolic hypertension on the erroneous
notion that diastolic hypertension correlates more
with maternal morbidity and mortality. Ten of
the 18 deaths related to preeclampsia in the last
triennium had fatal intracranial haemorrhage.
This type of haemorrhage and aortic dissection are
known to correlate more with systolic hypertension.
Furthermore evidence from pregnant women with
stroke is supportive of this hypothesis regardless of
ischaemic or haemorrhagic nature of the stroke.[32]
Current recommendation is for treatment of systolic
hypertension of 150mmHg or more.
NICE recommend the admission of patients for
blood pressure control and monitoring, testing
for proteinuria and preeclamptic toxaemia screen.
Blood pressure should be monitored at least four
times in 24h and treatment will depend on the
severity. Once proteinuria is identified further
quantification is not recommended. The frequency
of blood test in mild preeclampsia is twice a week
and three times in moderate to severe disease.[22]

Seizure prophylaxis and control


The role of magnesium sulphate in control
and prophylaxis of eclamptic seizures is well
established.[33,34] Its long term safety for mother
and baby is also proven.[35] So far the evidence for
prophylaxis is based on data among patients with
severe preeclampsia.[36] The evidence for the efficacy
of magnesium sulphate in seizure control dates back
to the 1920s in tetanus patients. Its widespread use
in obstetrics practice followed the publication of the
collaborative eclampsia trial in 1995. The magpie trial
examined its efficacy in seizure prophylaxis among
patients with preeclampsia. Recent Cochrane review
established its superiority over other anticonvulsants
with reference to control, prevention, recurrence of
seizure as well as maternal and fetal morbidity and
mortality.[37,38] Mechanism of action for this effect is
not known. The regimen for its administration has
been the subject of many researches but evidence
and experience are based mostly on the regimen
used in the collaborative eclampsia trial.[33] In this a
loading dose of 4g intravenously over510minutes
is followed with maintenance dose of 1g/hr for
24hrs. Recurrent seizures are treated with a further
bolus of 2g or increasing the infusion rate to 2g/hr.
The magnesium sulphate for prevention of
eclampsia(MAGPIE) trial involved 10141patients
with preeclampsia from 33 countries randomised
to magnesium or placebo in an intension to treat
randomised control trial(RCT) designed with
Annals of African Medicine

eclamptic convulsion as its main outcome. The


women in the magnesium arm had 58% lower
risk of progressing to eclampsia(95% CI=4071)
compared to the placebo group.
Safety of magnesium sulphate in the treatment
of preeclampsia and eclampsia is reported by
the Magpie study group18months and 2years
after.[39] At two years of follow up there were on
clear differences between the randomised groups
in childs behaviour, womens fertility and use of
health care services.[40]

Fluid and electrolyte management


This is the aspect of preeclampsia where limited
clinical evidence exists in the literature. Much of
existing guidance and recommendation are based
on consensus and retrospective reports. Despite
high rates of oedema preeclamptics have contracted
intravascular volume and high peripheral resistance,
poor fluid management is a recognised factor in
the death of women with severe preeclampsia
and eclampsia mostly resulting from pulmonary
oedema. These lead to the recommendation
for early senior obstetrician and anaesthetist
involvement in the management of these patients.[41]
The implementation of this has lead to marked
improvement in mortality from this cause in the
succeeding triennia 20032005 and 20062008.[42]
Current recommendation is for total intake of fluid
of not more than 1ml/kg/hr or 80ml per hour.
Input and output should be carefully monitored
and patients with complications should have central
venous pressure(CVP) monitoring where possible
to allow for optimal volume replacement. ACVP of
5mmHg indicate sufficient intravascular volume in
the absence of heart disease. Most patients on this
treatment will have transient postpartum oliguria.
The recommendation is to allow for urine output
less than 20ml/hr for up to 8 hrs before instituting
interventions. Volume expansion to improve urine
output is to be very carefully considered in women
with severe preeclampsia. This guideline has been
shown to be effective in temperate climes, whether
the same protocol will benefit patients in the tropics
remains to be tested and forms an area for further
research.

Fetal monitoring
The association of preeclampsia with adverse
fetal outcome, increased perinatal morbidity and
mortality is responsible for the evaluation and
employment of various biometric and biophysical
parameters to select fetuses that would benefit from
early delivery, intrauterine intervention or further
monitoring. Growth monitoring identifies the fetus
whose growth is impaired. Assessment of liquor
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Page | 79

Jido and Yakasai: Preeclampsia: Areview of the evidence

volume to assess fetal wellbeing[43] can be achieved


by amniotic fluid index or measurement of single
deepest vertical pool. Comparison between these
measures showed no difference with respect to
neonatal intensive care admission, caesarean section,
meconium staining of the liquor amnii, Apgar score
less than 7 at 5minutes, arterial cord pH less than
7.1 or perinatal death.[44]
Page | 80

Biophysical profile assessment showed no


significant difference in terms of neonatal care
unit admission or perinatal death when compared
to cardiotocography. There is tendency towards an
increase caesarean section.[45]
In a systematic review of RCTs Westergaad etal.
assessed the role of uterine artery Doppler in women
with high risk pregnancy compared to no Doppler
or routine monitoring. The use of Doppler was
associated with significantly less perinatal morbidity
and mortality, helps in deciding the time for delivery,
reduce rates of induction of labour, emergency
caesarean section, antenatal admission and low
apgar scores in 5minutes. The absence or reversal of
endiastolic flow correlated with neonatal morbidity
and mortality.[46]

Delivery
As delivery remained the definite treatment for
preeclampsia its timing in relation to the gestational
age is the critical consideration if increased foetal
morbidity and mortality due to prematurity is
not to be traded for maternal safety. Naturally
two groups of patients emerge on the basis of this
consideration, the early onset severe preeclampsia
prior to 34 completed weeks and those thereafter.
In both cases the primary goal of treatment involves
the stabilisation of patients with antihypertensive
therapy, seizure prophylaxis and in the early cases
administration of steroids to enhance lung maturity.
The hypertension and preeclampsia intervention
trial in the almost term patient(HYPITAT)
addressed the timing of delivery in preeclampsia
after 36weeks[47] where a policy of induction of
labour is favoured to reduce maternal morbidity
and caesarean section rate without a compromise
to neonatal outcome. There is no statistically
significant increase in maternal morbidity or
immediate neonatal morbidity with immediate
delivery after 37weeks. This approach is adopted by
NICE who recommend delivery after 37weeks in
severe preeclampsia. Asimilar trend is observed in
practice with mildmoderate preeclampsia although
the evidence base is less robust.[22]
Sibai etal. randomised patients with early onset
severe preeclampsia in to early delivery and
Vol. 12, April-June, 2013

expectant management. The early delivery groups


are stabilised as described above and delivery is
planned for 48 hours after steroids. In the expectant
group patients are conservatively managed and
delivery planned for after 34weeks except in the
event of deteriorating maternal or fetal condition.[48]
The early delivery group show significant increase
in respiratory distress syndrome and necrotising
enterocolitis. There was no difference in stillbirth,
neonatal death or caesarean section rates. Expectant
management is therefore justifiable to 34weeks in
severe preeclampsia, however beyond this gestation
there is no benefit seen. The gestation window
between 34weeks and 36 completed weeks is the
subject of current HYPITATII, the outcome of
which is eagerly awaited.[49]
Mode of delivery depends on clinical and obstetrics
circumstances and patients preference.

Postpartum management
Although delivery is the definitive treatment of
preeclampsia more eclamptic convulsions are
seen in the postpartum than before or during
labour in many countries in the world. Careful
monitoring of blood pressure in the immediate
postpartum is recommended by NICE in patients
with preeclampsia. [22] For some patients the
postpartum period is when antihypertensives are
required. Delivery brings about large volume
shift, vasoconstriction, increase osmolality and
hypercoagulability to aid the rapid physiologic
changes characteristic of the period. Most eclamptic
seizure occurs in the first 2448 hours of delivery,
seizure prophylaxis should therefore continue for
up to 24 hours postpartum.[50] Antihypertensive
treatment is commenced with blood pressure of
150/100mmHg and the goal remains the same
as in the prepartum period. Toxaemia screening
may be required for up to 72 hours, there is
no benefit in repeating it if it is normal. Rarely
elevated liver enzymes, thrombocytopenia persists
beyond this period with renal insufficiency.
These should herald the consideration for
haemolytic ureamic syndrome(HUS) and/or
thrombotic thrombocytopenic purpura(TTP)
and inform treatment with corticosteroids and
plasmapheresis.[51] Once the blood pressure is
maintained below 150/100mmHg for 24 hours
patients that are not symptomatic who have
acceptable toxaemia screen can be discharged to
community care.
A debriefing with the team leading in her care is
recommended in the case of eclampsia, severe
preeclampsia, delivery before 34weeks, HELLP
syndrome or adverse perinatal outcome. The focus
Annals of African Medicine

Jido and Yakasai: Preeclampsia: Areview of the evidence

of this should address the main event that has


occurred as well as advise the patient on her risk
in subsequent pregnancy. Women with high BMI
should be advised to optimise this before the next
pregnancy. Where delivery was necessitated before
34weeks the risk of recurrence of preeclampsia
is 25% and risk increases to over50% if delivery
before 28weeks.[52] Prepregnancy care and low
dose aspirin in early pregnancy is recommended.
In patients with background chronic hypertension
eventual discharge to general practice at 6weeks is
the normative practice.

Prevention
The limitation in our understanding of the
pathophysiology of preeclampsia means that its
prevention has been the subject of many studies. The
evidence so far seems to favour antiplatelet agents of
which most relates to low dose aspirin. ACochrane
systematic review of 59 trials including 37560 women
concluded that antiplatelet agents reduce the risk of
preeclampsia by 17%(RR 0.83; 95% CI:0.770.89;
NNT 72) with increasing benefit in the higher risk
group.[53] In high risk women(previous preeclampsia,
chronic hypertension, diabetes mellitus, chronic
renal disease, autoimmune diseases including
antiphospholipid antibodies) the risk reduction
increases to 25%, with 19 needed to treat(95% CI
3415%). Ahundred and nineteen women needed
to be treated in moderate risk group to achieve a
risk reduction of 14%(95% CI 21%5%). Patients
in this category are primigravidae, aproteinuric
mild hypertension, positive roll over test, abnormal
uterine artery Doppler, multiple pregnancy, teenage
and family history of preeclampsia.
Recent systematic review by Trivedi which
included 19 trials showed no benefit with low dose
aspirin in 16550 low risk women(RR 0.86; 95%
CI:0.641.17) and 21% risk reduction in 11687 high
risk women(RR 0.79; 95% CI: 0.650.97).[53] Rossi
etal. on the other hand showed no benefit in both
high risk(P=0.05; OR: 0.72; 95% CI: 0.511.0)
and low risk groupP=0.10; OR: 0.82; 95% CI:
0.631.12).[54]
Antiplatelet agents also reduce the risk of preterm
birth in preeclampsia(RR: 0.92; 95% CI: 0.880.97;
NNT 119); fetal and neonatal death(RR: 0.86; 95%
CI: 0.760.98; NNT 243) and small for gestational
age(RR: 0.90; 95% CI: 0.830.98).[55] Antiplatelet
agents are safe and cheap and therefore cost effective.
The NICE recommend their use from 12weeks
until delivery in high risk women(previous
preeclampsia, chronic renal disease, autoimmune
diseases including APS, diabetes mellitus and
chronic renal disease and chronic hypertension).
Annals of African Medicine

They further recommend the prophylaxis in patients


with BMI>35, first pregnancy, interpregnancy
interval>10years, those over40years, family
history and multiple pregnancy. An audit of this
practice will guide future recommendations on
antiplatelet agents.
There is large body of research on nutritional
supplements for the prevention of preeclampsia.
Supplements that have been evaluated are folic acid,
antioxidant vitamins, fish oil, garlic, magnesium and
calcium.[22] A Cochrane review of 12 RCT involving
15206patients confirm the ineffectiveness of all
except calcium which show some benefit in high
risk patients and those from communities with low
dietary calcium.[56] Overall women receiving calcium
supplementation had 50% reduction in incidence of
preeclampsia compared to a placebo group(RR
0.48; 95% CI 0.350.69). Further subgroup analysis
showed a 32% risk reduction amongst low risk
women n=14619;(RR 0.68; 95% CI 0.490.94)
and 78% risk reduction among high risk women
n=587;(RR 0.2295% CI 0.120.42). Thus the
evidence support supplementation amongst high
risk women in areas with low dietary calcium but
no statistical benefit is elicited in low risk women
with adequate dietary calcium intake.[56]
A single small RCT evaluated the role of low
molecular weight heparin which is shown to
be beneficial in patients with systemic lupus
erythematosus and APS in observational studies.
This showed a risk reduction(RR: 0.26; 95%
CI:0.080.86) which is impressive. This trial was
however criticised on its very high selectivity.
The patients were selected on the basis of history
of preeclampsia and possession of angiotensin
converting enzyme DD genotype.[57]
Historically diuretics were tried without success
with potential hazard of blood volume reduction
and adverse pregnancy outcome. Their role today
is limited to the treatment of severe pulmonary
oedema. Similarly Cochrane concluded that there is
no clear evidence for progesterone and the evidence
for nitric oxide agents(Larginine and glycerine
trinitrate) is insufficient for recommendation.[58]

Eclampsia
Eclampsia, the occurrence of new onset grand mal
seizures or unexplained coma in association with
signs and symptoms of preeclampsia is the most
serious complication of preeclampsia for which
high rates of maternal and perinatal morbidity and
mortality are reported. Rarely eclampsia occurs
without proteinuria(38%) and hypertension in16%.
The incidence of eclampsia in the Netherlands
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Jido and Yakasai: Preeclampsia: Areview of the evidence

was 6.2 per 10000 deliveries compared to 1.3%


of deliveries in parts of Nigeria. Similarly the
case fatality is higher in developing compared to
developed countries. Of the 63000 maternal deaths
annually attributed to preeclampsia and eclampsia
worldwide most are in the developing world. Of
112maternal deaths reported from Northern
Nigeria 46.4% were in eclamptic patients.[59]
Page | 82

Like the precursor preeclampsia the pathophysiology


of eclampsia remains speculative. However the
convulsions are attributed to diffuse cerebral
oedema, ischaemia and infarction based on CT
scan and autopsy findings.[1]
Eclamptic seizures last 6075seconds are grand
mal in nature. Starts with distortion of the face,
protrusion of the eyes and foaming of the mouth,
the respiration ceases and the body is rigid. This is
followed by generalised muscular contraction that
commences from the jaws, face and the eyelids and
spreads to the whole body in a sequence of strong
contractions alternating with relaxation. The patient
eventually lapsed into coma or unconsciousness
for variable period and has no recollection of the
preceding events.
Events leading to eclamptic convulsions have been
studied with a view to predicting and preventing the
seizures. Headache is the most consistent symptom
in 83% of patients, visual disturbance and right
upper quadrant or epigastric pain are noted in 44%
and 19% of patients respectively.
Hypereflexia was seen in 52% of patients while
others contend that the presence of ankle clonus is
more predictive of eclamptic seizures.[1,9] It is not
surprising that present strategy for prevention of
seizures seek to treat all cases of severe preeclampsia
with magnesium sulphate since the efficacy of the
drug was elicited in the MAGPIE trial.
Clinical management of eclampsia to avert maternal
mortality should be based on a drill that prevent
the patient from injury during convulsions while
maintaining a patent airway, suction of vomits and/or
excess secretions, administration of oxygen, control
of convulsions with magnesium sulphate, control
of hypertension, fluid management, monitoring
and the delivery of the patient when stable. These
measures can easily be achieved in the hospital
setting where skill, facilities and consumables are
available. In most instances in developing countries
however, eclamptic convulsions occur out with the
health facility and no skilled attendance is at hand
to administer established interventions. Details
of treatment of eclamptic convulsions including
recurrent seizures and blood pressure have been
Vol. 12, April-June, 2013

covered under treatment. When seizures persist


despite repeat dose of magnesium sulphate the next
line of action is diazepam in a slow intravenous dose
of 10mg and status eclampticus warrants treatment
with sodium thiopentone. This last measure will
require intubation and airway management and
should be decided in concert with the anaesthetist.[60]

HELLP syndrome
The occurrence of microangiopathic haemolysis,
elevated liver enzymes and low platelets is a
serious complication of pregnancy associated with
statistically significant increase in maternal and
fetal morbidity and mortality. The syndrome is
seen in 0.5%0.9% of pregnancies and 10%20% of
patients with severe preeclampsia.[61] Hypertensive
patients with the condition tend to be parous
with relatively mild to moderate hypertension.
Diagnosis is based on evidence of haemolysis,
raised liver enzymes and low platelets. However
respective thresholds for these parameters vary
between reports. Martin define haemolysis on
the basis of progressive anaemia, raised lactate
dehydrogenase>600IU/L; alanine transaminase
and aspartate transaminase>40IU/L and platelets
count less than 150000/mm.[62] Sibai[63]employed
LDH of 700IU/L, AST>70IU/l and platelets less
than 100000/mm3. The Mississipi classification
recognised three classes based on platelet counts
of 50000/mm 3, 100000/mm, and 150000/mm 3
respectively.[62]
Acute fatty liver is the main differential
diagnosis. In addition to the features of HELLP
syndrome hypoglycaemia, hyperammonaemia,
hypofibrigenaemia and prolonged partial
thromboplastin time points to acute fatty liver. If
in doubt the application of the Swansea criteria aids
the identification of the later condition.[64,65]
Corticosteroids used in the treatment of HELLP
syndrome improve the platelets count but have no
clear effect on maternal and foetal outcomes.[50]
Cochrane review of 550patients from 11 trials
showed no clear effect in reduction of maternal
death(RR: 0.95; 95% CI: 0.283.21), maternal
death and severe maternal morbidity(RR:0.27;
95% CI:0.032.12) and perinatal or infant
death(RR:0.64; 95% CI: 0.211.97).[66] Routine
use of steroids is not recommended for the
treatment of this condition. Delivery remained
the definitive treatment. This may be at a very
preterm gestation where the fetal role for steroids
still remained valid.
Maternal complications include acute renal
failure, hepatic failure, disseminated intravascular
Annals of African Medicine

Jido and Yakasai: Preeclampsia: Areview of the evidence

coagulation, pulmonary oedema, cerebrovascular


haemorrhage and infection. Preterm delivery may
be seen in up to 70% of cases and is at less than
28weeks in 15%. Prematurity is therefore common
and perinatal mortality is in the region of 14.1%.[67]

Challenges in the management of preeclampsia


in resource poor setting
Developing countries, where resource constraints in
maternity care abound correspond with areas of high
incidences of preeclampsia and eclampsia. Relatively
high incidences are attributed to biological factors
among the negroid population but more importantly
epidemiologic determinants such as high rates
of early child bearing, inadequate antenatal care
services and gross underutilisation of available ones
contributes to the high morbidity and mortality
associated with the disease.[1,8] Reports of eclampsia
from developing countries universally concur on
the absence of antenatal care attendance among the
patients.[8,68] Although doubts have been expressed
with regards to the capacity of antenatal screening
to adequately sieve out all cases of preeclampsia
and treat them before any complications. Assuming
similar incidences of preeclampsia the variations in
the rates of eclampsia can only be attributed to the
differences in early detection and management of
preeclampsia.
Factors responsible for non utilisation of services
are well enunciated and varying strategies
proposed, yet the most impact is seen where user
fees are abrogated.[69,70] The improved attendance
witnessed is not matched by reduction morbidity
and mortality. These partly is because of late
presentation often in the wake of complications
like eclampsia, inadequate resource allocation, poor
and non programmatic application of the limited
resources and maldistribution of expertise with
most concentrated in teaching and tertiary centres
away from where the vast majority of maternities
occur. The poor state of midwifery services means
that care is often medically driven with associated
cost and accessibility implications.

result there is lack of uniformity in the standard


of care that is provided such that the impact of
scientific and clinical advances are incoordinated
and often takes a long time to translate clinical
care. We concur with others that improvement in
maternal and perinatal outcomes in preeclampsia
demands the multidisciplinary management of the
disease based on clearly designed protocols that
integrate current evidence in the context of resource
availability.[68,71]

Conclusion
Over the years knowledge and understanding of
preeclampsia have progressed considerably. The
evolution in clinical management of the disease
has positively impacted on the maternal and fetal
morbidity and mortality. However, the gap in
unravelling its pathophysiology means that treatment
is still symptomatic; delivery remained the main
therapy and screening and preventive measures
elusive. Standardisation of management offers the
benefit in improving maternal outcome especially in
the developing world. Future focus at more precise
prediction and prevention of disease should form
the basis of research. Specific measures in improving
fetal growth dysfunction and preventing prematurity
would positively impact on perinatal outcome.

Acknowledgement
Miss Leila M for French translation of abstract.

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Cite this article as: Jido TA, Yakasai IA. Preeclampsia:
A review of the evidence. Ann Afr Med 2013;12:75-85.
Source of Support: Nil, Conflict of Interest: None
declared.

Vol. 12, April-June, 2013

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