Download Eclampsia HELLP Low Platelets

Pre-eclampsia, Severe Pre-eclampsia and
Hemolysis, Elevated Liver Enzymes and
Low Platelets Syndrome
What Is New?
Etienne Ciantar; James J Walker
Posted: 09/14/2011; Women's Health. 2011;7(5):555-569. © 2011 Future
Medicine Ltd.
Abstract and Introduction
Abstract
Pre-eclampsia and eclampsia have been known to us for centuries.
Significant improvements have been made in our knowledge of the
disease, however, delivery remains the only effective form of treatment.
There is widespread variation of practice in the management of
hypertensive disease in pregnancy, which may lead to substandard
care. The use of aspirin in preventing pre-eclampsia, the lack of
correlation between urinary protein and adverse outcome, and the
ineffectiveness of corticosteroids in the management of hemolysis and
elevated liver enzymes and low platelets syndrome are a few of the
developments that will alter the way this condition is managed. This
article aims to provide a general overview of pre-eclampsia, eclampsia
and hemolysis, hemolysis and elevated liver enzymes and low platelets
syndrome supported by the latest evidence, which will help the care
provider adopt a focused approach and use the latest knowledge to
understand and manage this old condition.
Introduction
Hypertension in pregnancy remains a leading cause of maternal and
fetal morbidity and mortality in the UK and worldwide. It is one of the
most common medical disorders in pregnancy and the most frequent
cause of iatrogenic prematurity. Pre-eclampsia occurs in 2–8% of all
pregnancies,[1] with the incidence of severe pre-eclampsia being around
1%. Between February 2005 and February 2006 there were 214
confirmed cases of eclampsia in the UK, representing an estimated
incidence of 2.7 per 10,000 births.[2]
Pre-eclampsia and eclampsia have been known to the ancient
civilizations of Egypt, China and India. However, it was only in the mid
to late 19 and early 20th century that hypertension and proteinuria, the
two key features of pre-eclampsia, were recognized. It was also
identified that delivery was the only effective treatment for this enigmatic
condition. Although advances in management have been made, this still
remains the case today.
Hypertension in pregnancy is defined as a diastolic blood pressure of 90
mmHg or more, taken on two occasions more than 4 h apart, or a single
diastolic blood pressure of more than 110 mmHg. This can occur either
in women who already have hypertension (which can be primary or
secondary) and who become pregnant, or can manifest itself de novo in
the second half of pregnancy in women who were previously
normotensive, when it is called pregnancy-induced hypertension or
gestational hypertension. It can be difficult to differentiate between
those with chronic hypertension and those with pregnancy induced
hypertension in the latter half of pregnancy. However, women who are
chronically hypertensive will have a high blood pressure at their first
antenatal booking visit or are known to be hypertensive prior to
pregnancy (e.g., while taking the oral contraceptive pill). However, since
both groups are at an increased risk of developing pre-eclampsia, they
need to be closely monitored.[3,4]
Pre-eclampsia is a multisystem disorder characterized by hypertension,
as described earlier, with the addition of proteinuria, defined as more
than 300 mg of protein in a 24 h urine collection or more than 30
mg/mmol in a spot urinary protein:creatinine sample. It occurs after 20
weeks of gestation with the hypertension and proteinuria resolving
postnatally. Occasionally women present with a severe complication of
pre-eclampsia such as eclampsia, or hemolysis, elevated liver enzymes
and low platelets (HELLP) syndrome.
The risk of pre-eclampsia is 4.1% in women in their first pregnancy and
1.7% in later pregnancies overall. However, this risk rises to 14.7% in
the second pregnancy in women who had pre-eclampsia in their first
pregnancy and 31.9% in women who had pre-eclampsia in their
previous two pregnancies.[5]
In the most recent Confidential Enquiry into Maternal and Child Health
in the UK (2003–2005), there were 18 reported deaths from preeclampsia and eclampsia, an increase of four deaths from the previous
triennium. Ten of these deaths were caused by intracranial hemorrhage,
highlighting the ineffective management of the systolic blood pressure in
these women.[6] A study from the USA also demonstrated a significant
rise in the prevalence of hypertensive disorders amongst hospitalized
pregnant women, from 67.2 per 1000 in 1998 to 81.4 per 1000 in
2006.[7]
It has been shown that there is still significant variation in practice
around the UK in the management of pre-eclampsia, which may
contribute to the substandard care of this potentially lethal condition. In
a survey of 370 women who developed pre-eclampsia, 34% did not
receive antihypertensive treatment with a systolic blood pressure of 160
mmHg or more, while only 17% of these women received magnesium
sulfate prophylactically.[8]
In view of this, the NICE has recently launched a new clinical guideline
on the management of hypertensive disorders during pregnancy in
order to standardize care and improve morbidity and mortality. This
guideline contains recommendations on the diagnosis and management
of hypertension in pregnancy during the antenatal, intrapartum and
postnatal period. It also offers guidance on the management of women
who suffer from chronic hypertension and wish to conceive as well as
advice to women whose pregnancy was complicated by hypertension. [9]
Pathophysiology
The pathophysiology of pre-eclampsia is complex and involves various
pathways and mechanisms that are interlinked. There is ongoing
research to help us further understand this condition and try to identify
preventive and therapeutic strategies. Apart from a few well
documented exceptions, pre-eclampsia appears to be triggered by the
placenta as it can occur in molar pregnancies where the fetus is absent.
Histopathological placental studies from hypertensive women have
established that trophoblastic invasion of the myometrium by the spiral
arteries is inhibited in women with hypertension in pregnancy. However,
this may be partial or incomplete, implying that the lack of trophoblastic
invasion in hypertensive pregnant women is not an 'all or none'
phenomenon.[10]
Interestingly, recent studies have identified the importance of
immunological factors in guaranteeing implantation success and how an
imbalance in the immunological milieu can lead to placental failure.
There seems to be an interaction between uterine natural killer cells and
trophoblastic cells, regulating trophoblastic invasion as well as
macrophage-derived TNF-α.[11,12] The fetal–maternal immunological
interaction at placentation involves maternal killer immunoglobulin-like
receptors and fetal HLA-C molecules. This interaction seems to fail in
pre-eclampsia, highlighting an immunological basis to trophoblastic
invasion deficiency.[13] This immunological influence also explains the
increased incidence of pre-eclampsia in primigravida and change in
paternity,[14] as well as the reduced incidence of pre-eclampsia in
women who received a blood transfusion.[15]
While abnormal placentation leads to placental insufficiency and fetal
growth restriction, the development of pre-eclampsia is not inevitable.
Further systemic changes are required. Increased inflammatory activity
leads to widespread damage to the vascular endothelium leading to
capillary leak, vasoconstriction and intravascular hemolysis, and platelet
activation.[16] This is further compounded by a heightening of the
immunological state in pre-eclampsia, through activation of circulating
leucocytes, which is similar to sepsis.[17] This inflammatory response
may be caused by 'placental debris', where the damaged placenta
releases fragments into the maternal circulation leading to systemic
inflammation and vascular dysfunction.[18] Therefore, the development of
pre-eclampsia is mediated through the degree of placental pathology
and the maternal inflammatory response to the results of damage.
One of the recognized functional changes in pre-eclampsia is the
dysfunction of the vascular endothelium. Although numerous
mechanisms have been suggested, recent studies show that the loss of
VEGF contributes towards these changes. It has been shown that
cancer patients receiving anti-VEGF therapy exhibit symptoms similar to
pre-eclampsia.[19] It is also postulated that pre-eclampsia occurs
because of the elevation of circulating soluble fms-like tyrosine kinase 1
(sFlt-1), which acts as a potent inhibitor of VEGF.[20] Studies have shown
that by reducing the levels of free sFlt-1 the symptoms of pre-eclampsia
have alleviated.[21] Cigarette smokers are known to have reduced levels
of circulating sFLT-1 and increased PGF.[22] Clinically, whereas smoking
increases the risk of preterm labor, intra-uterine growth restriction
(IUGR) and abruption, it reduces the risk of pre-eclampsia by a third.[23]
There is currently growing interest in therapeutically reducing the
elevated levels of sFlt-1 in pre-eclampsia to minimize its severity and
prolong the pregnancy in early-onset disease. Statins, so far
contraindicated in pregnancy, inhibit cytokine-mediated release of sFlt1.[24] Statins to Ameliorate Early Onset Pre-eclampsia (StAmP), the first
randomized placebo-controlled trial for the use of statins in early
pregnancy, is currently underway and the obstetric community is eager
to find out whether statins have a role in the treatment of preeclampsia.[25]
Prevention
In view of the potential severity of pre-eclampsia, there have been
various studies trying to identify preventive pharmaceutical agents, with
a particular emphasis on the use of antiplatelet agents.
A Cochrane systematic review of 59 trials including 37,560 women
revealed a reduction in the risk of pre-eclampsia with the use of
antiplatelet drugs, mainly low-dose aspirin. The participants were all
pregnant women at risk of developing the disease. There was found to
be a 17% reduction in the risk of pre-eclampsia associated with the use
of antiplatelet drugs (46 trials; 32,891 women; relative risk: 0.83; 95%
CI: 0.77–0.89, numbers needed to treat [NNT]: 72). This confidence
interval implies that the risk reduction (RR) could vary from a high of
23% to a low of 11%. However, the RR was increased in women with
an increased baseline risk with those considered to be at high risk on
entering the trial (previous pre-eclampsia, chronic hypertension,
diabetes, renal disease and autoimmune disease) having a RR of 25%
(95% CI: 34–15%). For moderate risk women (first pregnancy, mild
rise in blood pressure and no proteinuria, abnormal uterine artery
Doppler wave-forms, positive roll-over test, multiple pregnancies, family
history of severe pre-eclampsia and being a teenager), antiplatelet
agents were associated with a 14% reduction in pre-eclampsia risk
(95% CI: 21–5% reduction). The NNT based on absolute RR was
therefore 72 women (95% CI: 52–119 women). However, 19 high risk
women are needed to treat to prevent one case of pre-eclampsia (95%
CI: 13–34 women), while for moderate risk women this goes up to 119
(95% CI: 73–333 women).[26]
Antiplatelet agents were also associated with an 8% reduction in the
relative risk of preterm birth (29 trials, 31,151 women, relative risk: 0.92,
95% CI: 0.88–0.97); NNT 72 (52, 119), as well as a 14% reduction in
fetal and neonatal death (40 trials, 33,098 women, relative risk 0.86,
95% CI: 0.76–0.98); NNT 243 (131, 1666) and a 10% reduction in
small-for-gestational age babies (36 trials, 23,638 women, relative risk:
0.90; 95% CI: 0.83–0.98).[26]
There also seems to be evidence that RR improves with higher doses of
aspirin with a concurrent increased risk of adverse effects. Therefore,
the safety profile is limited to low-dose preparations. The moderate
efficacy of low-dose aspirin in preventing pre-eclampsia is perhaps not
as promising as one would expect. The NNT are relatively high,
although they are much lower for high-risk women.[26] However, the
safety and low cost of the intervention makes the use of low-dose
aspirin in preventing pre-eclampsia a cost-effective tool, albeit of
moderate efficacy. Further information is required to define the target
group of patients and the effective dose of aspirin.
The new NICE guideline on the management of hypertensive disorders
during pregnancy therefore recommends that all women with a high risk
of developing pre-eclampsia should start low-dose aspirin (75 mg) from
12 weeks until the birth of the baby.[9] The women considered to be at
high risk are the following:
• Hypertensive disease in the previous pregnancy
• Chronic kidney disease
• Autoimmune disease such as systemic lupus erythematosus and
antiphospholipid syndrome
• Type 1 or Type 2 diabetes
• Chronic hypertension
In addition, the same recommendation holds for women with more than
one moderate risk factor for developing pre-eclampsia. These include:
• First pregnancy
• Age 40 years or older
• Pregnancy interval of more than 10 years
• BMI of more than 35 kg/m2 or more at first visit
• Family history of pre-eclampsia
• Multiple pregnancies
There have been other numerous studies to evaluate the effectiveness
of other agents in the prevention of pre-eclampsia. A Cochrane
systematic review evaluating the role of nitric oxide agents (i.e.,
glycerine trinitrate, L-arginine) showed that there is insufficient evidence
to draw reliable conclusions in preventing pre-eclampsia and its
complications.[27]
Similarly, in another Cochrane review of two randomized controlled
trials comparing progesterone with placebo in preventing pre-eclampsia
and its complications, results showed that there was no clear evidence
on its role in preventing the disease.[28]
Diuretics have been used in the past to prevent or delay the onset of
pre-eclampsia. However, four trials investigating the role of diuretics
compared with placebo or no treatment in the prevention of preeclampsia did not show any benefit in terms of RR.[29] Since it is now
recognized that diuretics should not be used in pregnancy as they can
reduce the plasma volume with deleterious consequences, there is
limited evidence to support their use for the prevention of the disease.
However, diuretics may only be used cautiously in pre-eclampsia to
treat clinically significant pulmonary edema in women whose fluid
balance is being closely monitored.
One randomized controlled trial studied the role of low-molecular-weight
heparin in preventing pre-eclampsia. The study involved 80 women with
an angiotensin-converting enzyme DD genotype and a history of preeclampsia. A group of 41 women were assigned to receive dalteparin
5000 IU/day at the time of a positive pregnancy test, while 39 women
did not receive treatment. The treatment group had a lower risk of
developing pre-eclampsia compared with the control group (RR: 0.26;
95% CI: 0.08–0.86).[30] However, this was a poor quality trial although
it did show a statistically and clinically significant reduction in preeclampsia but in a highly selected group of women with a particular
genotype. Patients with systemic lupus erythematosus, whose risk of
developing pre-eclampsia is as high as 32–50%, have been shown to
improve their feto-maternal outcomes, especially their risk of developing
pre-eclampsia, if treated with low-molecular-weight heparin.[31]
The effect of nutritional supplements in preventing pre-eclampsia has
also been extensively studied. Magnesium, folic acid, fish oils, algal oils,
antioxidants and garlic do not seem to be effective in preventing the
disease.[9] Interestingly, a Cochrane review of 12 randomized controlled
trials involving 15,206 women has shown that women receiving calcium
supplementation were half as likely to develop pre-eclampsia compared
with placebo. Therefore, calcium supplementation appears to be
beneficial for women at high risk of developing hypertension in
pregnancy and in communities with low dietary calcium.[32] However,
there does not seem to be any statistically significant RR in
communities where dietary calcium intake is adequate.
Management of Pre-eclampsia
Proteinuria
The association between proteinuria and pre-eclampsia has long been
established and its presence is diagnostic of the disease and is
indicative of its multisystem nature leading to maternal and fetal
morbidity and mortality.
Pollak's work, published in 1960, revealed that the kidneys in preeclampsia underwent a series of unique pathological changes.[33] The
glomeruli were found to be enlarged, swollen and ischemic. Glomerular
involvement in pre-eclampsia is widespread, with all being affected to
the same degree. The most prominent pathological feature seems to be
the cellular edema of the glomerular tuft, affecting both endothelial and
epithelial cells. The swollen endothelial cytoplasm encroaches upon the
lumen of the glomerular capillaries, contributing to the tuft's ischemia.
The changes were not found to occur in other diseases affecting the
kidney. Therefore, these changes are diagnostic of pre-eclampsia,
which can be tested for by the presence of proteinuria.
Proteinuria is screened for by using a urinary dipstick test and can be
easily performed on the ward, clinic or in the community. Quantitative
measurements can be obtained using a 24 h collection or a spot urine
protein:creatinine ratio. Studies have linked the severity of the
proteinuria with maternal and fetal outcomes. In women with preeclampsia, the probability of an adverse maternal outcome increases
with increasing age and with higher spot urinary protein:creatinine
ratios. Therefore, there is a reduction of spot urine threshold values with
increasing age.[34]
The extent of severity of proteinuria is associated with higher obstetric
intervention rates (induction of labor and predelivery Cesarean
sections), as well as low birth weights.[35] The extent of proteinuria may
also be linked to the severity of fetal distress in labor, with high levels of
proteinuria being associated with an increased risk of recurrent late
decelerations on the cardio-tocograph.[36]
Owing to these findings, high levels of urinary protein have always been
looked upon with trepidation and delivery contemplated if significantly
high levels are present. Historically, a 24 h urinary collection of >5 g
mandated delivery. The trend now is to have a more rational approach
towards proteinuria. In a study of 598 women with a previous history of
pre-eclampsia, it was found that women who developed severe
gestational hypertension (without proteinuria) were more likely to have a
preterm delivery and a small-for-gestational-age baby compared with
women with mild pre-eclampsia. In addition, in the presence of severe
hypertension, proteinuria did not increase the rates of preterm delivery
and small-for-gestational-age babies.[37]
Similarly, in an interesting study by Newman et al., 299 patients with
pre-eclampsia who delivered before 37 weeks were studied
retrospectively.[38] These patients were divided into groups with mild (<5
g/24 h), severe (5–9.9 g/24 h) and massive (>10 g/24 h) proteinuria.
Massive proteinuria was associated with an earlier onset of preeclampsia, earlier gestational age at delivery and increased risk of
complications related to prematurity. However, after correction for
prematurity, massive proteinuria did not seem to have any effect on
neonatal outcomes. The authors concluded that neonatal morbidity is
related to prematurity and not to proteinuria per se.[38]
A systematic review of 16 primary articles involving 6749 women with
pre-eclampsia and varying levels of proteinuria concluded that the
estimations of levels of proteinuria in women with pre-eclampsia do not
correlate with maternal and fetal outcomes. Urinary protein estimation
was not found to be a clinically useful predictive test, disputing the
practice of deciding on delivery based on the severity of proteinuria.[39]
The new NICE guideline confers with the evidence highlighted in this
systematic review in that there does not seem to be a direct link
between changing urinary protein levels and adverse outcome.[9]
Therefore, contrary to the standard practice so far, it recommends that
once proteinuria has been diagnosed there is no benefit in repeating the
test. However, this important issue needs further investigation by welldesigned prospective studies.
Pre-eclampsia is a multisystem disorder with hypertension being one of
its manifestations and main clinical risks. Therefore, although lowering
the blood pressure has no effect on the pathological process of the
condition, controlling blood pressure is necessary to avoid maternal
risks such as maternal cerebrovascular accidents.
Monitoring of the blood parameters, often referred to as a pre-eclamptic
toxemia screen or 'hypertensive bloods', gives an indication on the
severity and progress of the disease.
Pre-eclamptic Toxemia Screen
Since pre-eclampsia is a multisystem disorder, this screen has
traditionally consisted of a group of blood tests that study different
organs and physiological systems such as a full blood count, particularly
the platelet count, kidney function tests, liver function tests and a
coagulation screen. In women with gestational hypertension without
proteinuria, there is little evidence that these blood parameters have
any link with disease progression and subsequent development to preeclampsia.
Uric Acid In a systematic quantitative review of a uric acid test to
determine the accuracy by which it predicts maternal and fetal
complications in women with pre-eclampsia, it was found that uric acid
is a poor predictor for complications.[40] The review showed that a
positive result (uric acid level of 350 µmol/l or more) predicted
progression to eclampsia with a pooled likelihood ratio (LR) of 2.1 (95%
CI: 1.4–3.5), with a negative result having a pooled LR of 0.38 (95%
CI: 0.18–0.81). A positive result predicted development of severe
hypertension with a LR of 1.7 (95% CI: 1.3–2.2), with a negative result
having a LR of 0.49 (95% CI: 0.38–0.64). The chance of requiring a
Cesarean section was 2.4 (95% CI: 1.3–4.7) and 0.39 (95% CI:
0.20–0.76) for positive and negative results respectively. Stillbirth and
neonatal death had respective LRs of 1.5 (95% CI: 0.91–2.6) and
0.51 (95% CI: 0.2–1.3), while for predicting small-for-gestational-age,
the LR was 1.3 (95% CI: 1.1–1.7) for a positive result and 0.60 (95%
CI: 0.43–0.83) for a negative result. It was therefore concluded that
use of therapeutic measures such as magnesium sulfate or planning
early delivery should not be based on uric acid levels.[40]
Renal Function Tests, Liver Function Tests & Platelet Count In a
Swedish study of 111 patients with pre-eclampsia it was found that the
only variable that significantly predicted maternal complications (HELLP
syndrome, placental abruption, oliguria and eclampsia) was diastolic
blood pressure.[41] Interestingly, serial blood sampling did not have any
predictive value on disease progression.[41] In another cohort study
conducted in Canada, the UK, Australia and New Zealand, a platelet
count of less than 100 × 109/l was associated with a statistically
significant increased likelihood of adverse maternal and perinatal
outcomes.[42] Similarly, elevated liver enzymes and creatinine levels
greater than 110 µmol/l were associated with adverse maternal
outcomes.[42]
Therefore, it can be inferred that platelet count, transaminases and
serum creatinine are good predictors of disease progression in women
who already have pre-eclampsia, while rising uric acid does not add any
additional information to these tests. In addition, coagulation studies are
of limited value when the platelet count is above 100 × 109/l.
Treatment
Labetalol is a widely used, safe and effective antihypertensive agent
that is licensed for use in pregnancy. It is now considered to be the firstline agent.[9] Alternative treatment may be necessary when labetalol is
contraindicated, such as in patients with asthma. Additionally women of
Afro–Caribbean origin seem to be resistant to β-blocker treatment.
Safe alternatives to labetalol are methyldopa and nifedipine. The latter
can be used safely in combination with either labetalol or methyldopa. In
extreme circumstances all three can be used together, however, 80% of
women with pre-eclampsia have their blood pressure controlled with
oral labetalol only.[43]
In a study of 200 primigravida women with mild pre-eclampsia at
26–35 weeks gestation, labetalol has been shown to reduce blood
pressure to statistically significant levels compared with hospitalization
only.[44] The reduction in blood pressure was not associated with an
improvement in perinatal outcome. This highlights the fact that the
principal aim of decreasing blood pressure is to reduce maternal
morbidity and to prolong the pregnancy to a gestation in which fetal
morbidity associated with prematurity is minimized.
Commencing antihypertensive treatment in pre-eclampsia depends on
the blood pressure readings. Mild hypertension (140/90 to 149/99
mmHg) does not require treatment. However, moderate hypertension
(150/100 to 159/109 mmHg) would require commencement of labetalol
with an aim to keep the diastolic blood pressure between 80–100
mmHg and the systolic blood pressure less than 150 mmHg. Similar
ranges are aimed for with severe hypertension, which is defined as a
blood pressure of 160/110 mmHg or higher.[9] Patients with preeclampsia should be admitted to hospital, have regular blood pressure
readings (at least four times a day), testing for proteinuria and
monitoring of blood parameters, namely kidney function, electrolytes,
full blood count, transaminases and bilirubin. The frequency of these
investigations depends on the severity of the condition – twice weekly
with mild hypertension and three times weekly with moderate/severe
hypertension. In addition, once proteinuria has been identified,
quantification need not be repeated.
Fetal Monitoring
Fetal Biometry & Umbilical Artery Doppler Velocimetry Patients with
pre-eclampsia have an increased risk of intrauterine growth restriction.
Growth scans and fetal biometry are therefore useful in identifying and
monitoring fetal growth in these patients.
In patients with hypertensive disease of pregnancy, the absence of enddiastolic velocities on umbilical artery Dopplers is crucial as this is
associated with increased neonatal morbidity and mortality. Therefore,
the presence of end-diastolic flow is generally reassuring, while its
absence indicates that delivery will be required in the near future.[45] A
systematic review of 13 randomized controlled trials with a total number
of 8633 participants looked into the use of umbilical artery Doppler
velocimetry in high-risk pregnancies compared with no Doppler or with
routine monitoring.[46] Perinatal mortality was statistically significantly
less in babies born to high-risk women who were monitored with
umbilical artery Doppler velocimetry (OR [odds ratio]: 0.67; 95% CI:
0.47–0.97) and they were less likely to have low Apgar scores at 5
min (OR: 0.89; 95% CI: 0.74–0.97). These women were also less
likely to be admitted antenatally (OR: 0.56; 95% CI: 0.43–0.72) and to
require an emergency Cesarean section (OR: 0.85; 95% CI:
0.74–0.97). Additionally, subgroup analysis of well defined studies
showed that women monitored with umbilical artery Doppler velocimetry
were less likely to be induced (OR: 0.78; 95% CI: 0.63–0.96) or to
have elective delivery (OR: 0.73; 95% CI: 0.61–0.88) or Cesarean
section (OR: 0.78; 95% CI: 0.65–0.94).[46]
Therefore, it can be concluded that in studies of high-risk pregnancies,
of which hypertension was a component, the use of umbilical artery
Doppler velocimetry reduces perinatal morbidity and mortality and helps
in deciding timing of delivery, especially when absent end-diastolic flow
was seen. However, there is little evidence on when the investigation
should be performed and subsequently repeated.
Biophysical Profile There is no evidence to support the use of a
biophysical profile (BPP) in pregnancies complicated by hypertension. A
Cochrane systematic review assessing the use of the BPP compared
with conventional monitoring (cardiotocography only or modified BPP)
showed that there were no statistically significant differences in
perinatal deaths or admission to neonatal special care between the two
groups.[47] There were also no statistically significant differences
amongst the two groups for the following parameters: Apgar scores less
than 7 at or after 5 min, small for gestational age, meconium-stained
liquor, respiratory distress syndrome and Cesarean section for fetal
distress. Subgroup analysis of the high-quality trials showed a
statistically significantly higher level of Cesarean section in the BPP
group.[47]
Liquor Volume Amniotic fluid is maintained at an equilibrium and has
various important functions, including protection from trauma,
bacteriostatic properties, protection of the umbilical cord and placenta,
and aiding in the development of the musculoskeletal system. It is also
an important measure of fetal well-being.[48]
A Cochrane review compared the use of the amniotic fluid index with
the use of the single deepest vertical pocket measurement as a
screening tool for decreased amniotic volume in the prevention of
adverse pregnancy outcomes.[49] It showed that there is no evidence
that one method is better than the other. There were no differences in
admission to neonatal special care, perinatal death, umbilical artery pH
less than 7.1, meconium, Apgar score less than seven at 5 min or
Cesarean section.[49]
Uterine Artery Doppler Velocimetry Since pre-eclampsia is
associated with a disturbance in utero–placental blood flow,
assessing uterine blood flow in the second trimester should help predict
development of the disease.
Chien et al. conducted a quantitative systematic review of 27 studies
involving 12,994 patients to evaluate the clinical usefulness of Doppler
analysis of the uterine artery velocity waveform in the prediction of preeclampsia and its associated complications of IUGR and perinatal
death.[50] The results showed that a positive result (flow velocity
waveform ratio ± diastolic notch) in the low-risk population predicted
pre-eclampsia with a pooled LR of 6.4 (95% CI: 5.7–7.1), while a
negative result had a pooled LR of 0.7 (95% CI: 0.6–0.8). For IUGR
the pooled LR for a positive result was 3.6 (95% CI: 3.2–4.0) and 0.8
for a negative result (95% CI: 0.8–0.9). Perinatal death had a pooled
LR of 1.8 (95% CI: 1.2–2.9) for a positive result and 0.9 for a negative
result (95% CI: 0.8–1.1). In the high-risk population a positive result
predicted pre-eclampsia with a pooled LR of 2.8 (95% CI: 2.3–3.4),
while a negative result hade a LR of 0.8 (95% CI: 0.7–0.9). IUGR was
predicted with a ratio of 2.7 (95% CI: 2.1–3.4) with a positive result
and 0.7 (95% CI: 0.6–0.9) for a negative result. In this population
perinatal death was predicted with a pooled LR of 4.0 (95% CI:
2.4–6.6) for a positive result and 0.6 (95% CI: 0.4–0.9) for a
negative result. Therefore, it was concluded that uterine artery Doppler
studies had limited accuracy in predicting pre-eclampsia and its
complications.
The NICE guideline states that the negative predictive ability and
sensitivity of the test is not sufficient to allow clinicians to alter their
management in women who are at a high risk of developing preeclampsia but have abnormal uterine artery Dopplers at 20–24
weeks.[9] Incidentally these women would already be on aspirin and
closely monitored so it is debatable how this test would alter the
patient's management.
Timing of Delivery
Ultimate treatment of pre-eclampsia is delivery, bearing in mind the
neonatal risks associated with iatrogenic prematurity.
Two randomized controlled trials investigated the maternal and neonatal
outcome when adopting an early delivery approach against expectant
management in women with severe pre-eclampsia at up to 34 weeks
gestation.[51,52] In both trials patients were stabilized with magnesium
sulfate and antihypertensives and given steroids for fetal lung
maturation. If they continued to meet the eligibility criteria they were
randomized into two groups – early delivery by Cesarean section or
induction 48 h after steroid administration and expectant management
with bed rest, oral antihypertensives and intensive antenatal fetal
monitoring until they were delivered at 34 weeks, or earlier if maternal
or fetal condition worsened. Neonates in the early delivery group
showed a greater frequency of hyaline membrane disease (relative risk:
2.3; 95% CI: 1.39–3.81) and necrotizing enterocolitis (relative risk:
5.54; 95% CI: 1.04–29.56) with no statistically significant difference in
rates of stillbirth or death after delivery (relative risk: 1.50; 95% CI:
0.42–5.41). There were also no statistically significant differences in
maternal complications (placental abruption and Cesarean section).
It seems sensible to adopt an expectant approach and aim for delivery
at 34 weeks unless there is clear maternal or fetal compromise. There is
no evidence of any benefit in prolonging pregnancy beyond 34 weeks in
severe pre-eclampsia. In addition, it is difficult to base timing of birth on
single biochemical and hematological parameters (including level of
proteinuria) as they are poor predictors of maternal and fetal outcome.
Therefore, it is imperative that the decision on timing of delivery is
knowledge by a senior obstetrician with an taken of the whole clinical
picture.
The Hypertension and Pre-eclampsia Intervention Trial in the Almost
Term patient (HYPITAT) showed that there was no maternal or
immediate neonatal disadvantage with immediate birth after 37 weeks
in women with pre-eclampsia and the NICE guideline recommends
delivery after 37 weeks since there is no evidence of benefit in
prolonging pregnancy.[9,53] Similar findings were seen for those with mildto-moderate hypertension but the NICE guideline states that delivery
should be offered to women after 37 weeks as the evidence is less
clear.
The mode of birth for women with severe pre-eclampsia or eclampsia
depends on the clinical circumstances and on the woman's preference.
Magnesium Sulfate: Treatment
Magnesium sulfate is the anticonvulsant of choice in the treatment of
eclampsia. The drug has been used since the 1920s when it was found
to be effective in the control of convulsions secondary to tetanus.[54] Its
mode of action is not clearly understood. In a Cochrane review
comparing it with diazepam, it was found that magnesium sulfate was
associated with less maternal death and recurrence of convulsions.[55]
Babies of women treated with magnesium sulfate were also less likely
to stay in special care for longer than 7 days and were less likely to
have Apgar sores less than seven at 1 and 5 min when compared with
diazepam.
Similar Cochrane reviews have demonstrated that magnesium sulfate is
superior to phenytoin and to a lytic cocktail (a combination of drugs
consisting of chlorpromazine, promethazine and pethidine).[56,57]
The regimen for administration of magnesium sulfate follows the
Collaborative Eclampsia Trial:[58]
• Loading dose of 4 g given intravenously over 5 min, followed by an
infusion of 1 g/h maintained for 24 h;
• Recurrent seizures should be treated with a further dose of 2–4 g
given over 5 min.
Magnesium Sulfate: Prevention
The Magnesium Sulphate for Prevention of Eclampsia (MAGPIE) Trial
Collaborative Group evaluated the use of magnesium sulfate in the
prevention of eclampsia in women with pre-eclampsia.[59] The study
consisted of 10,141 women in the antenatal period or less than 24 h
postpartum. They had a blood pressure of 140/90 mmHg or more and
1+ of proteinuria (30 mg/dl) on urinary dipstick. Women were
randomized in 33 countries to either magnesium sulfate (n = 5071) or
placebo (n = 5070). Women who were given magnesium sulfate had a
58% lower risk of developing eclampsia (95% CI: 40–71) than the
placebo group (40, 0.8%, vs 96, 1.9%; 11 fewer women with eclampsia
per 1000 women). Maternal mortality was also lower in the treatment
group (relative risk 0.55; CI: 0.26–1.14). A total of 24% of women
given magnesium sulfate reported side effects as opposed to 5% with
placebo.
Two follow-up studies investigating the long-term effects to the mother
and baby following treatment with magnesium sulfate during pregnancy
showed that there were no statistically significant differences in the
primary outcomes studied between the treatment and placebo
group.[60,61] The primary outcomes were death and serious morbidity
related to pre-eclampsia for the mother and death and noncongenital
neurosensory disability for the baby.
Magnesium sulfate has also been found to be cost effective in
preventing eclampsia, with the benefit increasing with the severity of the
disease.[62] Therefore, it should be considered in women with severe
pre-eclampsia who are in a critical care setting if birth is planned within
24 h.
Patients with severe pre-eclampsia who would benefit from magnesium
sulfate are those with severe hypertension and proteinuria or mild or
moderate hypertension and proteinuria with one or more of the
following:[9]
•
•
•
•
•
•
•
•
•
Symptoms of severe headache
Problems with vision, such as blurring or flashing before the eyes
Severe pain just below the ribs or vomiting
Papilledema
Signs of clonus (three or more beats)
Liver tenderness
HELLP syndrome
Platelet count falling to below 100 × 109/l
Abnormal liver enzymes (alanine transaminase or aspartate
transaminase rising to above 70 IU/l)
Antihypertensives in Severe Pre-eclampsia
Apart from treating and preventing convulsions, it is also important to
lower the blood pressure in women with severe pre-eclampsia.
However, the blood pressure should not be reduced too quickly and too
aggressively. The main aim is to stop the rise and maintain a stepwise
downward trend to levels below 150/100 mmHg. The Centre for
Maternal and Child Enquiries latest report has shown that that the single
most serious failing in the clinical care of women with pre-eclampsia is
the inadequate treatment of the systolic blood pressure.[6] There still
seems to be an erroneous understanding that the diastolic reading is
more associated with maternal morbidity and mortality than the systolic.
However, it is the latter that can lead to fatal intracranial hemorrhage or
aortic dissection. In a study of strokes in women during pregnancy and
the puerperium, it was found that hypertensive disorders are a common
comorbid condition, being present in 45% of patients with an ischemic
stroke and in 64% of patients with a hemorrhagic stroke. In addition,
strokes are more likely to occur in the third trimester and the first week
postpartum, possibly related to the large volume shifts,
hypercoagulability, vasoconstriction and increased osmolarity
superimposed on the damaged endothelium found in pre-eclampsia.[63]
There seems to be a predilection of the parieto-occipital and occipital
lobes in hypertensive encephalopathy and eclampsia. Posterior
reversible encephalopathy has been described in women with severe
pre-eclampsia and eclampsia. It manifests itself as seizures,
headaches, visual disturbances and characteristic imaging
abnormalities on CT scans and MRI, associated with a sudden rise in
blood pressure that leads to vasogenic edema owing to loss of the
cerebral vasculature autoregulatory capacity.[64,65]
It is therefore recommended by NICE that the maternal blood pressure
should be brought down to a level of 150/80–100 mmHg in women
with severe hypertension who are in critical care.
There is no evidence of any significant differences in efficacy between
the different antihypertensive preparations (labetalol, nifedipine and
hydralazine). A Cochrane review of all randomized trials looking at
different drugs for the treatment of very high blood pressure during
pregnancy concluded that there was insufficient data for reliable
conclusions to compare the efficacy of the various drugs used in this
setting.[66] In fact, more robust studies are needed to compare and
evaluate the different antihypertensive treatments. Labetalol is the only
drug licensed for the treatment of hypertension in pregnancy and has a
very low side-effect profile. It can be given both orally and intravenously,
in contrast to nifedipine, which is given orally and hydralazine
intravenously. The latter may cause sudden severe hypotension.
Smaller more frequent doses of hydralazine can be used, but labetalol
either orally or intravenously is generally considered to be a superior
drug.
The oral route is preferred to the intravenous one, owing to ease of
administration and cost–effectiveness.
Fluid Balance
The Confidential Enquiry into Maternal and Child Health in the UK
reported six deaths in the triennium 1994–1996 caused by adult
respiratory distress syndrome, related to poor fluid management in
women with pre-eclampsia or eclampsia.[67] This highlighted the
importance of having senior medical involvement in managing the fluid
balance of these patients. Subsequent reports showed a marked
improvement in the number of deaths reported for the same
complication, with no deaths in the last two triennia 2003–2005 and
2006–2008.
Volume expansion should not be used in women with severe preeclampsia. The only exception is the preloading of no more than 500 ml
of intravenous crystalloid fluid prior to birth in women being treated with
intravenous hydralazine.
The Yorkshire Obstetric Critical Care Group developed a common
guideline for the management of severe pre-eclampsia and eclampsia
for the 16 units within Yorkshire (UK).[43] This guideline ensures a
uniform standard of care amongst all units. It helps clinicians decide
appropriate management, especially in the more challenging aspects of
the disease such as fluid management. This guideline restricts fluids to
80 ml/h in the peripartum period, leading to a low rate of fluid-related
problems in the mothers. This is also related to the allowance of a
relatively low urine output, allowing 8 h with the equivalent of less than
20 ml/h of urine output prior to intervening. In a 5-year prospective study
on the risks of serious complications from severe pre-eclampsia and
eclampsia in the region following the introduction of this guideline, it was
found that amongst 1087 women diagnosed with pre-eclampsia or
eclampsia during the study period, 82 (3.9 per 10,000 deliveries) had
eclamptic fits and 49 (2.3 per 10,000 deliveries) required intensive care
admission. A total of 25 women (2.3%) developed pulmonary edema
and six required renal dialysis (0.55%). It was concluded that the
guideline, which could be easily implemented in other regions, may
contribute to lower rates of serious complications.
There are strong similarities amongst pre-eclampsia guidelines from
other countries. The American Congress of Obstetricians and
Gynecologists recommends that severe pre-eclampsia should be
managed in a tertiary center, while patients with mild disease who are
still remote from term can be treated conservatively.[68] Treatment with
labetalol or hydralazine is recommended if the diastolic blood pressure
is 105 mmHg or more. Magnesium sulfate is also recommended for the
prevention and treatment of seizures in women with pre-eclampsia or
eclampsia.[68] The Society of Obstetricians and Gynaecologists of
Canada recommend antihypertensive therapy when the blood pressure
exceeds 160/100 mmHg using labetalol, nifedipine or hydralazine with
magnesium sulfate also used for the prevention and treatment of
seizures.[69] These guidelines recommend expectant management for
women <34 weeks in centers capable to care for preterm infants, while
for women between 34–36 weeks with nonsevere pre-eclampsia,
there is insufficient evidence on the risks and benefits of expectant
management.[69] For women >37 weeks, immediate delivery is
advised.[69] The Society of Obstetric Medicine of Australia and New
Zealand recommend treating blood pressures exceeding 170/110
mmHg using methyldopa, labetalol or oxprenolol. Hydralazine,
nifedipine and prazosin are considered second-line drugs. Magnesium
sulfate is used for the treatment of eclampsia with arrangements for
delivery once the patient is stable. At mature gestational ages, delivery
should not be delayed after controlling the maternal blood pressure and
other derangements. In gestations between 24–32 weeks,
management should be restricted to centers with the appropriate
expertise and before 34 weeks delivery should be delayed for 24–48
h if the maternal and fetal conditions permits, to allow administration of
corticosteroids.[70] The Finnish Medical Society also recommends
labetalol and nifedipine for the treatment of hypertension in preeclampsia.[71]
HELLP Syndrome
Hemolysis, elevated liver enzymes and low platelets syndrome is one of
the serious complications of pre-eclampsia requiring level two critical
care and is associated with significant maternal and fetal morbidity and
mortality. Most women are usually parous and are often not very
hypertensive. Severe epigastric pain is a common presentation. The
main differential diagnosis is fatty liver which, in contrast to HELLP
syndrome, is associated with hypoglycemia, high ammonia, low
fibrinogen and a prolonged activated partial thromboplastin time.[72]
Hemolysis, elevated liver enzymes and low platelets syndrome
complicates 0.5–0.9% of all pregnancies and 10–20% of cases with
severe pre-eclampsia.[73] Diagnosis requires the presence of
microangiopathic hemolysis, thrombocytopenia and abnormalities of
liver enzymes. There is still controversy on the biochemical thresholds
required to diagnose the condition. Sibai uses the following criteria:
hemolysis as evidenced by a peripheral smear, lactate dehydrogenase
greater than 600 IU/l, or total bilirubin greater than 20.52 µmol/l;
aspartate transaminase greater than 70 IU/l and platelets less than
100,000 cells/mm3.[74,75] Women who do not have all these parameters
are considered to have partial HELLP syndrome. Martin et al. define the
condition as follows: hemolysis evidenced by an increased lactate
dehydrogenase and progressive anemia; liver dysfunction as evidenced
by an lactate dehydrogenase higher than 600 IU/l; aspartate
transaminase greater than 40 IU/l and alanine transaminase greater
than 40 IU/l, or both and a platelet count less than 150,000
cells/mm3.[76,77] The Mississippi HELLP Classification System classifies
women based on the lowest perinatal platelet count:
• Class one HELLP syndrome – platelet nadir less than or equal to
50,000 cells/mm3;
• Class two – platelet nadir less than or equal to 100,000 cells/mm3;
• Class three – platelet nadir less than or equal to 150,000
cells/mm3.[77]
Hemolysis, elevated liver enzymes and low platelets syndrome is
associated with severe maternal complications, including acute renal
failure and liver failure, disseminated intravascular coagulopathy,
pulmonary edema, cerebrovascular accident and sepsis.[74] It is also
closely linked to complications associated with prematurity and growth
restriction with a perinatal mortality of 14.1%.[78] It has also been shown
that up to 70% of patients with HELLP syndrome will require preterm
delivery with 15% occurring at extremely preterm gestational ages (less
than 27 weeks).[79]
Corticosteroids have been used in women with pre-eclampsia
complicated by HELLP syndrome. A Cochrane review of 11 trials
including 550 women comparing steroids with placebo or no treatment
in the management of women with HELLP syndrome showed that there
was no clear evidence of any effect of corticosteroids on clinical
outcomes.[80] There was no difference in risk of maternal death (risk
ratio: 0.95, 95% CI: 0.28–3.21), maternal death or severe maternal
morbidity (risk ratio: 0.27, 95% CI: 0.03–2.12) or perinatal/infant death
(risk ratio 0.64, 95% CI: 0.21–1.97). The only difference was in
improvement in platelet count in the treatment groups (standardized
mean difference 0.67; 95% CI: 0.24–1.10), especially in women who
started their treatment in the antenatal period. Corticosteroids should
therefore not be used in the management of HELLP syndrome.
The definitive treatment of HELLP syndrome is delivery. Unlike severe
pre-eclampsia not complicated by HELLP syndrome, this may require
delivering at significantly preterm gestations. Neonatal outcomes in
patients with HELLP syndrome is related to gestational age rather than
the condition itself.[79] However, patients with this complication are at an
increased risk of eclampsia or possibly intracerebral bleeding, which
can lead to seizure activity and death. Therefore, preterm delivery is
usually unavoidable in cases of established HELLP syndrome.
Postnatal Management
Up to 44% of eclamptic fits occur in the postnatal period. It is therefore
important that medical and midwifery staff remain vigilant until the
patient's overall clinical picture improves. Some patients will require
antihypertensives for the first time in the postnatal period. Treatment
needs to be started if the blood pressure exceeds 150/100 mmHg.
Women on antenatal antihypertensive therapy will continue the same
treatment postnatally, however, methyldopa is contraindicated owing to
the increased risk of depression. Treatment is reduced when the blood
pressure falls below 130/80 mmHg. A pre-eclamptic toxemia screen
should be repeated at 48–72 h postdelivery but not repeated if
normal. The patient can be discharged and followed-up in the
community when she has no symptoms of pre-eclampsia, blood
pressure is less than 149/99 mmHg and her blood tests are stable or
improving.[9]
Women who developed pre-eclampsia will require debriefing during the
postnatal period. Patients need to be reassured that the condition will
improve postnatally, with an increased risk of it redeveloping in
subsequent pregnancies. In women with severe pre-eclampsia requiring
delivery before 34 weeks the risk is 25%. This increases to 55% if the
pre-eclampsia necessitated delivery before 28 weeks.[81] Optimizing the
BMI will reduce the future risk.
Conclusion
Our knowledge of pre-eclampsia over the last few decades has evolved
rapidly. We are now able to understand the disease process better
while identifying the patients who are at a greater risk. Use of
antihypertensive medication, relevant investigations and treatment has
improved the outcome of pre-eclamptic patients.[82] Unfortunately we still
do not understand the pathophysiology well enough to devise effective
screening tools and in the 21st century delivery remains the only
effective treatment. However, with our more targeted investigations and
management strategies the maternal and fetal mortality is at its lowest.
Applying evidence-based medicine for the management of preeclampsia will ensure that the standards will be maintained and
improved.
Future Perspective
Currently, the mainstay of management of pre-eclampsia is screening
through antenatal care, close monitoring of those at risk, treatment of
signs and symptoms and then delivering on the best day in the best
way. The future lies in prediction and prevention with improvements in
management preventing growth restriction and premature delivery.
Early studies suggest that blood markers that increase the risk of
development of disease are present as early as the first trimester, and
the use of aspirin is known to reduce the incidence of disease
development by 15%. Obviously the combination of these two
approaches will both reduce the number of women requiring close
monitoring and admission to hospital as well as the number that
develop the more dangerous forms of disease that put the mother and
her baby at risk. Further improvement in prediction and prevention will
follow.
A better understanding of the systemic inflammatory changes will allow
a moderation of these to reduce the risks to the mother and the baby,
making prolongation of the pregnancy more possible for the benefit of
the baby without increasing the maternal risk. This builds on the
improvements in maternal care that we have seen in recent years.
Sidebar
Executive Summary
Pathophysiology
• Abnormal placentation leads to placental insufficiency and fetal
growth restriction.
• Increased inflammatory activity gives rise to widespread damage to
the vascular endothelium.
• This is compounded by a heightening of the immunological state
through circulating leucocytes, similar to sepsis.
• This inflammatory response is probably caused by 'placental debris'
leading to systemic inflammation and vascular dysfunction.
Prevention
• Low-dose aspirin is a cost-effective tool in the prevention of preeclampsia and should be recommended for use in moderate to
high risk women in early pregnancy.
Proteinuria
• Estimations of levels of proteinuria in women with pre-eclampsia do
not correlate with maternal and fetal outcomes.
• Once proteinuria has been diagnosed there is no benefit in repeating
the test.
Pre-eclamptic Toxemia Screen
• Platelet count, transaminases and serum creatinine are good
predictors of disease progression in women who already have
pre-eclampsia.
• Rising uric acid does not add any additional information to these tests.
Treatment
• Labetalol is now considered the first-line antihypertensive agent.
• Patients with pre-eclampsia should be admitted to hospital, have
regular blood pressure readings (at least four times a day),
testing for proteinuria and monitoring of blood parameters,
namely kidney function, electrolytes, full blood count,
transaminases and bilirubin.
Umbilical Artery Doppler Velocimetry
• In high-risk pregnancies, including those complicated by hypertensive
disease, the use of umbilical artery Doppler velocimetry reduces
perinatal morbidity and mortality.
• It helps in deciding timing of delivery, especially when end-diastolic
flow is absent.
Timing of Delivery
• There is no evidence of any benefit in prolonging pregnancy beyond
34 weeks in severe pre-eclampsia.
Magnesium Sulfate
• Magnesium sulfate is the anticonvulsant of choice in the treatment of
eclampsia.
• It also prevents eclampsia and should also be considered in women
with severe pre-eclampsia who are in a critical care setting if birth
is planned within 24 h.
Fluid Balance
• Volume expansion should not be used in women with severe preeclampsia.
Hemolysis, Elevated Liver Enzymes & Low Platelets Syndrome
• Corticosteroids have no beneficial effect on the clinical outcome of
patients with hemolysis, elevated liver enzymes and low platelets
syndrome.
Postnatal Management
• Women who developed severe pre-eclampsia requiring delivery
before 34 weeks have a 25% risk of the condition recurring in the
next pregnancy.
Conclusions
• Use of antihypertensives, relevant investigations and treatment has
improved the outcome of pre-eclamptic patients.
• Blood markers that increase the risk of development of the disease
are already present in the first trimester.
• The use of aspirin, in conjunction with the use of the first trimester
blood markers, will help reduce the number of women requiring
close monitoring, hospitalization and development of the more
severe forms of the disease.
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Papers of special
note have been highlighted as:
• of interest
•• of
considerable interest
Financial & competing interests disclosure The authors have no relevant
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interest in or financial conflict with the subject matter or materials discussed in the
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No
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Women's Health. 2011;7(5):555-569. © 2011 Future Medicine Ltd.