Volume 61, Number 10

OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright 2006
by Lippincott Williams & Wilkins

CME REVIEWARTICLE

28

CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA category 1 creditsTM can be earned in 2006. Instructions for how CME credits can be earned appear on the
last page of the Table of Contents.

Cerebral Hemodynamics in
Preeclampsia: Cerebral Perfusion and
the Rationale for an Alternative to
Magnesium Sulfate
Michael A. Belfort, MD, PhD,* Steven L. Clark, MD,
and Baha Sibai, MD
*Professor, St. Marks Hospital and University of Utah School of Medicine, Salt Lake City, Utah; Director of
MaternalFetal Medicine, St. Marks Hospital, Salt Lake City, Utah; and Professor, University of Cincinnati,
Cincinnati, Ohio
Preeclampsia and eclampsia continue to be major causes of maternal death. Currently, approximately
18% of U.S. maternal deaths are attributed to hypertensive disorders and eclampsia, and several hundred
women die from eclampsia and its complications every year. In the United States, preeclamptic women
have received magnesium sulfate as a seizure prophylaxis agent for 3 decades, and this practice is
becoming more widely accepted internationally. In addition to a recognized failure rate, there are financial,
logistic, and safety concerns associated with the universal administration of magnesium sulfate. Many
institutions in the developing world lack the necessary equipment and expertise to administer the medication, and many preeclamptic patients thus do not receive magnesium sulfate before their first seizure. As
effective as it has been in reducing mortality from eclampsia, magnesium sulfate is also associated with
appreciable morbidity and mortality from administration errors and magnesium toxicity. The availability of
an easily administered, cheap, safe, and orally administered alternative to magnesium sulfate would be
welcomed in the developing world and would provide an extremely useful alternative therapy to the current
standard of care. Recent advances in the understanding of the pathophysiology of preeclampsia and
eclampsia, primarily related to cerebral perfusion and blood flow, could allow us to reduce the seizure rate
in treated preeclamptic women even further than what is currently reported. This article deals with the
rationale behind the use of labetalol as an alternative to magnesium sulfate for the prevention of eclampsia.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this article, the reader should be able to recall that hypertensive
diseases of pregnancy contribute a significant portion of todays maternal mortality, explain that methods of
preventing eclampsia are not applicable worldwide, and state that understanding of the pathophysiology of
preeclampsia/eclampsia may assist in developing safe and effective medications that can be used universally.

Preeclampsia and eclampsia continue to be major

causes of maternal death (1,2). It is conservatively es-

timated that in the United States (3), over 100,000

women are treated for preeclampsia per year.

Dr. Belfort was a member of the speakers bureau for Symposia

Medicus and the Medical Intelligence Corporation. All other authors
have disclosed that they have no financial relationships with or interests
in any commercial companies pertaining to this educational activity.
The authors have disclosed that labetalol has not been approved by
the U.S. Food and Drug Administration for use in the prevention of
eclampsia. Consult product labeling for the approved use of this drug.

Lippincott Continuing Medical Education Institute, Inc. has

identified and resolved all faculty conflicts of interest regarding
this educational activity.
Reprint requests to: Michael A. Belfort, MD, PhD, MaternalFetal
Medicine, St. Marks Hospital, 1140E 3900S, Suite 390, Salt Lake City,
UT 84124. E-mail: Michael.Belfort@HCAhealthcare.com.

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Obstetrical and Gynecological Survey

Approximately 21,000 women develop severe preeclampsia. Currently, approximately 18% of maternal deaths in the United States are attributed to
hypertensive disorders and eclampsia, and several
hundred women die from eclampsia and its complications every year (3).
In the United States, preeclamptic women have
received magnesium sulfate as a seizure prophylaxis
agent for over 3 decades (4), and the introduction of
this drug has been associated with a significant reduction in maternal mortality. With demonstrated
efficacy in the treatment of eclampsia, and the prevention of eclampsia in women with severe preeclampsia, magnesium sulfate (MgSO4) currently
represents the standard of care for seizure prevention
in the United States. Many obstetricians also use this
drug in patients with mild preeclampsia despite a
lack of robust evidence to support a clear benefit, and
a guideline from ACOG that specifically excludes
mild preeclampsia (5). Based on available data (6,7),
it appears that the incidence of seizures in untreated
severely preeclamptic women is approximately 3%
to 4%, whereas for those receiving magnesium sulfate, the rate is generally thought to be just under 1%
(8). Given an estimated prevalence of eclampsia of
1% in women with preeclampsia who are receiving
magnesium sulfate prophylaxis, and an estimated
100,000 women per year with preeclampsia in the
United States, approximately 1000 women a year
will convulse despite our current best efforts. Of
these patients, an unknown number will experience
aspiration, asphyxia, cerebrovascular complications,
and death.
Since publication of the MAGPIE Study, which
showed a significant reduction in the rate of eclampsia in preeclamptic women treated with MgSO4 (9),
there has been a worldwide increase in the use of
MgSO4 for seizure prophylaxis in women with preeclampsia. The MAGPIE trial (9) involved 10,110
women with preeclampsia in 175 hospitals in 33
countries and revealed a significant reduction in the
rate of eclampsia in women assigned to MgSO4. This
benefit was primarily found in women enrolled in
developing countries, and there was no significant
reduction in the rate of eclampsia in women from
industrialized countries (relative risk, 0.67; 95% confidence interval, 0.192.37). However, the number of
women enrolled from industrialized countries was
small and the lack of significance may simply represent insufficient statistical power. Even so, it is
perhaps ironic that the majority of the increased use
of MgSO4 since the MAGPIE trial has occurred in
industrialized countries as opposed to nonindustrial-

ized ones, many of which still have significant financial, logistic, and safety concerns associated with the
universal administration of MgSO4 to all preeclamptic
women. Magnesium sulfate is not without risks; every
year, a significant number of women die, experience
severe morbidity, or experience permanent disability
from administration errors and magnesium toxicity. It is
extremely difficult to assess this number accurately as a
result of underreporting (or an assumption that the outcome was the result of the underlying condition itself).
Conversely, in many maternal transport situations,
MgSO4 is withheld from patients until they are admitted
to a center where adequate facilities and personnel are
available for the safe administration and monitoring of
the infusion. Some of these women convulse en route
and may die from aspiration, hypoxia, or other complications related to the seizure. Thus, the availability of an
easily administered, inexpensive, safe alternative to
MgSO4 would be welcomed in this and other countries
and would provide an extremely useful alternative therapy to the current standard of care. From a global
perspective, the availability of such an eclampsia prophylactic agent would be of even greater benefit. In
many developing countries, MgSO4 is not available or
practical as a management modality because of expense, logistics, lack of trained personnel, and lack of
resources. It is estimated that in these situations, seizures may occur in more than 4% of severely preeclamptic patients, and in some settings, as many as
15% of eclamptic women will die (10).
PATHOPHYSIOLOGY OF PREECLAMPSIA/
ECLAMPSIA
The etiology of eclamptic convulsions is unclear.
Cerebral vasospasm, hypertensive encephalopathy
(from cerebral overperfusion), excitation of brain
receptors, and a hyperactive sympathetic nervous
system have all been implicated (1114). We and
others have shown that both vasospasm (15) and
hypertensive encephalopathy (16,17) may be associated with seizures, but that in most cases, preeclamptic women have cerebral overperfusion rather than
ischemia (1820). The results of the Nimodipine
Study (8) (in which women with severe preeclampsia
were randomly assigned to receive a selective cerebral vasodilatornimodipinevs MgSO4) support
this by showing that deliberate cerebral vasodilatation, which interfered with protective physiological
vasoconstriction, actually increased the eclampsia
rate in women with severe preeclampsia over that
seen in women treated with MgSO4 (2.6% vs 0.8%).
The resulting 2.6% eclampsia rate is not statistically

Cerebral Hemodynamics in Preeclampsia Y CME Review Article

different from the approximately 3% rate of seizures

seen in untreated preeclamptic women.
In eclampsia, secondary vasospasm is thus more
likely to be the result of prolonged and untreated
hypertensive encephalopathy rather than the primary
pathology. Theoretically, either of these 2 perturbations (overperfusion or underperfusion) may result in
brain receptor stimulation and excitation of ectopic
foci to cause seizures. The relative contribution of
vasospasm versus cerebral barotrauma (20) and hypertensive encephalopathy as the primary mechanism
of eclampsia are discussed in more detail subsequently. Before detailing these arguments, however,
an overview of the current literature regarding cerebral perfusion in normal and preeclamptic pregnancy
will be helpful to allow the reader to fully consider
the arguments to follow.
Data from both normal pregnant (18) and preeclamptic women (2123) studied with Doppler ultrasound
have outlined a picture of the cerebral hemodynamics in
both normal pregnancy and preeclampsia. In normal
pregnancy, the systolic velocity and resistance index in
the middle cerebral artery both decrease approximately
20% over gestation (18), whereas the cerebral perfusion
pressure (CPP) increases by 50% from early pregnancy
to term (Fig. 1) (18). Cerebral perfusion, expressed as
the cerebral blood flow index (CFI) was shown to
increase approximately 10% from early pregnancy to
term (18,19). These Doppler derived data have recently
been confirmed by magnetic resonance imaging studies
that show that the middle and posterior cerebral artery

657

diameters remain static during normal late pregnancy,

whereas the flow (which in this instance is proportional
to the velocity) decreases by approximately 20% (17).
Cerebral autoregulation is very efficient during
pregnancy and despite a significant increase in perfusion pressure the cerebral blood flow changes by a
much smaller percentage. A small decrease in cerebral resistance is seen in normal pregnancy as blood
pressure increases within the normal range, and this
is believed to be the result of prostacyclin release as
the vessel walls are distended. However, as pressure
increases out of the normal range (in preeclamptic
women without headache; left panel in Fig. 2), a
physiological increase in cerebral resistance occurs to
limit perfusion (21), and this should not be regarded (as
was the case before normative data becoming available)
as a pathologic change.
Many studies performed before the publication of
normative data assumed that in preeclamptic patients, a
decrease in the middle cerebral artery resistance index
after delivery, or after treatment with MgSO4, was indirect evidence of recovery from cerebral vasospasm. In
retrospect, many of those patients had initial resistance
index (RI) values that were well within the normal
range for pregnancy, and the change in resistance simply reflected a vasodilator effect of fluids and antihypertensive drugs used in treatment of the hypertension/
eclampsia. The newer indices that incorporate blood
pressure (CPP [24], resistance area product [RAP] [25],
and CFI [26]) and the availability of normative data for
pregnancy (18) now allow a much better perception of

Fig. 1. Normal pregnancy Doppler derived cerebral hemodynamic parameters (18).

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Obstetrical and Gynecological Survey

Fig. 2. Cerebral flow index and cerebral perfusion pressure index data from women with mild and severe preeclampsia are shown on
a background of median and 95% prediction limits for normal pregnancy (19).

the state of cerebral perfusion than the RI or pulsatility

index that were previously used.
Using these indices, Belfort et al (19) compared cerebral perfusion (as depicted by CFI) in 72 women with
mild preeclampsia and 120 patients with severe preeclampsia (Fig. 3) and found that in most cases, it
remains within the normal limits. In severe preeclampsia, if cerebral blood flow is abnormal, it may be either
increased (14% of the patients) or decreased (10% of
the patients), whereas in mild preeclampsia, almost all
abnormal CFI (25% of the patients) is lower than normal. In those cases with low or normal cerebral blood
flow, severe preeclampsia is associated with a significantly higher perfusion pressure (CPP), RAP, and mean
arterial pressure (MAP) than mild preeclampsia (P
.05), whereas the CFI is not significantly different. A
significant proportion of severe preeclamptics have
high perfusion pressure (52%) versus only a minority of
mild preeclamptics (13%) (Fig. 3). Overall, in severe
preeclampsia, the resistance (RAP) is abnormally high,
whereas it is within the normal range in women with
mild preeclampsia. Magnetic resonance imaging data
from Zeeman et al (27) are consistent with the Doppler
data (19).
In most preeclamptic women with high CPP and
resistance, there is normal flow. However, the fact
that the flow is usually normal does not negate the
potential for damage from a high CPP. Under these
circumstances, a high middle cerebral artery (MCA)
perfusion pressure, in and of itself, may well lead to
vascular damage of the MCA and its branches, although the flow distal to the MCA may be adequate
to maintain brain function for a long period of time.
Depending on the time that the vessel is subjected to
abnormally high CPP, there may or may not be

Fig. 3. Failure of autoregulation in preeclamptic women with

headache as shown by failure to increase middle cerebral artery
resistance index in response to increasing mean arterial pressure
(21,29).

Cerebral Hemodynamics in Preeclampsia Y CME Review Article

endothelial damage, vasogenic edema, or muscularis

dysfunction. Abnormally high resistance will almost
always result in a low flow state with reduced perfusion, and very low resistance will usually result in
high flow state and overperfusion. By using the combination of these parameters (CPP, CFI, and RAP),
we are allowed a much more complete understanding
of what is taking place in the brain than with any
single parameter in isolation.
One of the fundamental differences between mild
and severe preeclampsia is the degree of cerebral
perfusion pressure to which the middle cerebral arteries are subjected. Because most preeclamptic
women, regardless of their degree of severity, have a
normal CFI (19), it appears that autoregulation is
generally intact until quite late in preeclampsia.
However, in those preeclamptic women who develop
headache, it can be seen that autoregulation in the
middle cerebral artery fails and there is no compensatory increase in MCA RI in response to increasing
blood pressure (Fig. 2, right panel) (21). It is quite
easy to hypothesize that the combination of 1) failed
cerebral autoregulation and 2) increased CPP can
lead to an overperfusion state in some small number of severely preeclamptic women. The fact that
women with severe preeclampsia and a headache are
more likely to have failed autoregulation and high
CPP support the current conviction that severe preeclamptics are more prone to cerebral catastrophe
than those with mild disease. We contend that this is,
at least in part, related to very elevated CPP, which
may cause barotrauma and vessel damage with hypertensive encephalopathy and overperfusion injury.
These findings underline the fact that therapeutic
strategies that ensure reduction of the CPP with
maintenance of cerebral perfusion seem most likely
to prevent the cerebral injuries (over- or underperfusion) that cause seizures/death in women with
preeclampsia/eclampsia.
CEREBRAL BAROTRAUMA AND
HYPERTENSIVE ENCEPHALOPATHY
As outlined previously, the data strongly suggest that
in preeclampsia, the proximal cerebral vasculature is in
a state of protective vasoconstriction that is autoregulated and which maintains normal blood flow in the
thinner-walled distal vessels. This autoregulation does
not come without a price, however. The increased perfusion pressure proximal to the areas of protective vasoconstriction subjects the arterial/arteriolar wall to a
shear force that, if persistent, can result in vascular
barotrauma, leakage of fluid into the interstitium, vaso-

659

genic (16) (and sometimes cytotoxic) edema (28)

around the blood vessels, disruption of the bloodbrain
barrier allowing stimulatory substances into the cerebral
extravascular compartment, and, in some cases, vasospasm (19). Damage to the vessel wall may result in
failure of autoregulation and an overperfusion state in
which flow increases and overwhelms distal capillaries.
Abnormal autoregulation has been shown to occur in
both the cerebral and renal circulations of preeclamptic
women (2931). Because most eclamptic seizures originate from the MCA distribution, the abnormal response in this vessel may indicate failure of local
autoregulation. A similar response, failure to protect an
organ from excessive blood pressure, has been reported
by Kublickas et al (31), who showed decreased resistance in the renal artery in preeclampsia despite increasing perfusion pressure. Others have shown differential
vascular abnormalities in the occipital lobes in eclamptic women, a finding that is in concert with the frequently encountered visual disturbances and occasional
reversible blindness seen in this disease (3234). These
data support the theory that in some preeclamptic patients, as a result of abnormal cerebral autoregulation,
overperfusion of the brain may occur with resulting
hypertensive encephalopathy. This might explain the
failure of prophylactic medications that tend to increase
cerebral perfusion (eg, nimodipine) and perhaps encourage the persistent seizures seen in some eclamptic
women.
What actually causes eclamptic seizures is still unknown. Seizures may occur early in the process, before
the development of vasospasm, and be the result of the
vasogenic/cytotoxic edema with breakdown of the
bloodbrain barrier. In some cases, hypertensive encephalopathy alone may be enough to set off an ectopic
electrical focus leading to seizure activity. In other
cases, this may not be sufficient, and the ensuing interference with endothelial production of vasodilators and
damage to the arteriolar muscularis may be required to
bring about a pathologic state of extreme and unrelenting vasoconstriction with resulting ischemia. This
ischemia may be the trigger required to start seizure
activity. The fact that vasospasm is present within hours
of the seizure may simply be an epiphenomenon after
initial hypertensive encephalopathy, or it may be the
cause of the seizure. In either case, vasospasm will be
present after the seizure.
THE CHOICE OF AN IDEAL AGENT FOR
THE PREVENTION OF ECLAMPSIA
From the data presented previously, it is assumed
that most women with preeclampsia (by blood pres-

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Obstetrical and Gynecological Survey

sure criteria) will have normal cerebral perfusion,

whereas some will be overperfused (hypertensive
encephalopathy) and a very small minority will be
underperfused (ischemic) (Fig. 3). Women with hypertensive encephalopathy will most likely benefit
from a drug that predominantly causes peripheral
vasodilatation (leading to reduction in CPP) but that
maintains cerebral blood flow within the normal
range. The few preeclamptic women with cerebral
ischemia are more likely to benefit from a drug with
predominant cerebral vasodilator effect.
MAGNESIUM SULFATE
Magnesium sulfate has been extensively used in
the management and prevention of eclamptic seizures in the United States (4,35). It has been shown
to be superior to both diphenylhydantoin and diazepam in the prevention of recurrent seizures in
eclamptic patients (36). Lucas et al (37) addressed
the prophylactic use of magnesium sulfate in gestational hypertension and preeclampsia and showed
that MgSO4 is more effective in preventing an initial
seizure than diphenylhydantoin. The recently published MAGPIE study (9) supported the use of MgSO4
as a prophylactic agent for eclampsia and demonstrated
a significant reduction in seizures when compared with
placebo. However, in this study, despite MgSO4, 0.8%
of women with preeclampsia (mild or severe) still developed eclampsia. Likewise, our own Nimodopine
study (8) of approximately 1600 severe preeclamptics
showed that 0.8% of women developed eclampsia despite MgSO4. Although the MAGPIE study did not
provide insight into the mechanism of eclampsia, the
Nimodipine study suggests that eclampsia is unlikely to
be the result of severe vasospasm.
The mechanism of action of MgSO4 is still undefined. We, and others, have suggested that MgSO4
has a cerebral (and retinal) vasodilator effect in
women with preeclampsia (3847), although the relative contribution of this effect to the prophylactic
and/or treatment efficacy is unknown. Hatab et al
(48) have recently contradicted this theory with magnetic resonance imaging data showing no vasodilator
effect of MgSO4 in severe preeclampsia. Their patients were, however, a select group and they excluded those with blood pressure 160/110 mm Hg
and those with symptoms of cerebral irritation, and
the applicability of their findings to all severely preeclamptic women may be questioned. Although their
study does not rule out a microvascular effect, it does
make it less likely that the predominant antiseizure
action of MgSO4 is at the level of blood flow regu-

lation in the larger brain arteries (middle cerebral,

anterior cerebral, or posterior cerebral arteries).
Despite conflicting data on the vasodilator effect of
MgSO4, our previously held opinion that it acts
predominantly through vasodilatation of constricted
cerebral vessels by opposing calcium-dependent arterial vasospasm is placed into doubt by the findings
of the Nimodipine study (8). The fact that MgSO4
dilates arterioles distal to the MCA in preeclamptic
women does not mean that these arterioles were
vasospastic to start with. They may be demonstrating
protective vasoconstriction (normal autoregulatory
state) or, as a result of aberrant autoregulation, they
may not be vasoconstricted at all. In some cases of
severe preeclampsia and eclampsia in which the resistance is low or normal, forced vasodilatation of
the downstream vasculature without simultaneous reduction in blood pressure/cerebral perfusion pressure
may actually be deleterious. We have shown that
MgSO4 reduces the CPP in preeclamptic patients
(49), whereas nimodipine increases it.
We have also shown that in some patients, MgSO4
has a sustained systemic (up to 6 hours) antihypertensive effect (in up to 30% of women with an admission
MAP 126 mm Hg) (8). One can perhaps explain
some of the prophylactic anticonvulsive action of
MgSO4 on the basis of a combination of its cerebral
vasodilator and simultaneous peripheral antihypertensive effects as well as an as yet unidentified membranestabilizing action. An agent that provides more rapid
and effective peripheral vasodilatation than cerebral
vasodilatation will decrease CPP and potentially prevent hypertensive encephalopathy. The combination of
simultaneous (but proportionately greater) systemic
blood pressure reduction with reliable cerebral vasodilatation is possibly the key to effective seizure prophylaxis with MgSO4. Magnesium sulfate may reduce the
cerebral perfusion pressure and decrease the risk of
cerebral barotrauma (both by diminishing the physical
distention of the blood vessels and by antagonizing the
increase in the intracellular calcium concentration
caused by sustained vasoconstriction) (38,39) and in
this way maintain normal cerebral blood flow.
LABETALOL
Labetalol is a rather unique substance in that it has
both selective, competitive alpha-1 and nonselective,
competitive beta-adrenergic-blocking actions (50). In
humans, the ratio of the alpha and beta blockade is
estimated to be approximately 1:3 and 1:7 for the oral
and intravenous compounds, respectively (50). At
higher doses than required for adrenoreceptor block-

Cerebral Hemodynamics in Preeclampsia Y CME Review Article

ade, labetalol has been shown to be a membrane

stabilizer (51).
Labetalol produces rapid dose-dependent decreases
in blood pressure without reflex tachycardia or significant reduction in heart rate. Hemodynamic effects
on cardiac output are minimal, and the predominant
effect appears to be a decrease in peripheral vascular
resistance (52). Satisfactory blood pressure control
has been achieved with either intravenous or oral
administration. In fact, oral labetalol has been used
for acute control of severe preeclampsia and has been
found to be comparable to hydralazine (53). Mabie
and coworker (54) compared bolus-dose intravenous
labetalol with intravenous hydralazine in the acute
treatment of severe hypertension. They found that
labetalol had a quicker onset of action and did not
result in reflex tachycardia (54). In terms of fetal
effects, blood pressure reduction with labetalol does
not result in fetal distress (54,55) unlike acute blood
pressure reduction with hydralazine in which 15% of
fetuses will exhibit distress frequently requiring immediate cesarean section for delivery (56).
Despite reduced maternal blood pressure, labetalol
does not decrease uteroplacental blood flow (57,58). As
with all beta-blockers, labetalol has been associated
with hypoglycemia, bradycardia, and hypotension, but
neonatal outcome is uniformly good (54,59,60).
In pregnant women with hypertension, the peak
serum level of labetalol has been shown to occur
within 20 to 60 minutes after a 100-mg oral dose with
a terminal elimination half-life of 1.7 0.27 hours
(61). The elimination half-life after intravenous administration in pregnant hypertensive patients is similar to that seen with oral administration (62). The
elimination half-life at steady state is significantly
less than that seen in nonpregnant individuals (68
hours) (63), and for this reason, more frequent dosing
is recommended in pregnancy (46 hours). Rogers et
al reported a fetal/maternal serum ratio of 0.5 0.15
and an amniotic fluid/maternal serum ratio of 0.16
0.13 (61).
Labetalol has some interesting and potentially important nonantihypertensive effects that may be beneficial
in preeclampsia. Among these are an antiplatelet aggregation action (64), a thromboxane-reducing effect (65),
and a fetal lung maturation-accelerating influence (66).
Labetalol has been successfully used for many
years in pregnant women with severe preeclampsia,
and although hydralazine is more commonly used for
the management of acute hypertension in preeclampsia in the United States, labetalol has been shown to
be equally effective (54) and is currently a first-line
recommendation of ACOG for blood pressure con-

661

trol in preeclampsia (5). Of great interest are the data

reported by Walker (67) on the experience at the
Glasgow Royal Maternity Hospital in Scotland. Over
a 10-year period, he and his colleagues managed over
36,000 pregnancies with a 10% rate of hypertension
in pregnancy (67). They had only one patient develop
eclampsia out of a total of 555 women who were
receiving treatment for their hypertension, and in
this patient, the hypertension was inadequately controlled. Fewer than 100 of these 555 patients received
MgSO4, and labetalol was the drug of choice for
hypertension control. Thus, their rate of seizures on
labetalol was on the order of one in 455 (0.2%).
LABETALOL LOWERS CEREBRAL
PERFUSION PRESSURE IN
PREECLAMPSIA: CURRENT DATA
We have recently published our findings on the cerebral hemodynamic effects of labetalol in pregnant
hypertensive women (23). Labetalol reduced the CPP
(Fig. 4) as well as the systolic, diastolic, and mean
blood pressure significantly at 60 and 180 minutes
without significantly affecting the heart rate, MCA velocities, RAP, or CFI (23). Labetalol effectively reduces
CPP, without affecting cerebral perfusion, and this is
thought to be primarily by a decrease in systemic blood
pressure. We recently compared the CPP effects of
MgSO4 and labetalol and showed that labetalol is a
more reliable CPP-lowering agent than MgSO4 (68).

RATIONALE FOR THE USE OF

LABETALOL AS AN ANTICONVULSANT
AGENT IN PREECLAMPSIA
We hypothesize that if reduction of CPP is an important part of the antiseizure prophylactic mechanism of
action of MgSO4 in preeclampsia, then the use of a
more specific, less toxic agent that can be administered
orally such as labetalol may greatly simplify the management of preeclamptic patients while at the same time
providing equivalent or improved efficacy. In addition,
the ease of administration, reduced risk of respiratory
and cardiac depression, lack of need for intensive monitoring of blood magnesium levels, suitability for use by
primary care personnel, safety, and low cost of the
regimen give labetalol very attractive risk/benefit and
cost/benefit ratios. We have demonstrated (23,68) that
labetalol has some important characteristics that may
make it an ideal agent to limit cerebral overperfusion,
control blood pressure, and prevent seizures in pre-

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Obstetrical and Gynecological Survey

Fig. 4. Labetalol significantly reduces cerebral perfusion pressure while maintaining a normal cerebral flow index (23).

eclampsia. This drug has been in use for over 2 decades

and thousands of preeclamptic women and their babies
have been safely treated with it. The potential advantages of using labetalol as a blood pressure-controlling
agent, as well as a seizure prophylaxis agent, in preeclamptic women are wide reaching. By adopting labetalol, if it is proven to be as (or more) effective as
MgSO4, there will be a simplification of the current
system in this country and a significant cost savings.
Given the potential risks of MgSO4, it is possible that
the use of labetalol will reduce maternal mortality from
MgSO4 toxicity. Patients who might not otherwise receive seizure prophylaxis (with MgSO4) as a result of
logistic, personnel, safety, or training issues will be in a
position to have treatment started earlier. This is because the administration of a tablet (with known safety
and no need for monitoring of blood levels) before
transport of a patient is simply easier and more accepted
by nursing staff and primary caregivers.
ETHICS OF NOT TREATING WOMEN
WITH PREECLAMPSIA WITH
MAGNESIUM SULFATE
In many European and Scandinavian countries,
MgSO4 is used sparingly, if at all, in the prophylaxis of
eclampsia, and the only agents used are those for blood
pressure control. Even after the MAGPIE study, there
has not been a significant change in many developed
European countries. Magnesium sulfate is used in cases
in which there is imminent eclampsia and not in cases
of mild preeclampsia or even severe preeclampsia if the
patient is not deemed to have cerebral irritation. The
reported eclampsia rate in these countries is no different
from that reported from countries with almost universal
use of MgSO4 in preeclampsia in the United States.
This statistic is borne out by the MAGPIE study (9) in
which the majority of the adverse outcomes and all of

the maternal mortality occurred in developing countries. It is felt in the developed European countries,
control of hypertension with drugs such as hydralazine
and labetalol provides sufficient protection against
eclampsia, and there is evidence to support this. Some
authors have theorized that MgSO4 is no more effective in the prevention of seizure activity than antihypertensive medication alone (hydralazine or labetalol) (67,69).
Sibai, on the basis of a review of the MAGPIE data,
calculated that in developed countries, 385 preeclamptic women need to be treated to prevent one case of
eclampsia and concluded that because of the rare case
of aspiration or hypoxia associated with eclampsia,
magnesium sulfate prophylaxis may be justified in
women with severe preeclampsia, but that the evidence
to date does not justify routine use of magnesium sulfate prophylaxis in women with mild preeclampsia
(70,71).
Finally, one of the principal reasons for observing
women with preeclampsia during labor is to monitor
their blood pressure. Although MgSO4 has some effect
on blood pressure (8), it is not a primary antihypertensive agent. The use of a primary antihypertensive drug
(labetalol) to treat preeclamptic women during labor
will certainly reduce the number of women who may
need emergency addition of an antihypertensive agent.
PRELIMINARY DATA FROM THE
LABETALOL VERSUS MAGNESIUM
SULFATE STUDY
Between 2002 and 2005, we conducted a pilot
study of labetalol versus magnesium sulfate (72).
Three hundred twenty-two patients were enrolled, of
which 175 women received labetalol and 147 patients MgSO4. Demographics, blood pressure on admission, and laboratory results were similar between

Cerebral Hemodynamics in Preeclampsia Y CME Review Article

663

Fig. 5. Antepartum (left panel) and postpartum (right panel) blood pressures for the labetalol and MgSO4 groups. The postpartum
systolic and diastolic blood pressures were significantly lower in the labetalol group than in the MgSO4 group (72).

the 2 groups. Two patients in each group developed

eclampsia (labetalol 1.1% vs MgSO4 1.4%, P .7).
One patient in the labetalol group died as a result of
pulmonary fat emboli and was diagnosed at autopsy
as having had fatty liver of pregnancy. There were no
differences in the rates of abruptio placentae (2.6%
for labetalol vs 0% for MgSO4), cesarean section for
fetal distress (35% for labetalol vs 46% for MgSO4),
postpartum hemorrhage (2.0% for labetalol vs 0.5%
for MgSO4), or postpartum pulmonary edema (0.5%
for labetalol vs 0% for MgSO4).
The MgSO4 group required significantly more additional antihypertensive therapy. Blood pressure
control in the labetalol group was characterized by
significantly lower postpartum systolic and diastolic
blood pressures (Fig. 5). Intrapartum blood control
was similar between the 2 groups. There were no
significant differences in terms of the other recorded
parameters between the 2 groups: headache, diplopia,
scotomata, hypotension, nausea, vomiting, allergic
reaction, and respiratory depression. There were also
no significant differences in intra-/postpartum complications or neonatal outcomes. The mean heart rate
was significantly lower in the labetalol group during
both antepartum and postpartum time periods.
Routine administration of labetalol to patients who
were not hypertensive after the first dose did not
result in hypotension or fetal compromise.
The neonatal outcomes were similar with no significant differences being detected. In particular,
neonatal bradycardia and hypoglycemia were not
seen. The nursing staff and doctors were very receptive to the protocol and preferred using labetalol,
which they found easier, less time-consuming, and
more comfortable for their patients than standard
MgSO4 therapy. Obviously, the numbers in this preliminary study are not sufficient to completely ad-

dress the issue of safety, and the preliminary study

was undertaken to test the protocol suitability for the
multicenter study, to identify any potential logistic
problems, and to assess the satisfaction of the patients, nurses, and physicians with the study. The
safety issues have been addressed by others, and we
feel comfortable that labetalol is both safe and efficacious for hypertension control in preeclampsia.
ACOG (5) has recommended this drug as an alternative to hydralazine, and Walker (67) has amassed
sufficient data to show that the drug is safe as a single
agent in preeclampsia and chronic hypertension.
Most units around the country use labetalol as either
their primary or secondary agent for the control of
hypertension in preeclampsia, and no safety issues
have been raised over the many years that this drug
has been in use.
THE LAMPET STUDY
On the basis of our pilot study, we have initiated
the LAMPET (Labetalol versus Magnesium Sulfate
for the Prevention of Eclampsia Trial) study, a multicenter, randomized, controlled clinical trial comparing the antiseizure effect of parenteral and/or oral
labetalol (n 4000) versus parenteral (intravenous
or intramuscular) MgSO4 (n 4000) with mild or
severe preeclampsia who are deemed to be at
sufficient risk to warrant seizure prophylaxis with
MgSO4. Patients receiving labetalol will either be
given a 20-mg intravenous loading dose followed by
a 200-mg oral dose every 6 hours from the time of
inclusion in the study until 24 hours postpartum or
will receive only the 200-mg oral dose every 6 hours
from inclusion. Whether or not an intravenous dose
is necessary will be decided by the clinician in
charge. Only patients thought to be at sufficient risk

664

Obstetrical and Gynecological Survey

to warrant immediate antihypertensive therapy will

receive the initial intravenous dose. Patients randomized to the MgSO4 group will receive intravenous
MgSO4 as a 4- or 6-g loading dose over 20 minutes
followed by a 1- or 2-g per hour continuous infusion
until 24 hours postpartum. The exact MgSO4 protocol used will be determined by the protocol in use at
each institution. We have previously shown in the
Nimodipine study (as have others with the MAGPIE
study) that there is no difference in seizure rates
between protocols that use 1-g per hour and 2-g per
hour maintenance infusions.
Patients on the labetalol arm of the study who
convulse will be treated with MgSO4. Patients on the
MgSO4 arm who convulse will continue to receive
MgSO4. All patients who convulse will be managed per the units standard protocol for eclampsia
treatment.
All patient data will be recorded in an Internetbased interactive computer database. The URL is www.
labetalol.org and a testing/training program can be
accessed by interested parties using the URL www.
medscinet.com/labetaloltest/, login name: training, password: training. This will allow the potential site principal investigator to review the training web site. The
database satisfies all HCA, HIPPA, FDA CRF 21 Part
11, and NIH security protocols. We are currently recruiting sites and any interested parties can contact the study
coordinator at janalee.thompson@HCAHealthcare.com.

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