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US Pharm. 2012;37(9):48-53.
According to the CDC’s Pregnancy Mortality Surveillance
System, hypertensive disorders account for 11.1% of all causes of
pregnancy-related death in the United States during the 2006–2007
period.1 Preeclampsia, in particular, represents a unique
form of pregnancy-related hypertension. It is characterized by a series
of multisystem abnormalities usually occurring after 20 weeks of
gestation with an ensuing diagnosis of new-onset hypertension (blood pressure [BP] >140/90 mmHg) and proteinuria (a finding of protein in the urine >300 mg over a 24-hour period).2,3
In contrast, women who develop new-onset grand mal seizures in the
presence of preeclampsia are deemed eclamptic and require immediate
medical intervention.3
A PATHOPHYSIOLOGIC GUMBO
Despite decades of extensive clinical research and
analysis, identifying the origin of preeclampsia remains an elusive
target. Preeclampsia is a heterogeneous syndrome in which pathogenesis
can be diverse among women with various risk factors. Pathologic
variations in preeclampsia in nulliparous women may be different from
those in women with preexisting cardiovascular disease, twin gestation,
diabetes mellitus, chronic hypertension, or various thrombophilias.4,5
In addition, the pathophysiology of early-onset preeclampsia may be
different from that of preeclampsia developing at term, during labor, or
in the postpartum period. Disparities in the onset of preeclampsia
might lead to different preventive and pharmacologic interventions.6
The causes of preeclampsia tend to reflect a pathophysiologic gumbo.
Theories most commonly proposed for the etiology of preeclampsia include
endothelial dysfunction, placental abnormalities, blood coagulation
disorders, cardiovascular and immunologic maladaptation, genetic
predisposition, and excessive inflammatory and oxidative stress, just to
name a few.4,7-9
PREECLAMPSIA AT A GLANCE
Preeclampsia is a syndrome that embraces a wide spectrum
of symptomatology. Traditionally, elevated BP and proteinuria served as
primary indicators for confirmation of this disorder. Other signs and
symptoms may also be present and can parallel expected symptoms seen
throughout the pregnancy stages. In some cases, preeclampsia can be
asymptomatic and only be discovered upon routine screening.10
Preeclampsia can be subdivided into two categories based on symptomatology—mild or severe. Mild preeclampsia
by definition is the presence of hypertension (BP >140/90 mmHg) on
two occasions at least 6 hours apart, but without evidence of end-organ
damage in the patient.10 Severe preeclampsia, on the
other hand, may include an array of signs and symptoms and significant
laboratory findings. At least one of the signs or symptoms presented in TABLE 1
must coexist with the indicators of preeclampsia for the condition to
be regarded as severe. Differentiating the characteristics of mild
preeclampsia from those of severe preeclampsia is essential because this
influences management.11
HIGH-RISK PREGNANCIES
Currently, there are no validated screening tools
recommended to predict or identify the patient at risk for development
of preeclampsia. Therefore, pregnant women should be informed and
vigilant in monitoring for the signs and symptoms and communicating with
their health care providers about any problems that could lead to
unfavorable complications.3 Pregnancies considered most at
risk are based on personal history, preexisting medical conditions, and
family history. Examples of high-risk pregnancies include woman’s age
≥35 years, first pregnancy, preeclampsia in a previous pregnancy,
chronic hypertension, gestational diabetes, multifetal gestations,
antiphospholipid antibody syndrome, and renal disease.4,5
Obesity has been shown to have a strong correlation with
the development of preeclampsia. In a study conducted in the United
Kingdom, results indicated that 9% of extremely obese women experienced
preeclampsia in comparison with 2% of matched controls.5,12
With the growing concerns about obesity worldwide, large studies are
needed for confirmation of this plausible relationship; preventive
measures will be crucial to thwart the potential impact upon the
incidence of preeclampsia.
MANAGEMENT OF PREECLAMPSIA
The clinical course of preeclampsia can lead to
devastating effects for both the mother and the fetus. Characteristics
such as gestational age and disease severity are key components in
identifying the most appropriate methods for managing patients at risk.10
Goals of management should emphasis safety of the mother and delivery
of a healthy infant, while minimizing risk to both. The American College
of Obstetricians and Gynecologists (ACOG) recommends that management of
women with severe preeclampsia remote from term be monitored in a
tertiary care setting or with the advice of an obstetrician-gynecologist
who specializes in high-risk pregnancies.3
In women with severe preeclampsia where HELLP (evidence of
Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome is
present, delivery is the management of choice, despite gestational age.3,5
HELLP is usually characterized by progressive and sometimes sudden
deterioration in both maternal and fetal condition. Maternal
complications can include eclampsia, abruptio placentae, acute renal
failure, and postpartum bleeding, whereas the unborn child may
experience intrauterine growth restriction (IUGR), thrombocytopenia, or
even perinatal death; thus, the management of HELLP syndrome is highly
controversial.5,11,13,14 Based on the weeks of gestation,
some clinicians may administer corticosteroids in the attempt to
accelerate fetal lung maturity followed by delivery after 24 hours, while
others may opt to prolong pregnancy until maternal or fetal indications
dictate delivery. In the latter case, expectant management is
instituted through the following measures: bed rest, antihypertensive
agents, antithrombotic agents, plasma volume expanders, and
corticosteroids.5,11 Current recommendations state that expectant management should only be considered in those with mild preeclampsia.3
THERAPEUTIC MODALITIES
The therapeutic options presented below are the most
common drugs used in the management of seizures and stabilization of BP
in severe preeclampsia.
Prophylaxis and Treatment of Seizures
Magnesium Sulfate: Magnesium sulfate has been
utilized for seizure control since the 1920s, but it received its first
confirmation as an efficacious treatment for severe preeclampsia and
eclampsia in 1995 through the Collaborative Eclampsia Trial.15
This was a multicenter, international, randomized, placebo-controlled
study that included over 10,000 women. Those treated with magnesium
sulfate had a 52% and 67% lower recurrence of convulsions than those
treated with diazepam and phenytoin, respectively. In patients with
severe preeclampsia, the use of magnesium reduced the risk of
progression to eclampsia by more than half and reduced maternal
mortality.15 A 2-year outcome follow-up trial was also
conducted and revealed that women receiving magnesium sulfate therapy
had a 58% lower risk of eclampsia (95% CI, 40%-71%) than women receiving
placebo (0.8% risk in patients receiving magnesium sulfate versus 1.9%
in patients receiving placebo). The results of this trial suggest that
magnesium sulfate therapy prevents eclampsia and may reduce the risk of
maternal death.16
Magnesium sulfate is considered first-line treatment for
the prevention of primary and recurrent eclamptic seizures. It is also
utilized for prophylactic treatment in all patients with severe
preeclampsia.15,16 The mechanism of action of magnesium
sulfate is thought to trigger cerebral vasodilation, thus reducing
ischemia generated by cerebral vasospasm during an eclamptic event. The
substance also acts competitively in blocking the entry of calcium into
synaptic endings, thereby altering neuromuscular transmission. The
recommended regimen of magnesium sulfate is a loading dose of 4 to 6 g
given over 15 to 20 minutes, followed by a maintenance dose of 2 g/h as a
continuous IV solution.3,17-19 Magnesium sulfate is
initiated at the beginning of the observation period and then continued
during labor and for at least 24 hours postpartum. In those with
abnormal renal function (oliguria or serum creatinine ≥1.2 mg/dL), the
dose of magnesium sulfate should be reduced and even discontinued.5,20
The therapeutic serum magnesium concentration range is considered to be
4 to 8 mg/dL. Signs of toxicity start with the loss of patellar deep
tendon reflexes, weakness, double vision, and dysarthria. Respiratory
depression/or arrest can occur with levels >14 mg/dL.17
Controlling Elevated Blood Pressure
Treating acute severe hypertension in preeclampsia is
crucial to preventing cerebrovascular and cardiovascular events as well
as maternal death. Antihypertensive therapies should be utilized in
women with systolic BP values of 160 to 180 mmHg or higher19 and diastolic BP values of 105 to 110 mmHg or higher.3,19 TABLE 2 summarizes these agents.
Hydralazine: Hydralazine is an
arteriolar vasodilator that has long been used for lowering BP in severe
hypertension and preeclampsia in pregnancy. It is administered as a 5-
to 10-mg dose IV or IM every 15 minutes up to a maximum dose of 20 mg IV
or 30 mg IM. The onset of action is 10 to 20 minutes. BP is recorded
every 15 minutes during therapy and every hour once the desired values
are achieved. If hydralazine does not lower BP adequately or if maternal
side effects such as tachycardia or headaches develop, another agent
should be considered.10,17-20
Labetalol: Labetalol is a nonselective, competitive beta-adrenergic and a selective, competitive alpha1-adrenergic
blocking agent. The mechanism of action is exerted by reduction of
peripheral vascular resistance without compromising blood flow to the
brain and peripheral, coronary, or renal systems. The recommended dose
of labetalol is 20 mg over slow-infusion IV (every 2 minutes) for a
maximum dosage of 300 mg.19,20 Potential benefits of
labetalol over hydralazine include quicker onset of action and less risk
for reflex tachycardia. Labetalol, however, should be avoided in
patients with moderate-to-severe asthma, bradycardia (heart rate <60
beats per minute), or congestive heart failure.17-20
Nifedipine: Nifedipine is an oral,
type 2 calcium channel blocker that inhibits the inward flow of calcium
across slow channels of cellular membranes. It reduces BP without
compromise to placental blood flow. Compared with hydralazine,
nifedipine has a quicker onset of action, as well as the added advantage
of oral administration. Nifedipine should only be given as an oral
short-acting preparation in an initial dose of 10 to 20 mg orally every
30 minutes for a maximum dosage of 50 mg.20 Common side
effects include tachycardia, headaches, and palpitations. Marked
hypotension with magnesium sulfate and nifedipine has been reported;
therefore, concomitant use should be avoided.10,20
Nicardipine: Nicardipine
hydrochloride is a calcium channel blocker that may be an alternative to
the agents previously discussed. It causes less tachycardia than
nifedipine and provides BP-lowering effects within an average of 15
minutes following IV administration. Nicardipine is initiated as an IV
infusion at a rate of 5 mg/h with increments of 2.5 mg/h every 5 minutes
to a maximum dosage of 10 mg/h or until the mean arterial pressure is
reduced by 15%.17,20
Sodium Nitroprusside: When the
aforementioned agents fail to lower the BP in severe preeclampsia,
sodium nitroprusside may be given. It is a vasodilatory agent that works
by releasing nitrous oxide, which reduces both preload and afterload.
The onset of action is very quick and can result in severe rebound
hypertension. Additionally, the patient may experience headaches,
palpitations, and cyanide poisoning. If severe hypertensive emergency
necessitates the use of sodium nitroprusside, the dosage should be
initiated as an IV infusion with a rate of 0.20 mcg/kg/min with gradual
titration every 5 minutes, not to exceed 4 mcg/kg/min.17,20
CONCLUSION
Without clear national consensus guidelines on the origin
of preeclampsia, the clinician is faced with management challenges and
maternal and fetal risk-versus-benefit issues. The key to prevention
lies in identifying those patients most at risk and closely monitoring
their clinical and laboratory progress. The main objectives of treating
preeclampsia include avoiding complications of severe hypertension,
preventing the development of eclampsia, and decreasing the morbidity
and mortality of the mother and unborn child. Pharmacists can play an
integral role in providing early education to those expectant mothers at
high risk for developing preeclampsia.
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To comment on this article, contact rdavidson@uspharmacist.com.
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