Preeclampsia (Toxemia of Pregnancy)

INTRODUCTION

Background: Preeclampsia is a disorder associated with pregnancy

consisting of hypertension, proteinuria, and new-onset nondependent
edema that presents, in most cases, after the 20th week of
pregnancy. Eclampsia is defined as seizure activity in a patient with
the presentation described above.

The hypertension component of the disease is present when the

systolic blood pressure is above 140 (30 mm Hg above the
prepartum levels), the diastolic blood pressure is above 90 (15 mm
Hg above the prepartum level). The diagnosis requires 2 such
abnormal blood pressure measurements at least 6 hours apart.

Proteinuria is present when the urinary protein concentration is

greater than 300 mg during a 24-hour period or 2+ proteinuria or
higher on a clean-catch urine specimen in a woman without a urinary
tract infection.

Pathophysiology: The etiology of preeclampsia is unknown.

However, placental delivery reverses the symptoms of preeclampsia,
suggesting that the placenta has a controlling role in the condition.
Additionally, women with increased placental tissue for gestational
age, such as hydatiform moles and twin pregnancies, have an
increased incidence of preeclampsia. In fact, the presence of
proteinuric hypertension prior to 20 weeks gestation should initiate a
search for molar pregnancy, because it raises the possibility of
increased placental tissue for a given gestational age, which could
cause the symptoms. Other causes include drug withdrawal or
chromosomal abnormality in the fetus (eg, trisomy).

Several theories, which are not mutually exclusive, attempt to explain

the pathophysiology of preeclampsia. One theory holds that an
increase of a number of active circulating mediators during
pregnancy causes the symptoms. For example, increased levels of
angiotensin II during pregnancy may lead to increased vasospasm. A
second theory holds that improper placental development results in
placental vascular endothelial dysfunction and a relative
uteroplacental insufficiency. The vascular endothelial dysfunction
results in increased permeability, hypercoagulability, and diffuse
vasospasm. Finally, another model suggests that the increased
cardiac output seen during pregnancy causes preeclampsia. The
increased blood flow and pressure is felt to lead to capillary dilatation,
which damages end organ sites, leading to hypertension, proteinuria,
and edema.

Additional theories have arisen from epidemiologic research,

suggesting the important role of genetic and immunologic factors.
The increased incidence seen in patients using barrier contraception,
in multiparous women conceiving with a new partner, and in
nulliparous women suggest an immunologic role. Also, inheritance
pattern analysis supports the hypothesis of transmission of
preeclampsia from mother to fetus by a recessive gene.

Newer research suggests primapaternity plays a larger role than

primagravidity as a risk factor for the development of preeclampsia.
Moreover, the duration of time the woman is exposed to the male
antigens prior to conception is inversely related to the risk of
developing preeclampsia.

The pathophysiology of eclamptic seizures is not understood. These

events are believed to arise from the same preeclamptic effects seen
in other areas of the body. In the brain, cerebral vasospasm, edema,
ischemia, and ionic shifts between intracellular and extracellular
compartments are believed to incite eclamptic seizures.

Nearly 10% of severely preeclamptic women and 30-50% of

eclamptic women are affected by the hemolysis, elevated liver
enzymes, and low platelet (count) (HELLP) syndrome. The exact
relationship between the HELLP syndrome and preeclampsia is
unknown. Preeclamptics with this syndrome develop hepatocellular
necrosis and liver dysfunction. They also have an increased mortality
and one third of women with preeclampsia develop disseminated
intravascular coagulation (DIC).

Frequency:

In the US: Preeclampsia occurs in 6-8% of all pregnancies.

The incidence of eclampsia is 0.05%. Preeclampsia is
associated with high perinatal morbidity and mortality, a result
of iatrogenic prematurity.
Mortality/Morbidity: Preeclampsia is the second leading cause of
maternal mortality, constituting 12-18% of pregnancy-related
maternal deaths.

Race: African American women have up to twice the relative risk of

whites of developing preeclampsia.

Age: Younger women have as much as 3 times the relative risk of

developing preeclampsia.

CLINICAL

History:

Seizures, coma, headache, focal neurologic complaints, and

visual disturbances in pregnant women all can be evidence of
the development of preeclampsia or a suggestion of cerebral
hemorrhage, edema, vasospasm, or thrombosis.

Patients note decreased urine output and abdominal pain.

Physical:

Asymptomatic hypertension is discovered on routine prenatal

examination.

Diffuse edema has a high specificity for preeclampsia.

Neurologic findings such as papilledema and hyperreflexia

must be addressed quickly, as they can herald the onset of
eclampsia.

Petechiae and bruising could suggest coagulopathy.

Right upper quadrant or mid epigastric tenderness develops as

a result of hepatocellular necrosis.

Causes: The exact cause of preeclampsia has not been elucidated.

Current research utilizes the known risk factors to help shape theory
about the exact etiology of preeclampsia.

Four times relative risk - Daughter or sister of a woman who

has had preeclampsia

Three times the relative risk - Young maternal age

 o Nulliparity (85% of preeclampsia cases occur in
primigravidas)

o Twin pregnancies

Up to twice the relative risk

o Multiparous women conceiving with a new partner

o Unmarried women

o African American women

Additional risk factors

o Diabetes - Gestational diabetics have a 15% increased

risk, pregestational diabetics have a 30% risk of
preeclampsia

o Hypertension

o Renal disease

Smokers have a decreased incidence of preeclampsia

DIFFERENTIALS

Disseminated Intravascular Coagulation

Fatty Liver
Hemolytic-Uremic Syndrome
Scleroderma
Systemic Lupus Erythematosus
Thrombotic Thrombocytopenic Purpura

Other Problems to be Considered:

Drugs, particularly cocaine intoxication

Primary renal disease

WORKUP

Lab Studies:
 Urine analysis of a clean-catch specimen

o Proteinuria 2+ or higher is significant and warrants

further evaluation to rule out preeclampsia.

A 24-hour urine collection with more than 300 mg of protein

requires further workup.

Uric acid level: Glomerular filtration rate and creatinine

clearance decrease 25% in preeclamptic patients, resulting in
elevated uric acid levels.

Transaminases and prothrombin time: Elevated transaminases

result from hepatocellular necrosis, but prothrombin time
remains normal, underscoring that hepatic function remains
intact.

Imaging Studies:

Ultrasound

o Confirmation of normal fetal development is important

and standard prenatal care in all pregnancies.

o In women developing signs and symptoms of

preeclampsia prior to 20 weeks gestation, ultrasound
should be utilized to rule out a molar pregnancy.

TREATMENT

Medical Care: The only definitive treatment for preeclampsia is

delivery of the fetus and placenta. This is a reasonable choice for
viable fetuses or in cases in which the mother's health is put at
significant risk. Examples of significant health risk include; eclampsia,
pulmonary edema, compromised renal function, abruptio placentae,
platelet count below 100,000, a ratio of serum alanine
aminotransferase to serum aspartate aminotransferase (ALT/AST)
twice normal, with concomitant epigastric and right upper quadrant
tenderness, persistent severe headache or visual changes, and
uncontrolled severe hypertension. In these cases, glucocorticoids
can be administered to women with preterm pregnancies, with
delivery postponed for 48 hours to allow the steroids to improve fetal
lung maturity.
However, symptoms often can be managed in women with preterm
pregnancies if symptoms are mild to moderate. Examples of this type
of preeclampsia include proteinuria of any amount, oliguria (<0.5
mL/kg/hour) that resolves with fluid intake, ALT/AST higher than
twice normal, no abdominal tenderness, and controlled hypertension.
In patients with controlled hypertension, the treatment is to lower
blood pressure.

Medical management focuses on antihypertensive treatment and

anticonvulsant prophylaxis.

Surgical Care: Failure of medical management necessitates

iatrogenic vaginal delivery. Maternal or fetal deterioration calls for
emergent caesarian section.

Consultations: An obstetrician must be consulted regarding the

initial management of a woman with preeclampsia. Any such
admission ought to be made to an obstetric inpatient floor. The
specialist's familiarity with the complications of pregnancy and their
treatment makes him or her uniquely suited to make decisions
regarding antihypertensive and anticonvulsant therapies.
Additionally, obstetricians can best weigh the risk/benefit of
continuing a preterm pregnancy.

MEDICATION

Drug therapy focuses on treatment of hypertension and prophylaxis

against seizures.

Hydralazine is the antihypertensive of choice. Notably, ACE inhibitors

are contraindicated in pregnancy, because of their harmful fetal
effects.

Seizures remain a great concern for any patient with preeclampsia.

Magnesium sulfate is the first-line therapy for seizures because it
prevents vascular spasm. The prevention of vasospasm in the brain
is believed to protect against seizures.

Drug Category: Antihypertensives -- Hydralazine is the drug of choice

for blood pressure control in preeclampsia. However, parenteral
hydralazine is only provided to pharmacists via a special emergency
request. Therefore, one must be comfortable in utilizing other
antihypertensive agents when hydralazine is not immediately
available. Labetalol has alpha- and beta-adrenergic blocking effects
and can be utilized to rapidly control severe hypertension.

Hydralazine (Apresoline) -- First-line therapy against

preeclamptic hypertension. Decreases systemic
resistance through direct vasodilation of arterioles
Drug Name resulting in reflex tachycardia. Reflex tachycardia
and resultant increased cardiac output helps reverse
uteroplacental insufficiency, a key concern when
treating hypertension in a preeclamptic patient.
Adverse effects to the fetus are uncommon.
Adult Dose 5-10 mg IV; repeat q20min to maximum of 60 mg
Pediatric Dose Not established
Documented hypersensitivity, dissecting aortic
Contraindications
aneurysm, mitral valve rheumatic heart disease
Precipitate a propranolol toxicity manifested as
bradycardia, fatigue, and bronchospasm; MAO
Interactions inhibitors and beta-blockers may increase
hydralazine toxicity; pharmacological effects of
hydralazine may be decreased by indomethacin
C - Safety for use during pregnancy has not been
Pregnancy
established.
Adverse effects include headache, flushing,
overshoot hypotension, peripheral edema, lupus
syndrome; implicated in myocardial infarction;
Precautions
caution in suspected coronary artery disease; caution
in renal insufficiency due to enhanced susceptibility
to decreases in BP
Labetalol (Normodyne) -- Second-line therapy that
produces vasodilatation and decrease in systemic
vascular resistance. Has alpha-1 and beta antagonist
Drug Name effects and beta-2 agonist effects. Has more rapid
onset than hydralazine and less overshoot
hypotension. The dosage and duration of labetalol is
more variable. Adverse effects to the fetus are
uncommon.
50-100 mg IV; repeat q30min to a maximum of 300
Adult Dose
mg
Pediatric Dose Not established
Documented hypersensitivity, cardiogenic shock,
Contraindications pulmonary edema, bradycardia, heart block,
uncompensated CHF, reactive airway disease
Labetalol decreases effect of diuretics and increases
toxicity of methotrexate, lithium, salicylates; may
diminish reflex tachycardia, resulting from
nitroglycerine use, without interfering with
Interactions hypotensive effects; cimetidine may increase
labetalol blood levels; glutethimide may decrease
labetalol effects by inducing microsomal enzymes;
decreases bronchodilatory effects and tachycardia of
beta-receptor agonist drugs
C - Safety for use during pregnancy has not been
Pregnancy
established.
 Caution in impaired hepatic function; discontinue
therapy if there are signs of liver dysfunction; in
elderly patients, a lower response rate and higher
Precautions
incident of toxicity may be observed; intensified
bronchospasms, heart block, CHF; cause
tremulousness and flushing
Nitroprusside (Nitropress) -- Used when hydralazine
and labetalol are ineffective. Reduces peripheral
Drug Name
resistance by acting directly on arteriolar and venous
smooth muscle. Nitroprusside has a very short half-
life and therefore allows titration to effect.
0.2 mcg/kg/min and increased as needed to desired
Adult Dose effective response
>10 mcg/kg/min may cause cyanide toxicity
Pediatric Dose Not established
Documented hypersensitivity; subaortic stenosis,
idiopathic hypertrophic and atrial fibrillation or
Contraindications
flutter; ventricular septal defect; arteriovenous shunt;
coarctation of the aorta
Interactions None reported
C - Safety for use during pregnancy has not been
Pregnancy
established.
Monitor cyanide and thiocyanate levels and stop
treatment if these levels approach toxicity
Associated adverse effects of nitroprusside include
tinnitus, blurred vision, altered mental status,
hypotension, and methemoglobinemia
Precautions
Caution in increased intracranial pressure, hepatic
failure, severe renal impairment, and
hypothyroidism; lowers BP and should only be used
in those patients with mean arterial pressures >70
mm Hg

Drug Category: Anticonvulsants

Magnesium Sulfate -- First-line therapy for seizure

prophylaxis. Antagonizes calcium channels of
Drug Name smooth muscle. Indicated in severe preeclampsia,
eclampsia, and preeclampsia in the near term. Give
IV/IM for seizure prophylaxis in preeclampsia. Use
IV for quicker onset of action in true eclampsia.
Adult Dose 4-6 g IV over 20 min, with maintenance of 1-2 g/h
Pediatric Dose Not established
Hypermagnesemia, heart block, severe hepatitis renal
Contraindications
disease, Addison disease, myocardial damage
Concurrent use with nifedipine may cause
hypotension and neuromuscular blockade; may
intensify neuromuscular blockade seen with
aminoglycosides and potentiate neuromuscular
Interactions
blockade produced by tubocurarine, vecuronium, and
succinylcholine; may increase CNS effects and
toxicity of CNS depressants, betamethasone, and
cardiotoxicity of ritodrine
 Pregnancy B - Usually safe but benefits must outweigh the risks.
Magnesium may alter cardiac conduction leading to
heart block in digitalized patients; respiratory rate,
deep tendon reflex, and renal function should be
monitored when electrolyte is administered
parenterally; caution when administering magnesium
Precautions
dose since may produce significant hypertension or
asystole; in overdose, calcium gluconate, 10-20 mL
IV of 10%; serum magnesium level should be
checked one hour after initiation of therapy with goal
of therapeutic level of 4-7 mEq/L
Phenytoin (Dilantin) -- The major site of action is the
motor cortex where it acts by preventing the spread
of seizure activity.
Drug Name Indicated for eclampsia.
Of note, a patient with eclampsia should be started
on Magnesium prior to phenytoin loading.
Neonatal toxicity has not been reported in patients
treated for a short duration prior to delivery.
20 mg/kg IV infused at a rate of 12.5 mg/min, not to
Adult Dose
exceed 1500 mg/24h
Pediatric Dose Not established
Documented hypersensitivity, sinoatrial block, sinus
Contraindications
bradycardia, Adam-Stokes syndrome
Numerous drugs increase or decrease serum levels of
phenytoin; serum levels of phenytoin should be
measure if there is suspicion of a drug interaction
Drugs that may increase phenytoin levels include
acute alcohol ingestion, amiodarone,
chloramphenicol, chlordiazepoxide, diazepam,
dicumarol, disulfiram, estrogens, histamine-2-
antagonists, halothane, isoniazid, methylphenidate,
phenothiazines, phenylbutazone, salicylates,
succinimide, sulfonamides, tolbutamide, and
trazodone
Interactions
Drugs that may decrease phenytoin levels include
carbamazepine, chronic alcohol abuse, reserpine,
sucralfate
Drugs that may increase or decrease phenytoin levels
include phenobarbital, sodium valproate, and
valproic acid
Drugs whose efficacy is decreased by phenytoin
include corticosteroids, coumadin, digitoxin,
doxycycline, estrogens, furosemide oral
contraceptives, quinidine, rifampin, theophylline, and
vitamin D
Pregnancy D - Unsafe in pregnancy
During intravenous load, monitor patient for
hypotension and cardiac arrhythmias, rapid infusion
may result in death from cardiac arrest, marked by
Precautions QRS widening, other signs of toxicity include
nystagmus and lethargy
Check phenytoin level one hour after infusion
completed, therapeutic level is 10-20 mcg/mL
Drug Name Diazepam (Valium) -- For treatment of seizures
resistant to magnesium sulfate. Depresses all levels
 of CNS (eg, limbic and reticular formation), possibly
by increasing activity of GABA.

Indicated for status epilepticus in eclamptic patients.

Adult Dose 5-10 mg IV, repeat prn to total of 30 mg
Pediatric Dose Not established
Documented hypersensitivity; narrow angle
glaucoma
Contraindications Fetal respiratory depression, fetal heart beat
variability, maternal respiratory depression, delivery
of fetus imminent
Several drugs are known to potentiate the effects of
diazepam phenothiazines, narcotics, barbiturates,
Interactions valproate, MAO inhibitors, and other
antidepressants; cimetidine can slow the clearance of
diazepam
Pregnancy D - Unsafe in pregnancy
Monitor respiratory status during administration;
patients with hepatic or renal disease have decreased
Precautions clearance of diazepam, caution must be used in these
patients to prevent excessive accumulation of
diazepam with the resultant symptoms of overdose

FOLLOW-UP

Further Outpatient Care:

Preeclamptic patients who have delivered must continue to

follow-up regularly with their Obstetrician, because eclamptic
seizures have been reported as late as 26 days postpartum.
Blood, urine, and blood pressures should be analyzed as
described above. This can help identify worsening
preeclampsia. Postpartum patients without a history of
preeclampsia rarely develop the disease.

Complications:

An unusual complication of preeclampsia and eclampsia is

maternal cardiopulmonary arrest. Causes include elevated
magnesium levels, hypoxia, massive hemorrhage, and stroke.
Cardiopulmonary resuscitation is necessary, but the presence
of the fetus impedes its efficacy. The outcome of the mother
and the fetus is improved by emergent caesarian section.
Infant morbidity and mortality are inversely related to the time
from maternal cardiopulmonary arrest to delivery of the fetus.
 MISCELLANEOUS

Medical/Legal Pitfalls:

Failure to diagnose preeclampsia

Failure to treat preeclampsia

Failure to treat the sequelae of preeclampsia

Failure to prevent eclampsia

Physicians may be sued for inducing a premature fetus when it

can be argued that the preeclampsia could have been
medically managed. Alternately, inaction during worsening
preeclampsia resulting in fetal or maternal morbidity can also
result in litigation.

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