Preeclampsia (Toxemia of Pregnancy) by Matthew Warden, MD & Brian Euerle,
Background: Preeclampsia is a disorder
associated with pregnancy that consists 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
The hypertension component of the disease is
present when the systolic blood pressure is
above 140 mm Hg (30 mm Hg above the prepartum
levels), and the diastolic blood pressure is
above 90 mm Hg (15 mm Hg above the prepartum
level). The diagnosis requires 2 such abnormal
blood pressure measurements recorded 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 those with 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,
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
observed 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,
Additional theories have arisen from epidemiologic
research, suggesting the important role of
genetic and immunologic factors. The increased
incidence observed in patients using barrier
contraception, in multiparous women conceiving
with a new partner, and in nulliparous women
suggests 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
The pathophysiology of eclamptic seizures is
not understood. These events are believed to
arise from the same preeclamptic effects observed
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 women with severe preeclampsia
and 30-50% of women with eclampsia 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. Women with preeclampsia
with this syndrome develop hepatocellular necrosis
and liver dysfunction. They also have an increased
mortality rate, and one third of women with
preeclampsia develop disseminated intravascular
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
rates, a result of iatrogenic prematurity.
Mortality/Morbidity: Preeclampsia is
the second leading cause of maternal mortality,
constituting 12-18% of pregnancy-related maternal
Race: Black women have as much as 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 Section 3 of 10
Author Information Introduction Clinical Differentials
Workup Treatment Medication Follow-up Miscellaneous
Seizures, coma, headache, focal neurologic
symptoms, and visual disturbances in pregnant
women can be evidence of the development
of preeclampsia or a suggestion of cerebral
hemorrhage, edema, vasospasm, or thrombosis.
Patients note decreased urine output and
Asymptomatic hypertension is discovered
on routine prenatal examination.
Diffuse edema has a high specificity for
Neurologic findings such as papilledema
and hyperreflexia must be addressed quickly
because they can herald the onset of eclampsia.
Petechiae and bruising can suggest coagulopathy.
Right upper quadrant or mid epigastric
tenderness develops as a result of hepatocellular
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
Nulliparity (85% of preeclampsia cases
occur in primigravid women)
As high as twice the relative risk:
- Multiparous women conceiving with
a new partner
- Unmarried women
- Black women
Additional risk factors:
- Diabetes: Women with gestational
diabetes have a 15% increased risk; women
with pregestational diabetes have a 30%
risk of preeclampsia.
- Renal disease
- Women who smoke have a decreased
incidence of preeclampsia.
Urine analysis of a clean-catch specimen: 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 women
with preeclampsia, resulting in elevated uric
Transaminases and prothrombin time: Elevated
transaminases result from hepatocellular necrosis,
but prothrombin time remains within the reference
range, underscoring that hepatic function remains
Confirmation of normal fetal development is
important and is standard prenatal care in
In women developing signs and symptoms of preeclampsia
prior to 20 weeks’ gestation, ultrasound
should be utilized to rule out a molar pregnancy.
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 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 (ALT) to serum aspartate
aminotransferase (AST) that is twice the reference
range 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, preeclampsia 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/h) that resolves
with fluid intake, an ALT/AST ratio higher
than twice the reference range, 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 requires emergent caesarian
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 risks and benefits of continuing a preterm
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
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
Further Outpatient Care:
Patients with preeclampsia 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 pressure recordings
should be analyzed as described above. This
can help identify worsening preeclampsia.
Postpartum patients without a history of preeclampsia
rarely develop the disease.
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 delivery. Infant morbidity
and mortality rates are inversely related to
the time from maternal cardiopulmonary arrest
to delivery of the fetus.
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 managed medically. Alternately,
inaction during worsening preeclampsia
resulting in fetal or maternal morbidity
also can result in litigation.
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Pregnancy Woe Uncovered: Protein
may underlie preeclampsia Kendall Morgan,
Many of the symptoms of preeclampsia,
a major cause of maternal death and premature
birth worldwide, stem from a single protein,
researchers have found. The discovery could
lead to new ways of detecting and treating
Preeclampsia strikes 1 in 20
pregnancies, usually in the final trimester.
Symptoms include high blood pressure and proteinuria—excessive
protein in the urine. Preeclampsia can escalate
to eclampsia, characterized by life-threatening
seizures and kidney damage in the mother.
Earlier research had implicated
the placenta, the vascular organ uniting mother
and fetus. Without more specifics about what
underlies the disease, however, early delivery
of the baby and placenta is often required
to dispel the symptoms. This treatment leads
to premature births and sometimes the baby's
In search of the condition's
molecular bases, nephrologist S. Ananth Karumanchi
of Harvard Medical School in Boston and his
colleagues compared gene activity in the placentas
of healthy and preeclamptic women. Of the hundreds
of differences the team uncovered, one stood
out. The gene encoding a protein called soluble
fms-like tyrosine kinase 1 (sFlt1) was overactive
in the preeclamptic placentas.
Scientists already knew that
sFlt1 thwarts blood vessel growth. Moreover,
previous research had shown that in some cancer
patients, a drug with activity similar to sFlt1's
induced preeclampsia-like symptoms.
Early in pregnancy, the placenta
produces proteins that keep it growing along
with the fetus. Later, Karumanchi suspects,
the placenta makes sFlt1 to halt that growth.
"In preeclampsia, that balance is shifted.
. . . The body makes more [sFlt1] too soon,"
Karumanchi hypothesizes. "Some of that
excess spills into the mother's blood,"
destroying endothelial cells in her body and
leading to at least some of the condition's
Karumanchi and his colleagues
uncovered plenty of evidence incriminating
sFlt1. For example, they found that blood concentrations
of the protein in pregnant woman with preeclampsia
were higher than in healthy pregnant women.
The abnormal sFlt1 concentrations dropped after
The researchers also found that
blood serum from preeclamptic women stifled
development of human blood vessel cells growing
in lab dishes, while serum from healthy women
stimulated cell growth. Treatment with blood
vessel promoters reversed the vessel-stunting
effects of preeclamptic women's blood. One
more thing: When injected into rats, sFlt1
elicited preeclampsia symptoms. The researchers
report their results in the March 1 Journal
of Clinical Investigation.
That an inhibitor of blood vessel
growth could play a role in preeclampsia "makes
a lot of sense in retrospect," says vascular
scientist Peter Carmeliet of the Katholieke
Universiteit in Leuven, Belgium.
"It's difficult to attack
a disease unless there is a known cause,"
adds Marshall D. Lindheimer, a nephrologist
at the University of Chicago and a medical
advisor to the Preeclampsia Foundation.
Now that sFlt1's role in preeclampsia
has come to light, scientists can work toward
a treatment that counteracts the protein's
nefarious effects, says Lindheimer. If sFlt1
concentrations rise before the onset of other
symptoms, he adds, the factor may also prove
useful for early disease detection and prevention.
Karumanchi points to another
benefit of the discovery. "There have
been no animal models that reproduce all the
disease symptoms," he says. Now, rats
injected with sFlt1 can serve that purpose,
and researchers can test potential preeclampsia
therapies on them.
Maynard, S.E. . . .and S.A. Karumanchi,
et al. 2003. Excess placental soluble fms-like
tyrosine kinase 1 (sFlt1) may contribute to
endothelial dysfunction, hypertension, and
proteinuria in preeclampsia. Journal of Clinical
Investigation 111(March 1):649-658. Available
Luttun, A., and P. Carmeliet.
2003. Soluble VEGF receptor Flt1: The elusive
preeclampsia factor discovered? Journal of
Clinical Investigation 111(March 1):600-602.
Available at http://dx.doi.org/10.1172/JCI200318015.
Center for Transgene Technology and Gene Therapy
Flanders Interuniversitary Institute for Biotechnology
Katholieke Universiteit Leuven
S. Ananth Karumanchi
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
Marshall D. Lindheimer
5807 South Dorchester
Chicago, IL 60637
From Science News, Vol. 163,
No. 10, March 8, 2003, p. 147.