Preeclampsia (Toxemia of Pregnancy)
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 described above.
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, 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 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, and edema.
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 preeclampsia.
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 coagulation (DIC).
Mortality/Morbidity: Preeclampsia is the second leading cause of maternal mortality, constituting 12-18% of pregnancy-related maternal deaths.
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
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.
Urine analysis of a clean-catch specimen: Proteinuria
2+ or higher is significant and warrants further
evaluation to rule out preeclampsia.
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 delivery.
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 pregnancy.
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.
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.
Pregnancy Woe Uncovered: Protein
may underlie preeclampsia
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 the disease.
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 death.
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 symptoms.
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 delivery.
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 at http://www.jci.org/cgi/content/full/111/5/649.
Harder, B. 2002. Drug cuts risk of seizures in pregnancy. Science News 161(June 22):398. Available to subscribers at http://www.sciencenews.org/20020622/note14.asp.
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.
Seppa, N. 2001. Study reveals male link to preeclampsia. Science News 159(March 24):181. Available to subscribers at http://www.sciencenews.org/20010324/fob3.asp.
For more information about preeclampsia, see the Preeclampsia Foundation Web site at http://www.preeclampsia.org/.
S. Ananth Karumanchi
Marshall D. Lindheimer
From Science News, Vol. 163,
No. 10, March 8, 2003, p. 147.
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