September 5, 2006
High levels of two proteins in the blood of pregnant women appear to indicate the subsequent development of preeclampsia, a life-threatening complication of pregnancy, report a team of researchers from the National Institutes of Health and Beth Israel Deaconess Medical Center. The proteins, which interfere with the growth and function of blood vessels, also signal the development of high blood pressure during pregnancy.
The findings appear in the September 7 New England Journal of Medicine.
"This finding appears to be an important step in developing a cure for preeclampsia," said Elias A. Zerhouni, M.D., Director of the National Institutes of Health. "It may also provide the basis for predicting whether or not a woman will develop the disorder."
The research team was led by Richard Levine, M.D., M.P.H., of the Division of Epidemiology, Statistics, and Prevention Research at NIH's National Institute of Child Health and Human Development (NICHD), and S. Ananth Karumanchi, M.D., of the Departments of Medicine and Obstetrics and Gynecology at the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston. Funding for the study was provided by the NICHD, as well as two other components of the NIH, the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases.
Preeclampsia is a leading cause of maternal death and often occurs without warning. The condition results in high blood pressure and protein in the urine. Preeclampsia may begin with mild symptoms, then progress to severe preeclampsia and to eclampsia-dangerously high blood pressure and convulsions-which may result in disability or death. When preeclampsia is not severe, the high blood pressure it causes can usually be treated in the short term. The only cure for preeclampsia is delivery of the baby. The condition is estimated to complicate from 3 to 5 percent of all pregnancies.
When preeclampsia occurs late in a pregnancy, the baby can be delivered with relatively few ill effects. However, if preeclampsia occurs early in pregnancy, delivery of the baby would result in premature birth, which increases the risk of death, and for such lifelong complications as blindness, cerebral palsy, and learning disabilities. In such instances, physicians are forced to weigh the mother's risk of severe disease or eclampsia against the consequences of preterm birth for the baby.
In the current study, the researchers present strong evidence that an imbalance of two proteins produced by the placenta is responsible for the symptoms of preeclampsia. Abnormally high levels of these proteins appear to deprive the blood vessels of substances needed to keep the lining of the blood vessels healthy. Deprived of these essential substances, the cells lining the blood vessels begin to sicken and die. As a result, the blood pressure increases, and the blood vessels leach protein into the tissues and urine.
The first of these two proteins is known as soluble endoglin. It begins accumulating in the blood of pregnant women 2 to 3 months before they develop preeclampsia. In women who developed preterm preeclampsia, levels of soluble endoglin began to rise in the 17 th to the 20 th week of pregnancy. In women who developed preeclampsia at full term, soluble endoglin levels rose at the 25 th to the 28 th week of pregnancy.
Similarly, soluble endoglin levels also rose in the 33 rd through the 36 th week of pregnancy for women who later developed gestational hypertension-hypertension without protein in the urine. Levels rose still further after the onset of gestational hypertension.
"This finding suggests that gestational hypertension is a mild form of preeclampsia," said Dr. Levine.
The second protein involved in the chemical imbalance is called soluble fms-like tyrosine kinase 1 (sFlt1). The women in the study who had developed preeclampsia had increased levels of sFlt1. The increase in sFlt1 was accompanied by reduced levels of a substance, placental growth factor (PlGF). Both women with term preeclampsia and women with gestational hypertension had a simultaneous rise in soluble endoglin, and an increase in the ratio of sFlt1 to PlGF (high levels of sFlt1 and low levels of PlGF.)
"Both soluble endoglin and the altered sFlt1/PlGF ratio appear to contribute to the development of preeclampsia, Dr. Levine said. "Severe disease usually occurs in women with high levels of both measures and not in women with high levels of only one or the other."
Dr. Levine added that detecting high levels of both soluble endoglin and sFlt1 early in pregnancy might be especially helpful in predicting the later development of preeclampsia. Detecting high levels of these molecules might also help in distinguishing preeclampsia from chronic high blood pressure, kidney disease and other conditions that can produce symptoms similar to preeclampsia.
Dr. Levine said that both sFlt1 and soluble endoglin are referred to as soluble because they circulate in the bloodstream. Both molecules exist in a non-soluble form, attached to the surface of cells lining blood vessels. In this non-soluble form, they are classified as receptors because they serve as targets for other molecules. When molecules attach, or bind, to the receptors, the binding process initiates a chain of events in the cells. PlGF binds to Flt1 on the lining of blood vessels. Another substance, vascular endothelial growth factor (VEGF) also binds to Flt1. This binding process is essential to keeping blood vessels healthy and maintaining normal blood pressure. Similarly, a molecule known as transforming growth factor beta (TGF beta) binds to endoglin, and this binding is also required to keep blood vessels healthy.
Dr. Levine explained that the prevailing theory holds that, when the placenta isn't able to absorb sufficient oxygen from the mother's blood, it begins secreting both sFlt1 and soluble endoglin into the mother's bloodstream. The sFlt1 binds to VEGF and PlGF and soluble endoglin binds TGF beta, diverting the compounds from the mother's blood vessels. In response, the mother's blood pressure rises, forcing more blood to the placenta. High levels of sFlt1 and soluble endoglin result in severe forms of preeclampsia.
"We've found specific molecules that appear to be causing the clinical signs of preeclampsia and so we now have an idea which molecules we would need to interfere with to treat the disease," Dr. Levine said.
A possible treatment for preeclampsia might involve reducing levels of sFlt1 or soluble endoglin or adding more of the molecules that they remove from the blood stream, Dr. Levine added, so that more VEGF, PlGF, and TGF beta would be available for the blood vessels that need them. One company has developed the means to produce a form of VEGF. Presumably, such a drug would raise the levels of circulating VEGF in the bloodstream. The surplus VEGF would bind to the high levels of sFlt1 produced during preeclampsia, but enough free VEGF would still be available to attach to cell surface receptors to promote the health of blood vessels.
Dr. Levine cautioned, however, that such attempts to develop a drug treatment would need to proceed cautiously. It's possible that restoring normal blood pressure and blood flow to the mother's circulatory system might deprive the fetus of blood.
The National Heart, Lung, and Blood Institute provides information about preeclampsia at http://www.nhlbi.nih.gov/health/resources/heart/hbp-pregnancy.htm and information about high blood pressure during pregnancy at http://www.nhlbi.nih.gov/health/public/heart/hbp/hbp_preg.htm.