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Substance in urine predicts development of preeclampsia

January 04, 2005

A substance found in the urine of pregnant women can be measured to predict the later development of preeclampsia, according to research from the National Institute of Child Health and Human Development of the National Institutes of Health.

"We may have reached a turning point in the extensive federal research investigation of this frequent, life-threatening complication of pregnancy," said Duane Alexander, M.D., Director of the NICHD. "This finding sets the stage for the development of a test to screen women for high risk of preeclampsia. Once these women are identified through such a test, we can target studies to find effective ways to prevent its progression or to keep the most dangerous complications from occurring."

The researchers found women were highly likely to develop preeclampsia if they had low levels of a substance known as placental growth factor (PlGF) in their urine. PlGF works in combination with a substance called vascular endothelial growth factor (VEGF). Together, the two substances foster the growth of new blood vessels, and maintain the health of cells that line the inside of blood vessels, including those in the placenta that support the developing fetus. The researchers believe that the high blood pressure and other symptoms characteristic of preeclampsia result from low levels of PlGF and VEGF.

Researchers are making plans to refine the finding into an accurate clinical test.

The study appears in the January 5 Journal of the American Medical Association. It was conducted by researchers at the NICHD, Harvard University Medical School, the Harvard School of Public Health, Beth Israel Deaconess Medical Center, Allied Technology Group, and the University of Cincinnati College of Medicine. Much of the funding for the study was provided by the NICHD and another of the NIH Institutes, the National Institute of Diabetes and Digestive and Kidney Diseases.

A few women--such as those pregnant with more than one baby or with long-term high blood pressure--are known to be at high risk for preeclampsia, explained the study's first author, Richard Levine, M.D., M.P.H., of NICHD's Division of Epidemiology, Statistics, and Prevention Research. However, the vast majority of cases strike without warning, in first-time mothers. Usually, a pregnant woman with preeclampsia develops dangerously high blood pressure and begins excreting protein in the urine. In some cases, the condition may progress to eclampsia, a series of potentially fatal seizures. Although the high blood pressure and seizures can be treated, the only cure for preeclampsia is delivery of the baby. Combined estimates of preeclampsia and other hypertension disorders during pregnancy range from 5.9 to 8 percent of all pregnancies in the United States.

In cases where the condition does not progress to eclampsia, infants born to mothers with preeclampsia may be extremely small for their gestational age or may be born prematurely. These conditions, in turn, place the infants at risk for a variety of other birth complications, among them blindness, cerebral palsy, or mental retardation.

To conduct the study, the researchers analyzed stored urine samples of 120 women who developed preeclampsia and compared them to samples from 118 women who did not develop preeclampsia. The analysis was performed on stored samples collected at three intervals during the women's pregnancies. The urine samples were collected as part of a separate NICHD study published in 1997, which found that pregnant women could not lower their chances of getting preeclampsia by taking calcium supplements.

In the current study, urinary levels of PlGF were significantly lower for the women who subsequently developed preeclampsia than they were for the 118 women who did not develop the condition. For the women who developed preeclampsia, low levels of PlGF were apparent beginning at the 25th through the 28th week of pregnancy. The differences in P1GF levels grew more pronounced by the 29th through the 36th week of pregnancy.

This study builds upon earlier findings by the last author, S. Ananth Karumanchi, M.D., of the Renal Division at the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston. Dr. Karumanchi and his coworkers had previously discovered that a substance called soluble fms-like tyrosine kinase 1 (sFlt-1) circulates in large quantities in the bloodstreams of women with preeclampsia and that sFlt-1 injected into the bloodstream of pregnant rats caused a preeclampsia-like illness.

Last year, Drs. Levine, Karumanchi and their coworkers reported that high levels of sFlt-1 likely influenced the development of preeclampsia, by binding to PlGF and VEGF. Because they were bound to sFlt-1, the two substances could not be used by the blood vessel cells that required them. A release describing that study is available at http://www.nichd.nih.gov/new/releases/preeclampsia.cfm.

Dr. Levine noted that a screening test for PlGF would probably need to be used in conjunction with other measures. He explained that a few of the 118 women who did not develop preeclampsia also had low levels of PlGF. To confirm that preeclampsia is present, women with low levels of PlGF could be referred for a blood test to measure their blood levels of sFlt-1.

A urinary test for PlGF could probably be performed less expensively than could a blood test for sFlt-1, because it wouldn't require the services of a medical professional to draw blood. Moreover, a urine sample could conceivably be collected at home, and then brought into a medical lab for testing. This would be an advantage over a blood test, especially in countries lacking trained medical staff to draw blood.

Currently, Dr. Levine is planning an additional study to more accurately predict the development of preeclampsia by measuring urinary levels of PlGF. The current study obtained urine samples from pregnant women only on 3 occasions during their pregnancies. In the planned study, researchers would measure urinary PlGF levels throughout pregnancy, in an effort to pinpoint precisely when levels of PlGF begin to drop. Similarly, another study is measuring urinary PlGF levels in a much larger number of women, to gain a better understanding of individual variations in PlGF levels.

Dr. Levine estimates that, pending the results of these studies, a urine test to screen for preeclampsia could be available in 4 to 5 years.

He added that it also might be possible to develop a treatment for preeclampsia, by supplying at risk women with additional PlGF and VEGF. Theoretically, these substances would bind to sFlt-1, allowing the PlGF and VEGF made by the body to be used by the blood vessel cells that require them.
-end-
Since the early 1990's, the NIH has funded numerous studies of preeclampsia. In addition to the study that tested calcium to prevent the condition, other studies have tested aspirin, magnesium, and fish oil, with no success.

The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.

NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development

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