Substance in Urine Predicts Development of Preeclampsia
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
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.
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
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.