Pregnancy Disorder Linked to 2 Proteins
Two proteins secreted by the placenta may be responsible for virtually all cases of preeclampsia, a severe complication of pregnancy that can be fatal to a mother or her baby, researchers report today.
Abnormally high levels of the proteins could be used to predict the development of the disorder weeks before symptoms occur, experts said, and the findings suggest new ways to treat the problem.
A World Health Organization team is organizing a test of the proteins’ predictive value among pregnant women in the Third World, and Fremont, Calif.-based biotech company Scios Inc. is looking for funding to test a potential treatment.
“This finding appears to be an important step in developing a cure for preeclampsia,” said Dr. Elias A. Zerhouni, director of the National Institutes of Health.
Researchers had identified one of the proteins in 2003 and showed that injecting it into rodents could mimic many -- but not all -- symptoms of the disorder. But injecting both proteins together produces the full spectrum of symptoms, yielding confidence that the pair is at the root of the problem.
“There could be other things that also have a role, but these are the major players,” said Dr. Richard J. Levine of the National Institute of Child Health and Human Development, who led the study reported today in the New England Journal of Medicine.
“We can now confidently state that a disorder once considered a mysterious disease is sufficiently understood to permit mechanistically rational studies of its prediction, diagnosis, prevention and treatment,” said an editorial in the same journal by Dr. Marshall D. Lindheimer of the University of Chicago and Dr. Jason G. Umans of Georgetown University.
More than 6 million women around the world and 270,000 in the United States suffer preeclampsia during pregnancy each year. The disorder, once known as toxemia, affects as many as 8% of pregnancies.
Usually diagnosed late in pregnancy, the disorder is characterized by sharp increases in blood pressure, swelling and proteins in the urine. It can progress to eclampsia, which produces seizures and often fatal complications of the liver, kidneys, lungs, blood and nervous system. Eclampsia causes 15% of maternal deaths during pregnancy in the U.S.
Mild cases can be helped by bed rest, but there is no effective treatment for the disorder other than delivery of the infant and removal of the placenta. If the fetus is delivered prematurely, it can develop a wide variety of problems. Premature birth associated with preeclampsia is considered one of the major sources of neurodevelopmental disorders in children.
In 2003, Dr. S. Ananth Karumanchi of the Beth Israel Deaconess Medical Center in Boston and his colleagues reported finding high levels of a protein called soluble fms-like tyrosine kinase 1 in the blood of women with preeclampsia.
This protein binds to two growth factors that play a key role in maintaining the health of blood vessels.
The team looked at blood samples from women with preeclampsia and found the second protein, called endoglin, that is also present in abnormally high levels in women with the disorder. Endoglin binds a third growth factor that also plays a role in maintaining blood vessel health.
Levels of both endoglin and fms-like tyrosine kinase 1 begin to rise as much as 10 weeks before the onset of preeclampsia symptoms, the team said.
Evidence suggests that the disorder is triggered when the fetus is not able to absorb sufficient amounts of oxygen from the placental blood supply. In response, the placenta releases the two proteins into the bloodstream, where they bind to and remove the three growth factors.
The result is an increase in the mother’s blood pressure, which provides more oxygen to the fetus, but which also endangers the mother’s health.
One potential treatment would be to administer one of the growth factors, called VEGF, which is manufactured by Scios in a form approved for use in humans, to tie up the excess fms-like tyrosine kinase 1 and remove it from circulation. Tests in rodents have shown that VEGF can ameliorate many symptoms of the disorder.
The problem, Levine said, “is that sometimes what is good for the mother is not good for the baby.” Any potential treatment would involve reaching a delicate balance between reducing hypertension in the mother and allowing the baby to continue to grow.
The baby could then be delivered later, he said, when there is a lower risk of complications.