Research Links Pregnancy Disorder to Protein Levels

Researchers have made a major step toward the diagnosis and possible treatment of preeclampsia, a sometimes lethal complication of pregnancy that affects as many as 200,000 American women each year.

A team in Boston and Washington found that the levels of one protein in the blood of pregnant women were sharply elevated and those of another protein were abnormally low as much as five weeks before the women developed preeclampsia.

Physicians have no way to diagnose the disorder until it strikes, and there is no treatment.

The protein test is not perfect. Not all women with altered levels developed preeclampsia, and some women who did develop it did not have abnormal levels of the proteins.

Nonetheless, Dr. Duane Alexander, director of the National Institute of Child Health and Human Development, lauded the research. “This is the most promising lead yet in the pursuit of a life-threatening disorder that has defied all attempts to prevent or cure it,” he said. “If we could predict the development of preeclampsia, we could offer treatment before it becomes a serious problem.”

Preeclampsia, which affects 5% to 8% of pregnant women, typically develops after the 20th week of pregnancy and is marked by high blood pressure and fluid retention. In about 2% of cases, it abruptly escalates to eclampsia, which is characterized by life-threatening seizures.

Children born to mothers with preeclampsia are often born prematurely and face a variety of developmental difficulties.

The incidence of preeclampsia has increased by about a third over the last decade. The disorder is one of the leading causes of maternal and fetal mortality worldwide.

The first important clue to the cause of preeclampsia was reported last year by Dr. S. Ananth Karumanchi and his colleagues at Beth Israel Deaconess Medical Center in Boston. Studying pregnant women with preeclampsia, they discovered that many had high levels of a circulating protein called soluble fms-like tyrosine kinase 1 (sFlt-1).

The protein blocks the growth of blood vessels by binding to two growth factors, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), and removing them from circulation. When Karumanchi’s team administered sFlt-1 to pregnant and non-pregnant mice, symptoms of preeclampsia were induced.

Karumanchi concluded that the protein plays a normal role at the end of pregnancy, blocking the formation of new blood vessels as the fetus comes to term.

In preeclampsia, for reasons not yet known, sFlt-1 acts “too hard and too soon, resulting in an exaggeration of the normal process governing placental growth and function,” he said.

“What appears to be happening is that blood vessels to the placenta become narrowed, which impedes the flow of blood and oxygen to the fetus,” Karumanchi said. That sets in motion the progression of potentially fatal complications involving the mother’s liver, kidneys, lungs, blood and nervous system.

To test their theory, Karumanchi and his colleagues turned to Dr. Richard Levine of the National Institute of Child Health and Human Development, who led a study to determine whether calcium supplements could prevent preeclampsia. (They can’t.)

The researchers analyzed stored blood samples from 120 women who developed preeclampsia and 120 who did not, looking for increased levels of sFlt-1 and lowered levels of PlGF. They did not know which samples were which.

The team is to report in next week’s New England Journal of Medicine that levels of sFlt-1 were, on average, about 2 1/2 times higher in women who developed preeclampsia and that levels of PlGF were about 50% lower. The paper was released early because of its clinical importance.

Further studies are needed to confirm the findings. In particular, Karumanchi said, researchers must monitor women throughout their pregnancies to determine levels of the proteins.

The findings do suggest paths for treatment, said Dr. Vikas P. Sukhatme of Beth Israel.

Drugs that block sFlt-1 could prevent the disorder, he said. Another approach might be to administer VEGF or PlGF to restore a woman’s depleted levels, he said.