NICHD-Funded Researchers Find Possible Mechanism of Preeclampsia Disorder of Pregnancy Attributed to Placenta Irregularity

A team of investigators has discovered that preeclampsia--a life threatening complication of pregnancy--results from a failure of the placenta to invade the wall of the uterus and to appropriately mimic the tissue which lines blood vessels. The finding has important implications for the diagnosis and treatment of this sudden, mysterious, and potentially fatal disorder of pregnancy.

The research, funded by the National Institute of Child Health and Human Development, appears in two papers published in the May 1 issue of The Journal of Clinical Investigation.

About 7 percent of first-time mothers and 1 to 2 percent of mothers having subsequent pregnancies develop preeclampsia. The condition occurs suddenly, without warning, and sometimes in as little as a few hours. 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.

Preeclampsia is still one of the leading causes of maternal mortality. The need to screen for and detect preeclampsia early was one of the original reasons the medical community began recommending regular prenatal visits many years ago.

In cases where the condition does not progress to eclampsia, the children born to mothers with preeclampsia may be extremely small for their age or may be born prematurely. This may, in turn, place them at risk for a variety of other complications of birth. Infants born to mothers with preeclampsia may also grow more slowly during infancy than infants whose mothers do not have the condition.

Although the high blood pressure accompanying preeclampsia can be treated with blood pressure lowering drugs, the only effective treatment for the condition is immediate delivery. Known risks for preeclampsia are: diabetes, pre-existing hypertension, kidney disease, being pregnant with twins, and having previously had the condition during an earlier pregnancy.

An earlier study has shown that in women who develop preeclampsia, the placenta fails to penetrate the wall of the uterus adequately, explained the senior investigator of the research team, Susan J. Fisher, PhD, a researcher at the University of California, San Francisco.

In the current study, Fisher and her co-investigators, Caroline Damsky, PhD and Yan Zhou, MD, determined that in normal pregnancies, fingerlike projections of placental cells, known as cytotrophoblasts, invade the inside wall of the uterus and then begin to mimic the vascular (vein and artery) cells found on the inside of blood vessels. Eventually, these placental projections break down the vessels, allowing the placenta to be bathed in maternal blood. This blood carries oxygen and nutrients to the placenta, and carries away fetal wastes.

In preeclampsia, however, few cytotrophoblast projections invade the uterine wall to the proper depth. Moreover, these projections remain in their early state of differentiation and fail to take on the characteristics of blood vessel cells.

Currently, the researchers are unsure exactly why, during preeclampsia, the placental cells fail to mimic blood vessel cells. However, in an earlier study of cells in laboratory dishes, the researchers have found that, under low oxygen conditions, cytotrophoblasts also fail to invade. Dr. Fisher cautioned that although preeclampsia could result from a variety of possible causes, clues to the nature of the disorder might be found in mothers who have conditions predisposing them to lower blood oxygen levels.

"This finding is a major advance in understanding this mysterious condition," said the project officer for the study, Don McNellis, MD, of the NICHD's pregnancy and perinatology branch. "Knowing the cellular pathology of the disease will help immensely in the search for ways to diagnose and treat it."

Because preeclampsia often occurs without warning in otherwise healthy pregnant women, Dr. McNellis explained, a test for the disorder would allow physicians to target those women with preeclampsia and intervene as early as possible.

Dr. Fisher theorized that the failure of invading cytotrophoblasts to take on the characteristics of blood vessel cells may provoke a reaction in the circulatory system of the mother, resulting in high blood pressure and causing blood vessel damage.

In the first paper they published, the researchers described how they had placed cytotrophoblasts in laboratory cultures that resembled the walls of the uterus. As they differentiated, the cytotrophoblasts took on characteristics of the cells that line the walls of veins and arteries. In the second paper, the researchers reported that samples of placental tissue taken from women who developed preeclampsia had failed to adequately mimic the lining of blood vessels, whereas the placental tissue samples from normal pregnancy did indeed mimic blood vessel lining.

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