February 5, 2004
Abnormal levels of two molecules found in the blood appear to predict the development of preeclampsia, a life-threatening complication of pregnancy, according to a study by researchers at the National Institute of Child Health and Human Development of the National Institutes of Health and the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston. The findings will appear in the February 12 issue of The New England Journal of Medicine but are scheduled for early release on the Journal's Web site at www.nejm.org to coincide with a presentation at the Society for Maternal-Fetal Medicine Annual Meeting.
When compared to women who did not have preeclampsia, women who later developed the condition had elevated blood levels of a substance known as soluble fms-like tyrosine kinase 1 (sFlt-1), before their preeclampsia occurred. Conversely, beginning early in their pregnancies, these women had lower levels of a substance known as placental growth factor (PlGF) in the blood than did women who did not develop preeclampsia.
Additional funding for the research was provided by another NIH institute, the National Institute of Diabetes and Digestive and Kidney Diseases.
Women who developed preeclampsia also had lower levels of another substance, vascular endothelial growth factor (VEGF). The researchers were unable to use VEGF levels to predict the development of preeclampsia; however, VEGF appears to be important for the healthy functioning of blood vessels, and the researchers theorize that the lack of VEGF as well as PlGF contributes to the health problems resulting from preeclampsia.
Preeclampsia can occur suddenly, without warning. 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. According to the study authors, preeclampsia affects about 5 percent of all pregnancies.
"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," said Duane Alexander, M.D., Director of the NICHD. "If we could predict the development of preeclampsia, we could offer treatment before it becomes a serious problem."
In cases where the condition does not progress to eclampsia, infants 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 birth complications.
The Flt-1 molecule belongs to a class of molecules known as receptors, explained the study's principal investigator, Richard Levine, M.D., of NICHD's Division of Epidemiology, Statistics, and Prevention Research. Flt-1 sits on the surface of the cells that line the inside of blood vessels. Like a key fits into a lock, VEGF and PlGF bind to Flt-1, and in the process trigger a chain of chemical reactions inside the cell. The Flt-1 molecule also exists in a soluble form as well, which does not sit on the cell surface but instead circulates in the bloodstream. The soluble Flt-1 (sFlt-1) binds to VEGF and PlGF, preventing them from acting on the cells that line the inside of blood vessels. Pregnant women who carry normal pregnancies to term also have sFlt-1 in their blood. In these women, however, sFlt-1 is present at much lower levels, and much later in the pregnancy- shortly before birth.
The finding builds upon earlier research led by the study's co-principal investigator, 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 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.
To conduct the current study, the researchers analyzed blood samples from a group of pregnant women who took part in an earlier study, which sought to determine if taking calcium supplements during pregnancy could prevent preeclampsia. That study found that women who took the supplements had the same chances of developing preeclampsia as those who did not. A release on the earlier study appears at http://www.nichd.nih.gov/news/releases/Pages/calc1397.aspx.
In the current study, the researchers analyzed blood samples of 120 women who had developed preeclampsia and compared these samples to blood samples from 120 women who had not developed preeclampsia. The women who developed preeclampsia had three times the blood levels of sFlt-1 as the women who had normal pregnancies. The blood levels of sFlt-1 were similar for the two groups of women at the beginning of their pregnancies. However, in the women with preeclampsia, sFlt-1 levels began to increase about 5 weeks before they developed the condition. Similarly, the women who developed preeclampsia had lower PlGF levels beginning in the 13th to 16th weeks of their pregnancies and lower VEGF levels during and shortly before preeclampsia.
Dr. Levine explained that he and his coworkers do not know if the finding could be used to distinguish women who develop preeclampsia from women who have gestational hypertension-the mysterious high blood pressure that sometimes occurs in pregnant women, but which usually doesn't lead to the serious complications associated with preeclampsia. The study did not include women with gestational hypertension, so it is not known whether these women also experience a rise in sFlt-1 and decreased levels of PlGF. Gestational hypertension differs from preeclampsia in that it usually does not lead to the dangerously high blood pressure that can occur in preeclampsia.
However, the finding does raise the possibility of preventing and treating preeclampsia through the design of drugs that bind to sFlt-1, Dr. Levine said. Similarly, physicians might also monitor the levels of s Flt-1 and PlGF during pregnancy, and prescribe drugs to prevent seizures before they occur and to treat high blood pressure as soon as it appears.
The study was also conducted by other researchers from the following institutions: NICHD, Beth Israel Deaconess Medical Center, Allied Technology Group, Massachusetts General Hospital, and the University of Cincinnati College of Medicine.
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. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Information Resource Center, 1-800-370-2943; e-mail NICHDInformationResourceCenter@mail.nih.gov.