BOSTON – Researchers have discovered that diminished levels of an angiogenic protein associated with preeclampsia can be detected in the urine of women mid-way through pregnancy, a finding that could help pave the way for the development of a screening test for this potentially life-threatening disease.
The research, led by scientists at Beth Israel Deaconess Medical Center (BIDMC) is reported in the January 5, 2005 issue of The Journal of the American Medical Association (JAMA).
Preeclampsia, or toxemia, typically develops after the 20th week of pregnancy and is characterized by high blood pressure, edema and protein in the urine. However, in severe cases -- and without warning -- it can rapidly escalate to eclampsia, a condition in which a massive rise in blood pressure causes the mother to suffer a series of potentially fatal complications and forces premature delivery of the infant. The condition develops in approximately five percent of all pregnancies, affecting an estimated 200,000 women in the U.S. each year. Worldwide, it is one of the leading causes of maternal and infant mortality.
"Unfortunately, the only means currently available to identify preeclampsia is weekly monitoring of women's blood pressure and testing for proteinuria [abnormal levels of protein in the urine] during the third trimester of pregnancy," explains the study's senior author Ananth Karumanchi, MD, a nephrologist in the Department of Medicine at BIDMC and Assistant Professor of Medicine, Obstetrics and Gynecology at Harvard Medical School. "And by the time a rise in blood pressure has been detected it may already be too late, as the condition can very rapidly spiral out of control."
In 2003, a study conducted by Karumanchi and his colleagues published in the Journal of Clinical Investigation suggested that preeclampsia was caused by an imbalance of circulating angiogenic growth factor molecules, which enable the growth of small blood vessels.
"In a normal pregnancy, the developing fetus signals the mother's body to widen blood vessels to the placenta, which supplies oxygen and nutrients to the fetus," explains Karumanchi. "But for women with preeclampsia, the blood vessels grow narrower, which causes a host of life-threatening complications. Our discovery suggested this was happening because the anti-angiogenic protein sFlt1 [soluble fms-like tyrosine kinase 1] was attaching to and absorbing two pro-angiogenic proteins, PIGF [placental growth factor] and VEGF [vascular endothelial growth factor]." Last year, in a study published in The New England Journal of Medicine, Karumanchi and co-investigators confirmed that sFlt1 levels do indeed rise – while PIGF levels fall – approximately five weeks prior to the onset of preeclampsia symptoms in pregnant women.
The objective of this latest study, he explains, was to find out if these same proteins could be measured in urine, the thinking being that if this proved to be the case a simple urine test could provide a less invasive and less expensive screening tool to detect preeclampsia at an early stage.
Because the sFlt1 molecule is too large to be filtered through urine, the investigators focused on the PIGF molecule, testing the hypothesis that urinary PIGF levels would drop prior to the development of hypertension and proteinuria in pregnant women and could, therefore, predict which women would go on to develop preeclampsia.
Using archived urine specimens from the Calcium for Preeclampsia Prevention Trial (a large cohort study based at the National Institute of Child Health and Development), Karumanchi, in collaboration with Richard Levine, MD, MPH, of the NICHD, compared the PIGF levels of 118 women who had normal pregnancies with those of 120 women who went on to develop preeclampsia.
The results demonstrated that urinary PIGF levels were dramatically lower in the preeclamptic patients at both the time of clinical symptoms and in the six to eight weeks prior to the onset of symptoms. To ascertain that decreased urinary PIGF is specific to preeclampsia, the researchers then performed a second study in which they analyzed urine specimens obtained at 21 and 23 weeks gestation from women with two other obstetrical conditions– gestational hypertension and delivery of a small-for-gestational-age (SGA) infant – which share characteristics similar to preeclampsia.
Their findings showed that at the same time that urinary PIGF levels are dropping among the women who go on to develop preeclampsia, levels remain stable among the pregnant women with the other two conditions. "This new study provides us with another important piece of evidence as we work toward developing the means to diagnose, and eventually to treat, this serious condition," says Benjamin P. Sachs, MBBS, DPH, Chairman of the Department of Obstetrics and Gynecology at BIDMC and an investigator on the study. "This is of especially critical importance in other regions of the world where preeclampsia poses a significant threat to the health of mothers and their infants."
Adds Karumanchi, "Diagnosing this condition earlier could help women with preeclampsia avoid major complications. A simple urine test could help predict the onset of this disease one to two months before the onset of clinical symptoms and that could make a tremendous difference in outcomes for patients, in particular those women who have limited access to specialized medical care."
Study co-authors in addition to Sachs include BIDMC investigators Chun Lam, MD, Franklin H. Epstein, MD, Vikas P. Sukhatme, MD, PhD, and Kee-Hak Lim, MD; National Institute of Child Health and Human Development investigators Richard J. Levine, MD, MPH, Kai F. Yu, PhD, and Anastasia L. Blink, MPH; Ravi Thadhani, MD, MPH, of Massachusetts General Hospital; Cong Qian, MS, of Allied Technology Group, Rockville, MD; and Baha M. Sibai, MD, of the University of Cincinnati College of Medicine.
This study was funded by awards and grants from the American Society of Nephrology, the National Institutes of Health, and the National Institute of Child Health and Human Development as well as the Beth Israel Deaconess Medical Center Departments of Medicine and Obstetrics & Gynecology.
Drs. Sukhatme and Karumanchi are named as coinventors on a pending patent filed by Beth Israel Deaconess Medical Center for the use of angiogenesis-related proteins for the diagnosis and treatment of preeclampsia.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www.bidmc.harvard.edu.
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