Feb. 5, 2004 -- There's a major new development in predicting preeclampsia, a life-threatening condition that occurs in about one of every 20 pregnancies: Researchers say that before symptoms emerge, testing levels of two molecules in the blood can indicate which women will get the disease that results in some 76,000 deaths each year.
In a new study, Harvard and NIH researchers say they detected abnormal levels of two substances in women who went on to develop preeclampsia weeks before telltale symptoms: Elevated levels of a protein called soluble fms-like tyrosine kinase 1 (sFlt-1) and decreased amounts of another substance known as placental growth factor (PlGF). However, no such fluctuations occurred in women whose pregnancies remained normal.
The changing levels of these substances -- which were noted to occur five to six weeks before any symptoms became apparent -- are believed to cause a cascade of effects "that eventually impairs blood vessel growth in the placenta, as well as the mother's kidneys, liver, and possibly the brain," says lead researcher S. Ananth Karumanchi, MD, of Harvard's Beth Israel Deaconess Medical Center.
Danger to Baby and Mother
Preeclampsia affects some 200,000 American women each year and is the leading cause of pregnancy-related death and a major contributor to premature birth. This condition is primarily characterized by an increase in blood pressure that occurs after 20 weeks of pregnancy in a woman with previously normal blood pressure. These women also have lots of protein in the urine -- a sign of kidney damage. Swelling, sudden weight gain, headaches, and vision changes may also occur.
The condition can also lead to seizures in pregnant women -- a condition known as eclampsia. It can slow fetal growth, force premature delivery, and cause severe bleeding and death of the fetus and possibly the mother.
Until now, doctors have been hard-pressed in predicting which women will develop preeclampsia in pregnancy, dubbed "the disease of theories" because despite many theories of its origin, its exact cause has eluded experts. Typically, risk is assessed on factors such as existing diabetes, high blood pressure, being overweight, being age 35 or older, being of African-American race, and having a history of multiple births or previous preeclampsia.
But with these new findings, Karumanchi says a diagnostic test to measure these protein levels can be developed -- as soon as within one year -- that can give doctors' a clue to who is likely to develop the condition.
"Pharmaceutical houses are now actively working on a diagnostic test, which still needs FDA approval," he tells WebMD. "Once we have identified in who the disease will happen, patients can be monitored more closely with bed rest, blood pressure medications, and other therapies. That way, we can better deal with the mother and baby before this disease explodes."
Until then, blood levels of these proteins can be evaluated at certain labs -- a process that takes about two hours.
Karumanchi's study will be published next week in The New England Journal of Medicine but was released Thursday to coincide with his presentation of these findings at the annual meeting of the Society of Maternal-Fetal Medicine in New Orleans.
Last March, a study in the Journal of Clinical Investigation headed by Karumanchi first implicated rising levels of sFlt-1 as a possible cause of preeclampsia.
"We did a preliminary study on 20 women with preeclampsia and found that all had elevated levels," he tells WebMD. "And when we took that protein and injected it in rats, they all developed preeclampsia symptoms -- high blood pressure, protein spillage in urine, edema, and changes that led to blood vessel damage."
In the new study, his Harvard team joined NIH investigators in measuring sFlt-1 and PIGF levels in 240 women. "Essentially, in every case, sFlt-1 levels started to rise five to six weeks prior to the onset of symptoms in women who went on to develop preeclampsia -- and the higher the levels, the more severe their condition," says Karumanchi, of Beth Deaconess Medical Center. "They did not rise in women who didn't develop preeclampsia. That suggests these elevated protein levels are a cause -- rather than a consequence -- of the disease."
In a prepared statement, Duane Alexander, MD, director of the NIH's National Institute of Child Health and Human Development calls Karumanchi's findings "the most promising lead yet in the pursuit of a life-threatening disorder that has defied all attempts to prevent or cure it." Alexander was not involved in the study, but researchers at his agency were.
Still, in an accompanying editorial to Karumanchi's study, Caren G. Solomon, MD, MPH, and Ellen W. Seely, MD, of Brigham and Women's Hospital -- another Harvard-affiliated institution -- write that the results "are intriguing, but questions still remain." They indicate that other, undiscovered factors may likely have a more direct link to preeclampsia.