Focus on Pregnancy : Preeclampsia Still Mystifies Researchers : More has been learned about the condition, the leading cause of maternal mortality in the U.S., but a cure remains elusive.
Kim’s Tuesday morning visit to the doctor on May 27, 1997, was supposed to be no big deal, just a regular checkup to see how everything was going. At the time, Kim was six months pregnant with our twin girls.
I was working in my home office that morning when Kim called from her doctor’s office in Winchester, Va.
“They’re sending me to the hospital,” Kim told me matter-of-factly. She said her blood pressure was high and that she had protein in her urine--two signs of a pregnancy-related disorder called preeclampsia. Kim said it probably meant she’d have to spend the summer on bed rest. They were planning to do more tests at the hospital.
When I asked how she was feeling, Kim said she was fine.
“I feel perfectly fine,” she said. “I don’t understand it.”
But Kim wasn’t fine. Tests showed she had a severe form of preeclampsia, and her life was in danger. She was sent by ambulance from the hospital in Winchester to the University of Virginia Medical Center in Charlottesville. Doctors told us our girls would have to be delivered in a matter of days, maybe hours, to save Kim’s life. At the university hospital, with its high-level newborn nursery, the babies would have a better chance to survive.
Removed from their mother’s womb two days later--nearly 16 weeks before they were due--the girls weighed 1 pound, 6 ounces and 1 pound, 2 ounces, and immediately were put on ventilators and sent to the newborn intensive-care unit. The smaller one, Nina, died 49 hours later after a valiant struggle for life. The other, Josie, now more than 2 years old, is an active toddler who delights in walking our dogs and eating grilled-cheese sandwiches. Although she is still a few months behind in her development, the doctors say it won’t even be an issue by the time she is in kindergarten.
After the delivery, Kim was over the preeclampsia symptoms in a matter of days.
Disorder Affects 1 in 10 Pregnancies in the U.S.
A mystifying condition that can lead to seizures and death, preeclampsia affects as many as one in 10 pregnancies in the United States. Researchers still are trying to understand what triggers it.
The primary signs of the disorder are high blood pressure, protein in the urine, and edema, swelling caused by fluid retention. Known in the past by a variety of names from “toxemia” to “pregnancy-induced hypertension,” preeclampsia is the leading cause of maternal mortality in the U.S., accounting for 75,000 maternal deaths each year worldwide. Babies born to preeclamptic women face a significantly higher risk of dying or developing lifelong disabilities than babies born to healthy mothers, primarily because the only known “cure” is delivery of the fetus. The condition accounts for one-third of all premature births, although many women bring the fetus to term with bed rest and medical treatment.
James M. Roberts, an obstetrician-gynecologist at the Magee-Women’s Research Institute in Pittsburgh, has spent more than 20 years researching preeclampsia. He heads a team of 20 physicians, PhDs and postdoctoral researchers who are part of the nation’s largest program to investigate the condition.
Roberts said he first became interested in preeclampsia while working on a postdoctoral fellowship at UC San Francisco. After he completed his residency, he wanted to learn more about hypertension. As he encountered significant numbers of pregnant women suffering from high blood pressure and preeclampsia’s other effects, Roberts became convinced that this was something different--that hypertension was the least of these women’s problems.
“It was so amazing to see how tremendously ill these women had become and what a major impact it had on them and their babies,” he said. “And yet when they’d come back six weeks after delivery, they were right back to normal. It was just amazing from a physiological perspective--really bizarre.”
In a 1989 article in the American Journal of Obstetrics and Gynecology, Roberts and other researchers first encouraged the medical profession to dismiss the notion that high blood pressure was preeclampsia’s defining feature and to focus instead on other changes occurring in the patient’s body.
As doctors studied preeclampsia more closely, they realized that it was a harmful condition in and of itself, even if the woman did not go on to have eclampsia, or the seizures that follow preeclampsia. The primary problem is “poor perfusion,” or reduced blood flow to the placenta and other vital organs. For the fetus, this can mean restricted growth; more than one-third of the babies of preeclamptic women are born small for their gestational age. For the mother, poor perfusion can cause damage to organs such as the liver and kidneys, among other problems.
Over the years, researchers have come up with a mishmash of theories and counter-theories about what causes preeclampsia.
In recent years, it was suggested that taking low doses of aspirin early in pregnancy might help prevent preeclampsia. The aspirin theory was based on several small studies that had shown a drop in the incidence of preeclampsia among women at high risk for the condition who were given the drug. Larger studies conducted under the aegis of the National Institutes of Health, however, threw the earlier conclusions into doubt.
The latest target of preeclampsia research was calcium. Epidemiological studies of women on low-calcium diets in Central and South America in the 1980s suggested that they were significantly more likely to develop preeclampsia. Again, however, a subsequent study by the institutes found “absolutely no effect” of increased calcium intake on the incidence of the disease.
Yet despite the years of false starts, the last decade has seen enormous progress in researchers’ understanding of preeclampsia.
Blood Vessels Undergo Stunning Transformation
Roberts and others now believe that the condition can be traced to events occurring very early in pregnancy. In a normal pregnancy, the maternal blood vessels to the area of the uterus where the pancake-like placenta attaches to the uterine wall undergo a stunning transformation.
To supply the uterus and placenta with a sufficient flow of blood to support the growing fetus, these blood vessels, called the “spiral arteries,” increase in diameter by a factor of four, the equivalent of a garden hose assuming the girth of a 24-ounce can of Foster’s Lager. These changes are accompanied by an equally dramatic increase in the mother’s total blood volume, which can expand by as much as 50% during the course of a pregnancy; two-thirds of the increase in blood volume happens by eight weeks gestation.
Why the spiral arteries in preeclamptic women remain small enough to inhibit the flow of blood and oxygen to the placenta is a question at the heart of Susan Fisher’s research at UC San Francisco. Fisher, a cell biologist, explained that the growth of the placenta in the early weeks of pregnancy is a result of the rapid division of placental cells called cytotrophoblasts. After 10 to 12 weeks, the cytotrophoblasts stop dividing and suddenly are transformed into wildly invasive cellular foot soldiers that penetrate the uterus and maternal blood vessels in the same way that tumors attack tissue.
During a process called “endovascular invasion,” the invading cells are capable of mimicking the function of the endothelial cells lining the mother’s blood vessels--a trait that earned the cytotrophoblasts the title “masters of disguise” in a recent medical journal headline. These “differentiated” placental cells thus replace the internal lining of the mother’s blood vessels, anchoring the placenta to the uterus and causing the spiral arteries to expand in diameter so they can bring increasing volumes of the mother’s blood to the placenta. The process by which the placenta attaches itself to the uterine wall is called “placentation.”
Fisher and her colleagues are trying to identify the various proteins produced by placental cells under normal and low-oxygen conditions. The hope is that they will find certain “marker” proteins that doctors can look for as a sign that the placentation process has gone awry.
It has long been suspected that abnormal placentation problems stem from the fact that the placenta and the fetus derive half of their genetic material from the father and thus are foreign tissue to the mother. According to this view, problems during pregnancy can be explained as immunological reactions taken to an extreme: The mother’s body is essentially trying to ward off an intrauterine invader.
Support for this idea comes from studies showing that the more the mother is exposed to the father’s genetic material--either through a prior pregnancy or after several years of intercourse--the less likely she is to develop preeclampsia. This could explain why first pregnancies account for as many as two-thirds of all preeclampsia cases. It also could explain why younger women are at a greater risk of developing the condition. There are even studies showing that women who use condoms or diaphragms are more likely to develop preeclampsia.
Roberts’ assertion from 1989 that injury to vascular endothelial cells plays an important part in preeclampsia still stands. Numerous studies over the last decade by Roberts and others have shown that blood from preeclamptic women, when applied to a culture of endothelial cells, will change the way they function in dramatic ways. Among other things, the “injured” cells are less able than before to prevent clotting inside the blood vessel. In addition, the injured endothelium loses its ability to keep the walls of the blood vessels relaxed and loose; instead, the blood vessels tend to stiffen and tighten. This “vasoconstriction” contributes to the high blood pressure and reduced blood flow associated with preeclampsia.
Clearly, then, there is something in the blood of preeclamptic women that is causing the endothelial cells to change their behavior. But what is it?
As Roberts and his colleagues have studied the problem over the last decade, they’ve found that a preeclamptic woman’s blood differs from the blood of a healthy pregnant woman in many ways.Specifically, they are looking at components of the blood that they know or suspect can have a deleterious effect on the functioning of vascular endothelium. One of their prime suspects: blood-borne lipids, or fats.
Numerous studies have shown that preeclamptic women have elevated levels of certain lipids in their blood--principally triglycerides and free fatty acids--and that this can be seen as early as 16 to 20 weeks into a pregnancy.
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William H. Woodwell Jr. is a freelance writer and editor in Maurertown, Va. He is working on a book about the birth of his daughters.
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New Research
* Vitamins C and E cut risk of preeclampsia in a study. S3
