Baby aspirin – Preeclampsia – evidence that a daily baby aspirin can help prevent preeclampsia
It is unlikely that stubbornly high rates of premature birth and infant mortality will yield to a simple solution. Yet there is both hope and evidence that a baby aspirin a day can help to prevent one of the major causes of problem pregnancy, preeclampsia (pre-e-CLAMP-see-a), or “toxemia of pregnancy,” to use the older term.
At least 5-6% of women develop preeclampsia during their first pregnancy (the frequency is much less with subsequent ones). The condition usually emerges in the final trimester, when the affected woman may note swelling of her feet and hands and her physician finds protein in her urine and a higher-than-normal blood pressure. Although this state of affairs may remain fairly stable, sometimes the disease progresses, as small blood vessels all over the body begin to constrict. Usually (but not always), blood pressure then rises to a very high level. As a result of reduced blood supply, hypertension, and perhaps increased leakiness of small blood vessels, many organs may be damaged. Typically the kidneys and central nervous system are involved, and often function of the liver or other organs is deranged. The next episode in this catastrophic chain of events, when nothing is done to prevent it, is likely to be a series of convulsions, which define the condition known as eclampsia.
At the root of the condition is an abnormality of the placenta. As soon as the placenta is removed — through either a normal or a cesarean delivery — the problems usually abate. Thus, eclampsia or rapid progression of preeclampsia almost always requires an emergency delivery. The underlying placental abnormality also affects the fetus, which may not survive or may be born with any of the various problems associated with prematurity and low birth weight.
The idea that aspirin may be able to alleviate this potentially dire condition has emerged from a reassessment of the nature of preeclampsia. Hypertension, once thought to be the main problem, is now believed to be a secondary feature of the illness, a byproduct of the abnormality affecting small arteries throughout the body.
Supply and demand
Because the growing fetus demands a rich supply of blood from the mother, controlling blood flow is an important task for the pregnant body. Early in pregnancy, the uterus develops a special set of arteries to supply the placenta. To meet the needs of accelerating fetal growth in the final trimester, a second phase of arterial growth is required. During the sixth month the placenta therefore reaches farther into the uterine wall for better access to nutrients in the mother’s blood. The arteries in the uterine wall dilate at least fourfold to facilitate this process.
If arterial growth fails or falters, fetal growth may slow, and the distressed placenta is believed to release one or more substances into the mother’s circulation. Researchers in the field are not sure exactly what it is, but Dr. Carl A. Hubel, of the University of Vermont College of Medicine, has made a strong case that it consists of abnormally oxidized fats (lipid peroxides) that are capable of damaging the tissue they contact.
There is more certainty about what happens next. The greatest damage is to two kinds of cells: those lining the blood vessels (endothelial cells) and the platelets circulating in the blood. These two types of cells form a working partnership that is vital to managing the circulation. Each secretes a wide array of substances that help to regulate the diameter of smaller blood vessels (and therefore the resistance to blood flow). They also maintain the balance between fluidity and clotting of the blood. In women with preeclampsia, the system is shifted in the direction of high resistance and a greater tendency of platelets to aggregate. The small vessels constrict, and microscopic clots form along their walls. Injury to delicate vessels in the kidney leads to protein loss in the urine, a well-recognized feature of the disease, and the function of almost any other organ may go awry.
Two of the critical regulatory substances involved in this process are prostaglandins. The platelets secrete thromboxane, which promotes constriction of vessels and clotting; the lining cells of the vessels secrete prostacyclin, which has the opposite effects. Although aspirin can interfere with production of both these substances, at low doses preferentially cuts off the supply of thromboxane. (This is precisely why a small does of aspirin is often recommended for the prevention of strokes and heart attacks.)
Milligrams of prevention
Preeclampsia is self perpetuating. Once the disease is established, it makes itself worse, and aspirin alone is not adequate to halt the downward spiral. Bed rest, treatment with antihypertensive drugs, and early delivery may be required. But if women at risk of developing preeclampsia can be identified in advance, 75-100 milligrams of aspirin a day can radically reduce the likelihood that the disease will occur or the rate at which its complications develop. Although this idea has been around for about a decade, strong confirmation has emerged only recently.
For example, in 1989 a team led by Dr. Eyal Schiff at Chaim Sheba Medical Center in Tel Hashomer, Israel, reported that 34 women treated with 100 milligrams of aspirin a day were less likely to develop high blood pressure and far less apt to suffer kidney damage from preeclampsia than were 31 who received a placebo. In June 1990 a group of researchers at St. George’s Hospital in London reported similar findings in a group of 48 women treated with 75 milligrams of aspirin a day and 52 who received only a placebo.
In both studies the treated mothers clearly benefited. Few of the babies in either the treated or the control group had problems, and this may be why the differences found between the two groups were not statistically significant. The results were highly suggestive, however. In the Israeli study, babies born to treated mothers were delivered closer to term and had higher birth weights for their gestational age than did those born to untreated women. The British researchers reported that three babies in their placebo group died of complications related to preeclampsia, whereas the only death in their treated group was related to a problem with the umbilical cord during delivery.
Should every pregnant woman take low-dose aspirin? The answer is almost certainly no. The drug probably has little value before the third trimester and could conceivably be harmful if taken early in pregnancy. Women who are not at risk of preeclampsia probably would not benefit from aspirin and could run a higher-than-average risk of abnormal blood loss (although there have been virtually no such complications in women studied so far).
Currently, certain information from a woman’s medical history provides the best indication of whether she is at risk for preeclampsia. The most important is preeclampsia during an earlier pregnancy. The risk is also higher than average if the pregnancy is the first or is multiple, if the woman already has diabetes or high blood pressure, if she is very young or very old to be pregnant, or if she has a family history of preeclampsia.
The presence of any of these criteria raises the risk. But even among women who meet more than one of them, only a fraction will develop preeclampsia. Unfortunately, such information is all that obstetricians have available when deciding whom to treat. Although newer diagnostic methods may soon make it possible to prescribe aspirin more selectively, for now it is common practice to give low doses of aspirin to women at highest risk.
Perhaps a hundred laboratory tests have been proposed to identify women on the verge of preeclampsia, but they have been either too inaccurate or too cumbersome to be useful. In 1990 two promising diagnostic methods have been described, but both require confirming research before they can become accepted as standard.
The investigators at St. George’s Hospital in London reported that a Doppler ultrasound evaluation can detect high resistance in the uterine blood vessels — a pattern present in nearly all women who develop preeclampsia. On the other hand, high resistance is also observed in many women who do not go on to develop the disorder, a fact that seriously reduces the predictive power of the test. The London results are currently regarded as very interesting, but not definitive.
A blood test developed by Dr. Michael B. Zemel and his colleagues at Wayne State University promises to identify women at risk with much greater precision. These researchers followed 48 young black women (a high-risk group) throughout their pregnancies. A platelet abnormality detected early in pregnancy predicted with considerable accuracy which women would later develop preeclampsia. If the Wayne State results hold up, the platelet test could become a standard method for deciding which mothers should receive a baby aspirin a day. As of now, however, it is still under study.
If a diagnostic test cannot be developed, deciding whether to prescribe aspirin for preeclampsia will often be difficult. Where should the line be drawn? The drug seems sure to help a minority of women at high risk. On the other hand, it is potentially somewhat hazardous, and women at very low risk might not benefit from it. Much more research is needed before the answer will be clear.
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