This week, Dr. Sydney Spiesel discusses individualized drug dosages, the link between maternal obesity and birth defects, and the heart risks of roller coaster thrills.
The perfect dose
Progress: Medicine is hovering on the edge of a real advance: the routine use of genetic testing to predict individual differences in response to medications. To be sure, this kind of testing raises serious ethical questions. A widely supported bill to prevent insurance companies from misusing the information sweepingly passed the House of Representatives and is awaiting introduction in the Senate. But the benefit of the testing is that we may soon be able to modify dosage amounts to reflect our individual differences.
Test: The first great test case for this method is likely to be warfarin. Two million people in the United States use this blood thinner—a medication that blocks the body’s production of materials needed for blood clotting—to prevent blood clots, heart attacks, and stroke. It is a drug of great importance, but hard to use because individual differences in patients that derive from small differences in genetic makeup make it hard to get the dose just right. And if it is wrong, a patient is at risk for problems associated with blood clots (like stroke), or for uncontrollable bleeding. Warfarin is the second-most common cause of medication-induced problems that bring patients to the emergency room. (Insulin is the most common cause.)
How it works: Currently, the right dose of warfarin is determined by trial and error: Some medicine is given, the blood clotting is measured, the dose is adjusted, and the patient is again tested and the adjustments fine-tuned. However, until the dose is made perfect the patient may be in danger from overactive or inadequate blood clotting. The differences in response to warfarin are controlled by variants in two genes. Through genetic testing, then, we can largely identify in advance patients who need unusually large or small doses of warfarin for optimum effect.
Cost: It has been persuasively argued that this kind of testing—called “pharmacogenomics”—is highly cost-effective when used to find a good starting dose for warfarin (and soon, I suspect, for other drugs, too). It is estimated that a quick genetic test to establish a best starting dose for warfarin would prevent 85,000 serious bleeding events and 17,000 strokes in the United States alone every year. After accounting for the cost of the testing, the health-care savings are likely to amount to more than $1 billion a year. And a great deal of misery will be prevented.
Conclusion: Such genetic testing is not yet required, but the FDA has just changed the labeling for warfarin products to point out the usefulness of appropriate genetic tests as a first step in determining a patient’s optimum dose. I suspect that soon the dose of many drugs will be adjusted in advance to take account of our individual genetic differences. And we will all be much healthier for it.
Maternal weight and birth defects
Question: Overweight people, including pregnant women, are at increased risks for a variety of medical conditions. But what about the babies of pregnant women who are heavy—are they also at higher risk for problems?
New study: It has been suspected that they might be. For instance, there is a clear relationship between certain heart defects in babies and uncontrolled diabetes during pregnancy, a maternal condition often associated with obesity. Now a new and rigorous study gives us better insight into the relationship between maternal weight and infant health. The data come from the National Birth Defects Prevention Study, a study of babies with birth defects born in eight states between 1997 and 2002. D.K. Waller of the University of Texas School of Public Health and colleagues selected more than 10,000 babies with birth defects and examined the pre-pregnancy weight of their mothers. Waller and her * co-authors compared these babies with 4,000 without birth defects to be sure that other qualities that might affect the rate of birth defects—maternal age, smoking habits, education, for instance—weren’t significantly different between the groups of mothers. They weren’t.
Findings: Many kinds of birth defects seemed completely unrelated to excess maternal weight. But some kinds of serious birth defects seemed associated with the mother’s weight just before pregnancy. The effect was stronger for mothers classified as “obese” according to their body mass index, but was also present when mothers were simply “overweight.” Spina bifida, heart defects, an abnormal location of the urethral opening in male children, and the presence of a closed anus or rectum all fall into this category. The risk for one kind of birth defect, gastroschisis (in which the abdominal wall is open and the intestines develop outside of the baby’s abdomen), is much less common in the children of obese or heavy mothers, compared with thin ones.
Explanation: We really don’t understand why maternal weight should affect the growing baby in these ways. It is possible that undiagnosed maternal diabetes played a significant role—when mothers with known diabetes were removed from the analysis, the frequency of birth defects fell. Because an inadequate supply of the vitamin folic acid is known to increase the risk of spina bifida, the authors tried to separate the effect of folic acid in a mother’s diet from the effect of her weight. They found no difference based on this factor, but it is very possible that heavy mothers may choose a diet subtly less rich in this vitamin. It’s also true that less maternal exercise increases the rate of spina bifida, and such inactivity may be more prevalent in overweight mothers. And fat produces the female hormone estrogen, so heavy mothers may have higher blood levels of this hormone which, in turn, might play a role in the observed genital birth defects of boy babies.
Conclusion: Whatever the cause, these findings are contributing to the recent change in the attitude of obstetricians toward maternal weight gain. When my wife was pregnant, her doctor didn’t want her to gain more than 17 pounds. Subsequent experience showed that limits like that harmed growing babies. Now excess weight is revealed to have its dangers. As with most things, the narrow path of moderation seems best.
Roller coaster thrills
Question: The thrill of a great roller coaster ride is that it “scares you to death.” But does that ever literally happen?
New study: Researchers from the universities of Heidelberg and Mannheim, working with Dr. Juergen Kuschyk, the lead author of this paper describing their study, decided to find out. They recorded the electrocardiograms of 55 men and women between the ages of 18 and 71 as they flew around on a modern, high-speed roller coaster at an amusement park in Germany. The two-minute ride began with a slow 200-foot rise, followed by a four-second free-fall drop (during which the riders felt the physical sensation of a force varying from 4.5 times gravity to negative-1.5 times gravity). The ride continued traveling at a maximum of 75 mph and went through a number of other free-fall drops and sharp turns before delivering its quivering passengers at the end.
Findings: Interestingly—if not surprisingly—the maximum increase in heart rate occurred not during the drops and racing, but in the anticipation phase, as the cars slowly ascended to their maximum height and the riders thought about what was to come. The maximum heart rate for some riders exceeded 200 beats per minute. Almost half experienced minor irregular heart rhythms in the five minutes after the ride ended, and one rider experienced a brief period of irregular heart rhythm that resulted in palpitations (the problem quickly fixed itself).
Implications: What does this mean? Maybe nothing: We’ve all experienced rapid heart rate when we are excited or frightened. Or maybe something: Of 29 fatalities in roller coaster riders reported over a 10-year period, seven deaths were attributed to a cardiac cause. Considering the huge number of roller coaster rides taken each year around the world, the individual risk must be very, very small. But perhaps people with known significant cardiovascular disease should pass on this thrill.
* Correction, Aug. 30, 2007: This sentence originally incorrectly referred to D.K. Waller as “he.” Waller is a woman. (Return to the corrected sentence.)
