Mother's Legacy

In many parts of the Southeast, strokes are twice as common as in the rest of the country. Regional differences in diet, exercise and lifestyle don't explain the disparity, and for decades scientists have been mystified by the so-called "Stroke Belt."

Epidemiologist Daniel Lackland thinks he's found at least part of the explanation. And it goes back to the womb.


Combing through health statistics, Lackland found that the high-stroke areas also have increased rates of low-birthweight babies. Many of those infants were found to be at greater risk of having a stroke later in life.

The link may seem random, but Lackland, a professor at the Medical University of South Carolina, says the data are clear: "There is a very good association between low birthweight and stroke."


His work is part of what some researchers call a brewing revolution in our understanding of chronic disease. Scientists are finding more and more evidence that what happens to a fetus in the womb can determine health risks decades later.

The theory is known as "fetal programming" because these early alterations seem to set a person's cellular code for life. Proponents say it could change the way we think about and treat common ailments such as heart disease, cancer and obesity.

"Clearly, what happens in utero sets the susceptibility for lots of disease," says Georgetown University cancer researcher Leena Hilakivi-Clarke, who is studying the connections between fetal programming and breast cancer.

For decades, scientists agreed that most chronic illness was caused by a combination of lifestyle factors - such as diet, exercise and stress - and genetic makeup.

But now, some researchers have focused on a third factor: how the body assembles itself during its 40 weeks in utero. Acting on signals from the mother's body, the fetus seems to permanently alter its development in ways that can profoundly influence future health.

The theory was first developed two decades ago by University of Southampton epidemiologist David Barker. While studying heart disease rates in England, he realized that low-birthweight babies were much more likely to suffer from cardiovascular illness as adults.

"Chronic heart disease is primarily determined by the failure of the mother to deliver nutrients to the fetus," says Barker. He has come to think that fetal programming also plays a central role in many other chronic ailments.

Long-term effects


Much of the research has centered on the long-term effects of low birthweight, which is usually defined as less than 5 pounds.. Scientists think low birthweight can be a fairly accurate way to gauge overall prenatal nutrition. Over the past decade, researchers have linked low birthweight to a range of adult conditions, including high blood pressure, obesity and even some mood disorders.

No one quite understands why smaller babies have higher disease risks. Some theorize that the internal organs of underweight infants are formed with fewer cells. Over decades of use, these cells could get overworked, and eventually wear out.

This may explain the Stroke Belt results. Strokes are often caused by high blood pressure, which is often linked to kidney problems. In those born underweight, small kidneys may begin to malfunction by middle age, raising blood pressure.

As for the tendency to put on pounds, underweight babies seem to burn calories more slowly - not just as infants, but throughout life.

"The game is set up very early, and then you live with it," says Duke University scientist Randy Jirtle, who has found that when mouse fetuses are deprived of folic acid and other nutrients in the womb, they tend to grow up to overweight and diabetic.

Many scientists think the mechanism works via a process called methylation, in which nutrients and other chemicals activate or deactivate specific genes in the fetus. These genetic changes are apparently permanent, which could explain why fetal programming seems to last throughout life.


The altered genes are also transmitted to offspring, which means that what a pregnant woman eats may affect not only her children but also her grandchildren.

Fetal programming remains controversial, and skeptics say that if it does exist, its effects are negligible compared with those of diet and exercise.

Michael Kramer, a McGill University epidemiologist, worries that the hot new theory will divert attention from these established health factors, which don't have the same cutting-edge cachet.

"From a public health standpoint," he says, "fetal programming is not really where the action should be."

But advocates say fetal programming is becoming more plausible all the time. The more scientists look, the more evidence they find. Last summer, for example, University of Southern California gerontologist Caleb Finch reported higher rates of heart disease among adults whose mothers had an infectious illness during pregnancy.

Finch thinks a mother's infection may lead to a chronic, low-grade inflammation in her child. Over decades, this condition might weaken the cardiovascular system, increasing the risk of heart disease. Maternal infection could also play a role in other ailments, he says, from cancer to schizophrenia.


Small babies aren't the only ones at risk. Scientists have also found that high-birthweight infants - generally defined as above nine pounds - have a higher incidence of breast and prostate cancer as adults.

At Georgetown, Hilakivi-Clarke suspects that prenatal hormone levels may influence this risk. In studies on rats, she's examining how the mother's food intake affects the offspring's later chances of breast cancer. So far, she's found that a high fat diet during pregnancy increases vulnerability, while a regimen packed with whole wheat lowers it.

Mysteries remain

Even as evidence mounts, many mysteries remain. Most details of the fetal programming language have yet to be unraveled. Researchers are realizing that the process involves far more than the number of calories the fetus gets from Mom. The fetal code likely uses a complex array of nutrients, hormones and other chemicals to tell the fetus what to expect.

This insight complicates the picture, because fetal programming is no longer just a concern for low or high birthweight babies. Even an infant in the normal weight range may have built-in disease risks if her mother's diet was somehow unbalanced.

"Caloric intake isn't nearly as important as the right nutrients," says Kent Thornburg, a heart researcher at the Oregon Health Sciences University. In studies on mice, pigs and sheep, he has shown that a low-protein prenatal diet greatly increases the offspring's chances of having both heart disease and stroke.


It's also not clear what purpose fetal programming serves. Many scientists think it's a kind of last-minute communication system to help the developing infant prepare for the specific environment it will soon inhabit.

If, for example, the mother ingests less of a key nutrient, this could signal that food will be limited, and so the fetus should optimize itself for an environment of scarcity. As a result, the infant will arrive with a smaller body, which requires less energy, and a slower metabolism, which helps store fat for times of shortage.

Help for survival

In evolutionary terms, the arrangement offers an advantage, says pediatrician Peter Gluckman, a leading proponent of the theory: The more closely an animal matches its environment, the better its chances of survival.

But problems arise when babies programmed for shortage wind up in a world crowded with McDonald's and free refills. This, says Gluckman, is exactly what is happening to millions of people around the world. Their bodies can't cope with this plenty, and the result is obesity, heart disease and a host of other illnesses.

"There's a mismatch between the environment that exists before birth and the environment that exists after," says Gluckman, who is a professor at the University of Auckland in New Zealand.


By unlocking the mechanisms behind fetal programming, Gluckman and others say, they can lower rates of many chronic diseases. To help this effort, the National Institutes of Health is spending more than $2.5 million on a series of fetal programming studies.

"If you could optimize the fetal environment, you may be able to get significant benefits later in life," says the project's director, Dr. Cathy Spong, chief of pregnancy and perinatalogy at National Institute of Child Health and Human Development.

In the meantime, is there hope for those born too light, or too heavy, or whose mothers ate too many doughnuts and not enough spinach during pregnancy?

Scientists emphasize that fetal programming doesn't determine future health. Instead, it probably sets risk levels. Eventually, researchers say, knowledge of fetal programming will help people get an early handle on these hazards.

"If you're a low-birthweight baby, you probably need to be more careful about diet and exercise," says Lackland, the Stroke Belt researcher. "But it's not a kiss of death."