Weight Matters, Even in the Womb.

Status at birth can foreshadow illnesses decades later

In the bathroom, at the gym, and in the doctor's office, most people in the United States keep an eye on the scale. We're usually more concerned about weighing too much than weighing too little. There's a social stigma to being heavy and public health messages regularly warn us that extra fat leads to a higher-than-average risk of developing high blood pressure, heart disease, diabetes, and other chronic ailments.

The public health message, though, would be very different if it targeted babies about to be born. A growing number of studies confirm that small, thin newborns are more likely to develop certain chronic diseases when they become adults than are babies who are born heavier.

Connections between low birth weight and adult disease were first discerned in England a little more than a decade ago. David Barker, an epidemiologist at the' University of Southampton, noticed that some low-income regions that had had high infant-mortality rates in the early part of the century also had higher-than-average rates of heart disease in their adult populations during the 1970s and 1980s.

High infant mortality is often attributed to low birth weight--defined as less than 5.5 pounds--since babies that small often have trouble breathing and develop other ailments. The observation that populations with high infant mortality were also prone to heart disease led Barker to propose that a full-term baby's weight could be linked to an adult's risk of developing a chronic disease. Even babies at the small end of the normal range are more likely to develop chronic diseases later in life than heavier infants are, he suggested.

Initially, Barker's idea was controversial. Yet many studies confirming the association--in different countries and ethnic groups--have convinced most doubters that something is going on.

The question is, What?

Early skeptics of Barker's conjecture wondered if the socioeconomic status of children might correlate more strongly with adult health and disease patterns than birthweight does. Others pointed to genetics, arguing that heredity might be responsible for both low birth weights and a person's risk of chronic diseases, and that one doesn't necessarily lead to the other.

Barker had a different explanation for the data. Poor nutrition for a mother restricts the normal growth of a fetus. He reasoned that this, in turn, hampers the growth and the function of the baby's developing organs and that this poor start influences the course of some major diseases in adults.

A growing number of animal studies are confirming Barker's hypothesis. Some suggest that fetal nutrition, like hormone exposure, shapes the expression of genes throughout a person's lifetime. "It's only by understanding the mechanisms [through which low birth weight has an effect] that we're going to change things," says Peter W. Nathanielsz of Cornell University. "This is the story of the future of public health."

One challenge to the research is that birth weight is an imperfect reflection of what's going on in the womb. "There's nothing wrong with being a 5-pound baby if your genes want you to be a 5-pound baby," Nathanielsz says. "The baby that's in trouble is the 5-pound baby whose genes wanted him to be a 9-pound baby."

For people born decades ago, birth weight is often all the information about newborn health that's available. More recently, physicians have measured an infant's length, plumpness, and the size of its head relative to the rest of its body.

Traits predisposing an infant to have a slow metabolism or a tendency to put on fat during childhood and adult life might be turned on in the nutrient-deprived womb, researchers speculate. Such characteristics presumably help babies stay alive during times of famine. According to Barker, however, those same traits can be troublesome if the infant is instead born into a world of plenty.

There's experimental evidence for the view that developmental patterns in the womb may influence an adult's disease risks. When female rats were fed a low-protein diet for just 4 days of their 21-day pregnancies, the developing rat embryos were made up of fewer cells than normal, Tom P. Fleming of the University of Southampton and his colleagues reported in the Sept. 7 DEVELOPMENT. Twelve weeks after birth, these rats also exhibited high blood pressure, which often presages later health problems.

Researchers propose that when a pregnant animal is underfed or when the blood flow to the fetus through the placenta is inadequate, the fetus diverts scarce resources to its brain. Other organs, especially the liver, kidney, and pancreas, suffer as a result. They develop fewer cells and an unusually high number of the cells that don't work properly.

Supporting this scenario, several studies have shown that the kidneys of animals deprived of nutrients in the womb have fewer nephrons, the tubular structures that filter blood. Other recent work suggests that nutrient deprivation during pregnancy fosters small livers without enough cells to adequately clear cholesterol from the blood, Barker says.

Some animal studies have found that blood vessels from undernourished fetuses are less flexible than blood vessels from well-nourished ones, a trait that may eventually lead to high blood pressure.

The relevance of such evidence to people remains unclear, however. Among 603 25-year-olds, the blood vessels of those who were light or short at birth were no stiffer than those of the participants who had been of normal size at birth, Yoav Ben-Shlomo of the University of Bristol in England and his colleagues reported in the June 17 LANCET. As in other studies, people who had had low birth weights did show slightly higher blood pressures than their normal-birth-weight counterparts, he says.

Researchers studying the potential links between birth weight and adult diseases often confront conflicting data. For example, a study of babies born during the siege of Leningrad from 1941-1944 found no link between low birth weights and diseases such as diabetes and heart disease. On the other hand, a study of Dutch babies whose pregnant mothers suffered through a 7-month famine in 1944-1945 did show a correlation.

One possible explanation for the discrepancy, says Barker, is the role of "catch-up growth." In the Netherlands, where food supplies were plentiful after the war, some small babies quickly put on weight, reaching average or above average weights by age 7. The babies born in wartime Leningrad, however, were malnourished throughout early childhood.

Barker speculates that unknown physiological mechanisms linked to catch-up growth are critical in determining risks of adult disease. A study now in progress could weigh in on that speculation. Among more than 2,000 Filipinos followed since their births in 1983 and 1984, those who were born small have higher blood pressure than teens of the same weight who had started out as larger babies, say Christopher Kuzawa of Emory University in Atlanta and Linda Adair of the University of North Carolina at Chapel Hill.

The researchers measured cholesterol concentrations in the blood of some of these young people. Among teens with similar levels of physical activity, those who were born small had higher cholesterol concentrations than the others did, Kuzawa reported at a meeting in April.

Kuzawa's studies show that small babies who become heavy teens are at highest risk of having high cholesterol and high blood pressure. Several other studies, show that people with low birth weights who later became overweight have higher rates of heart disease and diabetes compared with people of similar weights who were born heavier or to people born small but who stayed relatively thin.

"Things don't just stop when you're born," says Ben-Shlomo. "It may be particularly dangerous to be born small and then get fat."

"The relative importance of early and later nutritional factors may vary from place to place," says Adair. India, for example, is experiencing an epidemic of cardiovascular disease and diabetes. "A high prevalence of low birth weights is coupled with [the population's] rapid transition to higher-fat diets and more sedentary behavior," says Adair. In more developed countries, she adds, the relative importance of birth characteristics may be smaller.

Researchers suspect that nutrition isn't the only explanation that links life in the womb and adult diseases. Some scientists suggest that the prenatal environment affects which genes get turned on in each person.

In laboratory experiments, some rat genes are silent during embryonic development in one solution of nutrients but are active in embryos growing in a different solution, Marisa Bartolomei of the University of Pennsylvania reported this October at the American Society for Human Genetics meeting in Philadelphia. She suggests that, in people, altered environments in the womb also may influence the expression of genes and thereby predispose a child to disease later in life.

Maternal and fetal hormones also direct prenatal development. Insulin and other hormones regulate fetal growth and respond rapidly to changes in nutrition. In several studies of birth and health records, Barker and his colleagues have shown that low-weight babies tend to grow up more resistant to the action of insulin and more prone to adult-onset diabetes than normal-weight babies are. Overexposure to insulin in the womb might lead to insulin resistance, Barker speculates.

Fetal exposure to stress hormones, such as cortisol, also may have consequences in adulthood. For one thing, rats and sheep exposed to a stress hormone in the womb are born smaller and are more apt to develop higher blood pressure later on than are those not exposed to the hormone.

A study published in the Jan. 16, 1999 BRITISH MEDICAL JOURNAL found that women who reported feeling stressed during their pregnancies were more likely to have abnormal patterns of blood flow to their babies than were women who felt less stressed. Follow-up studies will track high blood pressure, heart disease, or diabetes in the offspring later in life.

To consider fetal exposure to certain hormones, Nathanielsz has monitored blood pressure and heart rate continuously in fetal sheep during the last third of gestation. He's found that glucocorticoids--synthetic hormones related to cortisol--cause the fetuses' heart rates to drop and their blood pressure to rise. Such boosts to blood pressure also appear persistent, he says. Sheep exposed just once to glucocorticoids in the womb have higher blood pressure at 3 years of age than sheep who weren't exposed to the hormones.

This finding could be clinically important since doctors frequently give glucocorticoids to women who are at high risk of delivering their babies prematurely. The compounds speed lung development and increase a premature baby's chance of surviving, Nathanielsz says. But because these hormones are widely viewed as safe, multiple doses are sometimes given. This practice could have harmful long-term consequences, he warns.

The concept that prenatal conditions can affect chronic diseases in adults "has been accepted only slowly," says Claude Lenfant, director of the National Heart, Lung, and Blood Institute in Bethesda, Md. "However, today the weight of the evidence is so strong it cannot be resisted."

That said, researchers disagree about the relative impact of prenatal environment, genetics, and adult lifestyle.

"In general, the effect of birth weight [on risk for chronic diseases] seems to be fairly small," says Brian Walker, a British Heart Foundation research fellow at Western General Hospital in Edinburgh. In the June 17 LANCET, Walker and his colleagues reported that when preterm babies reached their early 20s, they were more likely than young adults who had been full-term babies to have high blood pressure and high concentrations of sugar in their blood. The results were similar to those previously reported for babies born small but not early.

Premature babies who were smaller than expected for their gestational age were the same in this regard as those preemies who had birth weights appropriate for their gestational age, he says. This suggests that slower growth in the womb is not solely responsible for the risk factors that show up in later life, he cautions.

Between 1 percent and 35 percent of adult-onset diabetes might be attributed to low birth weights, according to a report in the September DIABETES CARE. Edward J. Boyko of the Veterans Affairs Medical Center in Seattle examined a variety of studies and applied a complex statistical analysis that took into account many risk factors. "Predestination according to birth weight is not the case, though the effects of birth weight may still be important," he concludes.

Nathanielsz takes a more deterministic view. "Your environment in the womb will have at least as much effect on your cardiovascular system as your genetics." he says.

Whatever the ultimate balance, "this field is transforming the way we think about health," says Ezra S. Susser of the Mailman School of Public Health at Columbia University. "There's a dynamic interplay between genes, the prenatal environment, and then the rest of your experiences throughout life."

As researchers attempt to untangle the complex give and take of these factors and to tease out the mechanisms that underlie correlations between birth weight and adult health, they hope that this knowledge will eventually help physicians prevent some chronic disease.