Theory Says Disease Tendencies Begin in Womb

By Rob Stein

Near the end of World War II, Germany blockaded food to the largest cities in the Netherlands. Nearly two decades later, when boys born to women who were pregnant during the ensuing famine underwent military physicals, doctors noticed something puzzling: The young men were unusually prone to obesity.

That oddity would become one of the cornerstones of a theory of disease that has been gaining acceptance in recent years. A growing body of evidence suggests that poor nutrition, stress and other factors can affect a woman's developing fetus in subtle but fundamental ways, predisposing offspring to health problems as adults. These include heart disease, diabetes, stroke, cancer and even possibly psychiatric conditions such as schizophrenia, bipolar disorder and depression.

"When living things develop, and human beings are no exception, they are very sensitive to the environment. And that includes the environment inside the womb," said David Barker of the University of Southampton in England, a leading proponent of the "fetal origins of adult disease" hypothesis. "Structures and systems of the body are different according to the conditions during development."

The provocative theory goes far beyond the well-known health problems that underdeveloped premature babies suffer, the genetic diseases or frailties children can inherit and the physical and developmental disabilities infants can be born with when pregnant women drink, smoke, use drugs or take medicine dangerous to the fetus. According to the theory, babies born a normal size with no genetic defects or family history of disease and in otherwise good health can nevertheless be fated to future problems because of subtle changes triggered in the womb.

"When the fetus is at specific, critical points in development, different organs in the body -- the pancreas, the brain -- are more vulnerable than others to a stressful situation," said Kent Thornburg of the Oregon Health Sciences University. "If they get too much of the stress hormone cortisol, or are malnourished, these organs will then undergo what we call programming. They will try to adjust in a way that will give them a survival advantage. But that modifies their gene expression for life in ways that may not in fact be advantageous."

The theory still has many skeptics, but it could help explain some of the most important public health problems, such as the epidemics of obesity in the United States and other parts of the world. It could also shed light on some of the most puzzling health mysteries, such as why immigrants and their descendants are more prone to heart disease, obesity, diabetes -- and perhaps even some forms of mental illness -- when they move from poor to rich nations.

"We always knew that nutrition was important for mothers. But it never dawned on us the magnitude of the importance," Thornburg said . "It means fetal development is really responsible for the health of our population. Population health has always been discussed in terms of what adults do as adults. Now we realize that what may be more important is what happens to you before you're born."

The evidence has come from studies around the world, ranging from following large numbers of people over long periods to link adult health with exposures in the womb, to detailed lab work demonstrating that the offspring of animals can be affected by feeding their mothers certain diets or exposing them to stressful conditions.

Based on these and other findings, some researchers suspect excess stress hormones and other nuances in female body chemistry may have an impact in the earliest stages of development, perhaps before a fertilized egg implants in the womb, or even when the eggs are still maturing.

"You actually have to worry about pre-pregnant women. If the hypothesis is true, then we need to be worrying about making sure adolescent girls are adequately nourished so they reach their genetic growth potential and are giving the right signals to their kids" when they become pregnant, said Aryeh D. Stein of Emory University.

In some cases, it appears the changes can become a legacy that is passed on for generations. In the July issue of the American Heart Association's journal Stroke, Barker is publishing a study that suggests high rates of stroke that have plagued parts of England and the United States for decades may be the result of poverty in those regions generations ago.

If confirmed, the fetal origins idea could have profound implications, opening up broad new avenues of research and public health measures, such as wider use of nutritional supplements before and during pregnancy to reduce the toll from some of the most common chronic diseases.

"The reason people are excited is because these prenatal conditions may be preventable," said Stephen Buka of the Harvard School of Public Health. "And by reducing them we may reduce the frequency of these devastating conditions."

The researchers are keenly aware that the theory could make women even more anxious about their future children's well-being, or prompt recriminations against women for endangering the health of their progeny. But proponents say the responsibility goes far beyond the behavior of individual women. Instead, it lies with prevailing conditions in society and environmental factors that are largely beyond women's control.

"When we're talking about the fetal origins of adult disease, there's a danger that we get into a blame game with women," said Matthew Gillman of Harvard Medical School. "We have to watch out for that."

In some cases, the effects could be the result of a malfunction in the placenta, the tissue that provides sustenance to the fetus, that has nothing to do with what a woman does.

Skeptics, however, do question the theory on scientific grounds, saying there could be many other explanations for the associations that researchers have attributed to fetal programming.

"I'm not sure the associations are causal, and I'm not sure that even if they are they're important from a public health point of view," said Michael Kramer of McGill University in Canada. "It's a lot easier and sexier to study that than why kids are spending too much time in front of the television. But that's a lot more important."

Proponents argue that the evidence for the theory is strong and getting stronger, buttressed by rapidly accumulating animal research, large observational studies of people, the latest insights into subtle variations in how the same genes behave in different individuals and a deepening understanding of human development. More than 700 scientists from 43 countries gathered outside London in June for the second international meeting devoted to the theory.

"We were able to answer the critics, of which there have been not a few," Barker said.

The strongest evidence is for heart disease. Barker's initial finding that people who are born small -- around six or seven pounds -- were much more likely to develop heart disease as adults has been confirmed by a number of later studies. The exact mechanism remains unclear, but animal and human studies suggest that smaller babies experienced inadequate nutrition in the womb. As a result, their bodies developed in ways that would help them survive in a world where food is scarce.

"The mom early on signals to the fetus what the environment is really like. 'You're going to grow up in a poor environment, so you'd better slow down your growth trajectory,' " Stein said. "If the fetus is then born into a poor environment, then the kid is well adapted. But if the fetus ends up being born into a different environment, where food is abundant and work is sedentary, then this fetus will be maladapted and deposit fat too easily."

Similar mechanisms could increase the risk for obesity and high blood pressure. It could also explain why rates of obesity and heart disease tend to skyrocket when people move from poor countries to rich ones.

"Their bodies are programmed to be very efficient with energy. They don't seem to have the capacity to handle high-energy diets without storing a lot of fat," Thornburg said. "The data is so overwhelming that there's no doubt in my mind that this phenomenon is real and it's important."

For cancer, researchers suspect that exposure to unusually high or low levels of hormones or growth factors in the womb may affect the resulting child's subsequent risk for certain malignancies.

Karin Michels of Harvard Medical School found that women who were heavy at birth appear to have twice the usual risk of breast cancer as adults. "It's the opposite of the cardiovascular risk," she said.

Similar evidence has been mounting for some psychiatric conditions.

"We think it's quite plausible that events during pregnancy, along with genes, influence the development of the nervous system and the development of what later on will be mental illness," Buka said.

Babies born after difficult pregnancies and deliveries appear to be at greatest risk. Some evidence suggests the mother's immune system, or exposure to infections, could affect the developing fetus's brain, Buka said.

"The consensus in the field is that it's not a specific infection itself but the mom's immune system fighting off the infection that has adverse impacts on the child's developing neurological system," Buka said.

The immune system could also play a role in the increased risk of schizophrenia among some groups after they move to more industrialized societies.

"Say you come from the Caribbean, where it's warm, to cold raw England. Your body isn't prepared to fight off all the new infections you're suddenly exposed to. If you live in crowded, sneezy London, your contact with infections increases," Buka said.

An assortment of research is underway or in the planning stages to validate the theory and tease out the causes and mechanisms.

The National Institutes of Health is planning the National Children's Study, which would follow 100,000 children from the womb onward to determine which social, physical, environmental and other factors influence their health.

In another study already underway, known as Project Viva, Gillman and colleagues at Harvard are following more than 2,100 women who gave birth since 1999. Researchers collected a wide range of data about the women before their babies were born, including their diets, exercise and whether they were exposed to violence or other stressful events.

And Stein and his colleagues at Emory and Columbia University are starting a follow-up study to further examine the offspring of the "Dutch Hunger Winter" to try to determine exactly what aspects of the diet may be responsible.

"This is cutting-edge research," Michels said. "And it's really only starting."