By Rob Stein
Washington Post Staff Writer
Monday, July 7, 2003; Page A04
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."
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