While a female Patagonian is with child, all disagreeable objects are kept
from her; she is awakened by musick; they study to divert her with amusements
most suitable to her taste; her mind is brightened with joy, without allowing
her to grow slothful for want of action, she has exercise…as is most agreeable
to her. The Patagonians do not doubt the mother’s influence over…the
physical…constitution of the child.” Journal of a Voyage Round the World in
the Dolphin, Anonymous (1767)
AND so the legendary Patagonian Giants of South America were said to believe
that the wellbeing of pregnant women was the key to their great stature and
robust health. While the giants might not have always got their health policies
right (apparently, they also encouraged children to smash their heads thinking
it strengthened their skulls), when it comes to maternal health, they were, it
seems, ahead of the game.
After all, modern day convention has it that as long as a pregnant woman
doesn’t do drugs, or smoke and drink too heavily, there’s little that can harm
her growing child. The fetus, meanwhile, is often considered the ultimate
parasite, capable of siphoning off all the nutrients it needs so that even a
near-starving woman can give birth to a normal baby.
Advertisement
But now almost two decades of research is questioning those reassuring
assumptions—and lending an aura of good sense to the tales told about the
fantastical giants of bygone Patagonia. It suggests that what happened to you in
the womb can affect your health fifty years later, altering your chances of
heart attacks, diabetes and chronic high blood pressure. “You always hear about
exercising, keeping weight down and the genetic component of diseases, but the
impact of intrauterine life could be even greater,” says physiologist Miodrag
Dodic of the Howard Florey Institute in Melbourne, Australia.
Researchers who study the effects of fetal life on adult health are quick to
point out that they don’t yet have enough information to make all but the most
tantalisingly general recommendations to pregnant women—eat well and avoid
stress. And they are also uncomfortably aware that their findings could be taken
as just another bid to make mothers feel guilty. Ultimately, however, they hope
that a detailed knowledge of what a pregnant woman should or shouldn’t do to
ensure the future health of her offspring will aid the battle against the
chronic diseases that plague modern society.
The notion that life in the womb can affect health in mid-life has its roots
among the cotton mills and coal mines of England and Wales at the turn of the
century. Then, poor regions had infant death rates as high as one in five.
Decades later, they also had higher than average rates of death among adult
males from coronary heart disease. The death rates of adult women from heart
disease, though not so dramatic because they are less susceptible than men,
pointed in the same direction.
David Barker, an epidemiologist from the University of Southampton, was the
first to notice that peculiar pattern while he was poring over maps of mortality
rates. And in the mid-1980s, he came up with a bold hypothesis to explain it.
High death rates in the first month of life are generally taken as a sign that a
society’s maternal health is bad, which means that infants are growing poorly in
the womb. Could the heart disease in middle age be a lingering effect of that
poor fetal growth?
The notion was disquieting: heart disease is, after all, usually blamed on
poor lifestyle choices made by fully-fledged adults or an unlucky roll of the
genetic dice, so initially few people were persuaded. But after several more
years of sleuthing that involved all sorts of collaborators, from historians to
midwives, and the examination of thousands of British medical records and
hundreds of middle-aged survivors, Barker was able to convince many of his
detractors that he was on the right track.
Going Dutch
Soon, similar correlations between the health of a society’s babies and high
blood pressure, diabetes and cardiovascular disease in later life were flooding
in from as far afield as Finland and India. Take, for instance, the Dutch Hunger
Winter of 1944-45. The offspring of women who were pregnant at that time
appeared normal at birth but they now have higher rates of diabetes. And whereas
the majority of those studies first found strong correlations in men—they
are easier to track since their names don’t change after marriage—later
studies confirmed that the link between fetal and middle-aged health holds good
for women too.
Barker rounded out his hypothesis. Poor maternal nutrition, he reasoned, not
only restricts normal growth of a fetus, but also “programs” the baby to develop
common chronic diseases in later life. “Those of us who were sceptics now see a
solid relationship between prenatal growth and lifelong health,” says Kent
Thornburg of Oregon Health Sciences University in Portland.
But there was still something the hypothesis lacked—a mechanism. When
pregnant women overdo drugs and alcohol, the consequences are usually visible
when the baby is born and it’s fairly easy to work out what went wrong.
Cigarettes, for instance, stunt a fetus’s growth by cutting the oxygen supply
and creating toxic levels of carbon monoxide. So how could a pregnant woman’s
diet cause lasting abnormalities in such organs as the pancreas, liver, blood
vessels and kidney—prerequisites for the development of chronic diseases
half a century later?
Now, a decade after Barker first put forward his hypothesis, dozens of
researchers worldwide are beginning to work out plausible mechanisms to explain
how fetal programming might work.
Scenario number one involves stress. Malnutrition triggers an increase in
stress hormones in the mother, and—in a double whammy—disrupts the
growth of the placenta and its enzyme barrier that usually stop those hormones
crossing into the unborn baby’s blood. As long as the woman is malnourished, the
stress hormones may breach the placenta, and upset the development of the baby’s
organs. Exposing sheep fetuses to a synthetic stress hormone for just 48 hours
led to hypertension in the lambs that worsened as they grew older, according to
a study by Dodic and his colleagues. Rats, too, are born smaller and have high
blood pressure and blood glucose levels if they are exposed to stress hormones
in the uterus.
Low-birthweight babies and rats also end up with high levels of stress
hormones as adults, suggesting an explanation for how nutrition-induced stress
could program the fetus: the brain itself may become hard-wired so that it
operates in permanent “fight or flight” mode, thereby triggering high blood
pressure. An alternative explanation, Dodic speculates, is that stress hormones
in the fetus alter the renin-angiotensin hormone system that regulates salt
balance, forcing blood pressure higher than normal.
No one knows how severe malnutrition must be before stress hormones reach
dangerous levels, but simply being thin during pregnancy may be enough, says
Barker. Of greater concern, Dordic points out, is that any stressful event,
whether it be life in a refugee camp or a brief episode stuck in a traffic jam,
can send a mother’s stress hormones through the roof. “We could soon be in a
position to caution pregnant women about the long-term deleterious effects of
stress during pregnancy,” he says.
A second scenario—which is not mutually exclusive with the
first—involves the rationing of nutrients and oxygen to different parts of
the fetus’s body. Studies of how blood is distributed in animal fetuses show
that when mothers are underfed, the growing offspring divert scarce resources to
their brains. Other vital organs—primarily the liver, kidney and
pancreas—get short shrift, and develop a paltry blood supply, have fewer
cells and more abnormal ones. The bottom line is a higher risk that the organs
will someday malfunction.
When, for instance, protein is reduced in the diets of pregnant rats, most
offspring have hypertension as adults, according to studies by Lori Woods and
her colleagues at Oregon Health Sciences University in Portland. The lack of
protein also leaves the offspring with fewer nephrons, the part of the kidney
that filters blood. “As no new nephrons are made after birth, people who get
more to start with are probably better off in terms of how well they can
regulate their blood pressure,” says Woods.
The third scenario ties in directly with ageing. Telomeres are the parts of a
cell’s DNA that dictate the number of possible cell divisions. Just as the
length of a candle wick determines how long a candle burns, so the length of a
cell’s telomeres determines the lifespan of a cell. It turns out that baby rats
who are born to mothers deprived of protein during pregnancy, and who later grow
rapidly, have kidney cells with shorter telomeres. That suggests, says Nick
Hales, a biochemist at the University of Cambridge who ran the study, that the
cells would prematurely stop dividing, and the kidney would run down, losing its
ability to perform functions such as regulating blood pressure.
A tendency toward high blood pressure can partly explain why low birthweight
appears to lead to heart disease, because the condition strains the heart. But
there’s also evidence for other changes in undernourished fetuses that could
program them to develop heart disease later in life.
In guinea pigs, even mild maternal malnutrition produces offspring that have
much higher levels of blood cholesterol—including “bad” low-density
lipoproteins—after a high-cholesterol meal, according to a forthcoming
report in the Journal of Physiology. Offspring of the underfed mothers
also tend to have small livers, and the organs may be short on the receptors
needed to clear cholesterol from the blood, says the paper’s co-author, Julie
Owens of the University of Adelaide in Australia. “We think malnutrition impairs
adult cholesterol homeostasis in large part because of altered liver
´ÚłÜ˛Ôł¦łŮľ±´Ç˛Ô.”
Less is known about how experiences in the uterus change the structure of the
circulatory system itself, although low birthweight has been linked to stiff
arteries. And in another soon-to-be published study, Christopher Martyn of the
University of Southampton and Stephen Greenwald at the Royal London Hospital
found that vessels from rats that are undernourished as fetuses are
thinner-walled and stiffer than normal. Elastin—the protein that gives
blood vessels flexibility—is laid down mostly during fetal life,
suggesting that this is where the deficiency lies.
“We’ve spent 30 years in the garage wondering what went wrong with broken
cars—now we might start looking at how the heart is made and why some are
built like a Rolls Royce and others like a cheap car,” says Barker.
But it’s when you consider what could happen in an unborn baby to trigger
diabetes later in life that the term “fetal programming” really comes into its
own. That’s because the nutrients the fetus receives in the womb appear to
directly program its expectations for nutrients in its life outside, by setting
up the mechanisms needed to metabolise food.
Embryos begin sensing the nutritional environment even before they have
implanted in the uterus, says David Hill, a developmental biologist at the
University of Western Ontario in London. “If you take these very early embryos
and culture them in media with different nutrient levels, you can see
developmental differences,” he says. “Even when the embryo is going down the
fallopian tube, this planning for the future has already begun. It’s a
mind-blowing idea.”
Trouble strikes when there’s a mismatch between life in the womb and life
outside. The pancreas, more specifically the beta cells that produce insulin, is
largely responsible for regulating blood sugar. Numerous animal studies have
shown that a low-protein diet in pregnancy stunts the growth of the pancreas in
the fetus, leading to poorly functioning beta cells, and fewer capillaries to
bring blood to and from the organ. For previous generations a stunted pancreas
may have been adequate, but today it’s a liability with modern diets of
hamburgers and ice cream.
So where does that leave us? So far, researchers can only advise pregnant
women—particularly teenagers, poor women and those prone to eating
disorders, who are all at risk of having underweight babies—to eat enough
of a balanced diet to achieve adequate weight gain and to keep stress to a
minimum.
Eat up
And they can also safely say that many pregnant women in developing countries
need to eat more protein. In fact, that recommendation may be the first to be
refined as specific amino acids needed for optimum fetal development are
identified. Already, Joseph Hoet of the Catholic University of Louvaine,
Belgium, has found that the amino acid taurine—which can only be obtained
from animal protein—is essential for beta cell development in the
pancreas, at least in rats.
Still, says Barker, just “whacking more protein into people” is not the
answer. High-protein diets take more energy to process and so can end up
stunting fetal growth, and no one knows what the best ratio of protein to
carbohydrates is.
And the recommendations remain sketchy for other reasons. It’s still any
one’s guess what adult lifestyle and fetal programming each contribute to the
chronic diseases of middle age. At one end of the spectrum is the current dogma:
make adults exercise, lose weight, and eat and drink sensibly and you’ll have
the biggest impact on health. At the other end, are people like Thornburg who
believe that the health of the fetus and newborn child is paramount. “Being born
small,” he says, “is a powerful risk factor for heart disease. It’s equal to, if
not more powerful than, other risk factors like lifestyle.” Meanwhile, Nevin
Scrimshaw of the United Nations University’s Food and Nutrition Programme in
Boston, thinks that it is the interplay between the two that matters
most—the problems laid down by poor fetal growth must be exacerbated by a
person’s lifestyle in order for chronic diseases to develop.
“It is a great mistake to interpret the Barker hypothesis as fixed
programming,” he says. Scrimshaw points to studies of atherosclerosis, thickened
arteries, in populations in Latin America and in New Orleans during the 1960s.
Although low birthweight was far more prevalent in the Latin Americans, they had
very limited atherosclerosis. The opposite was true in New Orleans. This
suggests that lifestyle may be more important than fetal growth in determining
who gets atherosclerosis and coronary heart disease.
But then there are the French, who baffle the experts by eating rich foods
while maintaining low death rates from heart disease. This so-called French
Paradox has often been attributed to red wine consumption, but now Barker
suggests that the real reason may be because France began promoting maternal
health over a century ago in an effort to reduce infant mortality and provide
fresh supplies of men for its military.
“Did better nourishment of girls, better nutrition in pregnancy, and better
infant feeding protect the generations of French people born from the turn of
the century onwards from coronary heart disease?” Barker wrote in the 29 May
issue of the British Medical Journal.
If so, those pampered pregnant Patagonian Giants may be pointing the way to
the future.
Once a new baby has arrived and it’s clear that he or she is growth retarded,
can anything be done to undo the early damage? Instinctively, parents feed these
infants extra to help them catch up. But this may do more harm than good.
The risk of hypertension, diabetes and heart disease in adulthood is not only
linked to thinness at birth, but also to rapid postnatal growth, says David
Barker of the University of Southampton. Barker’s epidemiological studies in
Finland showed that death from heart disease is greatest in men who were small
at birth, and then gained heavily in childhood, and the same pattern is now
emerging in women. In another study, Swedish men who were small at birth, but
grew taller than average later, had very high blood pressure.
There are at least three possible explanations for those counterintuitive
findings. One is that small babies who grow quickly later may have high
fat-to-muscle ratios—a body composition that predisposes adults to
diabetes.
Alternatively, rapid growth may force a limited number of cells to divide too
many times. Support for this theory comes from studies in rats by Nick Hales of
the University of Cambridge. His group found that growth-retarded baby rats who
caught up after birth died young. They had kidney cells with shorter than normal
telomeres, the parts of a cell’s DNA that determine how many cell divisions are
possible. “If you’re born with fewer kidney cells and these have to divide
rapidly to catch up, you will soon run out of cells,” says Hales. Once cells
loose their ability to divide, an organ such as the kidney may malfunction.
The third explanation is that the hormones driving catch-up growth in small
babies may ultimately be damaging. Julie Owens of the University of Adelaide has
discovered that growth-retarded guinea pigs and sheep are very sensitive to
insulin just after birth. Insulin spurs cells to take up sugar and amino acids
from the blood. But then, mysteriously, “something happens that completely
reverses this,” she says. The animals’ tissues become highly insulin-resistant,
much like people with adult-onset diabetes.
While this may seem like bad news for low birthweight babies, Owens says it
hints at an opportunity for intervention. “The animals are going from healthy to
unhealthy—what drives that change? If we could understand that, we may one
day be able to prevent it.”
A dangerous game of catch-up
-
Further reading:
Life in the Womb: The Origin of Health and Disease
by P. W. Nathanielsz, Promethean Press (1999) -
Mothers, Babies and Health in Later Life
by D. J. P. Barker, Churchill Livingstone (1998) -
Early growth determines longevity in male rats and may be
related to telomere shortening in the kidney
by B.J. Jennings and others, FEBS Letters, 448(1) (1999) -
Can excess glucocorticoid, in utero, predispose to cardiovascular
and metabolic disease in middle age?
by M. Dodic and others, TEM, vol 10, no 3, p 86 (1999)