Shaped By Life In The Womb

When John Carter was born, 73 years ago, the doctor in the town of Ware just north of London wasn't sure if the little guy would make it: he weighed a mere 3.4 pounds. "They laid me on a hot-water bottle, wrapped me in cotton soaked in cod-liver oil and gave me brandy through the nib of a fountain pen," Carter says. "Surviving was rather a miracle." But the little boy grew to manhood, landing a job as a warehouseman and enjoying normal health--until his early 50s. That's when a physical discovered that Carter had sky-high blood pressure. Another test found that he had adult-onset diabetes.

Carter had no reason to suspect it, but his illnesses may not stem from the usual culprits: genetic defects, unhealthy living or environmental toxics. Cutting-edge research suggests instead that the roots of both his high blood pressure and his diabetes stretch back decades--to his life in the womb. Scientists now think that conditions during gestation, ranging from the torrent of hormones that flow from Mom to how well the placenta delivers nutrients to the tiny limbs and organs, shape the health of the adult that fetus becomes. "Recent research," says Dr. Peter Nathanielsz of Cornell University, whose new book "Life in the Womb" explores this science, "provides compelling proof that the health we enjoy throughout our lives is determined to a large extent by the conditions in which we developed, [conditions that] can program how our liver, heart, kidneys and especially our brain function." It is no exaggeration to call these findings a revolution in the making. The discovery of how conditions in the womb influence the risk of adult disease casts doubt on how much genes contribute to disease (because what scientists classify as a genetic influence may instead reflect gestational conditions) and suggests that adult illnesses long blamed on years of living dangerously (like dining on pizza and cupcakes) instead reflect "fetal programming." "Two years ago no one was even thinking about this," says Dr. Matthew Gillman of Harvard Medical School. "But now what we are seeing is nothing short of a new paradigm in public health."

What is so startling is that the findings go far beyond the widespread recognition that conditions during gestation shape the health of the newborn. We've known for a while that alcohol reaching the fetus can lead to mental retardation and heart defects and that the stew of toxins in tobacco can cause upper-respiratory-tract and ear infections. But these compounds work by more or less poisoning the baby. The result is often a child who, at birth or soon after, has detectable problems. The new findings are dramatically different. First of all, the gestational conditions scientists are talking about fall far short of toxic. They are, instead, paragons of subtlety. They are conditions that reprogram the fetus's physiology so that, for instance, the child's (and eventually the adult's) metabolism turns just about everything she eats into body fat. This is the woman who needn't bother actually eating the french fries; she might as well just insert them directly into her hips. Second, unlike the toxic influences whose effects on a fetus are apparent immediately, the effects of fetal programming often show up only decades later. The nine-pound bouncing girl will be perfectly healthy for decades. But the same influences that gave her layers of baby fat--"growth factors" like estrogen's crossing the placenta from Mom--prime her mammary tissue so that exposure to estrogen after puberty gives her breast cancer at 46.

There is one thing the findings do not mean. While they may tempt you to blame Mom for even more of your ills, or make you feel powerless against a fate that was set before you cried your first cry, forget it: how you live your life outside the womb still matters. Since the conditions in which the fetus develops influence adult health, learning what those conditions are (through measurements of length, weight, girth and head size at birth) tells you what extra risks you carry with you into the world. And that suggests ways to keep these risks from becoming reality. If as a newborn your abdomen was unusually small, for instance, then your liver may be too small to clear cholesterol from your bloodstream as well as it should, and you may have an extra risk of elevated cholesterol at the age of 50. So scrutinize those baby pictures: if your tummy was scrawny compared with the rest of chubby-cheeked you, be careful about controlling your cholesterol levels.

The discovery of fetal programming might never have happened if Dr. David Barker of England's University of Southampton had not noticed, in 1984, some maps that did not seem to make sense. They displayed measures of health throughout England and Wales. Barker saw that neonatal mortality in the early 1900s was high in the same regions where deaths from heart disease were high. That was odd. In general, infant mortality rises in pockets of poverty; heart disease is supposedly a disease of affluence (butter, meat and all that). They shouldn't go together. Barker wondered whether the search for the cause of heart disease should begin in the womb. To embark on his quest, he needed birth records, and lots of them, going back decades, to link conditions at the beginning of life with the health of the adults he would study. Lending a hand, Britain's Medical Research Council hired an Oxford University historian to scour the country for such records. During a two-year hunt, the historian found records in archives, lofts, sheds, garages, boiler rooms and even flooded basements--but the best records were in Hertfordshire. There, the "lady inspector of midwives" had recorded the weight of every baby born in the shire (including John Carter) from 1911 to 1945. Barker had his data.

Soon Barker and his colleagues had their "Aha!" moment. Studying 13,249 men born in Hertfordshire and Sheffield, Barker found that a man who weighed less than 5.5 pounds at birth has a 50 percent greater chance of dying of heart disease than a man with a higher birth weight, even accounting for socioeconomic differences and other heart risks. "Death rates from both stroke and coronary heart disease tended to be highest in men whose birth weight had been low," says Barker, especially when it was low compared with their length or head size (an indication that the baby's growth was stunted). Using other birth records from India, Barker found the same link in a 1996 study. Again, low birth weight predicted coronary heart disease, especially in the middle-aged: 11 percent of 42- to 62-year-olds who weighed 5.5 pounds or less at birth got it, compared with 3 percent of those born chubbier. The link between low birth weight and cardiovascular disease is now one of the strongest in the whole field of fetal programming, holding across continents as well as genders. Researchers led by Dr. Janet Rich-Edwards of Harvard reported, in 1997, that of 70,297 American women studied, those born weighing less than 5.5 pounds had a 23 percent higher risk of cardiovascular disease than women born heftier.

But it is not smallness per se that causes heart disease decades later. Instead, what seems to happen is that the same suboptimal conditions in the womb that stunt a baby's growth also saddle it with risk factors that lead to heart disease. "Birth weight is a proxy for something," says Rich-Edwards. "It's a marker for a complex set of factors that influence both growth in the womb and susceptibility to disease later on." Scientists have some suspects. Nathanielsz suggests it may be as simple as having undersized kidneys: these organs help regulate blood pressure, but if they are not up to the task, the result can be hypertension, a leading cause of heart disease. Or, animal studies have shown that if a fetus does not receive adequate protein, then an enzyme in the placenta loses its punch and can no longer disarm harmful hormones trying to sneak into the fetus. One such hormone is cortisol. Cortisol raises blood pressure, as you are reminded every time stress makes your veins bulge. In the fetus, cortisol seems to raise the set point for blood pressure--irreversibly. "You are talking about hard-wiring the system," says Jonathan Seckl of the University of Edinburgh.

The discoveries are drawing throngs of excited scientists. A year ago the Society for Epidemiologic Research half-filled a small room at its annual meeting for a session on fetal programming. This spring the same subject packed a whole lecture hall. "This whole topic is just now catching fire," says Rich-Edwards. The surge in interest reflects the lengthening list of diseases that scientists are tracing back to the womb. The National Institutes of Health held a conference in January on the link between conditions in the womb and breast cancer; in September, another NIH confab examined the link to cardiovascular disease, kidney disease and other ills. A conference at Harvard will explore the topic in November.

The breast-cancer link is one of the most surprising. The very existence of the disease is bad enough. What terrifies women is that it strikes so many who have no known risk factor--such as age, close relatives with the disease or not bearing a child before 30. Dr. Karin Michels of the Harvard School of Public Health has identified one overlooked cause. After collecting health data from tens of thousands of nurses, Michels and colleagues reported in 1997 that women who had weighed about 5.5 pounds at birth had half the risk of breast cancer compared with women who had weighed about 9 pounds at birth. That was especially true of breast cancers in women 50 or younger. "There is increasing evidence," says Michels, "that breast cancer may originate before birth."

A very high birth weight may be a marker for uterine influences that "prime" mammary tissue for cancer. Growth factors, living up to their name, make a fetus larger. Such factors include insulin, leptin and estrogen. If the mother has high levels of these substances (being obese raises levels of estrogen, for instance), and if they reach her fetus, the hormones may do more than act like Miracle-Gro on backyard tomatoes: they may alter nascent mammary tissue in such a way that it responds to estrogen during puberty by becoming malignant. This is no reason to starve your girl fetus--stunted fetal growth leads to other problems. But it does suggest that if you were a pudgy newborn you might want to be extra vigilant about breast exams.

The same message emerges from the other links that scientists are turning up. Weight and other traits at birth may offer a map of where your personal disease land mines are buried:

Cholesterol: The smaller the abdomen at birth, the higher the cholesterol level in adulthood. What may happen is that if the mother is poorly nourished or if a problem with the placenta keeps the fetus from receiving adequate nutrition, then the fetus switches into emergency mode: it shunts blood to the brain, the most vital organ, at the expense of organs in the abdomen. That includes the liver, which plays a key role in regulating cholesterol levels. A smaller liver can't clear cholesterol as well as a hefty one. This suggests an answer to the longstanding puzzle of how some people can eat high-fat and cholesterol-laden diets with impunity: these lucky folks were programmed as fetuses to process fat and cholesterol as efficiently as a sewage-treatment plant. The others have defective treatment plants. "When a fetus adapts to conditions in the womb," says Southampton's Barker, "that adaptation tends to be permanent."

Obesity: This was the first trait suspected of reflecting life in the womb. In World War II, the Nazis tried to starve the population of western Holland from September 1944 until the following May (sidebar). Men who were fetuses during all or part of the period showed a telling pattern. If their mothers were starving during the first trimester--from March to May 1945--but got adequate food later, the men were born heavier, longer and with larger heads than babies in normal periods. As adults, they were more likely to be obese. If their mothers went hungry only in the final trimester--if the boys were born in November 1944, say--the men usually stayed svelte. What may happen is this: if food is scarce during the first trimester, the fetus develops a so-called thrifty phenotype. Its metabolism is set so that every available calorie sticks. Or, the availability or scarcity of food may affect the appetite centers in the fetal brain. In that case, undernutrition early in fetal life could dial up the appetite controls to the setting "eat whatever's around: you never know when famine will hit." An abundance of food early keeps the dial at "no need to pig out." Fetuses undernourished later in gestation may develop fewer fat cells (it is in the later months that most cells are added). That makes it harder to become fat after birth.

Diabetes: Being skinny at birth puts an individual at high risk for diabetes in middle age, finds David Leon of the London School of Hygiene and Tropical Medicine. The effect is powerful: diabetes is three times more common in 60-year-old men who, as newborns, were in the bottom fifth on a scale of plumpness (technically, it's birth weight divided by length cubed) than in more rotund babies. "One explanation is that inadequate nutrition programs the fetus to develop a thrifty metabolism," says Leon. "That includes insulin resistance, so the body saves and marshals existing glucose stores." When this metabolism meets junk food, the body is flooded with glucose and becomes diabetic. But diabetes is a prime example of how life in the womb is not an immutable sentence. Although thinness at birth raises the risk of developing diabetes in middle age, finds Leon, that risk is much reduced if you stay thin.

Brain: Research on how life in the womb influences the brain is only beginning. But already there are hints, from both animal and human research, that something is going on. In a 1997 paper, biologists reported on a study of people with asymmetries in traits like feet, fingers, ears and elbows. IQs were lower in asymmetric people by about as much (percentage-wise) as their measurements deviate from perfect symmetry. Some sort of stress during fetal development probably causes asymmetries, suggests Randy Thornhill of the University of New Mexico. The same stress may cause imperfections in the developing nervous system, leading to less efficient neurons for sensing, remembering and thinking. Here, too, asymmetry is a marker for something going wrong in the womb. Thornhill estimates that between 17 and 50 percent of IQ differences reflect in utero causes.

The new science of fetal programming suggests that we may have gone overboard in ascribing traits to genes. "Programming," concludes Nathanielsz, "is equally if not more important than our genes in determining how we perform mentally and physically." Consider one of the standard ways that scientists assess how much of a trait reflects genetic influences and how much reflects environment: they compare twins. If identical twins share a trait more than other siblings do, the trait is deemed to be largely under genetic control. But twins share something besides genes: a womb. Some of the concordance attributed to shared genes might instead reflect a shared uterine environment. The womb may have another effect. Merely having a gene is not enough to express the associated trait. The genes must be turned on to exert an effect, otherwise they are silent--just as having a collection of CDs doesn't mean that your home is filled with music unless you play them. In the womb, a flood of stress hormones may actually turn off genes associated with the stress response; the response becomes less effective, which is another way of saying this child is at risk of growing into an adult who can't handle stress. "The script written on the genes is altered by... the environment in the womb," says Nathanielsz.

As fetal programming becomes better understood, it may even resurrect the long-discredited theory known as Lamarckism. This idea holds that traits acquired by an organism during its lifetime can be passed on to children--that if a woman spends the 10 years before pregnancy whipping herself into a body-builder physique, her baby will emerge ready to pump iron. Modern genetics showed that inheritance does not work that way. But according to fetal programming, some traits a mother acquires can indeed be visited on her child. If she becomes diabetic, then she floods her fetus with glucose; waves of glucose may overwhelm the developing pancreas so that fetal cells that secrete insulin become exhausted. As a result, the child, too, becomes diabetic in adulthood. When this child becomes pregnant, she, too, floods her fetus with glucose, stressing its pancreas and priming it for adult-onset diabetes. This baby will develop diabetes because of something that happened two generations before--a kind of grandmother effect.

In "Brave New World," Aldous Huxley describes how workers at the Central London Hatchery, where fetuses grow in special broths, adjust the ingredients of the amniotic soup depending on which kind of child they need. Children destined to work in chemical factories are treated so they can tolerate lead and cadmium; those destined to pilot rockets are constantly rotated so that they learn to enjoy being upside-down. The quest for the secrets of fetal programming won't yield up such simple recipes. But it is already showing that the seeds of health are planted even before you draw your first breath, and that the nine short months of life in the womb shape your health as long as you live.

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