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Womb to Tomb

What your mom ate as a child could give you a stroke in middle age

I’m not a big fan of death. Given a choice, I’d rather skip it.

But nobody (or would that be Nobody?) is asking me. So I turn my attention to the next best thing — figuring out how long I might be likely to live. A quick investigation shows me that heart disease, cancer and stroke are responsible for well over half the deaths in this country each year. If I can dodge those successfully, I’ll have to look out next for lung disease, Alzheimer’s and accidents. Constant vigilance and a healthy lifestyle seem my best bets for a long and, hopefully, happy life.

Full disclosure: I’m a mostly healthy 39-year-old female with three children. I probably drink a bit more than I should and exercise a lot less. I don’t smoke and I always wear my seatbelt, but I’ve not had a medical checkup in years. My body mass index is 22.8 — not horrible — but I’m certainly much more pear-shaped than hourglass. Finally, my family has a history of heart disease, cancer and diabetes: a deadly genetic trifecta of longevity busters that I try not to think about. There’s some good news, though. As a woman, I have a five-year edge over my sorry husband, who has a life expectancy of 76 years to my 81.

But does any of this even matter? A growing body of evidence suggests your pre-birth environment might dictate much of your adult health and affect whether you develop a chronic, possibly fatal condition such as heart disease or hypertension. The data extend beyond the well-known relationships between maternal folic acid intake and fetal spinal development, and prenatal care and prematurity. We’re talking about full-term, seemingly healthy babies who carry within them the seeds of potentially life-shortening disorders. If that’s the case, maybe I was doomed from the get-go.

“Hey mom,” I imagine saying one evening. “How was it being pregnant with me? Anything stick out? Were you sick a lot? Did you eat well? Were you worried or anxious?”

“What are you talking about, honey?” she would say, wiping out my kitchen sink. “That was so long ago.” (Gee thanks, Mom.) “You need more garbage bags. And what’s that you’ve got behind your back?”

“Nothing,” I would say, stuffing the tape measure in my pocket and eyeing her hips. (One recent finding even indicated that daughters of mothers with relatively wide, round hips are more likely to develop breast cancer than those who sprang from less-curvy loins.)

If you’re surprised that your mother’s imbalanced diet, morning sickness medications, severe anxiety or undercover sugar binges might contribute to all manner of grown-up woes — from cardiovascular disease to mental disorders, osteoporosis and reduced fertility — brace yourself. There’s even evidence that your adult health might be affected by what happened to your mother before she was born. But how could your grandmother’s pregnancy diet affect your health when you’re 60?

Let’s be clear here. We’re not talking about genetics. Genetics happens at conception, when a particular sperm and egg pool their chromosomal resources to create the alphabet soup that is uniquely you. We’ve got decades of research showing that certain genes carry with them particular disease-causing baggage. We’re talking about how the environment to which you were exposed as a fetus can dictate, or program, whether the appropriate genes leap into action in response to a physiological assault in the form of a sugary snack, for example, or whether they simply loll about drumming their metaphorical fingers and ignoring the body’s reveille.

“We understand that the fetus might have a certain genetic inheritance that sets the stage for what your potential is as an adult, but the environment in the womb and in infancy impacts the way that your genes are going to be expressed,” says David Stevenson, MD, chief of neonatology at Lucile Packard Children’s Hospital and the Harold K. Faber Professor in Pediatrics at the medical school. “That impact is something not fully apparent until later in life, when you are confronted with a variety of challenges that will test how you are able to use your inherited machinery. If you’re programmed to deal with one set of circumstances, you may not be able to handle another set.”

Before you settle back onto the couch, warmed by the twin fires of indignation and futility, you should know that the jury is still out as to exactly where these effects rank in the litany of things bad for you. There’s a clear effect of your prenatal experiences on your adult health, but it’s not written in stone. Many experts believe the intervening decades offer plenty of chances to fix, or to mess up, the cards you’ve already been dealt.

“It’s a mistake that many people make to think that by the time a child is 2 years old, that person’s life course is already determined,” says Stanford and Packard Children’s health policy expert Paul Wise, MD, MPH. “That would suggest that adolescent medicine is palliative care.”

That’s obviously not the case. But what’s really going on here and how important is it?

Doomed if you do and doomed if you don’t

the idea of predestination is already out there and accepted,” says David Barker, MD, PhD, who pioneered the long-arm-of-fetal-life idea (now known as the Barker hypothesis) in the 1980s when he found that the lower a child’s birth weight, the higher that child’s risk of developing and dying of cardiovascular disease as an adult.

“We hear every day how important genes are,” says Barker, a physician and professor of clinical epidemiology at the University of Southampton, in England, and a professor of medicine at the Oregon Health & Science University. “What we’re starting to accept is that genes have to be expressed, and that many expression patterns are set up during development.”

“I’m not saying that it doesn’t matter how people live, just that it’s not the biggest factor.”

In other words, like a savvy bridge player, an organism can pick and choose which of its inherited genes to express when, and how strongly, based on external cues. Although it wasn’t clear at the time Barker began his research, we now know that these choices are solidified through the addition of specially placed chemical tags on the DNA and its packaging proteins — a phenomenon known as epigenetics. Some of these epigenetic changes can even be passed from mother to offspring for generations.

Barker’s original findings have been reproduced in several additional studies, which have also identified increased risks for stroke, type-2 diabetes, hypertension and obesity as birth weight decreases. Perhaps most surprising, the effect persists even among healthy, full-term babies of normal weight. That is, a 6-pound baby is at greater risk than a 7-pound baby, and so on. The implication is that the nature of a woman’s diet or nutritional status even before she’s pregnant could have long-term effects on an infant’s future health and life span.

“The baby lives off the mother’s muscle, fat, stored nutrients,” says Barker. “The mother’s body is a product of her nutrition throughout her life. What happens to her at different stages of her life affects the health of the next generation.”

Animal and human studies have shown that these reverberations of diet can echo through generations. Smaller-than-usual female babies of undernourished women tend to grow up to have small babies themselves, regardless of their diet while pregnant. Furthermore, exposure of pregnant female rats to certain toxins can impair the fertility of not only their own pups but of their pups’ pups as well.

But wait. There’s more. Further research indicates that it’s not just the size of a baby at birth that’s important, but also how quickly the infant gains weight after birth. Small babies who rapidly catch up or even surpass their peers in growth — a feat recounted with pride by solicitous parents — are more likely to develop diabetes than those who favor the slow-but-steady approach. The thought is that a fetus denied adequate nutrients in the womb is ill-equipped to deal with the onslaught of plenty that can occur after birth.

The key lies in the theory of developmental plasticity. Developing fetuses can do nothing about the genetic hand they were dealt. But they can tweak when and how certain genes are expressed and how organs are structured to optimize their chances of survival after birth. To do so, they depend on external cues (moms, that means you!) as to conditions outside the womb.

Such intrauterine gambles, in contrast to the glacial pace of evolution, allow individual fetuses to quickly respond to changing conditions. Poorly nourished mothers deliver babies primed to take advantage of every spare calorie. But if the perceived famine is an aberration, the strategy can backfire and the fetus has an increased risk of developing chronic disorders like Syndrome X, also known as metabolic disorder or insulin resistance, in adulthood.

“Prenatal conditions can make people vulnerable,” says Barker, “and if a vulnerable person does what everyone else does, he or she will pay a cost. I’m not saying that it doesn’t matter how people live, just that it’s not the biggest factor.”

Sometimes conditions in the womb are so dire the fetus must make some immediate trade-offs. Low oxygen levels or very low calories can require the diversion of blood from less-critical organs, such as the kidneys and liver, to more-vital locations, such as the brain and the heart. This act of desperation can ensure a fetus lives until birth, but it pays a price in the development of the abandoned organs. One example is in the formation of fewer nephrons — a functional unit in the kidney responsible for eliminating waste and regulating blood pressure. In general, having fewer nephrons leads to higher blood pressure — particularly as individuals put on weight.

“You can’t study fetal development and ignore the placenta — although most people do.”

Barker compares the prenatal development theory to driving a car carelessly on a rough road. Although it’s not the best way to treat a vehicle, most well-built cars will handle the challenge just fine. In contrast, a car with an engine prone to overheating might be fine on flat roads at sea level but conk out when you start your climb over the mountain pass.

While the details still need to be hammered out, many investigators are satisfied that the effect of fetal environment on adult health should not be ignored. The Pregnancy and Perinatology Branch of the National Institute of Child Health and Human Development’s strategic plan for 2005 to 2010 identifies fetal development and programming in response to intrauterine stress as a new area of emphasis for institutionally funded research.

What remains to be determined is how exactly things go awry during fetal development and what we can do about it.

A perfect place for clues

the placenta is a vastly unappreciated organ,” says Packard Children’s researcher and physician Anna Penn, MD, PhD. “It’s the only fully functional organ that happens to be transient. Most of the time, it ends up in a bucket. You can’t study fetal development and ignore the placenta — although most people do.”

The placenta’s role as a gatekeeper between a mother and her fetus is well-known. What’s less understood is how it performs that function. In addition to acting as a bouncer for unruly, possibly damaging maternal factors such as the stress hormone cortisol, the placenta also manufactures and delivers hormones to the developing fetus. If it falters, the fetus can be permanently affected.

Penn is investigating how the placentally derived sex hormones estrogen, progesterone and testosterone affect fetal brain development. Her interest stems from the fact that severely premature girls, who have abruptly lost access to the placenta, tend to have better outcomes than do equally premature boys.

“Premature infants, who no longer have access to the placenta and the factors it makes, are a good model to increase our understanding of general development,” says Penn. “In reality, anything that interferes with the placenta — structural or genetic defects in the placenta itself, or infections that compromise its function — may interfere with hormones and have long-term effects.”

For example, animal studies have shown that feeding pregnant rats or guinea pigs low-protein or calorie-restricted diets compromises the ability of the placenta to screen out stress hormones. This flood of cortisol somehow resets an interactive feedback system called the hypothalamic-pituitary-adrenal axis in the fetus and results in offspring that are themselves compromised in their ability to handle stress. They are also likely to have high blood pressure. A similar result occurs in pregnant sheep injected with large amounts of cortisol.

The placenta usually provides a barrier between the results of maternal infections as well. When it fails, the fetus must grapple with a host of unfamiliar factors that can have long-term effects. Recent research shows that mothers who contracted respiratory infections during the pregnancy are between three to seven times more likely to have a child with schizophrenia. Furthermore, identical twins are more likely to share a diagnosis of schizophrenia if they shared a placenta in utero than are those who had their own placentas.

For doctors tending to premature babies, the challenge is not to make things worse. About 12 percent of all infants in this country are born too early. Without a clear understanding of what these babies are missing out on, it’s nearly impossible to ensure that they grow and develop just as they would in utero. Our comparatively clumsy attempts to replace the physiological and nutritional environment of the womb may actually mimic maternal malnutrition or starvation and set these infants up for a lifetime of problems.

“Prematurity demands an understanding of how catch-up growth can be safely managed,” says neonatologist Stevenson. “If we can’t nourish an infant perfectly as a preemie, that baby will leave the nursery undergrown. We need to avoid unintentionally contributing to bad programming.”

A light at the end of the tunnel

Being a pessimist, all this information makes me feel gloomy. Obviously I’m already born, as are my children. Who knows what I may have unwittingly afflicted them with. Is it time for me to just throw up my hands? No, says Wise.

“There is nothing to suggest that events that take place early in life are less amenable to intervention than those that take place later,” the health policy expert says. Wise argues that knowing and understanding the possible increases in risk due to fetal events means we should pay even more attention to managing childhood precursors of chronic disease — obesity, high blood pressure and diabetes. We should also be paying a lot more attention to women’s health, he says.

“Over half of all pregnancies in this country are unintended,” says Wise. “Furthermore, prenatal care in this country doesn’t usually start until several weeks into a pregnancy. If we want to improve women’s health and, by extension, fetal health, we can start by providing health insurance for all women of childbearing age regardless of their pregnancy status.”

“The level of ignorance about health care for pregnant women and children in this country is shocking,” agrees Stevenson. “It’s becoming apparent that prenatal events can impact the health of our whole society. We’re just beginning to understand this phenomenon.”

That phenomenon, termed “integrative physiology” by Stevenson, takes as credo the idea that we are the product not just of our genes and not just of our environment, but of the interaction between these two forces.

“They are inseparable,” says Stevenson. “As physicians, it’s vital to understand the context in which you are viewing the biology of an individual. The public tends to categorize diseases as social, psychological or biological, which doesn’t acknowledge the interdependencies of these effects. I believe multipronged approaches will be the most effective way to manage and maybe even prevent many of these conditions.”

Multipronged doesn’t mean easy, though. As you might imagine, tracking the effect of a mother’s nutritional status on her offspring’s adult health, for example, demands a remarkable amount of both time and money. Large groups of people must be followed for decades, likely filled with all manner of risky behaviors, to build a convincing case.

In the meantime, scientists at Stanford and Packard are delving into the nitty-gritty biological details with their eyes on prevention and intervention. Ashima Madan, MD, a neonatologist at Packard Children’s, is interested in why some premature babies fare better than others of the same gestational age and size. She and her colleagues found that umbilical cord blood from babies who developed severe retinopathy of prematurity, an eye problem that in its most severe state can lead to blindness, was more likely to contain a certain protein than those who did not develop the condition. The finding was of interest to neonatologists because this type of retinopathy was previously thought to be primarily the result of conditions like high oxygen levels to which the infant was exposed after birth.

“Clearly something is going on with these babies before birth that affects the expression of genes involved in abnormal blood vessel growth in the retina,” says Madan. “Although we can’t yet rule out the possibility of a genetic component, it’s possible that what we’re looking at is an interaction between the intrauterine environment and gene expression.” Comparisons of protein expression profiles, a field of study known as proteomics, could be the key to understanding how the prenatal environment affects lifelong genetic expression and how best to intervene. Mapping epigenetic changes may also be important.

“We don’t know how to reprogram somebody in a safe way,” says Stevenson. “Maybe it’s not possible. You may have to change the way you expose yourself to food fuels, for example, rather than persistently testing yourself beyond the limits of your biology.”

So where does that leave me? Right back at square one. Healthy living and regular checkups for both me and my children seem to be my best bet for now. But I’m hopeful that one day we’ll not only know how to identify whose fetal environment leaves them at risk for which diseases, but also how to avoid bad programming in the first place. Maybe we’ll even be able to reprogram those already affected by tinkering with specific epigenetic changes. In the meantime, I’ll try not to worry about my own kids too much. After all, in the “screwing them up” arena, there are still plenty of bullets left to dodge.






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