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| Acknowledgments | vii | ||||
| Foreword | xiii | ||||
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| Index | 361 |
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Chapter One: The Science -- Eating for Your Child's Future
"What do you want? A boy? Or a girl?"
If you're expecting, or are even thinking about getting pregnant, no doubt you've heard that question a thousand times by now. You may be secretly hoping for either a little son or daughter, but like most expectant mothers, you have an even more important wish: "I just want a healthy baby." Certainly, this overriding concern will be uppermost in your mind in the delivery room until the doctor or midwife proclaims, "The baby is perfect!"
Now, I want you to take this lovely scenario one giant step further. As if in a time machine, think about your baby's health years later, when he or she is an adult. A new branch of science -- the basis of this book -- provides evidence that how you take care of yourself during pregnancy can do much more than give your unborn child a great start in life. You can also help reduce his or her risk of several common and serious diseases that strike in adulthood, ensuring the health of the adult your baby will eventually become.
Margaret's Story
Forty-nine-year-old Margaret exercises regularly, eats a low-fat diet, maintains a trim body weight, and doesn't smoke. Still, she has already had a double bypass because of coronary artery disease (hardening of the arteries that supply blood to the heart) that was causing chest pain and shortness of breath. On top of that, she was recently diagnosed with adult-onset diabetes. Margaret always thought that these health problems happened only to overweight couch potatoes who ate large amounts of French fries and cheesecake. Trying to understand the source of her maladies, Margaret's doctor asked if she had a family history of these illnesses, but searching through the family tree revealed no links.
Startling new research that I alluded to above may provide a clue about the genesis of Margaret's health woes. At least part of the explanation may trace much further back than we've ever thought possible -- to the days before her birth, to Margaret's time in her mother's womb.
The Concept
Scientists call this revolutionary new field of study the fetal origins of chronic disease. Fetal origins refers simply to the growing realization that some adult conditions, such as heart disease and breast cancer, may be impacted by conditions during pregnancy. It is meant to convey how life in the womb impacts not only the baby that is born but also the adult he or she will one day become. The fetal environment is shaped by the nutrients and the hormones that flow from mother to baby. In turn, these are partially influenced by a mom's diet, how much weight she gains, and the pattern in which she gains weight.
Fetal origins research focuses on the long-lasting effects of either positive or negative conditions at a sensitive or critical period of development of the baby's organs, tissue, and other body systems while in the womb. Examples of sensitive periods of development are when heart tissue differentiates into the four heart chambers or when the number of fat cells is decided. Two quintessential examples of negative conditions are undernutrition and overnutrition. Others can occur when the mother takes drugs, smokes, or drinks alcohol.
The fetal environment is critical to the health of the developing baby and the adult she or he will become because budding tissues are pliable, which means they can easily be molded and reshaped. By design, fetal tissues have to be pliable because they grow so rapidly and must differentiate into so many different types of cells, from liver and kidney cells to brain and muscle cells. To create a visual image of these happenings, think of the elasticity of a balloon. Only because it is elastic or pliable can it grow so fast and change when you blow air into it. In a very simplistic sense, a developing fetus must be just as elastic to grow as rapidly as nature intended. The elasticity that is so necessary also means that fetal tissue can be affected -- in both positive and negative ways -- by the environment in which it is developing.
The Birth of an Idea
The concept of fetal origins of chronic disease, although revolutionary in that recent advances have finally brought it to the public's attention, is not entirely new. Let's take a look back in history.
Fetal origins was born of observations made in the mid-twentieth century. We learned important things about the effect of maternal nutrition on babies' future health from the tragedies of World War II. Autumn 1944 brought two huge problems to people in the western area of the Netherlands: a Nazi blockade of supplies and an early, hard winter. Together, they triggered a famine, which came to be called the Hunger Winter, or Dutch Famine.
Food became so scarce that people from the city fled to the countryside to scavenge for food and soon took to eating tulip bulbs. According to records kept during that time, the daily calorie intake in January 1945 dropped to a dangerously low 750, and soon after, most people were eating a mere 500 calories daily. (In comparison, nutritionists know that most women, depending on their age, gender, and physical activity level, need 1,700 to 2,100 calories daily to maintain a healthy weight, and pregnant women require 1,900 to 2,200.)
By the time the Hunger Winter ended on May 5, 1945, it had taken the lives of 20,000 people. Some two decades later, the husband-and-wife research team of Mervyn Susser and Zena Stein found that it had also impacted the lives of those in the womb during the famine. Studying the people who had been conceived during or before the famine, Susser and Stein found many consequences of starvation conditions in the womb. Babies poorly nourished early in pregnancy, when the body organs are forming, had an increased risk of central nervous system birth defects, such as spina bifida, but paradoxically enough, also a substantially increased risk of being overweight as an adult. Continuing his parents' early research in the 1980s, Ezra Susser found that fetuses who were poorly nourished early on in pregnancy were also twice as likely to develop schizophrenia as fetuses who were well nourished.
Moving the Concept Forward in Expanding Research
As I mentioned in the Introduction, it was a British epidemiologist, David Barker, at the Medical Research Council Environmental Epidemiology Unit at the University of Southampton who greatly advanced the concept of fetal origins of disease. He also introduced the term fetal programming to explain his observations. Since 1986, Dr. Barker and his team have published over 200 scientific articles supporting his hypothesis that part of our risk of cardiovascular disease and diabetes in adulthood is "programmed" while we are in our mother's womb. (So pivotal were his findings that the concept of fetal programming as it pertains to cardiovascular disease is often called The Barker Hypothesis.) Other research teams, including mine, have enthusiastically joined in these exciting and critically important investigations of life in the womb and its effect on babies' future health risks.
Applying the results from this research to a woman's pregnancy -- to your days in waiting -- may give us the chance to prevent many cases of heart disease, diabetes, hypertension, obesity, mental illness, cancer, and other common diseases that have such a negative impact on so many people's lives. And we may be able to stop these diseases literally before they begin.
Nutrition: A Critical Prenatal Environment
The primary environment I'm discussing in this book is the nutrition mom provides to her developing child. But I'll also help you understand the role drugs and other lifestyle factors have in the process. In Chapter Eleven, I explain how exposures during the entire course of a person's life modify the effect the early events may have. Do also note that a mom's nutrition can impact the hormones her body produces and that these, in turn, can also affect the environment in the womb. We'll talk more about that in the next chapters.
As an aside, scientists know that the impact of early life course events doesn't stop at birth; it extends into early infancy. A famous example noted by researchers in this area is that of early twentieth-century Japanese soldiers and settlers taken to climates much hotter than they were accustomed to. Japanese physiologists noted that there was a wide variety of responses to the sweltering heat, and they soon discovered that the people who "took the heat better," or who cooled down faster, had more functioning sweat glands.
Further study revealed why some people have more functioning sweat glands than others. At birth, everyone has the same number of sweat glands, but none of them function. Conditions during the first 3 years determine, or "program," what proportion of those sweat glands become functional. As it turns out, babies growing up in warmer conditions during the first 3 years of life "program" more sweat glands to become functional than do infants raised in cooler conditions early in life and hence will be more comfortable living in a hot climate.
The Role of Epidemiology, or Where Medicine Meets Math
As I detail in the next section of this chapter, researchers got an inkling about the far-reaching effects of life in the womb and the fetal origins of disease after noticing that adults with greater risks of cardiovascular disease, diabetes, and chronic bronchitis were more likely to have been born tiny.
Noticing that specific lifestyle or environmental or genetic factors are more common in people with certain health conditions is the basis of the science of epidemiology. It was the field of epidemiology that allowed scientists to make the associations that led to the development of the fetal origins hypothesis.
Epidemiology is my area of expertise. Epidemiologists are detectives trying to uncover the relation between risk factors and specific diseases. As epidemiologists, we study the characteristics of people who all suffer from a certain disease. For example, the critical knowledge that smoking is an important causal factor for lung cancer came after epidemiologists discovered that the majority of those afflicted were smokers.
Certainly, not all risk factordisease relations have such a direct association. In fact, some relations that seem to offer a clue as to why diseases occur are subsequently found to be noncausal and the factor identified is only an innocent bystander to the association between a second factor and disease. For example, a study may reveal that people who get lung cancer are more likely to carry matches than people without lung cancer. We know today that carrying matches is only a marker for the true risk factor, smoking. But such observations are what ultimately allow epidemiologists to discover the clues to what causes disease -- and that's the first step in finding effective means of preventing disease.
One of the ways epidemiologists find clues to the causes of disease is to map the geographical occurrence of the disease in question. Then, they superimpose on the map nondisease factors such as affluence (reflected in the gross national product, or GNP), living conditions, or dietary habits. When simultaneous pockets crop up -- say, an infectious disease such as influenza is found to occur more frequently in areas of poverty -- epidemiologists have a clue that they may be related; for example, that crowded living conditions and unsanitary quarters may play some role. Indeed, this is a well-known relation to experts on infectious disease.
Once clues are uncovered in one population, epidemiologists seek to find the same association in other groups of people. This is called replicating the data. If the data cannot be replicated, then the initial clues are more likely regarded as coincidental, or spurious, in epidemiologic terms.
Another key step in drawing a relation between an apparent risk factor and a disease is to account for other factors. This is called controlling for confounders. For example, when studying the link between smoking and heart disease, researchers have "to control for" or take into account the nutritional intake of smokers. This is because smokers often don't eat as well as nonsmokers, and poor nutrition can also increase the risk of heart disease.
Once epidemiologists collect all the data, they try to determine if one factor or a combination of factors increases the occurrence of a certain condition. Then, they calculate the difference in disease frequency between people with and without this factor. The next step is to apply statistical standards to decide if this difference is within the normal "plus or minus" category or if it is so different that it is unlikely to be due to chance and is thus called "statistically significant."
Here's an analogy: If you were making a quilt and were cutting out squares of fabric for the design by first tracing a pattern onto the fabric and then cutting out the squares, each one you cut would be slightly different from the next. A tiny bit of difference wouldn't matter -- it would be within the normal give-and-take‹but if one square was considerably off, it would be so different as to be noticeable. It would, in epidemiologic terms, be significantly different.
Early Evidence for the Fetal Origins of Disease: Coronary Heart Disease
After the early leads from the Dutch Hunger Winter, scientists in England focused on the role of the fetal environment in the development of coronary heart disease (CHD), commonly known as atherosclerosis; it is the process by which the arteries that nourish the heart become clogged.
In 1984, Dr. David Barker was puzzling over maps of England detailing concentrated pockets of disease. One disease pattern he and his colleagues were studying was CHD. The team was simultaneously looking at maps detailing other factors, including a map showing pockets of neonatal mortality during the early 1900s.
The Barker epidemiology group's close scrutiny revealed a big surprise: The same areas that had a high incidence of contemporary CHD had a very high rate of neonatal mortality in the early 1900s. It had already been found that babies born smaller than expected -- that is, with a very low birth weight -- were more likely to die in the neonatal period. That same research showed that when there were pockets of neonatal mortality, those same geographical pockets also had a large number of babies born with very low birth weight who survived. Dr. Barker's stroke of genius was to ask the right question: Could it be that the babies who were born so small but survived anyway were the ones who had a higher chance of heart disease as adults?
This idea was intriguing but seemed counterintuitive. Conventional wisdom held that the two phenomena should be unrelated. After all, neonatal mortality is more likely to occur in poverty-stricken populations, because neonatal care is often lacking, as is good nutrition for the mom and therefore for the developing baby.
In contrast, heart experts -- then, as today -- think of cardiovascular disease as the consequence of excesses: too much food, too many calories, too much dietary fat, too many excess pounds, and too little physical activity. These adult lifestyle factors remain significant contributors to CHD. But Dr. Barker's discoveries taught us that adult excesses don't explain the whole picture.
Trying to "connect the dots" between the neonatal mortality data and adult heart disease, Dr. Barker set out on a mission to find data that might give clues to the association. If there was an answer, it would lie in birth records dating from the early 1900s.
The problem was tracking down such old files. To facilitate the search, he and his team enlisted the help of a University of Oxford historian. His detective work was a fascinating part of the story. Birth records turned up in archives, lofts, sheds, garages, boiler rooms, and flooded basements. The most complete -- and helpful -- records turned up in Hertfordshire, a shire (similar to a county in the United States) in the south of England. A health official known as the "lady inspector of midwives" had kept meticulous records on every baby born from 1911 onwards in that shire.
The Barker epidemiology team delved into the records describing the births of approximately 16,000 men and women from 1911 to 1930, matching them with death certificates, in particular, death certificates that stated cardiovascular disease. It didn't take the researchers long to make the connection. They found that Dr. Barker's initial, seemingly odd hypothesis about low birth weight and adult risk of heart disease had struck a bull's-eye.
According to these data, men and women who weighed 5.5 pounds at birth or less had almost double the chance of dying of cardiovascular disease (both coronary artery disease and stroke) than those with a birth weight of more than 9.5 pounds. The researchers delved deeper into the issue of low birth weight: Was it low because the baby was born too early (in which case a lower birth weight is expected), or was it low because the baby didn't grow properly in utero but went full term? In the latter case, conditions in the womb are not optimal; for instance, a mom might not have gotten proper nutrition. After investigating this question, the researchers found that in the majority of cases, low birth weight was associated with an increased incidence of cardiovascular disease later in life for babies who were born full term but who didn't grow properly in utero. Incidentally, the association remained even after the investigators accounted for socioeconomic differences and other adult life risk factors for cardiovascular disease.
Just another note about how researchers regard low birth weights. In addition to asking the question about whether or not the baby was of low birth weight because of being born too early or because of suboptimal growing conditions in the womb, researchers compare birth weight to birth length and head circumference. The three factors should correspond to each other. When a baby is thin for his or her length and/or has a head that is disproportionately large, he or she probably didn't have the benefit of optimal growing conditions. The most common culprit: Mom's poor nutrition.
Research on Fetal Origins and Heart Disease Continues
Today, the strongest evidence about the fetal origins of disease comes from its link to cardiovascular disease.
Such a link is apparent in India, where the average birth weight is below 6 pounds (2.7 kilograms), much lower than the norm of 7.1 to 8.5 pounds (3.2-3.9 kilograms) for girls and 7.0 to 8.4 pounds (3.2-3.8 kilograms) for boys in developed countries. Dr. Barker's research team found this link after scrutinizing the birth records of 517 men and women born during the period between 1934 and 1953 in one hospital in south India and then looking at their current health records. The researchers discovered almost a fourfold increase in the rate of CHD for those born very small: The prevalence of CHD was 15% in those who weighed 5.5 pounds (2.5 kilograms) or less at birth, in contrast to 4% in the group who weighed 7.0 pounds (3.2 kilograms) or more. Just as with the group of people born in Hertfordshire, England, the association became even stronger when researchers separated out those babies who had low birth weight at full term, due to adverse conditions in the womb, from those who had low birth weight just because they were born too early.
Further analysis uncovered yet another association: Those with the highest rates of heart disease were more likely to have been born to mothers who were considered too thin during pregnancy. This discovery about low maternal weight provided more important evidence that poor fetal growth as a consequence of undernutrition during pregnancy may lead to coronary artery disease.
My Harvard colleagues, led by Dr. Janet Rich-Edwards, have also studied birth weight and the incidence of heart disease, analyzing both the birth weight and adult health information of 70,797 women from a large and very well known study population, the Nurses' Health Study.
To give greater credence to any associations that might surface, my Harvard colleagues used very stringent criteria for heart disease. In addition, they tightened their study even further by controlling for, or taking into account, several factors that are known or suspected to increase heart disease risk, such as adult body weight, high blood pressure, diabetes, and dietary factors. In research, we use the term control for to mean that we have taken into account extenuating circumstances that could distort the results.
The results confirmed those of earlier studies: the lower the birth weight, the greater the risk of heart disease. Women with a birth weight of 5.5 pounds or less (2.5 kilograms or less) had a 23% greater risk of heart disease compared with women born weighing more than 5.5 pounds. As the August 16, 1997, issue of the prestigious British Medical Journal reported, their study provided "strong evidence of an association between birth weight and adult coronary heart disease and stroke."
Prenatal Conditions and Hypertension
According to the American Heart Association, one in four Americans has hypertension, or high blood pressure. Worse than having high blood pressure is lack of knowledge about it: An alarming one third of affected people don't know their blood pressure hovers at a dangerously elevated level.
In the vast majority of people with hypertension, there is no apparent cause. Hypertension without an identifiable cause is called "essential hypertension." Now, researchers of early life think that fetal conditions in the womb may offer at least a partial explanation of why essential hypertension occurs.
One of the first findings Dr. Barker made after examining health records from the Hertfordshire residents was that low birth weight raised the risk of suffering hypertension as an adult. Subsequent studies of people in different parts of England confirmed that low birth weight upped the incidence of adult hypertension.
In these next studies, researchers asked another question: Was the hypertension found in infants who had been born full term but small for their age, or in babies who had a low birth weight because they were born prematurely? Obviously, conditions in the womb would have been different in the two groups. The answer was clear: The hypertension was found in babies born at term but smaller than normal, babies who had received less nutrition than they needed before birth. This further strengthened the relation between low birth weight and adult hypertension.
To date, in Europe alone, the health records of over 8,000 adults have been compared to their birth weights. The results have been reported in more than 40 articles in the medical literature. Consistently, these studies have confirmed that low birth weight raises the risk of suffering hypertension as an adult.
In the United States, the birth weight of nearly 185,000 people has been related to their frequency of developing hypertension. My Harvard colleagues who analyzed data from the two Nurses' Health Studies and the male equivalent, the Health Professionals' Follow-Up Study, investigated the low birth weightadult hypertension association in over 160,000 women and nearly 23,000 men. As do the European studies, these U.S. studies provide evidence that birth weight predicts adult risk of hypertension.
Prenatal Conditions and Adult Weight Problems
While we've learned from the observations about birth weight and heart disease that it's not good to be born too small, the next lesson is that tipping the scales in the other direction at birth is not advantageous, either. I guess you'd say that striving for a happy medium -- a healthy average birth weight -- is best of all.
A weight problem in adult life was one of the first conditions found to be related to life in the womb. This revelation came from the tragedy of World War II you read about earlier in this chapter, the Nazis' attempt to starve the people of western Holland. Babies who were conceived during the famine -- and therefore were undernourished during their first trimester -- were surprisingly far more likely to become overweight as adults.
The next wave of research on fetal life and adult weight produced a new, and seemingly contradictory, revelation: Being too well fed in the womb and being born much heavier than the norm also significantly increases the risk of adult weight problems. Colleagues of mine at Harvard University, led by Gary C. Curhan, MD, used the three large studies mentioned above to search for a connection between birth weight and becoming overweight as an adult.
Women, Their Birth Weight, and Their Risk of Adult Weight Problems
One study population was a group of women from the Nurses' Health Study mentioned above in the heart disease discussion. The researchers compared the women's birth weight with their body mass index, or BMI, a measure that tells whether a person is underweight, normal weight, or overweight. (We'll talk more about BMI in Chapter Three.) Compared with women who weighed between 7.1 and 8.5 pounds at birth, the optimal birth weight for females, those born with a birth weight greater than 10 pounds had a 62% greater chance of becoming overweight. Women born with a weight between 8.6 and 10 pounds still had a 19% increased risk of becoming overweight.
Men, Their Birth Weight, and Adult Obesity Risk
Similar results for men emerged from our large study of nearly 52,000 male health-care professionals. Compared with men born in the optimal weight range (7.0 to 8.4 pounds), those born at 10 pounds or greater had more than a 200% increased risk of being overweight.
How can starvation conditions early in pregnancy produce the same consequence as overabundance in the last trimester? This has to do with two different critical or sensitive periods of development. Refer to Chapter Three, pages 58 and 59, for a complete explanation of this seemingly paradoxical situation.
Prenatal Conditions and Body Shape: Apples Versus Pears
For adults (and even children and adolescents), excess weight alone is bad enough in terms of increasing the risk of diseases such as heart disease, diabetes, and hypertension. But continued study of weight problems has taught us that where people store their surplus pounds may be just as important as how much extra weight they gain.
To be more specific, we now know that carrying excess weight around the waist more rapidly increases the risk of diabetes and heart disease. In medical terms, people who carry excess weight around the waist are said to have "abdominal obesity." More commonly, this is called having an apple shape. On the other hand, people who carry their excess weight below the belt, on their hips and upper thighs (called a pear shape) don't tend to have such an elevated risk of the diseases noted.
A child with a low birth weight is more likely to be apple-shaped as an adult. We first learned this from the men in Hertfordshire, England. Three other studies, (one of 30-year-old Mexican and non-Hispanic Americans, one of English teenage girls, and a third of children aged 7 to 12 years in Philadelphia) confirmed this relation between low birth weight and the chance of being apple-shaped.
Life in the Womb and Diabetes Mellitus
An estimated 14 million to 15 million Americans have type 2 diabetes mellitus (also called adult-onset diabetes), the most common type of diabetes or blood sugar abnormality. With this disease, it's not just that blood sugars run too high. Today, the complications of diabetes, such as heart disease, kidney damage, nerve damage, and cancer, make type 2 diabetes the seventh leading cause of death in the United States. Alarmingly, one third of people with type 2 diabetes don't know their blood sugars are raging out of control and possibly damaging their body systems.
Although being overweight and leading a sedentary lifestyle put a person at increased risk of this type of diabetes, not everyone who develops it is obese. The environment in the womb may be one factor that influences a person's risk of diabetes mellitus, as we first learned from the people in Hertfordshire. In a group of 370 men, the risk of diabetes was increased nearly sevenfold in those born very small, which means they had low weight gain while in the womb.
My Harvard colleagues also queried our databases for such an association, confirming these earlier results. The Nurses' Health Study uncovered a 83% increased risk of diabetes in women born weighing under 5 pounds, compared with those born in the normal range of 7.1 to 8.5 pounds, and a 76% increased risk for women born weighing between 5 and 5.5 pounds. The risk was still slightly elevated -- at 23% -- in women born between 5.6 and 7.0 pounds. To clarify the genesis of their results, the researchers controlled for (or took into account) all the other things that may increase the risk for diabetes, including whether or not the women studied were overweight or had a family history of diabetes, the women's ethnicity, and their adult lifestyle factors.
Conditions in the Womb and Breast Cancer Risk
Now, on to my area of research -- life in the womb and breast cancer. As I described to you in the Introduction when I told you how I embarked on this line of research, the breast is very vulnerable to hormones, growth factors, and other substances that can act as carcinogens (substances that may cause cancer). For reasons I'll explain in Chapter Two, this is especially true when a tiny baby girl is in the womb.
Before I started my research on prenatal influences on breast cancer, I had learned a lot from my colleagues who work on animal models and who described how vulnerable the breast tissue of a young female rat is in the first days of life. I also received a huge impetus from my epidemiology pal and dear friend from Sweden, Dr. Anders Ekbom. Dr. Ekbom, a surgeon and epidemiologist, was similarly obsessed with unveiling the causes of breast cancer. He is a very gifted scientist, full of innovative ideas and new concepts regarding why things are the way they are and which avenues we should pursue in our quest for the causes of cancer. Anders Ekbom has done some pioneering work in Sweden: He was fortunate to have some data on women's health during pregnancy and on their offsprings' health status. He found that women who suffered from a special condition called preeclampsia during pregnancy were much less likely to have daughters who developed breast cancer as adults. The main symptoms of preeclampsia are protein in the urine and high blood pressure during pregnancy. Dr. Ekbom was puzzled by this startling observation, but he is very clever, and he was aware of one important fact: Women who experience preeclampsia generally have lower pregnancy estrogen levels. Could it be that these pregnancy estrogen levels played a role in the female baby's future breast cancer risk?
Pregnancy estrogen levels also influence birth weight. Although I realized this could be a factor in future breast cancer risk, it was not my only consideration as I approached the question of whether this disease was influenced by conditions prior to birth. I wanted to know about everything that happened during the mother's pregnancy: what she ate, how much she weighed, how much weight she gained, whether she drank coffee or alcohol, whether she smoked, whether she experienced nausea, whether she took prescription drugs, how much the baby weighed at birth, whether the baby was born prematurely or carried to term, whether the baby was breast-fed or bottle-fed, and so on. I was lucky to have the opportunity to tag on to two very large studies of women that were (and still are) going on at Harvard University: the previously mentioned Nurses' Health Study and its younger equivalent, the Nurses' Health Study II. I was equally fortunate to get a research grant to pursue my plans. We already knew a lot about these nurses, including their health status and whether they had breast cancer, but we needed to find out about their mothers! So I mailed questionnaires to the nurses' mothers, asking them about everything they did and experienced during their pregnancy with their nurse daughter, and I named the study the Nurses' Mothers' Study.
Naturally, it took some time to collect all the relevant data and have it entered into our computer system, but finally, the day arrived when I could begin my analyses. It was a rainy Monday morning in February 1995 in Boston, and I was sitting in my office in the Department of Epidemiology at the Harvard School of Public Health. I had skimmed through the data during the previous week and I had not noticed anything in particular. Then, that morning, I decided to focus on the analysis of birth weight. I related the birth weight of the nurses, as reported to us by their mothers, to the frequency of breast cancer among the nurses. When the computer spilled out the results, I could not believe my eyes! I looked at the printout again and again. The data staring at me told me that women weighing 5.5 pounds (2.5 kg) or less at birth had half the risk of breast cancer than women who weighed 8.8 pounds (4 kg) or more when they were born. But there was another thing about my data that struck me almost more. It is very rare in epidemiology that we see a clear association between a factor and a disease across all levels of that factor. The relation between birth weight and breast cancer risk was a straight line: the higher the birth weight, the higher the frequency of breast cancer among the women I was studying. I had never seen anything like this in my career as an epidemiologist. I was so excited I had to share the news! It just so happened that my friend, Anders Ekbom, was visiting the department that day. I rushed up the stairs and ran into him in the hall: "Anders, Anders, you won't believe this -- it's a straight line!" Of course, Dr. Ekbom did not know what I was referring to, but when I showed him my data, he smiled. He was not really surprised. We shared the news with Dr. Dimitrios Trichopoulos, another distinguished breast cancer epidemiologist and supporter of the theory that prenatal factors might influence breast cancer risk. He looked at my computer printout and just nodded his head. Our hypothesis was confirmed.
We succeeded in publishing our findings in the prestigious medical journal The Lancet, which resulted in a great deal of international attention for our research. But, of course, we have not stopped at birth weight. Our quest continues to identify more factors that influence the unborn child's risk of cancer.
Prenatal Life and Prostate Cancer
My Swedish research colleagues, led by Dr. Anders Ekbom, studied the cancer incidence of a group of 366 men born in 1913 in Gothenburg, Sweden. The men were enrolled in the study and their birth weight was known from midwife records. The medical team tracked them for the development of prostate cancer. During 30 years of observation, 21 of the 366 men developed prostate cancer.
The research team then divided the men into birth weight categories and checked to see if there was any difference in the occurrence of prostate cancer by birth weight category. Indeed there was. Men born in the highest one fourth of the birth weight range, or above 8.7 pounds, were five times more likely to develop prostate cancer as an adult than were men in the lower three quarters of birth weight range (below 8.7 pounds).
Conditions in the Womb and Testicular Cancer
The risk of developing testicular cancer also seems related to birth weight. Some early research suggested that the hormonal milieu during gestation could influence the later risk of developing testicular cancer. This is what led Dr. Ekbom and my other Swedish colleagues to delve further into how life in the womb might impact the future risk of testicular cancer.
They studied 232 men with invasive testicular cancer, comparing them with 904 men of similar age and socioeconomic status. They analyzed the research in even greater detail: They separated the men with testicular cancer into the two main types of this cancer, seminoma and nonseminoma cancer. The testes contains different types of tissue, one of which includes the tubules that transfer semen. Tumors that affect this type of tissue are called seminomas, whereas those that affect the other tissue in the testes are called nonseminomas.
When both types of tumors were analyzed together, the researchers found that those men with either a low or a high birth weight had an increased risk of testicular cancer in adult life. Those men born at a birth weight below 5.5 pounds had a risk about 2.5 times that of men born at an average birth weight, whereas men born heavier than the average, with a birth weight greater than or equal to 8.8 pounds, had a risk that was increased about 1.5 times. When the research team divided the men into two groups on the basis of their type of tumor, they found that the low birth weight was more likely to be associated with nonseminoma tumors. On the other hand, it was a heavier placenta (which is weighed after a baby is delivered) rather than birth weight that was far more likely to be associated with seminoma tumors (you'll read more about the relevance of placental weight in Chapter Two).
Prenatal Life and Childhood Cancers
Cancer is a little-understood disease, causing much fear‹especially when it occurs in children. Epidemiologists from around the world have found evidence that prenatal factors, or life in the womb, may impact the risk of certain childhood cancers.
Cancer researchers from the Fred Hutchinson Cancer Research Center in Seattle conducted one of the first studies that documented a tendency for children with higher birth weight to have a higher risk of cancer during childhood. They found that among children diagnosed with cancer during the first several years of life, there was an increased proportion with a high birth weight, or a birth weight over 8.8 pounds. The risk was most pronounced for children under age 2 years, and was virtually absent after age 4.
Perhaps the most common malignancy, or cancer, in children is leukemia -- in particular, a type of leukemia called acute lymphatic leukemia. Previous research found that certain genetic disorders, including Down syndrome, as well as being an identical twin increases the risk of developing acute lymphatic leukemia. Because this type of cancer peaks in occurrence at 2 to 4 years of age, researchers have long speculated that prenatal factors play a role in its cause.
Dr. Ekbom's team in Sweden studied 613 children with acute lymphatic leukemia, and compared them with over 3,000 children of similar age and with similar other characteristics. They found that several prenatal factors were associated with an increased risk. One was birth weight: They found that babies weighing more than 9.9 pounds at birth had a 70% increased risk of developing this type of leukemia as very young children. Another prenatal factor that increased the risk of acute lymphatic leukemia was maternal hypertension, which accelerated the risk by 40%.
A Danish team of researchers studied children with two other types of leukemia, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) to try to identify risk factors. As did the Swedish group that studied acute lymphatic leukemia, the Danish researchers found that higher birth weight increased the risk of these two other forms of leukemia. For both subtypes of leukemia, they found that increasing birth weight over the average of 7.7 pounds increased the risk. The increased risk for ALL was about 1.5 times, whereas for AML, the risk was over twice as much.
Brain cancer is the second most frequent type of cancer in children under the age of 14 in the United States. Researchers from the Johns Hopkins School of Hygiene and Public Health in Maryland and the National Cancer Institute delved into the possible risk factors for brain tumors in children. They found that children with brain tumors (as well as children with other cancers) were more likely to have been born with higher birth weights. Specifically, they found that children weighing more than 8.0 pounds at birth had 2.6 times the risk of developing a brain tumor.
Prenatal Life and Asthma
Researchers from four different corners of the globe -- Australia, Germany, Great Britain, and the United States -- have studied how life in the womb influences the development of childhood asthma.
Australian researchers, led by Dr. William H. Kitchen, studied nearly 600 children born between 1977 and 1982, dividing them into three birth weight groups. One group consisted of infants born at very low birth weight, less than 2.2 pounds. Another group was composed of infants who weighed between 2.2 and 5.5 pounds. The last group was composed of 60 children weighing more than 5.5 pounds at birth. The children were examined at the age of 8 years for the presence of asthma symptoms, which included wheezing; they also underwent pulmonary (lung) function tests that revealed the presence of asthma. These researchers found no compelling evidence that respiratory health at 8 years of age was related to perinatal events.
German researchers, however, did find an association. Their research, of 1,812 children, found that a lower birth weight was associated with childhood risk of having asthma: Children with a birth weight under 5.5 pounds were two times more likely to suffer from asthma symptoms. This team of researchers also found evidence that a woman smoking during pregnancy increased the risk of her child suffering from asthma symptoms during childhood.
Similarly, the British research team, led by Dr. S. Lewis of the City University of London, found that low birth weight and maternal smoking increased the risk that a child would suffer asthma. A birth weight less than 5.5 pounds increased the risk by 26%. Babies born to mothers who smoked 15 or more cigarettes during pregnancy had a 39% increased risk of developing asthma. Interestingly, these risk percentages were higher in babies who were boys. Low birth weight and maternal smoking appear to operate independently from each other, but each seems to be related to asthma-associated wheezing by the time children are 5 years old. The researchers also found that asthma associated with low birth weight or maternal smoking generally goes away by the teenage years, namely 16 years of age. Asthma persisting after age 16 is generally thought to be due to factors other than low birth weight or maternal smoking, such as low maternal age and high socioeconomic status. Researchers do not fully understand why high socioeconomic status increases the risk of asthma. They do believe that high socioeconomic status is simply a marker for something in the lifestyle that increases asthma risk. Research continues to try to sort this out.
A fourth research team came from the United States and was composed of medical experts from the U.S. Environmental Protection Agency and a multidisciplinary team from Harvard University and Harvard Medical School. They analyzed data from the Second National Health and Nutritional Examination Survey (NHANES II), which was conducted between February 1976 and February 1980. Included among the over 20,000plus people in this study were 5,672 children aged 11 years and younger.
Among other factors, the researchers found that low birth weight (below 7.2 pounds) increased the risk of having childhood asthma by 40%. Like the British researchers, the American team found that the likelihood of getting asthma as a child was greater in boys than in girls.
Life in the Womb and Schizophrenia
It was the tragic Dutch Hunger Winter that taught us the most about how life in the womb can increase the risk of developing schizophrenia. A large, multifaceted research study helped us understand how conditions in the womb might affect the risk for schizophrenia.
A large amount of evidence gives us good knowledge that poor prenatal nutrition is a very pivotal factor in causing birth defects of the spinal column and brain, spina bifida being perhaps the most well known example of such defects. (As you'll learn later in this book, a deficiency of folic acid, a B vitamin, is thought to cause a significant percentage of spinal column defects.) Thus, it was logical to look into the possibility that poor prenatal nutrition might cause abnormalities in brain structure and function that can lead to the constellation of symptoms known as schizophrenia. The behavior of a person diagnosed with schizophrenia is characterized by disordered thinking that includes hallucinations (for example, a person might see spiders crawling on her skin when really there are none present), delusions (believing that something is true that is not; someone might believe that he is Napoleon, for example), and other problems with reality-based thinking.
It was a research team led by Dr. Ezra Susser that delved deeply into the effects of poor nutrition on schizophrenic disorders. As you learned earlier, it was Ezra Susser's parents who first made the connection between poor nutrition in the womb and health in adulthood.
About 40,000 babies exposed to famine at some point in gestation were born during or after the Hunger Winter. As you read earlier, the clear demarcation of the famine in time and place provided good information regarding who was suffering from inadequate in utero nutrition and during which stages of their prenatal development the undernourishment occurred. In other words, any individual could be identified as being malnourished during early, middle, or late gestation‹or more than one of these periods. The researchers also had knowledge of those people who had schizophrenic conditions many decades later and they compared the incidence of schizophrenia among the individuals who were malnourished in utero with the incidence among people who were born in the same cities where the famine occurred but who either were born in the time period just before or were conceived after it ended.
The researchers found an increased incidence of schizophrenia among the people conceived at the height of the famine and subsequent birth defects of the nervous system. The risk of schizophrenia clearly peaked in the people who experienced famine while in their mother's womb. Both men and women who experienced famine in utero during the Dutch Hunger Winter were about twice as likely to have schizophrenia as their comrades who did not develop in the womb under famine conditions. Further analysis, this time separating those people who were conceived at the peak of the famine, found an even greater increase in schizophrenia; their risk was increased nearly threefold.
In another aspect of their research, investigators studied whether famine in utero also increased the risk of schizoid personality disorder, which includes a broader spectrum of symptoms associated with schizophrenia. They found that the risk for the famine-exposed men (they studied only men) was slightly more than doubled by the time they reached 18 years of age.
Prenatal Life and Other Conditions
There is also mounting evidence that the prenatal environment influences a person's risk of several other conditions and affects other body systems, including cholesterol levels. For example, there is preliminary evidence that the smaller the abdomen at birth, the higher the cholesterol level in adult life.
Beyond Birth Weight
Indeed, birth weight is an important predictor of your child's future health. But as birth weight is just a marker in the link between conditions in the womb and the long term health of your child, we scientists are looking to find other traces that help us to understand the relation between mom's diet and baby's long-term health more directly.
Our new research takes us beyond the birth weight observations. We know that it's not just the number of calories and the amount of weight a woman gains, but the quality of her diet or the types of foods she eats is emerging as ever more important.
These "precious" and exciting links between an expectant mom's diet and her child's risk of disease later in life can sometimes even be completely independent of her baby's size at birth. These are the links, based on scientific evidence that I want to share here.
The first one returns to the observations made during the Dutch Famine winter of 19441945, which was mentioned earlier. The children born to women who were malnourished early in the pregnancy suffered many consequences as adults. Some of them seem to work via the birthweight route, others seem to operate directly, independent of the children's birthweight.
For one, we now know that the children of women pregnant during this grim period often have, in their adult life, what is technically called a lower glucose tolerance. This means that their bodies do not respond normally to sugar in the bloodstream. As a result, they are at much higher risk for developing type 2 diabetes mellitus in middle age and beyond, and possibly even sooner if they become overweight and/or sedentary.
Another ill effect of children deprived nutritionally during the first trimester of pregnancy that shows up in adult life is an abnormality in blood fats. The most common blood fat is cholesterol: research has now shown us that when cholesterol levels were measured around age 50, they had too-high levels of bad cholesterol (officially known as low density lipoprotein or LDL-cholesterol) and too-low levels of good cholesterol (high density lipoprotein, HDL-cholesterol) as compared to other men and women of the same age whose mothers were well nourished during their pregnancy. These effects were found to be independent of birth weight. (Incidentally, these abnormal levels of blood fats were also independent of adult obesity, which is a known risk factor for this problem.)
David Barker's group in England made other observations between a mother-to-be's eating habits and her child's adult health. Studying a Scottish population, Barker's group found that when mom ate an unbalanced diet during pregnancy, her child was more likely to have high blood pressure as an adult. Specifically, Barker found that if mom consumed a diet very high in carbohydrate and too low in protein, as well as vice versa: a diet that is too low in carbohydrate and too high in protein, during late pregnancy, the offspring were more likely to have elevated blood pressure at age 40. Again, this observation was independent of calorie intake during pregnancy.
Greek researchers have found some evidence that quality of the mom's diet during pregnancy may impact the risk of cerebral palsy in the child. Mothers in the Greater Athens area who gave birth to children with cerebral palsy were asked about what they ate during pregnancy. Compared with mothers of healthy children, the mothers of children with cerebral palsy had consumed considerably more meat and eggs and less fish during their pregnancy.
The last thing I would like to discuss relates to my area of interest: breast cancer. While data on maternal diet and the risk of breast cancer in the daughter are not yet available for humans, interesting observations have been made in study animals. For example, in rodent studies, the female offspring born to mothers fed a very high fat diet (43% of calories) during the entire pregnancy had a much higher chance of developing breast cancer when they were exposed to known cancer-causing substances. In these studies, the rodents were fed a specific type of oil, corn oil. The type of oil may be significant. Corn oil consists mainly of linoleic acid, a type of oil that increases levels of the hormone estradiol. We suspect that the consumption of the oil was sufficient to raise hormones and expose the fetuses to elevated estradiol levels. In these studies, it was also noted that the female offspring had earlier onset puberty (yes, rodents have a defined puberty, too!). In addition, the cells of their breasts were slightly abnormal, which made them more susceptible to becoming cancerous.
What I would like you to take away from all of this is that while we want you to eat an appropriate number of calories during your pregnancy, we also want to make sure you eat a healthy and well-balanced diet. That's why you'll see very specific foods and recipes in our meal plans. We've done our best to translate the science into food -- and delicious at that -- that you can put on your plate each and every day with a tremendous peace of mind that you are doing the best you can to nourish your baby in the womb‹and for his or her good health throughout life.While olive oil is the primary source of fat in Southern European populations who have the world's highest longevity, some other fats -- in small amounts -- may also be of value. These can be found in soybeans, walnuts, flaxseed and flaxseed oil, canola oil and fish, especially salmon, mackerel, tuna, and trout.
Putting All of This Research into Perspective
After reading this evidence, I want to reemphasize one very important point: Fetal origins of chronic disease is only one of several factors that may determine your child-to-be's adult health risks. Although the conditions in the womb are an important factor, genetics and lifestyle also have a tremendous impact on how fetal influences play out. I believe in the life course approach, which stresses the full range of physical, emotional, and environmental issues that affect a person's life, from the time in the womb through the teen and adult years. So if you have already had one (or more) children or if you are already into your pregnancy, don't worry: There are many things you can do today and tomorrow to promote the good health of your children.
Please remember, too, that although what you do during your pregnancy is very important, you shouldn't try to influence birth weight to the extreme. Never overindulge or starve yourself in an attempt to control your baby's birth weight. As you have learned while reading through this chapter, birth weight seems to be an important marker of prenatal events. But as we also know now, different birth weight levels affect the risk of chronic disease in different ways. For instance, birth weight is related to both cardiovascular disease and breast cancer but in opposite ways: Whereas babies born very heavy may have a lower risk of heart disease and stroke, they also may have a higher chance of experiencing cancer in later life.
This is why my best advice to you is to achieve the middle road, gain the recommended amount of weight (25 to 35 pounds) during your pregnancy, follow the guidelines in this book, and always concentrate on maintaining good eating habits as best you can.
Now, please read on for more details on how you can help your baby and child-to-be from this moment forward. You'll begin to see that moms make a huge difference -- throughout their offsprings' life!
Copyright © 2001 by The Philip Lief Group and Karin B. Michels
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